Enzyme Hydrolysates from Stichopus horrens as a New Source for Angiotensin-Converting Enzyme Inhibitory Peptides.

PubMed

Forghani, Bita; Ebrahimpour, Afshin; Bakar, Jamilah; Abdul Hamid, Azizah; Hassan, Zaiton; Saari, Nazamid

2012-01-01

Stichopus horrens flesh was explored as a potential source for generating peptides with angiotensin-converting enzyme (ACE) inhibitory capacity using 6 proteases, namely alcalase, flavourzyme, trypsin, papain, bromelain, and protamex. Degree of hydrolysis (DH) and peptide profiling (SDS-PAGE) of Stichopus horrens hydrolysates (SHHs) was also assessed. Alcalase hydrolysate showed the highest DH value (39.8%) followed by flavourzyme hydrolysate (32.7%). Overall, alcalase hydrolysate exhibited the highest ACE inhibitory activity (IC(50) value of 0.41 mg/mL) followed by flavourzyme hydrolysate (IC(50) value of 2.24 mg/mL), trypsin hydrolysate (IC(50) value of 2.28 mg/mL), papain hydrolysate (IC(50) value of 2.48 mg/mL), bromelain hydrolysate (IC(50) value of 4.21 mg/mL), and protamex hydrolysate (IC(50) value of 6.38 mg/mL). The SDS-PAGE results showed that alcalase hydrolysate represented a unique pattern compared to others, which yielded potent ACE inhibitory peptides with molecular weight distribution lower than 20 kDa. The evaluation of the relationship between DH and IC(50) values of alcalase and flavourzyme hydrolysates revealed that the trend between those parameters was related to the type of the protease used. We concluded that the tested SHHs would be used as a potential source of functional ACE inhibitory peptides for physiological benefits.

Cytotoxicity evaluation of a new set of 2-aminobenzo[de]iso-quinoline-1,3-diones.

PubMed

Al-Salahi, Rashad; Alswaidan, Ibrahim; Marzouk, Mohamed

2014-12-04

A new series of 2-amino-benzo[de]isoquinoline-1,3-diones was synthesized and fully characterized in our previous paper. Here, their cytotoxic effects have been evaluated in vitro in relation to colon HCT-116, hepatocellular Hep-G2 and breast MCF-7 cancer cell lines, using a crystal violet viability assay. The IC50-values of the target compounds are reported in µg/mL, using doxorubicin as a reference drug. The findings revealed that compounds 14, 15, 16, 21 and 22 had significant cytotoxic effects against HCT-116, MCF-7 and Hep-G2 cell lines. Their IC50 values ranged between 1.3 and 8.3 μg/mL in relation to doxorubicin (IC50 ≈ 0.45-0.89 μg/mL). Therefore, these compounds could be used as templates for furthering the development and design of more potent antitumor agents through structural modification.

Monoclonal antibodies with group specificity toward sulfonamides: selection of hapten and antibody selectivity.

PubMed

Wang, Zhanhui; Beier, Ross C; Sheng, Yajie; Zhang, Suxia; Jiang, Wenxiao; Wang, Zhaopeng; Wang, Jin; Shen, Jianzhong

2013-05-01

Immunoassays based on the current available antibodies for large multi-sulfonamide screening programs have suffered from high selectivity for individual sulfonamides and a wide range of selectivities for different sulfonamides. In this study, five synthesized haptens, HS, BS, CS, SA10, and TS and two sulfonamides, SG and SMX were used as haptens, which may or may not contain a ring structure at the N1 position of the sulfonamides, were selected to evaluate the effectiveness for producing group-specific monoclonal antibodies (MAbs). Mice immunized with three different two-ring haptens were used for hybridoma production, which resulted in three unique MAbs recognizing 10, 13, and 15 sulfonamides showing 50 % inhibition (IC50) at concentrations below 100 ng mL(-1). MAb 4D11 derived from one novel immunizing hapten could recognize 12 sulfonamides with IC50 values ranging from 1.2 to 12.4 ng mL(-1), almost within 1 order of magnitude. These produced MAbs show lower IC50 values in addition to significantly improved group specificity compared with previously generated MAbs. This study clearly indicates that the careful selection of the immunizing hapten has an important effect on the specificity of the generated antibodies.

Evaluation of in vitro aldose reductase inhibitory potential of alkaloidal fractions of Piper nigrum, Murraya koenigii, Argemone mexicana, and Nelumbo nucifera.

PubMed

Gupta, Sakshi; Singh, Nirmal; Jaggi, Amteshwar Singh

2014-05-01

Aldose reductase is primarily involved in development of long-term diabetic complications due to increased polyol pathway activity. The synthetic aldose reductase inhibitors are not very successful clinically. Therefore, the natural sources may be exploited for safer and effective aldose reductase inhibitors. In the present study, the aldose reductase inhibitory potential of hydroalcoholic and alkaloidal extracts of Piper nigrum, Murraya koenigii, Argemone mexicana, and Nelumbo nucifera was evaluated. The hydroalcoholic and alkaloidal extracts of the selected plants were prepared. The different concentrations of hydroalcoholic and alkaloidal extracts of these plants were evaluated for their goat lens aldose reductase inhibitory activity using dl-glyceraldehyde as substrate. The aldose reductase inhibitory potential of extracts was assessed in terms of their IC50 value. Amongst the hydroalcoholic extracts, the highest aldose reductase inhibitory activity was shown by P. nigrum (IC50 value 35.64±2.7 μg/mL) followed by M. koenigii (IC50 value 45.67±2.57 μg/mL), A. mexicana (IC50 value 56.66±1.30 μg/mL), and N. nucifera (IC50 value 59.78±1.32 μg/mL). Among the alkaloidal extracts, highest inhibitory activity was shown by A. mexicana (IC50 value 25.67±1.25 μg/mL), followed by N. nucifera (IC50 value 28.82±1.85 μg/mL), P. nigrum (IC50 value 30.21±1.63 μg/mL), and M. koenigii (IC50 value 35.66±1.64 μg/mL). It may be concluded that the alkaloidal extracts of these plants possess potent aldose reductase inhibitory activity and may be therapeutically exploited in diabetes-related complications associated with increased activity of aldose reductase.

Capsofulvesins A-C, cholinesterase inhibitors from Capsosiphon fulvescens.

PubMed

Fang, Zhe; Yang Jeong, Su; Ah Jung, Hyun; Sue Choi, Jae; Sun Min, Byung; Hee Woo, Mi

2012-01-01

Activity-directed isolation of the n-hexane and dichloromethane fractions of Capsosiphon fulvescens resulted in the identification of four new glycolipids (1-3): (2S)-1-O-(6Z,9Z,12Z,15Z-octadecatetraenoyl)-2-O-(4Z,7Z,10Z,13Z-hexadecatetraenoyl)-3-O-β-D-galactopyranosyl glycerol (1, capsofulvesin A), (2S)-l-O-(9Z,12Z,15Z-octadecatrienoyl)-2-O-(10Z,13Z-hexadecadienoyl)-3-O-β-D-galactopyranosyl glycerol (2, capsofulvesin B), (2S)-1-O-(6Z,9Z,12Z,15Z-octadecatetraenoyl)-3-O-β-D-galacatopyranosyl glycerol (3, capsofulvesin C). Compounds 1-6 exhibited acetylcholinesterase (AChE) inhibitory activities with IC(50) values ranging from 50.90 to 82.83 µM, whereas 2-6 showed butyrylcholinesterase (BChE) inhibitory activities with IC(50) values of 114.75-185.55 µM. Although most of the compounds isolated lacked scavenging activity for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and peroxynitrite (ONOO(-)), compound 8 showed ONOO(-) scavenging activity with an IC(50) value of 26.23 µg/mL.

Steroidal constituents from the edible sea urchin Diadema savignyi Michelin induce apoptosis in human cancer cells.

PubMed

Thao, Nguyen Phuong; Luyen, Bui Thi Thuy; Kim, Eun Ji; Kang, Jung Il; Kang, Hee Kyoung; Cuong, Nguyen Xuan; Nam, Nguyen Hoai; Kiem, Phan Van; Minh, Chau Van; Kim, Young Ho

2015-01-01

Bioassay-directed fractionation and purification were used to isolate 12 steroids (1-12) from a CH(2)Cl(2) extract of the edible Vietnamese sea urchin Diadema savignyi Michelin. The cytotoxic activity of the CH(2)Cl(2) extract and 12 steroids was evaluated in three human cancer cell lines (HL-60, PC-3, and SNU-C5). Relative to the effects of the positive control, mitoxantrone, the CH(2)Cl(2) extract (with an inhibitory concentration of 50% [IC(50)] values ranging from 1.37±0.15 to 3.11±0.15 μg/mL) and compounds 2 (with IC(50) values ranging from 5.29±0.11 to 6.80±0.67 μM) and 11 (with IC(50) values ranging from 4.95±0.07 to 6.99±0.28 μM) exhibited potent cytotoxic effects against all three tested human cancer cell lines. In addition, the CH(2)Cl(2) extract and compounds 2 and 11 were found to induce apoptosis. The induction of apoptosis was accompanied by alterations of the apoptosis-related protein expression, inactivation of ERK1/2 mitogen-activated protein kinase signaling, and decreased c-Myc expression. These data suggest that compounds 2 and 11 from the edible sea urchin D. savignyi may have potential for the treatment of colon cancer, leukemia, and prostate cancer as complementary cancer remedies.

ICECAP: an integrated, general-purpose, automation-assisted IC50/EC50 assay platform.

PubMed

Li, Ming; Chou, Judy; King, Kristopher W; Jing, Jing; Wei, Dong; Yang, Liyu

2015-02-01

IC50 and EC50 values are commonly used to evaluate drug potency. Mass spectrometry (MS)-centric bioanalytical and biomarker labs are now conducting IC50/EC50 assays, which, if done manually, are tedious and error-prone. Existing bioanalytical sample preparation automation systems cannot meet IC50/EC50 assay throughput demand. A general-purpose, automation-assisted IC50/EC50 assay platform was developed to automate the calculations of spiking solutions and the matrix solutions preparation scheme, the actual spiking and matrix solutions preparations, as well as the flexible sample extraction procedures after incubation. In addition, the platform also automates the data extraction, nonlinear regression curve fitting, computation of IC50/EC50 values, graphing, and reporting. The automation-assisted IC50/EC50 assay platform can process the whole class of assays of varying assay conditions. In each run, the system can handle up to 32 compounds and up to 10 concentration levels per compound, and it greatly improves IC50/EC50 assay experimental productivity and data processing efficiency. © 2014 Society for Laboratory Automation and Screening.

Bioactive metabolites from the fungus Nectria galligena, the main apple canker agent in Chile.

PubMed

Gutiérrez, Margarita; Theoduloz, Cristina; Rodríguez, Jaime; Lolas, Mauricio; Schmeda-Hirschmann, Guillermo

2005-10-05

The phytopathogenic fungus Nectria galligena Bres. is the most common canker disease agent of hardwood trees. The terpenoids colletochlorin B, colletorin B, ilicicolin C, E, and F, as well as the phytotoxin alpha,beta-dehydrocurvularin have been isolated from liquid cultures of N. galligena obtained from the xylem of infected apple trees in central Chile. Ilicicolin C and F and alpha,beta-dehydrocurvularin were active against Pseudomonas syringae with IC50 values of 28.5, 28.5, and 14.2 microg/mL, respectively, in the same range as streptomycin and penicillin G (11 and 15 microg/mL, respectively). All of the compounds showed moderate inhibitory activity toward the enzymes acetylcholinesterase (AChE) and beta-glucuronidase. The most active enzyme inhibitors were colletochlorin B and ilicicolin C and E, with IC50 values of 30-36 microg/mL in the AChE assay and 32-43 microg/mL in the beta-glucuronidase test. All of the chlorinated compounds showed some toxicity toward human lung fibroblasts, with IC50 values in the range of 64-120 microg/mL. alpha,beta-Dehydrocurvularin proved to be the most toxic compound, showing IC50 values less than 12 microg/mL. The effect of the isolated compounds on seed germination and radicle and epicotyl growth was assessed in lettuce and millet seeds. At 100 and 200 microg/disk, alpha,beta-dehydrocurvularin significantly reduced radicle length and epicotyl growth in Lactuca sativa. This is the first report on the occurrence of colletochlorin B, colletorin B, ilicicolin C, E, and F, as well as alpha,beta-dehydrocurvularin associated to N. galligena.

Antimicrobial and antioxidant activity of kaempferol rhamnoside derivatives from Bryophyllum pinnatum

PubMed Central

2012-01-01

Background Bryophyllum pinnatum (Lank.) Oken (Crassulaceae) is a perennial succulent herb widely used in traditional medicine to treat many ailments. Its wide range of uses in folk medicine justifies its being called "life plant" or "resurrection plant", prompting researchers' interest. We describe here the isolation and structure elucidation of antimicrobial and/or antioxidant components from the EtOAc extract of B. pinnatum. Results The methanol extract displayed both antimicrobial activities with minimum inhibitory concentration (MIC) values ranging from 32 to 512 μg/ml and antioxidant property with an IC50 value of 52.48 μg/ml. Its partition enhanced the antimicrobial activity in EtOAc extract (MIC = 16-128 μg/ml) and reduced it in hexane extract (MIC = 256-1024 μg/ml). In addition, this process reduced the antioxidant activity in EtOAc and hexane extracts with IC50 values of 78.11 and 90.04 μg/ml respectively. Fractionation of EtOAc extract gave seven kaempferol rhamnosides, including; kaempferitrin (1), kaempferol 3-O-α-L-(2-acetyl)rhamnopyranoside-7-O-α-L-rhamnopyranoside (2), kaempferol 3-O-α-L-(3-acetyl)rhamnopyranoside-7-O-α-L-rhamnopyranoside (3), kaempferol 3-O-α-L-(4-acetyl)rhamnopyranoside-7-O-α-L-rhamnopyranoside (4), kaempferol 3-O-α-D- glucopyranoside-7-O-α-L-rhamnopyranoside (5), afzelin (6) and α-rhamnoisorobin (7). All these compounds, except 6 were isolated from this plant for the first time. Compound 7 was the most active, with MIC values ranging from 1 to 2 μg/ml and its antioxidant activity (IC50 = 0.71 μg/ml) was higher than that of the reference drug (IC50 = 0.96 μg/ml). Conclusion These findings demonstrate that Bryophyllum pinnatum and some of its isolated compounds have interesting antimicrobial and antioxidant properties, and therefore confirming the traditional use of B. pinnatum in the treatment of infectious and free radical damages. PMID:22433844

Chemical composition and cytotoxicity evaluation of essential oil from leaves of Casearia sylvestris, its main compound α-zingiberene and derivatives.

PubMed

Bou, Diego Dinis; Lago, João Henrique G; Figueiredo, Carlos R; Matsuo, Alisson L; Guadagnin, Rafael C; Soares, Marisi G; Sartorelli, Patricia

2013-08-08

Casearia sylvestris (Salicaceae), popularly known as "guaçatonga", is a plant widely used in folk medicine to treat various diseases, including cancer. The present work deals with the chemical composition as well as the cytotoxic evaluation of its essential oil, its main constituent and derivatives. Thus, the crude essential oil from leaves of C. sylvestris was obtained using a Clevenger type apparatus and analyzed by GC/MS. This analysis afforded the identification of 23 substances, 13 of which corresponded to 98.73% of the total oil composition, with sesquiterpene a-zingiberene accounting for 50% of the oil. The essential oil was evaluated for cytotoxic activity against several tumor cell lines, giving IC50 values ranging from 12 to 153 mg/mL. Pure a-zingiberene, isolated from essential oil, was also evaluated against the tumor cell lines showing activity for HeLa, U-87, Siha and HL60 cell lines, but with IC50 values higher than those determined for the crude essential oil. Aiming to evaluate the effect of the double bonds of a-zingiberene on the cytotoxic activity, partially hydrogenated a-zingiberene (PHZ) and fully hydrogenated a-zingiberene (THZ) derivatives were obtained. For the partially hydrogenated derivative only cytotoxic activity to the B16F10-Nex2 cell line (IC50 65 mg/mL) was detected, while totally hydrogenated derivative showed cytotoxic activity for almost all cell lines, with B16F10-Nex2 and MCF-7 as exceptions and with IC50 values ranging from 34 to 65 mg/mL. These results indicate that cytotoxic activity is related with the state of oxidation of compound.

Copper (II) and zinc (II) complexes with flavanone derivatives: Identification of potential cholinesterase inhibitors by on-flow assays.

PubMed

Sarria, André Lucio Franceschini; Vilela, Adriana Ferreira Lopes; Frugeri, Bárbara Mammana; Fernandes, João Batista; Carlos, Rose Maria; da Silva, Maria Fátima das Graças Fernandes; Cass, Quezia Bezerra; Cardoso, Carmen Lúcia

2016-11-01

Metal chelates strongly influence the nature and magnitude of pharmacological activities in flavonoids. In recent years, studies have shown that a promising class of flavanone-metal ion complexes can act as selective cholinesterase inhibitors (ChEIs), which has led our group to synthesize a new series of flavanone derivatives (hesperidin, hesperetin, naringin, and naringenin) complexed to either copper (II) or zinc (II) and to evaluate their potential use as selective ChEIs. Most of the synthesized complexes exhibited greater inhibitory activity against acetylcholinesterase (AChE) than against butyrylcholinesterase (BChE). Nine of these complexes constituted potent, reversible, and selective ChEIs with inhibitory potency (IC 50 ) and inhibitory constant (K i ) ranging from 0.02 to 4.5μM. Copper complexes with flavanone-bipyridine derivatives afforded the best inhibitory activity against AChE and BChE. The complex Cu(naringin)(2,2'-bipyridine) (11) gave IC 50 and K i values of 0.012±0.002 and 0.07±0.01μM for huAChE, respectively, which were lower than the inhibitory values obtained for standard galanthamine (IC 50 =206±30.0 and K i =126±18.0μM). Evaluation of the inhibitory activity of this complex against butyrylcholinesterase from human serum (huBChE) gave IC 50 and K i values of 8.0±1.4 and 2.0±0.1μM, respectively. A Liquid Chromatography-Immobilized Capillary Enzyme Reactor by UV detection (LC-ICER-UV) assay allowed us to determine the IC 50 and K i values and the type of mechanism for the best inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

Flavonoid alkaloids from Scutellaria moniliorrhiza with anti-inflammatory activities and inhibitory activities against aldose reductase.

PubMed

Han, Qing-Tong; Ren, Yan; Li, Gui-Sheng; Xiang, Kang-Lin; Dai, Sheng-Jun

2018-05-11

Four undescribed flavonoid alkaloids, as two pairs of enantiomers, were initially isolated as a racemate from the whole plant of Scutellaria moniliorrhiza. By means of chiral HPLC, four isomers, named scumonilines A-D, were successfully separated, and their chemical structures including absolute configurations were established by mass as well as NMR spectroscopy and CD technique. In vitro, four flavonoid alkaloids showed anti-inflammatory activities, with IC 50 values against the release of β-glucuronidase from polymorphonuclear leukocytes of rats being in the range 5.16-5.85 μΜ. Moreover, four compounds were evaluated for their inhibitory activities against aldose reductase, and gave IC 50 values in the range 2.29-3.03 μΜ. Copyright © 2018 Elsevier Ltd. All rights reserved.

Synthesis of heteroaromatic tropeines and heterogeneous binding to glycine receptors.

PubMed

Maksay, Gábor; Vincze, Zoltán; Nemes, Péter

2009-10-01

Heteroaromatic carboxylic esters of (nor)tropine were synthesized. Tropine esters displaced [(3)H]strychnine binding to glycine receptors of rat spinal cord with low Hill slopes. Two-site displacement resulted in nanomolar IC(50,1) and micromolar IC(50,2) values, and IC(50,2)/IC(50,1) ratios up to 615 depending on the heteroaromatic rings and N-methyl substitution. Nortropeines displayed high affinity and low heterogeneity. IC(50,1) and IC(50,2) values of tropeines did not correlate suggesting different binding modes/sites. Glycine potentiated only the nanomolar displacement reflecting positive allosteric interactions and potentiation of ionophore function. Affinities of three (nor)tropeines were different for glycine receptors but identical for 5-HT(3) receptors.

Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

PubMed

Jacobs, Leon; de Kock, Carmen; de Villiers, Katherine A; Smith, Peter J; Smith, Vincent J; van Otterlo, Willem A L; Blackie, Margaret A L

2015-12-01

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

3-Coumaranone derivatives as inhibitors of monoamine oxidase.

PubMed

Van Dyk, Adriaan S; Petzer, Jacobus P; Petzer, Anél; Legoabe, Lesetja J

2015-01-01

The present study examines the monoamine oxidase (MAO) inhibitory properties of a series of 20 3-coumaranone [benzofuran-3(2H)-one] derivatives. The 3-coumaranone derivatives are structurally related to series of α-tetralone and 1-indanone derivatives, which have recently been shown to potently inhibit MAO, with selectivity for MAO-B (in preference to the MAO-A isoform). 3-Coumaranones are similarly found to selectively inhibit human MAO-B with half-maximal inhibitory concentration (IC50) values of 0.004-1.05 µM. Nine compounds exhibited IC50<0.05 µM for the inhibition of MAO-B. For the inhibition of human MAO-A, IC50 values ranged from 0.586 to >100 µM, with only one compound possessing an IC50<1 µM. For selected 3-coumaranone derivatives, it is established that MAO-A and MAO-B inhibition are reversible since dialysis of enzyme-inhibitor mixtures almost completely restores enzyme activity. On the basis of the selectivity profiles and potent action, it may be concluded that the 3-coumaranone derivatives are suitable leads for the development of selective MAO-B inhibitors as potential treatment for disorders such as Parkinson's disease and Alzheimer's disease.

3-Coumaranone derivatives as inhibitors of monoamine oxidase

PubMed Central

Van Dyk, Adriaan S; Petzer, Jacobus P; Petzer, Anél; Legoabe, Lesetja J

2015-01-01

The present study examines the monoamine oxidase (MAO) inhibitory properties of a series of 20 3-coumaranone [benzofuran-3(2H)-one] derivatives. The 3-coumaranone derivatives are structurally related to series of α-tetralone and 1-indanone derivatives, which have recently been shown to potently inhibit MAO, with selectivity for MAO-B (in preference to the MAO-A isoform). 3-Coumaranones are similarly found to selectively inhibit human MAO-B with half-maximal inhibitory concentration (IC50) values of 0.004–1.05 µM. Nine compounds exhibited IC50<0.05 µM for the inhibition of MAO-B. For the inhibition of human MAO-A, IC50 values ranged from 0.586 to >100 µM, with only one compound possessing an IC50<1 µM. For selected 3-coumaranone derivatives, it is established that MAO-A and MAO-B inhibition are reversible since dialysis of enzyme–inhibitor mixtures almost completely restores enzyme activity. On the basis of the selectivity profiles and potent action, it may be concluded that the 3-coumaranone derivatives are suitable leads for the development of selective MAO-B inhibitors as potential treatment for disorders such as Parkinson’s disease and Alzheimer’s disease. PMID:26491258

Chemical profile, radical scavenging and cytotoxic activity of yellow gentian leaves (Genitaneae luteaefolium) grown in northern regions of Montenegro.

PubMed

Balijagić, Jasmina; Janković, Teodora; Zdunić, Gordana; Bosković, Jelena; Savikin, Katarina; Godevac, Dejan; Stanojković, Tatjana; Jovancević, Miodrag; Menković, Nebojsa

2012-11-01

LC-ESI-MS and HPLC were used for the identification of the constituents from G. lutea leaves collected at different localities, as well as for quantification of the main compounds. Seven secoiridoids, five C-glucoflavones and three xanthones, were identified. Swertiamarin derivatives, namely eustomorusside (2), eustomoside (3) and septemfidoside (5), were detected in G. lutea for the first time. Concentrations of five constituents (swertiamarin, gentiopicrin, isovitexin, mangiferin and isogentisin) were determined. The relationship between concentrations of y-pyrones and altitude was observed with statistically significant correlation (r = 0.94). The extracts were also evaluated for their content of total phenolics, and antiradical and cytotoxic activities. The total phenolics content ranged from 7.7 to 12.7 mg GAE/g, and the IC50 values for DPPH radical scavenging activity varied between 0.45 to 2.02 mg/mL. The leaf extract exhibited moderate cytotoxic effects toward HeLa cells with an IC50 value of 41.1 microg/mL, while gentiopicrin, mangiferin and isogentisin exerted strong activity against HeLa cells, with IC50 values ranging from 5.7 to 8.8 microg/mL. The results confirm the traditional usage of G. lutea leaves and also suggest their possible utilization as hepatoprotective, hypoglycemic and anti-inflammatory agents.

Anti-Inflammatory Components of the Starfish Astropecten polyacanthus

PubMed Central

Thao, Nguyen Phuong; Cuong, Nguyen Xuan; Luyen, Bui Thi Thuy; Quang, Tran Hong; Hanh, Tran Thi Hong; Kim, Sohyun; Koh, Young-Sang; Nam, Nguyen Hoai; Kiem, Phan Van; Minh, Chau Van; Kim, Young Ho

2013-01-01

Inflammation is important in biomedical research, because it plays a key role in inflammatory diseases including rheumatoid arthritis and other forms of arthritis, diabetes, heart disease, irritable bowel syndrome, Alzheimer’s disease, Parkinson’s disease, allergies, asthma, and even cancer. In the present study, we describe the inhibitory effect of crude extracts and steroids isolated from the starfish Astropecten polyacanthus on pro-inflammatory cytokine (Interleukin-12 (IL-12) p40, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α)) production in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs). Among those tested, compounds 5 and 7 showed potent inhibitory effects on the production of all three pro-inflammatory cytokines with IC50 values ranging from 1.82 ± 0.11 to 7.00 ± 0.16 μM. Potent inhibitory activities were also observed for compound 1 on the production of IL-12 p40 and IL-6 with values of 3.96 ± 0.12 and 4.07 ± 0.13 μM, respectively, and for compounds 3 and 4 on the production of IL-12 p40 with values of 6.55 ± 0.18 and 5.06 ± 0.16 μM, respectively. Moreover, compounds 2 (IC50 = 34.86 ± 0.31 μM) and 6 (IC50 = 79.05 ± 2.05 μM) exhibited moderate inhibitory effects on the production of IL-12 p40, whereas compounds 3 (IC50 = 22.80 ± 0.21 μM) and 4 (IC50 = 16.73 ± 0.25 μM) moderately inhibited the production of TNF-α and IL-6, respectively. PMID:23945602

Synthesis of cyclic 1,9-acetal derivatives of forskolin and their bioactivity evaluation.

PubMed

Ponnam, Devendar; Shilpi, Singh; Srinivas, K V N S; Suiab, Luqman; Alam, Sarfaraz; Amtul, Zehra; Arigari, Niranjan Kumar; Jonnala, Kotesh Kumar; Siddiqui, Lubna; Dubey, Vijaya; Tiwari, Ashok Kumar; Balasubramanian, Sridhar; Khan, Feroz

2014-11-24

A new series of 1,9-acetals of forskolin were synthesized by treating with aromatic and aliphatic aldehydes using Ceric ammonium nitrate as catalyst and evaluated for anticancer and α-glucosidase inhibition activities. Among the synthesized compounds 2a, 2b and 3a showed potential cytotoxic activity towards human cancer cell lines MCF-7 (Human Breast Adenocarcinoma), MDA-MB (Human Breast Carcinoma), HeLa (Human Cervix Adenocarcinoma), A498 (Human Kidney Carcinoma), K562 (Human Erythromyeloblastoid leukemia), SH-SY5Y (Human Neuroblastoma), Hek293 (Human Embryonic Kidney) and WRL68 (Human Hepatic) with IC50 values ranging between 0.95 and 47.96 μg/ml. Osmotic fragility test revealed compound 3a as non-toxic to human erythrocytes at the tested concentrations of 50 and 100 μg/ml. Compounds 1g (IC50 value 0.76 μg/ml) and 1p (IC50 value 0.74 μg/ml) significantly inhibited α-glucosidase in in vitro system. In silico based docking, ADME and toxicity risk assessment studies also showed discernible α-glucosidase activity for compounds 1g, 1p compared to standard acarbose. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors

NASA Astrophysics Data System (ADS)

Khan, Khalid M.; Ambreen, Nida; Taha, Muhammad; Halim, Sobia A.; Zaheer-ul-Haq; Naureen, Shagufta; Rasheed, Saima; Perveen, Shahnaz; Ali, Sajjad; Choudhary, Mohammad Iqbal

2014-05-01

Using structure-based virtual screening approach, a coumarin derivative ( 1) was identified as β-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of β-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against β-glucuronidase, however, their potency varied substantially from IC50 = 9.9-352.6 µM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 µM, respectively. We further studied their dose responses and also checked our results by using detergent Triton ×-100. We found that our results are true and not affected by detergent.

Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors.

PubMed

Khan, Khalid M; Ambreen, Nida; Taha, Muhammad; Halim, Sobia A; Zaheer-ul-Haq; Naureen, Shagufta; Rasheed, Saima; Perveen, Shahnaz; Ali, Sajjad; Choudhary, Mohammad Iqbal

2014-05-01

Using structure-based virtual screening approach, a coumarin derivative (1) was identified as β-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of β-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against β-glucuronidase, however, their potency varied substantially from IC50 = 9.9-352.6 µM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 µM, respectively. We further studied their dose responses and also checked our results by using detergent Triton ×-100. We found that our results are true and not affected by detergent.

Isatin based Schiff bases as inhibitors of α-glucosidase: Synthesis, characterization, in vitro evaluation and molecular docking studies.

PubMed

Rahim, Fazal; Malik, Fazal; Ullah, Hayat; Wadood, Abdul; Khan, Fahad; Javid, Muhammad Tariq; Taha, Muhammad; Rehman, Wajid; Ur Rehman, Ashfaq; Khan, Khalid Mohammed

2015-06-01

Isatin base Schiff bases (1-20) were synthesized, characterized by (1)H NMR and EI/MS and evaluated for α-glucosidase inhibitory potential. Out of these twenty (20) compounds only six analogs showed potent α-glucosidase inhibitory potential with IC50 value ranging in between 2.2±0.25 and 83.5±1.0μM when compared with the standard acarbose (IC50=840±1.73μM). Among the series compound 2 having IC50 value (18.3±0.56μM), 9 (83.5±1.0μM), 11 (3.3±0.25μM), 12 (2.2±0.25μM), 14 (11.8±0.15μM), and 20 (3.0±0.15μM) showed excellent inhibitory potential many fold better than the standard acarbose. The binding interactions of these active analogs were confirmed through molecular docking. Copyright © 2015 Elsevier Inc. All rights reserved.

Synthesis and β-glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones.

PubMed

Khan, Khalid Mohammed; Saad, Syed Muhammad; Shaikh, Nimra Naveed; Hussain, Shafqat; Fakhri, Muhammad Imran; Perveen, Shahnaz; Taha, Muhammad; Choudhary, Muhammad Iqbal

2014-07-01

2-Arylquinazolin-4(3H)-ones 1-25 were synthesized by reacting anthranilamide with various benzaldehydes using CuCl2·2H2O as a catalyst in ethanol under reflux. Synthetic 2-arylquinazolin-4(3H)-ones 1-25 were evaluated for their β-glucuronidase inhibitory potential. A trend of inhibition IC50 against the enzyme in the range of 0.6-198.2μM, was observed and compared with the standard d-saccharic acid 1,4-lactone (IC50=45.75±2.16μM). Compounds 13, 19, 4, 12, 14, 22, 23, 25, 15, 8, 17, 11, 21, 1, 3, 18, 9, 2, and 24 with the IC50 values within the range of 0.6-44.0μM, indicated that the compounds have superior activity than the standard. The compounds showed no cytotoxic effects against PC-3 cells. A structure-activity relationship is established. Copyright © 2014 Elsevier Ltd. All rights reserved.

Bioactive components from the heartwood of Pterocarpus santalinus.

PubMed

Wu, Shou-Fang; Hwang, Tsong-Long; Chen, Shu-Li; Wu, Chin-Chung; Ohkoshi, Emika; Lee, Kuo-Hsiung; Chang, Fang-Rong; Wu, Yang-Chang

2011-09-15

One new phenanthrenedione, pterolinus K (1), and one new chalcone, pterolinus L (2) were isolated from the heartwood extract of Pterocarpus santalinus. The structures were elucidated by spectroscopic methods. Both 1 and 2 showed inhibitory effect on elastase release by human neutrophils in response to fMLP with an IC(50) value of 4.24 and 0.95 μM, and compound 1 also inhibited superoxide anion generation with IC(50) value of 0.99 μM. In addition, compound 1 showed selective cytotoxicity against HepG2 with IC(50) value of 10.86 μM, while compound 2 showed a moderate cytotoxicity against KB with IC(50) values of 17.18 μM. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis and biological evaluation of novel bis-aromatic amides as novel PTP1B inhibitors.

PubMed

Wang, Wen-Long; Huang, Chao; Gao, Li-Xin; Tang, Chun-Lan; Wang, Jun-Qing; Wu, Min-Chen; Sheng, Li; Chen, Hai-Jun; Nan, Fa-Jun; Li, Jing-Ya; Li, Jia; Feng, Bainian

2014-04-15

A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors with IC50 values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them, compound 15 displayed an IC50 value of 2.34±0.08 μM with 5-fold preference over TCPTP. More importantly, the treatment of CHO/HIR cells with compound 15 resulted in increased phosphorylation of insulin receptor (IR), which suggested extensive cellular activity of compound 15. These results provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Anti-Proliferative Effect of Triterpenoidal Glycosides from the Roots of Anemone vitifolia through a Pro-Apoptotic Way.

PubMed

Bai, Changcai; Ye, Yunyun; Feng, Xiao; Bai, Ruifeng; Han, Lu; Zhou, Xiuping; Yang, Xinyao; Tu, Pengfei; Chai, Xingyun

2017-04-17

A cytotoxicity-guided phytochemical investigation of Anemone vitifolia roots led to the isolation of six oleanane saponins ( 1 - 6 ), which were reported from the species for the first time. Their structures were determined by comparing its MS and NMR data with those in literature. Compounds 1 - 4 showed significant inhibitory effects on the proliferation of hepatocellular carcinoma HepG2 cells with IC 50 values ranging from 2.0 to 8.5 μM, compared to positive control methotrexate with IC 50 value of 15.8 μM. Flow cytometry analysis revealed that compounds 1 - 4 exerted anti-proliferative effects through a pro-apoptotic way of hepatocellular carcinoma cells.

Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors.

PubMed

Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Murugaiyah, Vikneswaran; Basiri, Alireza; Perumal, Subbu; Wahab, Habibah A; Bing, Choi Sy

2013-04-01

Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 μM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 μM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay. Copyright © 2013 Elsevier Ltd. All rights reserved.

Antioxidant activity and total phenolic content of ethanolic extract of Caesalpinia bonducella seeds.

PubMed

Shukla, Shruti; Mehta, Archana; John, Jinu; Singh, Siddharth; Mehta, Pradeep; Vyas, Suresh Prasad

2009-08-01

The aim of this study was to assess the in vitro potential of ethanolic extract of Caesalpinia bonducella seeds as a natural antioxidant. The DPPH activity of the extract (20, 40, 50, 100 and 200 microg/ml) was increased in a dose dependent manner, which was found in the range of 38.93-74.77% as compared to ascorbic acid (64.26-82.58%). The IC(50) values of ethanolic extract and ascorbic acid in DPPH radical scavenging assay were obtained to be 74.73 and 26.68 microg/ml, respectively. The ethanolic extract was also found to scavenge the superoxide generated by EDTA/NBT system. Measurement of total phenolic content of the ethanolic extract of C. bonducella was achieved using Folin-Ciocalteau reagent containing 62.50mg/g of phenolic content, which was found significantly higher when compared to reference standard gallic acid. The ethanolic extract also inhibited the hydroxyl radical, nitric oxide, superoxide anions with IC(50) values of 109.85, 102.65 and 89.84 microg/ml, respectively. However, the IC(50) values for the standard ascorbic acid were noted to be 70.79, 65.98 and 36.68 microg/ml respectively. The results obtained in this study clearly indicate that C. bonducella has a significant potential to use as a natural antioxidant agent.

Sirc-cvs cytotoxicity test: an alternative for predicting rodent acute systemic toxicity.

PubMed

Kitagaki, Masato; Wakuri, Shinobu; Hirota, Morihiko; Tanaka, Noriho; Itagaki, Hiroshi

2006-10-01

An in vitro crystal violet staining method using the rabbit cornea-derived cell line (SIRC-CVS) has been developed as an alternative to predict acute systemic toxicity in rodents. Seventy-nine chemicals, the in vitro cytotoxicity of which was already reported by the Multicenter Evaluation of In vitro Toxicity (MEIC) and ICCVAM/ECVAM, were selected as test compounds. The cells were incubated with the chemicals for 72 hrs and the IC(50) and IC(35) values (microg/mL) were obtained. The results were compared to the in vivo (rat or mouse) "most toxic" oral, intraperitoneal, subcutaneous and intravenous LD(50) values (mg/kg) taken from the RTECS database for each of the chemicals by using Pearson's correlation statistics. The following parameters were calculated: accuracy, sensitivity, specificity, prevalence, positive predictability, and negative predictability. Good linear correlations (Pearson's coefficient; r>0.6) were observed between either the IC(50) or the IC(35) values and all the LD(50) values. Among them, a statistically significant high correlation (r=0.8102, p<0.001) required for acute systemic toxicity prediction was obtained between the IC(50) values and the oral LD(50) values. By using the cut-off concentrations of 2,000 mg/kg (LD(50)) and 4,225 microg/mL (IC(50)), no false negatives were observed, and the accuracy was 84.8%. From this, it is concluded that this method could be used to predict the acute systemic toxicity potential of chemicals in rodents.

A role for the anandamide membrane transporter in TRPV1-mediated neurosecretion from trigeminal sensory neurons

PubMed Central

Price, Theodore J.; Patwardhan, Amol M.; Flores, Christopher M.; Hargreaves, Kenneth M.

2007-01-01

Many n-acylethanolamines utilize the anandamide membrane transporter (AMT) to gain facilitated access to the intracellular compartment, hence, we hypothesized that this mechanism might be important for anandamide (AEA)- and N-arachidonoyl-dopamine (NADA)-evoked CGRP release from cultured trigeminal ganglion (TG) neurons. Using [14C]AEA we demonstrated that TG neurons transported AEA in a FAAH- and AMT-inhibitable fashion. Although TRPV1-positive TG neurons were found to express fatty acid amide hydrolase, the application of FAAH inhibitors had no effect on AEA-evoked CGRP release. In contrast, application of the AMT inhibitors OMDM-2 or VDM-11 significantly reduced the potency and efficacy of AEA-, NADA- and capsaicin-evoked CGRP release. Moreover OMDM-2 (IC50 values ranging from 6.4–9.6 μM) and VDM-11 (IC50 values ranging from 5.3–11 μM) inhibited CGRP release evoked by EC80 concentrations of AEA, NADA and CAP and these values were consistent with IC50s obtained for inhibition of uptake. OMDM-2 had no effect on CGRP release per se while VDM-11 evoked CGRP release on its own (EC50 ~35 μM) in a CPZ-insensitive, but ruthenium red (RR)-sensitive fashion. This is the first demonstration that TG sensory neurons possess an AMT-like mechanism suggesting that this mechanism is important for the pharmacological action of AEA and NADA at native TRPV1 channels. PMID:15992578

Inhibition of chemiluminescence and chemotactic activity of phagocytes in vitro by the extracts of selected medicinal plants.

PubMed

Jantan, Ibrahim; Harun, Nurul Hikmah; Septama, Abdi Wira; Murad, Shahnaz; Mesaik, M A

2011-04-01

The methanol extracts of 20 selected medicinal plants were investigated for their effects on the respiratory burst of human whole blood, isolated human polymorphonuclear leukocytes (PMNs) and isolated mice macrophages using a luminol/lucigenin-based chemiluminescence assay. We also tested the effect of the extracts on chemotactic migration of PMNs using the Boyden chamber technique. The extracts of Curcuma domestica L., Phyllanthus amarus Schum & Thonn and C. xanthorrhiza Roxb. were the samples producing the strongest oxidative burst of PMNs with luminol-based chemiluminescence, with IC(50) values ranging from 0.5 to 0.7 μg/ml. For macrophage cells, the extracts which showed strong suppressive activity for luminol-based chemiluminescence were C. xanthorrhiza and Garcinia mangostana L. Among the extracts studied, C. mangga Valton & Vazsjip, Piper nigrum L. and Labisia pumila var. alata showed strong inhibitory activity on lucigenin-amplified oxidative burst of PMNs, with IC(50) values ranging from 0.9 to 1.5 μg/ml. The extracts of Zingiber officinale Rosc., Alpinia galangal (L.) Willd and Averrhoa bilimbi Linn showed strong inhibition on the chemotaxic migration of cells, with IC(50) values comparable to that of ibuprofen (1.5 μg/ml). The results suggest that some of these plants were able to modulate the innate immune response of phagocytes at different steps, emphasizing their potential as a source of new immunomodulatory agents.

Multinormal In Vitro Distribution Model Suitable for the Distribution of Plasmodium falciparum Chemosusceptibility to Doxycycline▿

PubMed Central

Briolant, Sébastien; Baragatti, Meili; Parola, Philippe; Simon, Fabrice; Tall, Adama; Sokhna, Cheikh; Hovette, Philippe; Mamfoumbi, Modeste Mabika; Koeck, Jean-Louis; Delmont, Jean; Spiegel, André; Castello, Jacky; Gardair, Jean Pierre; Trape, Jean Francois; Kombila, Maryvonne; Minodier, Philippe; Fusai, Thierry; Rogier, Christophe; Pradines, Bruno

2009-01-01

The distribution and range of 50% inhibitory concentrations (IC50s) of doxycycline were determined for 747 isolates obtained between 1997 and 2006 from patients living in Senegal, Republic of the Congo, and Gabon and patients hospitalized in France for imported malaria. The statistical analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to doxycycline. A triple normal distribution was fitted to the data using a Bayesian mixture modeling approach. The IC50 geometric mean ranged from 6.2 μM to 11.1 μM according to the geographical origin, with a mean of 9.3 μM for all 747 parasites. The values for all 747 isolates were classified into three components: component A, with an IC50 mean of 4.9 μM (±2.1 μM [standard deviation]); component B, with an IC50 mean of 7.7 μM (±1.2 μM); and component C, with an IC50 mean of 17.9 μM (±1.4 μM). According to the origin of the P. falciparum isolates, the triple normal distribution was found in each subgroup. However, the proportion of isolates predicted to belong to component B was most important in isolates from Gabon and Congo and in isolates imported from Africa (from 46 to 56%). In Senegal, 55% of the P. falciparum isolates were predicted to be classified as component C. The cutoff of reduced susceptibility to doxycycline in vitro was estimated to be 35 μM. PMID:19047651

Inhibition of P-glycoprotein in Caco-2 cells: effects of herbal remedies frequently used by cancer patients.

PubMed

Engdal, S; Nilsen, O G

2008-06-01

1. The herbal products Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic were investigated for in vitro inhibitory potential on P-glycoprotein (P-gp)-mediated transport of digoxin (30 nM) in differentiated and polarized Caco-2 cells. 2. Satisfactory cell functionality was demonstrated through measurements of assay linearity, transepithelial electric resistance (TEER), cytotoxicity, mannitol permeability, and inclusion of the positive inhibition control verapamil. 3. The most potent inhibitors of the net digoxin flux (IC(50)) were mistletoe > Natto K2 > Agaricus > green tea (0.022, 0.62, 3.81, >4.5 mg ml(-1), respectively). Mistletoe also showed the lowest IC(25) value, close to that obtained by verapamil (1.0 and 0.5 microg ml(-1), respectively). The IC(50)/IC(25) ratio was found to be a good parameter for the determination of inhibition profiles. Garlic and noni juice were classified as non-inhibitors. 4. This study shows that mistletoe, Natto K2, Agaricus and green tea inhibit P-gp in vitro. Special attention should be paid to mistletoe due to very low IC(50) and IC(25) values and to Natto K2 due to a low IC(50) value and a low IC(50)/IC(25) ratio.

Withanolides derived from Physalis peruviana (Poha) with potential anti-inflammatory activity.

PubMed

Sang-Ngern, Mayuramas; Youn, Ui Joung; Park, Eun-Jung; Kondratyuk, Tamara P; Simmons, Charles J; Wall, Marisa M; Ruf, Michael; Lorch, Sam E; Leong, Ethyn; Pezzuto, John M; Chang, Leng Chee

2016-06-15

Three new withanolides, physaperuvin G (1), with physaperuvins I (2), and J (3), along with seven known derivatives (4-10), were isolated from the aerial parts of Physalis peruviana. The structures of 1-3 were determined by NMR, X-ray diffraction, and mass spectrometry. Compounds 1-10 were evaluated in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells. Compounds 4, 5, and 10 with potent nitric oxide inhibitory activity in LPS-activated RAW 264.7 cells, with IC50 values in the range of 0.32-7.8μM. In addition, all compounds were evaluated for potential to inhibit tumor necrosis factor-alpha (TNF-α)-activated nuclear factor-kappa B (NF-κB) activity with transfected human embryonic kidney cells 293. Compounds 4-7 inhibited TNF-α-induced NF-κB activity with IC50 values in the range of 0.04-5.6μM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes.

PubMed

Hemmert, Catherine; Ramadani, Arba Pramundita; Boselli, Luca; Fernández Álvarez, Álvaro; Paloque, Lucie; Augereau, Jean-Michel; Gornitzka, Heinz; Benoit-Vical, Françoise

2016-07-01

A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro- and submicromolar range, correlated with their lipophilicity. Structure-activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50=210nM) close to the value obtained with chloroquine (IC50=514nM) and a weak cytotoxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L

PubMed Central

2012-01-01

A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC50 values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC50 = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure–activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L. PMID:24900494

Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates.

PubMed

Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína; Švarcová, Markéta; Vinšová, Jarmila

2016-02-11

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman's method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM). Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

Four new compounds isolated from Psoralea corylifolia and their diacylglycerol acyltransferase (DGAT) inhibitory activity.

PubMed

Lin, Xin; Li, Ban-Ban; Zhang, Le; Li, Hao-Ze; Meng, Xiao; Jiang, Yi-Yu; Lee, Hyun-Sun; Cui, Long

2018-05-14

A new bakuchiol compound Δ 11 -12-hydroxy-12-dimethyl bakuchiol (1), a new flavanone compound 2(S)-6-methoxy-7- hydroxymethylene-4'-hydroxyl-flavanone (8), and two new isoflavanone compounds 4',7-dihydroxy-3'-(6"β-hydroxy-3″,7″-dimethyl-,2″,7″-dibutenyl)-geranylisoflavone (9) and 4',7-dihydroxy-3'-(7″-hydroxy-7″-methyl-2″,5″-dibutenyl)-geranylisoflavone (10) together with eight known compounds (2-7, 11, 12) were isolated from the P. corylifolia. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against DGAT1/2. Among them, compounds 3, 9 and 10 were found to exhibit selective inhibitory activity on DGAT1 with IC 50 values ranging from 93.7 ± 1.3 to 96.2 ± 1.1 μM. Compound 1 showed inhibition activity on DGAT1 with IC 50 values 73.4 ± 1.3 μM and inhibition of DGAT2 with IC 50 value 121.1 ± 1.3 μM. Copyright © 2018 Elsevier B.V. All rights reserved.

Bisindolylmethane thiosemicarbazides as potential inhibitors of urease: Synthesis and molecular modeling studies.

PubMed

Taha, Muhammad; Ullah, Hayat; Al Muqarrabun, Laode Muhammad Ramadhan; Khan, Muhammad Naseem; Rahim, Fazal; Ahmat, Norizan; Javid, Muhammad Tariq; Ali, Muhammad; Khan, Khalid Mohammed

2018-01-01

Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1 H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC 50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC 50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Malaysian brown seaweeds Sargassum siliquosum and Sargassum polycystum: Low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), α-amylase, and α-glucosidase inhibition activities.

PubMed

Nagappan, Hemlatha; Pee, Poh Ping; Kee, Sandra Hui Yin; Ow, Ji Tsong; Yan, See Wan; Chew, Lye Yee; Kong, Kin Weng

2017-09-01

Two Malaysian brown seaweeds, Sargassum siliquosum and Sargassum polycystum were first extracted using methanol to get the crude extract (CE) and further fractionated to obtain fucoxanthin-rich fraction (FRF). Samples were evaluated for their phenolic, flavonoid, and fucoxanthin contents, as well as their inhibitory activities towards low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), α-amylase, and α-glucosidase. In LDL oxidation assay, an increasing trend in antioxidant activity was observed as the concentration of FRF (0.04-0.2mg/mL) and CE (0.2-1.0mg/mL) increased, though not statistically significant. As for serum oxidation assay, significant decrease in antioxidant activity was observed as concentration of FRF increased, while CE showed no significant difference in inhibitory activity across the concentrations used. The IC 50 values for ACE inhibitory activity of CE (0.03-0.42mg/mL) were lower than that of FRF (0.94-1.53mg/mL). When compared to reference drug Voglibose (IC 50 value of 0.61mg/mL) in the effectiveness in inhibiting α-amylase, CE (0.58mg/mL) gave significantly lower IC 50 values while FRF (0.68-0.71mg/mL) had significantly higher IC 50 values. The α-glucosidase inhibitory activity of CE (IC 50 value of 0.57-0.69mg/mL) and FRF (IC 50 value of 0.50-0.53mg/mL) were comparable to that of reference drug (IC 50 value of 0.54mg/mL). Results had shown the potential of S. siliquosum and S. polycystum in reducing cardiovascular diseases related risk factors following their inhibitory activities on ACE, α-amylase and α-glucosidase. In addition, it is likelihood that FRF possessed antioxidant activity at low concentration level. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lead toxicity to Lemna minor predicted using a metal speciation chemistry approach.

PubMed

Antunes, Paula M C; Kreager, Nancy J

2014-10-01

In the present study, predictive measures for Pb toxicity and Lemna minor were developed from bioassays with 7 surface waters having varied chemistries (0.5-12.5 mg/L dissolved organic carbon, pH of 5.4-8.3, and water hardness of 8-266 mg/L CaCO3 ). As expected based on water quality, 10%, 20%, and 50% inhibitory concentration (IC10, IC20, and IC50, respectively) values expressed as percent net root elongation (%NRE) varied widely (e.g., IC20s ranging from 306 nM to >6920 nM total dissolved Pb), with unbounded values limited by Pb solubility. In considering chemical speciation, %NRE variability was better explained when both Pb hydroxides and the free lead ion were defined as bioavailable (i.e., f{OH} ) and colloidal Fe(III)(OH)3 precipitates were permitted to form and sorb metals (using FeOx as the binding phase). Although cause and effect could not be established because of covariance with alkalinity (p = 0.08), water hardness correlated strongly (r(2)  = 0.998, p < 0.0001) with the concentration of total Pb in true solution ([Pb]T_True solution ). Using these correlations as the basis for predictions (i.e., [Pb]T_True solution vs water hardness and %NRE vs f{OH} ), IC20 and IC50 values produced were within a factor of 2.9 times and 2.2 times those measured, respectively. The results provide much needed effect data for L. minor and highlight the importance of chemical speciation in Pb-based risk assessments for aquatic macrophytes. © 2014 SETAC.

Synthesis of (benzimidazol-2-yl)aniline derivatives as glycogen phosphorylase inhibitors.

PubMed

Galal, Shadia A; Khattab, Muhammad; Andreadaki, Fotini; Chrysina, Evangelia D; Praly, Jean-Pierre; Ragab, Fatma A F; El Diwani, Hoda I

2016-11-01

A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC 50 values in the 400-600μM range. Arylsulfonyl derivatives 7 (Ar: phenyl) and 9 (Ar: o-nitrophenyl) of 1 exhibited the highest activity (series 2) among the studied compounds (IC 50 324μM and 357μM, respectively) with stronger effect than the p-tolyl analogue 8. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development of Quantum Chemical Method to Calculate Half Maximal Inhibitory Concentration (IC50 ).

PubMed

Bag, Arijit; Ghorai, Pradip Kr

2016-05-01

Till date theoretical calculation of the half maximal inhibitory concentration (IC50 ) of a compound is based on different Quantitative Structure Activity Relationship (QSAR) models which are empirical methods. By using the Cheng-Prusoff equation it may be possible to compute IC50 , but this will be computationally very expensive as it requires explicit calculation of binding free energy of an inhibitor with respective protein or enzyme. In this article, for the first time we report an ab initio method to compute IC50 of a compound based only on the inhibitor itself where the effect of the protein is reflected through a proportionality constant. By using basic enzyme inhibition kinetics and thermodynamic relations, we derive an expression of IC50 in terms of hydrophobicity, electric dipole moment (μ) and reactivity descriptor (ω) of an inhibitor. We implement this theory to compute IC50 of 15 HIV-1 capsid inhibitors and compared them with experimental results and available other QASR based empirical results. Calculated values using our method are in very good agreement with the experimental values compared to the values calculated using other methods. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Two novel assays for the detection of haemin-binding properties of antimalarials evaluated with compounds isolated from medicinal plants.

PubMed

Steele, J C P; Phelps, R J; Simmonds, M S J; Warhurst, D C; Meyer, D J

2002-07-01

Forty-two compounds isolated from nine plants used within South America for the treatment of malaria were tested for haemin binding using two novel, rapid screening methods. The data obtained were analysed with respect to IC(50) values for in vitro toxicity to Plasmodium falciparum trophozoites. One method, a multiwell assay based on the inhibition of the interaction of haemin with glutathione (GSH), is sensitive in the 10 microM range, takes c. 1 h and is suitable for either a high throughput screen or rapid assay during natural product isolation. Of 19 compounds showing antiplasmodial activity (IC(50) < 40 microM), 16 (84%) showed >40% inhibition of GSH-haemin reaction. The sensitivity and specificity of the assay were 0.85 and 0.82, respectively. The positive predictive value was 0.81 and the negative predictive value 0.86. A more sensitive assay (0.1 microM range) is based on the reversal by haemin-binding compounds of the haemin inhibition of the L-dopachrome-methyl ester tautomerase activity of human macrophage migration inhibitory factor. This assay gives a better idea of the affinity of interaction and uses very small amounts of test compound. The log[RI(50)] of eight of the compounds that tested positive in the above assays together with those of quinine and chloroquine showed a positive correlation with log[antiplasmodial IC(50)] for strain T9-96 (r = 0.824) and strain K1 (r = 0.904). Several of the antimalarial compounds that bind haemin are isoquinolines, a class not shown previously to interact with haemin.

Ganoboninketals A-C, Antiplasmodial 3,4-seco-27-Norlanostane Triterpenes from Ganoderma boninense Pat.

PubMed

Ma, Ke; Ren, Jinwei; Han, Junjie; Bao, Li; Li, Li; Yao, Yijian; Sun, Chen; Zhou, Bing; Liu, Hongwei

2014-08-22

Three new nortriterpenes, ganoboninketals A-C (1-3), featuring rearranged 3,4-seco-27-norlanostane skeletons and highly complex polycyclic systems were isolated from the medicinal mushroom Ganoderma boninense. The structures of the new metabolites were established by spectroscopic methods. The absolute configurations in 1-3 were assigned by electronic circular dichroism (ECD) calculations. Compounds 1-3 showed antiplasmodial activity against Plasmodium falciparum with IC50 values of 4.0, 7.9, and 1.7 μM, respectively. Compounds 1 and 3 also displayed weak cytotoxicity against A549 cell line with IC50 values of 47.6 and 35.8 μM, respectively. Compound 2 showed weak cytotoxicity toward HeLa cell line with an IC50 value of 65.5 μM. Compounds 1-3 also presented NO inhibitory activity in the LPS-induced macrophages with IC50 values of 98.3, 24.3, and 60.9 μM, respectively.

A Novel Two-Step Hierarchial Quantitative Structure-Activity ...

EPA Pesticide Factsheets

Background: Accurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public–private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening. Methods and results: A database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC50) and in vivo rodent median lethal dose (LD50) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET ; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments) . The application of conventional quantitative structure–activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD50 values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC50 and LD50. However, a linear IC50 versus LD50 correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC50 and LD50 values: One group comprises compounds with linear IC50 versus LD50 relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models t

Impact of wines and wine constituents on cyclooxygenase-1, cyclooxygenase-2, and 5-lipoxygenase catalytic activity.

PubMed

Kutil, Zsofia; Temml, Veronika; Maghradze, David; Pribylova, Marie; Dvorakova, Marcela; Schuster, Daniela; Vanek, Tomas; Landa, Premysl

2014-01-01

Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63-94%, cyclooxygenase-2 (COX-2) activity in the range of 20-44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72-84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41-68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50 = 0.76 μM) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50 = 2.25 μM), quercetin (IC50 = 3.29 μM), and myricetin (IC50 = 4.02 μM). trans-Resveratrol was identified as an inhibitor of COX-1 (IC50 = 2.27 μM) and COX-2 (IC50 = 3.40 μM). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway.

Impact of Wines and Wine Constituents on Cyclooxygenase-1, Cyclooxygenase-2, and 5-Lipoxygenase Catalytic Activity

PubMed Central

Temml, Veronika; Maghradze, David; Vanek, Tomas

2014-01-01

Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63–94%, cyclooxygenase-2 (COX-2) activity in the range of 20–44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72–84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41–68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50 = 0.76 μM) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50 = 2.25 μM), quercetin (IC50 = 3.29 μM), and myricetin (IC50 = 4.02 μM). trans-Resveratrol was identified as an inhibitor of COX-1 (IC50 = 2.27 μM) and COX-2 (IC50 = 3.40 μM). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway. PMID:24976682

6-Nitrobenzimidazole derivatives: potential phosphodiesterase inhibitors: synthesis and structure-activity relationship.

PubMed

Khan, K M; Shah, Zarbad; Ahmad, V U; Ambreen, N; Khan, M; Taha, M; Rahim, F; Noreen, S; Perveen, S; Choudhary, M I; Voelter, W

2012-02-15

6-Nitrobenzimidazole derivatives (1-30) synthesized and their phosphodiesterase inhibitory activities determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition with IC(50) values between 1.5±0.043 and 294.0±16.7 μM. Compounds 30 (IC(50)=1.5±0.043 μM), 1 (IC(50)=2.4±0.049 μM), 11 (IC(50)=5.7±0.113 μM), 13 (IC(50)=6.4±0.148 μM), 14 (IC(50)=10.5±0.51 μM), 9 (IC(50)=11.49±0.08 μM), 3 (IC(50)=63.1±1.48 μM), 10 (IC(50)=120.0±4.47 μM), and 6 (IC(50)=153.2±5.6 μM) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA (IC(50)=274±0.007 μM), and thus are potential molecules for the development of a new class of phosphodiesterase inhibitors. A structure-activity relationship is evaluated. All compounds are characterized by spectroscopic parameters. Copyright © 2011 Elsevier Ltd. All rights reserved.

Mechanism of the effect of pH and biochar on the phytotoxicity of the weak acid herbicides imazethapyr and 2,4-D in soil to rice (Oryza sativa) and estimation by chemical methods.

PubMed

Liu, Kailin; He, Ying; Xu, Shiji; Hu, Lifeng; Luo, Kun; Liu, Xiangying; Liu, Min; Zhou, Xiaomao; Bai, Lianyang

2018-06-18

The existing form of an ionizable organic compound can simultaneously affect its soil adsorption and plant bioactivity. In this experiment, the adsorption and bioactivity of two weak acid herbicides (WAHs), imazethapyr and 2,4-D, were studied to explore the predominant mechanism by which the soil pH and the addition of biochar can influence the phytotoxicity of WAHs in soil. Then, the WAH concentration extracted by hollow fiber-based liquid-phase microextraction (C HF-LPME ), the in situ pore water concentration (C IPW ) and the added concentration (C AC ) were employed to estimate the phytotoxicity. The results showed that with increased pH from 5.5 to 8.5, the phytotoxicity of the WAHs to rice increased about 1-fold in the soil, but decreased in aqueous solutions, the IC 50 values for imazethapyr and 2,4-D at pH 5.0 were 3- and 2-fold higher than that at pH 8.0. In addition, the soil adsorption decreased, indicating that the adsorption process was the dominant factor for the variation of the phytotoxicity of the WAHs in the tested soil instead of the decreasing bioactivity. The concentration that inhibits plant growth by 50% (IC 50 ) calculated by the C AC in different pH and biochar soils ranged from 0.619 to 3.826 mg/kg for imazethapyr and 1.871-72.83 mg/kg for 2,4-D. The coefficient of variation (CV) of the IC 50 values reached 65.61% for imazethapyr and 130.0% for 2,4-D. However, when IC 50 was calculated by C IPW and C HF-LPME , the CVs of the IC 50 values decreased to 23.51% and 36.23% for imazethapyr and 40.21% and 50.93% for 2,4-D, respectively. These results suggested that C IPW and C HF-LPME may be more appropriate than C AC for estimating the phytotoxicity of WAHs. Copyright © 2018 Elsevier Inc. All rights reserved.

In vitro evaluation of novel antiviral activities of 60 medicinal plants extracts against hepatitis B virus.

PubMed

Arbab, Ahmed Hassan; Parvez, Mohammad Khalid; Al-Dosari, Mohammed Salem; Al-Rehaily, Adnan Jathlan

2017-07-01

Currently, >35 Saudi Arabian medicinal plants are traditionally used for various liver disorders without a scientific rationale. This is the first experimental evaluation of the anti-hepatitis B virus (HBV) potential of the total ethanolic and sequential organic extracts of 60 candidate medicinal plants. The extracts were tested for toxicity on HepG2.2.15 cells and cytotoxicity concentration (CC 50 ) values were determined. The extracts were further investigated on HepG2.2.15 cells for anti-HBV activities by analyzing the inhibition of HBsAg and HBeAg production in the culture supernatants, and their half maximal inhibitory concentration (IC 50 ) and therapeutic index (TI) values were determined. Of the screened plants, Guiera senegalensis (dichloromethane extract, IC 50 =10.65), Pulicaria crispa (ethyl acetate extract, IC 50 =14.45), Coccinea grandis (total ethanol extract, IC 50 =31.57), Fumaria parviflora (hexane extract, IC 50 =35.44), Capparis decidua (aqueous extract, IC 50 =66.82), Corallocarpus epigeus (total ethanol extract, IC 50 =71.9), Indigofera caerulea (methanol extract, IC 50 =73.21), Abutilon figarianum (dichloromethane extract, IC 50 =99.76) and Acacia oerfota (total ethanol extract, IC 50 =101.46) demonstrated novel anti-HBV activities in a time- and dose-dependent manner. Further qualitative phytochemical analysis of the active extracts revealed the presence of alkaloids, tannins, flavonoids and saponins, which are attributed to antiviral efficacies. In conclusion, P. crispa, G. senegalensis and F. parviflora had the most promising anti-HBV potentials, including those of C. decidua , C. epigeus, A. figarianum , A. oerfota and I. caerulea with marked activities. However, a detailed phytochemical study of these extracts is essential to isolate the active principle(s) responsible for their novel anti-HBV potential.

The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo.

PubMed

Yamamoto, Satoshi; Sugahara, Shingo; Naito, Ryo; Ichikawa, Atsushi; Ikeda, Ken; Yamada, Toshimitsu; Shimizu, Yasuaki

2006-07-10

YM-393059, (+/-)-N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl]benzenesulfonamide difumarate, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC50=14 nM) and PDE4 with a moderate potency (IC50=630 nM). In a cell-based assay, YM-393059 was found to inhibit anti-CD3 antibody, Staphylococcal enterotoxin B, and phytohaemagglutinin-induced interleukin (IL)-2 production in mouse splenocytes with IC50 values ranging from 0.48 to 1.1 microM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-gamma and IL-4 production in splenocytes with IC50 values of 1.8 and 2.8 microM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-gamma, and IL-4) production was 20- to 31-fold weaker than that of YM976, a selective PDE4 inhibitor. However, orally administered YM-393059 and YM976 inhibited anti-CD3 antibody-induced IL-2 production equipotently in mice. In addition, YM-393059 inhibited lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo more potently than IL-2 (ED50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of alpha2-adrenoceptor agonist-induced sleep in mice, which is a model for the assessment of the typical side effects caused by PDE4 inhibitors, nausea and emesis. YM-393059 is a novel and attractive compound for the treatment of a wide variety of T-cell-mediated diseases.

In vitro anti-proliferative and anti-inflammatory activity of leaf and fruit extracts from Vaccinium bracteatum Thunb.

PubMed

Landa, Premysl; Skalova, Lenka; Bousova, Iva; Kutil, Zsofia; Langhansova, Lenka; Lou, Ji-Dong; Vanek, Tomas

2014-01-01

The aim of this study was to evaluate in vitro anti-proliferative (tested on MCF-7, MDA-MB-231, and MCF-10A cell lines) and anti-inflammatory (evaluated as inhibition of prostaglandin E2 synthesis catalyzed by cyclooxygenase-2) effect of various extracts from Vaccinium bracteatum leaves and fruits. The highest anti-proliferative effect possessed leaf dichloromethane extract with IC50 values ranging from 93 to 198 μg/mL. In the case of cyclooxygenase-2 inhibition, n-hexane, dichloromethane, and ethanol fruit extracts showed the best activity with IC50 values = 2.0, 5.4, and 12.7 μg/mL, respectively. These results indicate that V. bracteatum leaves and fruits could be useful source of anti-cancer and anti-inflammatory compounds.

Synthesis, docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity.

PubMed

Chinthala, Yakaiah; Thakur, Sneha; Tirunagari, Shalini; Chinde, Srinivas; Domatti, Anand Kumar; Arigari, Niranjana Kumar; K V N S, Srinivas; Alam, Sarfaraz; Jonnala, Kotesh Kumar; Khan, Feroz; Tiwari, Ashok; Grover, Paramjit

2015-03-26

A series of novel chalcone-triazole derivatives were synthesized and screened for in vitro anticancer activity on the human cancer cell lines IMR32 (neuroblastoma), HepG2 (hepatoma) and MCF-7 (breast adenocarcinoma), DU-145 (prostate carcinoma), and A549 (lung adenocarcinoma). Among the tested compounds, 4r showed the most promising anticancer activity in all the cell lines whereas, compounds 4c (IC50 65.86 μM), 4e (IC50 66.28 μM), 4o (IC50 35.81 μM), 4q (IC50 50.82 μM) and 4s (IC50 48.63 μM) showed better activity than the standard doxorubicin (IC50 69.33 μM) in A549 cell line alone. Rat intestinal α-glucosidase inhibitory activity of the synthesized derivatives showed 4m (IC50 67.77 μM), 4p (IC50 74.94 in μM) and 4s (IC50 102.10 μM) as most active compared to others. The in silico docking of synthesized derivatives 4a-4t with DNA topoisomerase IIα revealed the LibDock score in the range of 71.2623-118.29 whereas, compounds 4h, 4m, 4p and 4s with docking target α-glucosidase were in the range of 100.372-107.784. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Antioxidant, antihypertensive, and antibacterial properties of endophytic Pestalotiopsis species from medicinal plants.

PubMed

Tejesvi, Mysore V; Kini, Kukkundoor R; Prakash, Harishchandra S; Subbiah, Ven; Shetty, Hunthrike S

2008-09-01

Pestalotiopsis species were most dominant endophytic species isolated from four medicinal plants including Terminalia arjuna, Terminalia chebula, Azadirachta indica, and Holarrhena antidysenterica. Thirty Pestalotiopsis species isolated from different parts of the medicinal plants were selected for the study. The antioxidant and antihypertensive properties of Pestalotiopsis isolates were determined by measuring 1,1-diphenyl-2-picrylhydrazyl inhibitory activity, lipid peroxidation, and angiotensin-converting enzyme inhibition activity. Pestalotiopsis isolates of T. arjuna origin exhibited maximum radical scavenging activity compared with the others. The IC50 values of Pestalotiopsis extracts for 1,1-diphenyl-2-picrylhydrazyl scavenging activity ranged from 14 to 27 microg/mL compared with 15 and 6 microg/mL for butylated hydroxytoluene and ascorbic acid, respectively. The DNA damage study was also done for three isolates, TC-315, TA-37, and TA-60; TA-37 gave 80% protection. The IC50 values of Pestalotiopsis extracts for lipid peroxidation ranged between 30 and 35.5 microg/mL, while for the positive control butylated hydroxytoluene, it was 26 microg/mL. Out of 32 fungal extracts screened for antihypertensive assay, five (TA-37, TA-60, TA-102, TA-103, and TC-320) showed >60% inhibition of angiotensin-converting enzyme. The IC50 values for five extracts ranged from 21 to 37 microg/mL and was 20 microg/mL for captopril used as a positive control. The antibacterial activity was measured by the microplate-based turbidity measurement method. Four Pestalotiopsis extracts (TA-04, TA-37, TA-60, and TA-102) showed >75% inhibition against five bacterial strains including Bacillus subtilis, Escherichia coli, Pseudomonas fluorescens, Xanthomonas axonopodis pv. malvacearum, and Staphylococcus aureus. The antioxidant, antibacterial, and antihypertensive activities demonstrated the potential of Pestalotiopsis extracts as therapeutic targets.

Characterization of poly(allylamine) as a polymeric ligand for ion-exchange protein chromatography.

PubMed

Li, Ming; Li, Yanying; Yu, Linling; Sun, Yan

2017-02-24

This work reports poly(allylamine) (PAA), as a polymeric ion-exchange ligand for protein chromatography. Sepharose FF was modified with PAA, and six anion exchangers with ionic capacities (ICs) from 165 to 618mmol/L were prepared. Inverse size exclusion chromatography, adsorption equilibrium, uptake kinetics and column elution were performed. It was found that both the adsorption capacity and effective diffusivity maintained low values in the IC range of 165-373mmol/L, but they started to increase beyond 373mmol/L, and increased by 80% and 23 times, respectively, when the IC reached 618mmol/L. Interestingly, a drastic decrease of pore size was observed around the IC of 373mmol/L. The results suggest that the PAA chains played an important role in protein adsorption by altering the inner pore structure of the gels. It is considered that, PAA chains turn from inextensible states with multipoint-grafting on the pore surface at low coupling densities (IC<373mmol/L) to closer, extended and flexible grafting states with less coupling points at higher coupling densities (IC>373mmol/L). These characters of the grafted chains at higher IC values benefit in protein adsorption by three-dimensional binding and encouraged the happening of "chain delivery" of bound proteins on the chains. Besides, the ion exchangers showed favorable adsorption and uptake properties in a wide ionic strength range, 0-500mmol/L NaCl, indicating much better salt tolerance feature than the so-far reported ion exchangers. Moreover, a mild condition of pH 5.0 offered effective recovery of bound proteins in elution chromatography. The results indicate that the PAA-based anion exchanger of a high IC value is promising for high-capacity protein chromatography dealing with feedstock of a wide range of ionic strengths. Copyright © 2016 Elsevier B.V. All rights reserved.

Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever.

PubMed

Carreño Otero, Aurora L; Vargas Méndez, Leonor Y; Duque L, Jonny E; Kouznetsov, Vladimir V

2014-05-06

Girgensohnine alkaloid was used as a natural model in the design and generation of new alkaloid-like α-aminonitrile series that was completed by the use of SSA-catalyzed Strecker reaction between commercial and inexpensive substituted benzaldehydes, piperidine (pyrrolidine, morpholine and N-methylpiperazine) and acetone cyanohydrin. Calculated ADMETox parameters of the designed analogs revealed their good pharmacokinetic profiles indicating lipophilic characteristics. In vitro AChE enzyme test showed that obtained α-aminonitriles could be considered as AChEIs with micromolar IC50 values ranging from 42.0 to 478.0 μM (10.3-124.0 μg/mL). Among this series, the best AChE inhibitor was the pyrrolidine α-aminonitrile 3 (IC50 = 42 μM), followed by the piperidine α-aminonitriles 2 and 6 (IC50 = 45 μM and IC50 = 51 μM, respectively), and the compound 7 (IC50 = 51 μM). In vivo insecticidal activity of more active AChEIs against Aedes aegypti larvae was also performed showing a good larvicidal activity at concentrations less than 140 ppm, highlighting products 2 and 7 that could serve as lead compounds to develop new potent and selective insecticides. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Antimicrobial and anti-inflammatory activities of Pleurostylia capensis Turcz (Loes) (celastraceae).

PubMed

Razwinani, Mapula; Tshikalange, Thilivhali Emmanuel; Motaung, Shirley C K M

2014-01-01

Pleurostylia capensis is a large tree that can reach the maximum height of 20 m long, and it have been traditionally used as cosmetic, for steam bath, ritual body wash, and as a purgative to treat symptoms of witchcraft. Using ethanol, chloroform, dichloromethane (DCM), ethyl acetate (EA), and water extracts, leaves, bark and roots of Pleurostylia capensis were investigated scientifically for their effectiveness in antimicrobial, antioxidant and anti-inflammatory activities using standard methods. The extracts were evaluated for antimicrobial activity against Gram positive (Staphylococcus aureus, Bacillus cereus, and Mycobacterium smegmatis), Gram negative (Escherichia coli, Klebsiella pneumonia, Klebsiella oxytoca, Streptococcus pyogenes, Pseudomonas aeruginosa and Salmonella typhimurium), and Candida albicans. The antioxidant activity was investigated using 2, 2-diphenlyl-1-picrylhadrazyl (DPPH), free radical scavenging assay. The anti-inflammatory activity of P. capensis extracts was evaluated against both cyclooxygenase enzymes (COX 1 and 2). The ethyl acetate extracts of P. capensis showed a strong antimicrobial activity against B. cereus, K. pneumonia, S. pyogenes, and M. smegmatis with MIC value of 0.39 and 0.78 mg/ml. While the ethanol bark extract was most active against M. smegmatis with MIC value of 0.78 mg/ml; the least potent activity was observed with dichloromethane, chloroform and water extracts, with an MIC value ranging from 1.56 mg/ml to 50.0 mg/ml. The plant extracts proved to be good antioxidant agent, whereas extracts of ethanol were the most active, with IC50 ranging from 1.00 to 1.74 µg/ml, which is lower, and in close range to Vitamin C (1.40 µg/ml). Its moderation to potent inhibitory activity was observed in all extracts. Ethanol and dichloromethane extracts were among the most potent when compared to water and petroleum ether extracts. The water extracts showed to be nontoxic on the Hek cell line with an IC50 value of 204.0, and 207.3 µg/ml (roots and bark) respectively. The dichloromethane, ethyl acetate, chloroform and ethanol extracts showed to be toxic on the Hek cell, with IC50 range from 5.94 to 42.91µg/ml. The results obtained indicate the effectiveness of these plants.

Assessment of antimalarial activity against Plasmodium falciparum and phytochemical screening of some Yemeni medicinal plants

PubMed Central

Alshawsh, Mohammed A.; Al-shamahy, Hassan A.; Alsllami, Salah F.; Lindequist, Ulrike

2009-01-01

Developing countries, where malaria is one of the most prevalent diseases, still rely on traditional medicine as a source for the treatment of this disease. In the present study, six selected plants (Acalypha fruticosa, Azadirachta indica, Cissus rotundifolia, Echium rauwalfii, Dendrosicyos socotrana and Boswellia elongata) commonly used in Yemen by traditional healers for the treatment of malaria as well as other diseases, were collected from different localities of Yemen, dried and extracted with methanol and water successfully. The antiplasmodial activity of the extracts was evaluated against fresh clinical isolates of Plasmodium falciparum. The selectivity parameters to evaluate the efficacy of these medicinal plants were measured by in vitro micro test (Mark III) according to World Health Organization (WHO) 1996 & WHO 2001 protocols of antimalarial drug tests. Among the investigated 12 extracts, three were found to have significant antiplasmodial activity with IC50 values less than 4 µg/ml, namely the water extracts of A. fruticosa, A. indica and D. socotrana. Six extracts showed moderate activity with IC50 values ranging from 10 to 30 µg/ml and three appeared to be inactive with IC50 values more than 30 µg/ml. In addition, preliminary phytochemical screening of the methanolic and aqueous extracts indicated the presence of saponins, tannins, flavonoids, terpenoids, polysaccharides and peptides. PMID:18955251

Constituents of PG201 (Layla(®)), a multi-component phytopharmaceutical, with inhibitory activity on LPS-induced nitric oxide and prostaglandin E2 productions in macrophages.

PubMed

Kim, Hyun Ji; Kim, Hye Mi; Ryu, Byeol; Lee, Woo-Seok; Shin, Ji-Sun; Lee, Kyung-Tae; Jang, Dae Sik

2016-02-01

Fourteen compounds, coumarin (1), demethylsuberosin (2), xanthotoxin (3), psoralen (4), decursinol (5), decursin (6), decursinol angelate (7), chikusetsusaponin IVa (8), chikusetsusaponin IVa methyl ester (9), ethyl caffeate (10), syringaresinol (11), cnidilide (12), farnesol (13), and linoleic acid (14), were isolated from phytopharmaceutical PG201 (Layla(®)) by activity-guided fractionation utilizing inhibitory activity on nitric oxide (NO) production in vitro. The isolates 1-14 were evaluated for their inhibitory activity on LPS-induced NO and prostaglandin E2 (PGE2) productions in RAW 264.7 cells. All the compounds except 14 displayed suppressive effects on LPS-induced NO and PGE2 production with IC50 values ranging from 8 to 60 μM. Among these, compound 10 showed the most potent inhibitory effect on NO production from RAW 264.7 cells with an IC50 value of 8.25 μM. Compounds 2, 9, and 10 exhibited high inhibitory effects on PGE2 production with the IC50 values of 9.42, 7.51, and 6.49 μM, respectively. These findings suggest that compounds 2, 9, and 10 are the potential anti-inflammatory active constituents of PG201 and further study may be needed to explain their mechanism of action.

Inhibition of α-glucosidase activity by ethanolic extract of Melia azedarach L. leaves

NASA Astrophysics Data System (ADS)

Sulistiyani; Safithri, Mega; Puspita Sari, Yoana

2016-01-01

Development of α-glucosidase inhibitor derived from natural products is an opportunity for a more economic management of diabetes prevention. The objective of this study was to test the activity of α-glucosidase with or without potential inhibitor compounds. By in vitro method, α-glucosidase hydrolizes p-nitrophenyl-α-D-glucopiranoside to glucose and the yellow of p-nitrophenol which can be determined with spectrophotometry at 400 nm. The ability of ethanolic leaf extract of Melia azedarach L. as a-glucosidase inhibitor was compared with that of commercial acarbose (Glucobay®). Acarbose showed strong inhibitory activity against a-glucosidase with IC50 values of 2.154 µg/mL. The crude ethanolic leaf extract of M. azedarach, however, showed less inhibitory activity with IC50 value of 3, 444.114 µg/mL. Total phenolics of M. azedarach leaves EtOH extract showed 17.94 µg GAE/mg extract and flavonoids total compound of 9.55 µg QE/mg extract. Based on the published wide range of IC50 values of extracts reported as a-glucosidase inhibitor which were between 10, 000 ppm-0.66 ppm, our result suggests that extract of M.azedarach leaves is potential candidate for development of anti-hyperglycemic formulation.

Terpenes increase the lipid dynamics in the Leishmania plasma membrane at concentrations similar to their IC50 values.

PubMed

Camargos, Heverton Silva; Moreira, Rodrigo Alves; Mendanha, Sebastião Antonio; Fernandes, Kelly Souza; Dorta, Miriam Leandro; Alonso, Antonio

2014-01-01

Although many terpenes have shown antitumor, antibacterial, antifungal, and antiparasitic activity, the mechanism of action is not well established. Electron paramagnetic resonance (EPR) spectroscopy of the spin-labeled 5-doxyl stearic acid revealed remarkable fluidity increases in the plasma membrane of terpene-treated Leishmania amazonensis promastigotes. For an antiproliferative activity assay using 5×10(6) parasites/mL, the sesquiterpene nerolidol and the monoterpenes (+)-limonene, α-terpineol and 1,8-cineole inhibited the growth of the parasites with IC50 values of 0.008, 0.549, 0.678 and 4.697 mM, respectively. The IC50 values of these terpenes increased as the parasite concentration used in the cytotoxicity assay increased, and this behavior was examined using a theoretical treatment of the experimental data. Cytotoxicity tests with the same parasite concentration as in the EPR experiments revealed a correlation between the IC50 values of the terpenes and the concentrations at which they altered the membrane fluidity. In addition, the terpenes induced small amounts of cell lysis (4-9%) at their respective IC50 values. For assays with high cell concentrations (2×10(9) parasites/mL), the incorporation of terpene into the cell membrane was very fast, and the IC50 values observed for 24 h and 5 min-incubation periods were not significantly different. Taken together, these results suggest that terpene cytotoxicity is associated with the attack on the plasma membrane of the parasite. The in vitro cytotoxicity of nerolidol was similar to that of miltefosine, and nerolidol has high hydrophobicity; thus, nerolidol might be used in drug delivery systems, such as lipid nanoparticles to treat leishmaniasis.

Terpenes Increase the Lipid Dynamics in the Leishmania Plasma Membrane at Concentrations Similar to Their IC50 Values

PubMed Central

Camargos, Heverton Silva; Moreira, Rodrigo Alves; Mendanha, Sebastião Antonio; Fernandes, Kelly Souza; Dorta, Miriam Leandro; Alonso, Antonio

2014-01-01

Although many terpenes have shown antitumor, antibacterial, antifungal, and antiparasitic activity, the mechanism of action is not well established. Electron paramagnetic resonance (EPR) spectroscopy of the spin-labeled 5-doxyl stearic acid revealed remarkable fluidity increases in the plasma membrane of terpene-treated Leishmania amazonensis promastigotes. For an antiproliferative activity assay using 5×106 parasites/mL, the sesquiterpene nerolidol and the monoterpenes (+)-limonene, α-terpineol and 1,8-cineole inhibited the growth of the parasites with IC50 values of 0.008, 0.549, 0.678 and 4.697 mM, respectively. The IC50 values of these terpenes increased as the parasite concentration used in the cytotoxicity assay increased, and this behavior was examined using a theoretical treatment of the experimental data. Cytotoxicity tests with the same parasite concentration as in the EPR experiments revealed a correlation between the IC50 values of the terpenes and the concentrations at which they altered the membrane fluidity. In addition, the terpenes induced small amounts of cell lysis (4–9%) at their respective IC50 values. For assays with high cell concentrations (2×109 parasites/mL), the incorporation of terpene into the cell membrane was very fast, and the IC50 values observed for 24 h and 5 min-incubation periods were not significantly different. Taken together, these results suggest that terpene cytotoxicity is associated with the attack on the plasma membrane of the parasite. The in vitro cytotoxicity of nerolidol was similar to that of miltefosine, and nerolidol has high hydrophobicity; thus, nerolidol might be used in drug delivery systems, such as lipid nanoparticles to treat leishmaniasis. PMID:25101672

Chemical composition and in vitro evaluation of antioxidant, antimicrobial, cytotoxicity and anti-acetylcholinesterase properties of Tunisian Origanum majorana L. essential oil.

PubMed

Hajlaoui, Hafedh; Mighri, Hedi; Aouni, Mahjoub; Gharsallah, Néji; Kadri, Adel

2016-06-01

This study investigated the chemical composition and evaluated the antioxidant, antimicrobial, cytotoxic and anti-acetylcholinesterase properties of Tunisian Origanum majorana essential oil. The findings showed that the oil exhibited high activity, particularly in terms of reducing power and β-Carotene bleaching, inducing higher IC50 values than BHT. The oil showed an important antimicrobial activity against 25 bacterial and fungal strains. In fact, the IZ, MIC and MBC values recorded for the bacterial strains were in the range of 8 ± 0-18.33 ± 0.57 mm, 0.097-3.125 and 0.39-6.25 mg/mL, respectively. The IZ, MIC and MFC values of the fungal strains varied between 11±0-28 ± 0 mm, 0.058-0.468 mg/mL and 0.234-1.875 mg/mL, respectively. A low cytotoxic effect was observed against cancer (Hep-2 and HT29) and continuous cell lineage (Vero), with CC50 values ranging from 13.73 to 85.63 mg/mL. The oil was also evaluated for anti-acetylcholinesterase effects, which showed that it exhibited significant activity with IC50 values reaching 150.33 ± 2.02 μg/mL. Copyright © 2016 Elsevier Ltd. All rights reserved.

Histamine H1-receptor antagonists against Leishmania (L.) infantum: an in vitro and in vivo evaluation using phosphatidylserine-liposomes.

PubMed

Pinto, Erika G; da Costa-Silva, Thais A; Tempone, Andre Gustavo

2014-09-01

Considering the limited and toxic therapeutic arsenal available for visceral leishmaniasis (VL), the drug repositioning approach could represent a promising tool to the introduction of alternative therapies. Histamine H1-receptor antagonists are drugs belonging to different therapeutic classes, including antiallergics and anxyolitics. In this work, we described for the first time the activity of H1-antagonists against L. (L.) infantum and their potential effectiveness in an experimental hamster model. The evaluation against promastigotes demonstrated that chlorpheniramine, cinnarizine, hydroxyzine, ketotifen, loratadine, quetiapine and risperidone exerted a leishmanicidal effect against promastigotes, with IC50 values in the range of 13-84μM. The antihistaminic drug cinnarizine demonstrated effectiveness against the intracellular amastigotes, with an IC50 value of 21μM. The mammalian cytotoxicity was investigated in NCTC cells, resulting in IC50 values in the range of 57-229μM. Cinnarizine was in vivo studied as a free formulation and entrapped into phosphatidylserine-liposomes. The free drug was administered for eight consecutive days at 50mg/kg by intraperitoneal route (i.p.) and at 100mg/kg by oral route to L. infantum-infected hamsters, but showed lack of effectiveness in both regimens, as detected by real time PCR. The liposomal formulation was administered by i.p. route at 3mg/kg for eight days and reduced the parasite burden to 54% in liver when compared to untreated group; no improvement was observed in the spleen of infected hamsters. Cinnarizine is the first antihistaminic drug with antileishmanial activity and could be used as scaffold for drug design studies for VL. Copyright © 2014 Elsevier B.V. All rights reserved.

Preparation of a monoclonal antibody against amantadine and rimantadine and development of an indirect competitive enzyme-linked immunosorbent assay for detecting the same in chicken muscle and liver.

PubMed

Peng, Dapeng; Wei, Wei; Pan, Yuanhu; Wang, Yulian; Chen, Dongmei; Liu, Zhenli; Wang, Xu; Dai, Menghong; Yuan, Zonghui

2017-01-30

A monoclonal antibody (mAb) was produced in order to monitor the illegal use of amantadine and rimantadine in animals. The produced mAb 2G3 exhibited an IC 50 value of 15.8μgL -1 for amantadine and exhibited cross-reactivity to both amantadine (100%) and rimantadine (70.6%). Standard curves ranged from 5 to 80μgL -1 for 2G3. The limits of detection of the developed indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) ranged from 5.0μgkg -1 to 5.4μgkg -1 in chicken muscle and liver. The recoveries were 81.3% to 98.1% with a coefficient of variation less than 15.7%. Good correlations were observed between the results of the ic-ELISA and liquid chromatography-mass spectrometry in the incurred tissues. These results suggest that ic-ELISA is a sensitive, accurate, and low-cost method that could be a useful tool for screening the residues of amantadine and rimantadine in chicken muscle and liver. Copyright © 2016 Elsevier B.V. All rights reserved.

The Anti-Inflammatory Activity of Boron Derivatives in Rodents

PubMed Central

Hall, Iris H.; Burnham, Bruce S.; Chen, Shang Y.; Sood, Anup; Spielvogel, Bernard F.; Morse, Karen W.

1995-01-01

Acyclic amine-carboxyboranes were effective anti-inflammatory agents in mice at 8 mg/kg x 2. These amine-carboxyboranes were more effective than the standard indomethacin at 8 mg/kg x 2, pentoxifylline at 50 mg/kg x 2, and phenylbutazone at 50 mg/kg x 2. The heterocyclic amine derivatives as well as amine-carbamoylboranes, carboalkoxyboranes, and cyanoboranes were generally less active. However, selected aminomethyl-phosphonate-N-cyanoboranes demonstrated greater than 60% reduction of induced inflammation. The boron compounds were also active in the rat induced edema, chronic arthritis, and pleurisy screens, demonstrating activity similar to the standard indomethacin. The compounds were effecive in reducing local pain and decreased the tail flick reflex to pain. The derivatives which demonstrated good anti-inflammatory activity were effective inhibitors of hydrolytic lysosomal, and proteolytic enzyme activities with IC50 50 values equal to -6M in mouse macrophages, human leukocytes, and Be Sal osteofibrolytic cells. In these same cell lines, the agents blocked prostaglandin cyclooxygenase activity with IC50 values of -6M. In mouse macrophage and human leukocytes, 5′ lipoxygenase activity was also inhibited by the boron derivatives with IC50 values of 10-6M. These IC50 values for inhibition of these enzyme activities are consistent with published values of known anti-inflammatory agents which target these enzymes. PMID:18472741

Xanthatin and xanthinosin from the burs of Xanthium strumarium L. as potential anticancer agents.

PubMed

Ramírez-Erosa, Irving; Huang, Yaoge; Hickie, Robert A; Sutherland, Ronald G; Barl, Branka

2007-11-01

Xanthatin and xanthinosin, 2 sesquiterpene lactones isolated from the burs of Xanthiun strumarium L. (cocklebur), showed moderate to high in vitro cytotoxic activity in the human cancer cell lines WiDr ATCC (colon), MDA-MB-231 ATCC (breast), and NCI-417 (lung). Xanthatin and xanthinosin were purified as the result of a multi-screening bioassay-guided study of wild plant species of the family Asteraceae, collected from various sites in Saskatchewan, Canada. Seventy-five extracts at a single concentration of 100 microg/mL were evaluated for in vitro cytotoxicity to the human cancer cell lines used. The chloroform extract of Carduus nutans L. (nodding thistle) aerial parts (IC50, 9.3 microg/mL) and the hexane extract of Echinacea angustifolia DC. (narrow-leaved purple coneflower) root (IC50, 4.0 microg/mL) were moderately to highly cytotoxic to the lung cancer cell line. The chloroform extracts of X. strumarium L. burs and Tanacetum vulgare L. (tansy) aerial parts exhibited the highest cytotoxicity for all cell lines tested; their IC50 values, obtained from multidose testing, ranged from 0.1 to 6.2 microg/mL (X. strumarium) and from 2.4 to 9.1 microg/mL (T. vulgare). Further purification of the chloroform fraction of X. strumarium yielded xanthatin and xanthinosin in high yields. This is the first time that these compounds have been reported in the burs of X. strumarium. Their IC50 values are also reported herein.

Molecular rationale delineating the role of lycopene as a potent HMG-CoA reductase inhibitor: in vitro and in silico study.

PubMed

Alvi, Sahir Sultan; Iqbal, Danish; Ahmad, Saheem; Khan, M Salman

2016-09-01

This study initially aimed to depict the molecular rationale evolving the role of lycopene in inhibiting the enzymatic activity of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase via in vitro and in silico analysis. Our results illustrated that lycopene exhibited strong HMG-CoA reductase inhibitory activity (IC50 value of 36 ng/ml) quite better than pravastatin (IC50 = 42 ng/ml) and strong DPPH free radical scavenging activity (IC50 value = 4.57 ± 0.23 μg/ml) as compared to ascorbic acid (IC50 value = 9.82 ± 0.42 μg/ml). Moreover, the Ki value of lycopene (36 ng/ml) depicted via Dixon plot was well concurred with an IC50 value of 36 ± 1.8 ng/ml. Moreover, molecular informatics study showed that lycopene exhibited binding energy of -5.62 kcal/mol indicating high affinity for HMG-CoA reductase than HMG-CoA (ΔG: -5.34 kcal/mol). Thus, in silico data clearly demonstrate and support the in vitro results that lycopene competitively inhibit HMG-CoA reductase activity by binding at the hydrophobic portion of HMG-CoA reductase.

Synthesis and biological evaluation of novel tacrine derivatives and tacrine-coumarin hybrids as cholinesterase inhibitors.

PubMed

Hamulakova, Slavka; Janovec, Ladislav; Hrabinova, Martina; Spilovska, Katarina; Korabecny, Jan; Kristian, Pavol; Kuca, Kamil; Imrich, Jan

2014-08-28

A series of novel tacrine derivatives and tacrine-coumarin heterodimers were designed, synthesized, and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Of these compounds, tacrine-coumarin heterodimer 7c and tacrine derivative 6b were found to be the most potent inhibitors of human AChE (hAChE), demonstrating IC50 values of 0.0154 and 0.0263 μM. Ligands 6b, 6c, and 7c exhibited the highest levels of inhibitory activity against human BuChE (hBuChE), demonstrating IC50 values that range from 0.228 to 0.328 μM. Docking studies were performed in order to predict the binding modes of compounds 6b and 7c with hAChE/hBuChE.

Bioactive steroids and sorbicillinoids isolated from the endophytic fungus Trichoderma sp. Xy24.

PubMed

Zhao, Jin-Lian; Zhang, Min; Liu, Ji-Mei; Tan, Zhen; Chen, Ri-Dao; Xie, Ke-Bo; Dai, Jun-Gui

2017-10-01

A new steroid glucoside (1), along with nine known steroids (2-10) and four known sorbicillinoids (11-14), were isolated from the endophytic fungus Trichoderma sp. Xy24. Their structures were elucidated on the basis of spectroscopic data analyses and by comparison with reported data. Compounds 3, 5-7, 9, 10, and 13 exhibited significant inhibitory effects on HIV-1 virus with IC 50 values ranging 1.9-9.3 μM; compounds 10, 13, and 14 showed potent inhibitory activity on LPS-induced NO production in BV2 microglia cells with inhibitory rates of 108.2, 100, and 75.1% at 10 μM, respectively. In addition, compound 10 displayed moderate cytotoxicity against BCG823 and HePG2 cell lines with IC 50 values of 11.1 and 17.7 μM, respectively.

Cytotoxic activity screening of Bangladeshi medicinal plant extracts.

PubMed

Akter, Raushanara; Uddin, Shaikh J; Grice, I Darren; Tiralongo, Evelin

2014-01-01

The cytotoxic activity of 23 crude methanol extracts from 19 Bangladeshi medicinal plants was investigated against healthy mouse fibroblasts (NIH3T3), healthy monkey kidney (VERO) and four human cancer cell lines (gastric, AGS; colon, HT-29; and breast, MCF-7 and MDA-MB-231) using MTT assay. High cytotoxicity across all cell lines tested was exhibited by Aegiceras corniculatum (fruit) and Hymenodictyon excelsum (bark) extracts (IC50 values ranging from 0.0005 to 0.9980 and 0.08 to 0.44 mg/mL, respectively). Fourteen extracts from 11 plant species, namely Clitoria ternatea (flower and leaf), Dillenia indica (leaf), Diospyros peregrina (leaf), Dipterocarpus turbinatus (bark and leaf), Ecbolium viride (leaf), Glinus oppositifolius (whole plant), Gnaphalium luteoalbum (leaf), Jasminum sambac (leaf), Lannea coromandelica (bark and leaf), Mussaenda glabrata (leaf) and Saraca asoca (leaf), were also significantly cytotoxic (IC50 < 1.0 mg/mL) against at least one of the cancer cell lines tested. More selectively, Avicennia alba (leaf), C. ternatea (flower and leaf), Caesalpinia pulcherrima (leaf), E. viride (leaf) and G. oppositifolius (whole plant) showed cytotoxicity only against both of the breast cancer cell lines (MCF-7 and MDA-MB-231). In contrast, C. ternatea (flower and leaf) exhibited high cytotoxic activity against MDA-MB-231 (IC50 values of 0.11 and 0.49 mg/mL, respectively), whereas E. viride and G. oppositifolius whole plant extracts exhibited high activity against MCF-7 cells (IC50 values of 0.06 and 0.15 mg/mL, respectively). The cytotoxic activity test results for 9 of the plant species correlate with their traditional use as anticancer agents, thus making them interesting sources for further drug development.

Inhibitors of 15-lipoxygenase from orange peel.

PubMed

Malterud, K E; Rydland, K M

2000-11-01

A series of polymethoxylated flavonoids has been isolated from orange peel, and their inhibitory activity toward soybean 15-lipoxygenase was determined. The strongest inhibition was shown by 3,5,6,7,3',4'-hexamethoxyflavone (IC(50) = 49 +/- 5 microM). Sinensetin, nobiletin, tangeretin, tetramethylscutellarein, and 3,5, 6,7,8,3',4'-heptamethoxyflavone were somewhat less active, with IC(50) values of 70-86 microM, comparable to the positive control quercetin (IC(50) = 68 +/- 5 microM). Demethylation apparently results in less active compounds, with 5-O-demethylsinensetin having an IC(50) value of 144 +/- 10 microM. Some other orange peel constituents were isolated and tested as well, hesperidin (IC(50) = 180 +/- 10 microM) and ferulic acid (111 +/- 2 microM), showing moderate activity. The polymethoxylated flavonoids were virtually inactive as scavengers of the diphenylpicrylhydrazyl radical. Hesperidin was only slightly active (24.2 +/- 0.7% scavenged at a concentration of 2 mM), and ferulic acid showed good activity (IC(50) = 86.4 +/- 0.7 microM). From this, it appears that orange peel constituents may counteract enzymatic lipid peroxidation processes catalyzed by 15-lipoxygenase in vitro. The radical scavenging activity of orange peel extracts is only modest.

A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters.

PubMed

O'Connor, Michael; Lee, Caroline; Ellens, Harma; Bentz, Joe

2015-02-01

Current USFDA and EMA guidance for drug transporter interactions is dependent on IC50 measurements as these are utilized in determining whether a clinical interaction study is warranted. It is therefore important not only to standardize transport inhibition assay systems but also to develop uniform statistical criteria with associated probability statements for generation of robust IC50 values, which can be easily adopted across the industry. The current work provides a quantitative examination of critical factors affecting the quality of IC50 fits for P-gp inhibition through simulations of perfect data with randomly added error as commonly observed in the large data set collected by the P-gp IC50 initiative. The types of errors simulated were (1) variability in replicate measures of transport activity; (2) transformations of error-contaminated transport activity data prior to IC50 fitting (such as performed when determining an IC50 for inhibition of P-gp based on efflux ratio); and (3) the lack of well defined "no inhibition" and "complete inhibition" plateaus. The effect of the algorithm used in fitting the inhibition curve (e.g., two or three parameter fits) was also investigated. These simulations provide strong quantitative support for the recommendations provided in Bentz et al. (2013) for the determination of IC50 values for P-gp and demonstrate the adverse effect of data transformation prior to fitting. Furthermore, the simulations validate uniform statistical criteria for robust IC50 fits in general, which can be easily implemented across the industry. A calibration of the t-statistic is provided through calculation of confidence intervals associated with the t-statistic.

A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters

PubMed Central

O'Connor, Michael; Lee, Caroline; Ellens, Harma; Bentz, Joe

2015-01-01

Current USFDA and EMA guidance for drug transporter interactions is dependent on IC50 measurements as these are utilized in determining whether a clinical interaction study is warranted. It is therefore important not only to standardize transport inhibition assay systems but also to develop uniform statistical criteria with associated probability statements for generation of robust IC50 values, which can be easily adopted across the industry. The current work provides a quantitative examination of critical factors affecting the quality of IC50 fits for P-gp inhibition through simulations of perfect data with randomly added error as commonly observed in the large data set collected by the P-gp IC50 initiative. The types of errors simulated were (1) variability in replicate measures of transport activity; (2) transformations of error-contaminated transport activity data prior to IC50 fitting (such as performed when determining an IC50 for inhibition of P-gp based on efflux ratio); and (3) the lack of well defined “no inhibition” and “complete inhibition” plateaus. The effect of the algorithm used in fitting the inhibition curve (e.g., two or three parameter fits) was also investigated. These simulations provide strong quantitative support for the recommendations provided in Bentz et al. (2013) for the determination of IC50 values for P-gp and demonstrate the adverse effect of data transformation prior to fitting. Furthermore, the simulations validate uniform statistical criteria for robust IC50 fits in general, which can be easily implemented across the industry. A calibration of the t-statistic is provided through calculation of confidence intervals associated with the t-statistic. PMID:25692007

The antioxidant activity test by using DPPH method from the white tea using different solvents

NASA Astrophysics Data System (ADS)

Darmajana, Doddy A.; Hadiansyah, Firman; Desnilasari, Dewi

2017-11-01

The solvents used in this study are: aquades, ethanol and glacial acetic acid. The raw material as the source of antioxidants is white tea. Pure Quercetin is used as a comparing antioxidant. The treatment design was the solvent type for extraction, while the antioxidant activity was tested using DPPH method, with IC50 as the reference of antioxidant activity value. The results of antioxidant activity tests with three different solvent types are IC50 of 22,499 µg/mL for aquades, IC50 of 13,317 µg/mL for Ethanol and IC50 of 60,555 µg/mL for Glacial Acetic Acid. As a control of the standard antioxidant activity value of Quercetin is 4,313 µg/mL.

A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity.

PubMed

Sadashiva, Maralinganadoddi P; Gowda, Raghavendra; Wu, Xianzhu; Inamdar, Gajanan S; Kuzu, Omer F; Rangappa, Kanchugarakoppal S; Robertson, Gavin P; Gowda, D Channe

2015-08-01

Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM. Several carboxylic group-derivatives of abietic acid were moderately active with IC50 values of ~8.2 to ~13.3 µM. These results suggest that a detailed understanding of the structure-activity relationship of abietane diterpenoids might provide strategies to exploit this class of compounds for malaria treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Study of the sensitivity of neonates to digoxin: contribution of erythrocyte /sup 86/Rb uptake test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zannad, F.; Marchal, F.; Royer, R.J.

1981-01-01

In general, there is little agreement how digoxin should be used in newborn, and the results of studies in this field seem contradictory. This study attempts a quantitative assessment of the number and the sensitivity of cellular receptors for digoxin in the organism, by the in vitro measurement of erythrocyte /sup 86/Rb neonates compared with adults and old people. Red blood cells are first incubated with differing concentrations of digoxin, and then incubated with /sup 86/Rb. The initial level of /sup 86/Rb uptake (Rbi) is that observed in the absence of digoxin. The 50% index of captation (IC50) is themore » digoxin concentration in nanograms per ml at which /sup 86/Rb uptake is half Rbi. Three grups of patients were studied: Group I: 12 neonates, less that 5 days old; Group II: 11 adults (26 to 57 years old); Group III: 9 elderly people (71 to 82 years old). Rbi was significantly lower in neonates (Mean +/- SD: 25.8% +/- 3.5, P less than 0.001) and in the elderly (29.9% +/- 3.1) than in adults (36.8% +/- 4.6). IC50 was significantly lower in the elderly (12.1 mg/ml +/- 2.4) than in the adult patients (20.5 ng/ml +/- 5.5, P less than 0.001). In the newborns, values of IC50 were widely scattered (16.2 ng/ml +/- 7.2). The authors suggest that since Rbi reflects Na+, K+-ATPase activity, this activity is diminished in newborn and old people, and indicates that they have fewer cellular recaptors for digoxin than adults. In the elderly, the low IC50 would imply increased sensitivity to digoxin. In neonates, the wide range of values for IC50 suggests considerable individual variation in sensitivity to digoxin. The results aer consistent with the recently recomnended lower dosages of digoxin i neonates.« less

PTP1B, α-glucosidase, and DPP-IV inhibitory effects for chromene derivatives from the leaves of Smilax china L.

PubMed

Zhao, Bing Tian; Le, Duc Dat; Nguyen, Phi Hung; Ali, Md Yousof; Choi, Jae-Sue; Min, Byung Sun; Shin, Heung Mook; Rhee, Hae Ik; Woo, Mi Hee

2016-06-25

Two new flavonoids, bismilachinone (11) and smilachinin (14), were isolated from the leaves of Smilax china L. together with 14 known compounds. Their structures were elucidated using spectroscopic methods. The PTP1B, α-glucosidase, and DPP-IV inhibitory activities of compounds 1-16 were evaluated at the molecular level. Among them, compounds 4, 7, and 10 showed moderate DPP-IV inhibitory activities with IC50 values of 20.81, 33.12, and 32.93 μM, respectively. Compounds 3, 4, 6, 11, 12, and 16 showed strong PTP1B inhibitory activities, with respective IC50 values of 7.62, 10.80, 0.92, 2.68, 9.77, and 24.17 μM compared with the IC50 value for the positive control (ursolic acid: IC50 = 1.21 μM). Compounds 2-7, 11, 12, 15, and 16 showed potent α-glucosidase inhibitory activities, with respective IC50 values of 8.70, 81.66, 35.11, 35.92, 7.99, 26.28, 11.28, 62.68, 44.32, and 70.12 μM. The positive control, acarbose, displayed an IC50 value of 175.84 μM. In the kinetic study for the PTP1B enzyme, compounds 6, 11, and 12 displayed competitive inhibition with Ki values of 3.20, 8.56, and 5.86 μM, respectively. Compounds 3, 4, and 16 showed noncompetitive inhibition with Ki values of 18.75, 5.95, and 22.86 μM, respectively. Molecular docking study for the competitive inhibitors (6, 11, and 12) radically corroborates the binding affinities and inhibition of PTP1B enzymes. These results indicated that the leaves of Smilax china L. may contain compounds with anti-diabetic activity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase.

PubMed

Kilic, Burcu; Gulcan, Hayrettin O; Aksakal, Fatma; Ercetin, Tugba; Oruklu, Nihan; Umit Bagriacik, E; Dogruer, Deniz S

2018-05-08

A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC 50 values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC 50  = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC 50 for AChE = 0.16 µM and IC 50 for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC 50 for AChE = 0.59 µM and IC 50 for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Copyright © 2018 Elsevier Inc. All rights reserved.

Synthesis of benzimidazole derivatives as potent β-glucuronidase inhibitors.

PubMed

Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Selvaraj, Manikandan; Rashwan, Hesham; Farhanah, Fatin Ummi; Rahim, Fazal; Kesavanarayanan, Krishnan Selvarajan; Ali, Muhammad

2015-08-01

Twenty five 4, 6-dichlorobenzimidazole derivatives (1-25) have been synthesized and evaluated against β-glucuronidase inhibitory activity. The compounds which actively inhibit β-glucuronidase activity have IC50 values ranging between 4.48 and 46.12 μM and showing better than standard d-saccharic acid 1,4 lactone (IC50=48.4 ± 1.25 μM). Molecular docking provided potential clues to identify interactions between the active molecules and the enzyme which further led us to identify plausible binding mode of all the benzimidazole derivatives. This study confirmed that presence of hydrophilic moieties is crucial to inhibit the human β-glucuronidase. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparsion of an immunochromatographic strip with ELISA for simultaneous detection of thiamphenicol, florfenicol and chloramphenicol in food samples.

PubMed

Guo, Lingling; Song, Shanshan; Liu, Liqiang; Peng, Juan; Kuang, Hua; Xu, Chuanlai

2015-09-01

Rapid and sensitive indirect competitive enzyme-linked immunosorbent assays (ic-ELISA) and gold nanoparticle immunochromatographic strip tests were developed to detect thiamphenicol (TAP), florfenicol (FF) and chloramphenicol (CAP) in milk and honey samples. The generic monoclonal antibody for TAP, FF and CAP was prepared based on a hapten [D-threo-1-(4-aminophenyl)-2- dichloroacetylamino-1,3-propanediol], and the haptenwas linked to a carrier protein using the diazotization method. After the optimization of several parameters (coating, pH, sodium chloride content and methanol content), the ic-ELISA was established. The quantitative working range for TAP was 0.11-1.36 ng/mL, with an IC50 of 0.39 ng/mL. The optimized ELISA showed cross-reactivity to CAP (300%) and FF (15.6%), with IC50 values of 0.13 and 2.5 ng/mL, respectively. The analytical recovery of TAP, FF and CAP in milk and honey samples in the ic-ELISA ranged from 81.2 to 112.9%. Based on this monoclonal antibody, a rapid and sensitive immunochromatographic test strip was also developed. This strip had a detection limit of 1 ng/mL for TAP, FF and CAP in milk and honey samples. Moreover, the test was completed within 10 min. Our results showed that the proposed ic-ELISA and immunochromatographic test strip method are highly useful screening tools for TAP, FF and CAP detection in milk and honey samples. Copyright © 2015 John Wiley & Sons, Ltd.

Characterization of Cladosporols from the Marine Algal-Derived Endophytic Fungus Cladosporium cladosporioides EN-399 and Configurational Revision of the Previously Reported Cladosporol Derivatives.

PubMed

Li, Hong-Lei; Li, Xiao-Ming; Mándi, Attila; Antus, Sándor; Li, Xin; Zhang, Peng; Liu, Yang; Kurtán, Tibor; Wang, Bin-Gui

2017-10-06

Four new cladosporol derivatives, cladosporols F-I (1-4), the known cladosporol C (5), and its new epimer, cladosporol J (6), were isolated and identified from the marine algal-derived endophytic fungus Cladosporium cladosporioides EN-399. Their structures were determined by detailed interpretation of NMR and MS data, and the absolute configurations were established on the basis of TDDFT-ECD and OR calculations. The configurational assignment of cladosporols F (1) and G (2) showed that the previously reported absolute configuration of cladosporol A and all the related cladosporols need to be revised from (4'R) to (4'S). Compounds 1-6 showed antibacterial activity against Escherichia coli, Micrococcus luteus, and Vibrio harveyi with MIC values ranging from 4 to 128 μg/mL. Compound 3 showed significant cytotoxicity against A549, Huh7, and LM3 cell lines with IC 50 values of 5.0, 1.0, and 4.1 μM, respectively, and compound 5 showed activity against H446 cell line with IC 50 value of 4.0 μM.

Modulating effects of plasma containing anti-malarial antibodies on in vitro anti-malarial drug susceptibility in Plasmodium falciparum.

PubMed

Monatrakul, Preeyaporn; Mungthin, Mathirut; Dondorp, Arjen M; Krudsood, Srivicha; Udomsangpetch, Rachanee; Wilairatana, Polrat; White, Nicholas J; Chotivanich, Kesinee

2010-11-16

The efficacy of anti-malarial drugs is determined by the level of parasite susceptibility, anti-malarial drug bioavailability and pharmacokinetics, and host factors including immunity. Host immunity improves the in vivo therapeutic efficacy of anti-malarial drugs, but the mechanism and magnitude of this effect has not been characterized. This study characterized the effects of 'immune' plasma to Plasmodium falciparumon the in vitro susceptibility of P. falciparum to anti-malarial drugs. Titres of antibodies against blood stage antigens (mainly the ring-infected erythrocyte surface antigen [RESA]) were measured in plasma samples obtained from Thai patients with acute falciparum malaria. 'Immune' plasma was selected and its effects on in vitro parasite growth and multiplication of the Thai P. falciparum laboratory strain TM267 were assessed by light microscopy. The in vitro susceptibility to quinine and artesunate was then determined in the presence and absence of 'immune' plasma using the 3H-hypoxanthine uptake inhibition method. Drug susceptibility was expressed as the concentrations causing 50% and 90% inhibition (IC50 and IC90), of 3H-hypoxanthine uptake. Incubation with 'immune' plasma reduced parasite maturation and decreased parasite multiplication in a dose dependent manner. 3H-hypoxanthine incorporation after incubation with 'immune' plasma was decreased significantly compared to controls (median [range]; 181.5 [0 to 3,269] cpm versus 1,222.5 [388 to 5,932] cpm) (p= 0.001). As a result 'immune' plasma reduced apparent susceptibility to quinine substantially; median (range) IC50 6.4 (0.5 to 23.8) ng/ml versus 221.5 (174.4 to 250.4) ng/ml (p = 0.02), and also had a borderline effect on artesunate susceptibility; IC50 0.2 (0.02 to 0.3) ng/ml versus 0.8 (0.2 to 2.3) ng/ml (p = 0.08). Effects were greatest at low concentrations, changing the shape of the concentration-effect relationship. IC90 values were not significantly affected; median (range) IC90 448.0 (65 to > 500) ng/ml versus 368.8 (261 to 501) ng/ml for quinine (p > 0.05) and 17.0 (0.1 to 29.5) ng/ml versus 7.6 (2.3 to 19.5) ng/ml for artesunate (p = 0.4). 'Immune' plasma containing anti-malarial antibodies inhibits parasite development and multiplication and increases apparent in vitro anti-malarial drug susceptibility of P. falciparum. The IC90 was much less affected than the IC50 measurement.

Evaluation of the anticancer potential of six herbs against a hepatoma cell line

PubMed Central

2012-01-01

Background Six herbs in the Plant Genetics Conservation Project that have been used as complementary medicines were chosen on the basis of their medicinal value, namely Terminalia mucronata, Diospyros winitii, Bridelia insulana, Artabotrys harmandii, Terminallia triptera, and Croton oblongifolius. This study aims to evaluate the potential anticancer activity of 50% ethanol-water extracts of these six herbs. Methods Fifty percent ethanol-water crude extracts of the six herbs were prepared. The cytotoxicity of the herbal extracts relative to that of melphalan was evaluated using a hepatoma cell line (HepG2), and examined by neutral red assays and apoptosis induction by gel electrophoresis and flow cytometry after 24 h. Results A significant difference was found between the cytotoxicity of the 50% ethanol-water crude extracts and melphalan (P = 0.000). The 50% ethanol-water crude extracts of all six herbs exhibited cytotoxicity against HepG2 cells, with IC50 values ranging from 100 to 500 μg/mL. The extract of T. triptera showed the highest cytotoxicity with an IC50 of 148.7 ± 12.3 μg/mL, while melphalan had an IC50 of 39.79 ± 7.62 μg/mL. The 50% ethanol-water crude extracts of D. winitii and T. triptera, but not A. harmandii, produced a DNA ladder. The 50% ethanol-water crude extracts of D. winitii, T. triptera, and A. harmandii induced apoptosis detected by flow cytometry. Conclusion The 50% ethanol-water crude extracts of D. winitii, T. triptera, and A. harmandii showed anticancer activity in vitro. PMID:22682026

2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.

PubMed

Tasdemir, Deniz; Sanabria, David; Lauinger, Ina L; Tarun, Alice; Herman, Rob; Perozzo, Remo; Zloh, Mire; Kappe, Stefan H; Brun, Reto; Carballeira, Néstor M

2010-11-01

Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 μg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC(50) 20.2 μg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes. Copyright © 2010 Elsevier Ltd. All rights reserved.

2-Hexadecynoic Acid Inhibits Plasmodial FAS-II Enzymes and Arrest Erythrocytic and Liver Stage Plasmodium Infections

PubMed Central

Tasdemir, Deniz; Sanabria, David; Lauinger, Ina L.; Tarun, Alice; Herman, Rob; Perozzo, Remo; Zloh, Mire; Kappe, Stefan H.; Brun, Reto; Carballeira, Néstor M.

2010-01-01

Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of P. yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC50 value 6.6. μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC50 value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescense analysis (IC50 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory against the PfFAS-II enzymes PfFabI and PfFabZ with IC50 values of 0.38 and 0.58 μg/ml (IC50 control drugs 14 and 30 ng/ml) respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC50 values 3.7–31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC50 20.2 μg/ml), and Leishmania donovani (IC50 values 4.1–13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature and calculated pharmacokinetic properties suggest that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes. PMID:20855214

Risk assessment of drug-drug interactions using hepatocytes suspended in serum during the drug discovery process.

PubMed

Kosugi, Yohei; Hirabayashi, Hideki; Igari, Tomoko; Fujioka, Yasushi; Okuda, Teruaki; Moriwaki, Toshiya

2014-04-01

1. This study optimized the reported approach for the prediction of drug-drug interactions (DDIs) using hepatocytes suspended in serum (HHSS) and provided a practical usage of HHSS in the early and late phases of drug discovery. 2. First, the IC50 was determined using HHSS and evaluated as a qualitative index for DDI risks in the early phase. A retrospective study on clinical DDI cases revealed that inhibitors with IC50 < 100 μmol/L caused clinical DDIs while those with IC50 > 100 μmol/L showed weak or no potential for DDIs. Meanwhile, a pragmatic cutoff value could not be determined using previously reported Ki values of recombinant human cytochrome P450s. 3. Second, for a more substantial DDI risk assessment in the later phase, quantitative predictions of clinical DDI based on a static model were attempted by optimizing the most appropriate inhibitor concentration ([I]). The use of hepatic input plasma concentrations as a surrogate for [I] achieved the most successful predictions of the magnitude of increase in the AUC (within a 2-fold range of the observed values for 93.8% of inhibitors). 4. Through this study, we proposed the practical application of HHSS for an effective workflow to explore and profile candidates with less DDI liability.

Synthesis and anti-parasitic activity of a novel quinolinone-chalcone series.

PubMed

Roussaki, Marina; Hall, Belinda; Lima, Sofia Costa; da Silva, Anabela Cordeiro; Wilkinson, Shane; Detsi, Anastasia

2013-12-01

A series of novel quinolinone-chalcone hybrids and analogues were designed, synthesized and their biological activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum evaluated. Promising molecular scaffolds with significant microbicidal activity and low cytotoxicity were identified. Quinolinone-chalcone 10 exhibited anti-parasitic properties against both organisms, being the most potent anti-L. infantum agent of the entire series (IC50 value of 1.3±0.1 μM). Compounds 4 and 11 showed potency toward the intracellular, amastigote stage of L. infantum (IC50 values of 2.1±0.6 and 3.1±1.05 μM, respectively). Promising trypanocidal compounds include 5 and 10 (IC50 values of 2.6±0.1 and 3.3±0.1 μM, respectively) as well as 6 and 9 (both having IC50 values of <5 μM). Chemical modifications on the quinolinone-chalcone scaffold were performed on selected compounds in order to investigate the influence of these structural features on antiparasitic activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Inhibitory effects of some drugs on carbonic anhydrase enzyme purified from Kangal Akkaraman sheep in Sivas, Turkey.

PubMed

Koçyiğit, Ümit M; Durna Daştan, Sevgi; Taslimi, Parham; Daştan, Taner; Gülçin, İlhami

2018-01-01

In this study, carbonic anhydrase (CA) enzyme was purified and characterized from blood samples of Kangal Akkaraman sheep and inhibitory properties on certain antibiotics were examined. CA purification was composed of preparation of the hemolysate and conducting the Sepharose-4B-tyrosine-sulfanilamide affinity gel chromatography in having specific activity of 11626 EU mg -1 , yield of 14.40%, and 242.76-fold purification. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was performed to assess the enzyme purity and a single band was observed. Some antibiotics were exhibited in vitro inhibition on the CA activity. IC 50 values of these inhibitors were calculated by plotting activity percentage. IC 50 values of certain drugs (dexamethasone; caffeine; metamizole sodium; tetramisol; ceftiofur HCl; ivermectin; tavilin 50; penokain G; neosym; and sulfamezathine) were found as 0.38, 8.24, 285.53, 114.77, 5.33, 2.76, 27.58, 213.50, 208.28, and 36.60 μM, respectively. K i values of different drugs on Kangal Akkaraman sheep blood CA activity were found in the range of 0.21 ± 0.038-266.64 ± 37.11 μM. © 2017 Wiley Periodicals, Inc.

Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation.

PubMed

Tripathi, Rati K P; Rai, Gopal K; Ayyannan, Senthil R

2016-06-06

A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032 μm), MAO-B (IC50 =0.059±0.002 μm), and AChE (IC50 =0.0087±0.0002 μm) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO-A and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Two new cytotoxic stilbenoid dimers isolated from Cajanus cajan.

PubMed

Zhang, Nenling; Shen, Xiangchun; Jiang, Xiaofei; Cai, Jiazhong; Shen, Xiaoling; Hu, Yingjie; Qiu, Samuel X

2018-01-01

Two new stilbenoid dimers, cajanstilbenoids A (1) and B (2), were isolated from the leaves of Cajanus cajan. Planar structures of these compounds were verified by NMR (1D and 2D) and high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS). Absolute configurations were assigned by comparing experimental and calculated electronic CD values. The cytotoxicity of 1 and 2 against human hepatoma (HepG2), human breast adenocarcinoma (MCF-7), and human lung cancer (A549) cells were evaluated in vitro. Compound 1 showed strong cytotoxicity against all the tested cell lines (IC 50 values: 2.14-2.56 µM), whereas compound 2 showed strong toxicity only against HepG2 (IC 50 value: 5.99 µM) and A549 cells (IC 50 value: 6.18 µM).

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents.

PubMed

Figueiredo, Joana; Serrano, João L; Cavalheiro, Eunice; Keurulainen, Leena; Yli-Kauhaluoma, Jari; Moreira, Vânia M; Ferreira, Susana; Domingues, Fernanda C; Silvestre, Samuel; Almeida, Paulo

2018-01-01

Barbituric and thiobarbituric acid derivatives have become progressively attractive to medicinal chemists due to their wide range of biological activities. Herein, different series of 1,3,5-trisubstituted barbiturates and thiobarbiturates were prepared in moderate to excellent yields and their activity as xanthine oxidase inhibitors, antioxidants, antibacterial agents and as anti-proliferative compounds was evaluated in vitro. Interesting bioactive barbiturates were found namely, 1,3-dimethyl-5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6c) and 1,3-dimethyl-5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6e), which showed concomitant xanthine oxidase inhibitory effect (IC 50 values of 24.3 and 27.9 μM, respectively), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC 50 values of 18.8 and 23.8 μM, respectively). In addition, 5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6d) also revealed DPPH radical scavenger effect, with an IC 50 value of 20.4 μM. Moreover, relevant cytotoxicity against MCF-7 cells (IC 50  = 13.3 μM) was observed with 5-[[(2-chloro-4-nitrophenyl)amino]methylene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (7d). Finally, different 5-hydrazinylethylidenepyrimidines revealed antibacterial activity against Acinetobacter baumannii (MIC values between 12.5 and 25.0 μM) which paves the way for developing new treatments for infections caused by this Gram-negative coccobacillus bacterium, known to be an opportunistic pathogen in humans with high relevance in multidrug-resistant nosocomial infections. The most promising bioactive barbiturates were studied in silico with emphasis on compliance with the Lipinski's rule of five as well as several pharmacokinetics and toxicity parameters. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation.

PubMed

Li, Yan-Ping; Ning, Fang-Xian; Yang, Meng-Bi; Li, Yong-Cheng; Nie, Min-Hua; Ou, Tian-Miao; Tan, Jia-Heng; Huang, Shi-Liang; Li, Ding; Gu, Lian-Quan; Huang, Zhi-Shu

2011-05-01

A series of 3-substituted (5c-5f, 6c-6f) and 4-substituted (10a-10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid β (Aβ) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure-activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC50 values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer's disease. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Cytotoxic triterpenoid saponins from Clematis tangutica.

PubMed

Zhao, Min; Da-Wa, Zhuo-Ma; Guo, Da-Le; Fang, Dong-Mei; Chen, Xiao-Zhen; Xu, Hong-Xi; Gu, Yu-Cheng; Xia, Bing; Chen, Lei; Ding, Li-Sheng; Zhou, Yan

2016-10-01

Eight previously undescribed oleanane-type triterpenoid saponins, clematangoticosides A-H, together with eight known saponins, were isolated from the whole plants of Clematis tangutica (Maxim.) Korsh. Their structures were elucidated by extensive spectroscopic analysis, in combination with chemical methods (acid hydrolysis and mild alkaline hydrolysis). Clematangoticosides D-G were found to be unusual 23, 28-bidesmosidic glycosides. The cytotoxic activities of all of the isolated saponins were evaluated against the four human cancer cell lines SGC-7901, HepG2, HL-60 and U251MG. Clematoside S, sapindoside B, kalopanax saponin A, and koelreuteria saponin A exhibited cytotoxicity against all of the test cancer cell lines with IC50 values in the range of 1.88-27.20 μM, while clematangoticoside D and F showed selective cytotoxicity against SGC-7901 with IC50 values of 24.22 and 21.35 μM, respectively. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ionic liquid mediated synthesis and molecular docking study of novel aromatic embedded Schiff bases as potent cholinesterase inhibitors.

PubMed

Abd Razik, Basma M; Osman, Hasnah; Basiri, Alireza; Salhin, Abdussalam; Kia, Yalda; Ezzat, Mohammed Oday; Murugaiyah, Vikneswaran

2014-12-01

Novel aromatic embedded Schiff bases have been synthesized in ionic liquid [bmim]Br and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activities. Among the newly synthesized compounds, 5f, 5h and 7j displayed higher AChE enzyme inhibitory activities than standard drug, galanthamine, with IC50 values of 1.88, 2.05 and 2.03μM, respectively. Interestingly, all the compounds except for compound 5c displayed higher BChE inhibitories than standard with IC50 values ranging from 3.49 to 19.86μM. Molecular docking analysis for 5f and 7j possessing the most potent AChE and BChE inhibitory activities, disclosed their binding interaction templates to the active site of AChE and BChE enzymes, respectively. Copyright © 2014 Elsevier Inc. All rights reserved.

Antiproliferative and anti-inflammatory furostanol saponins from the rhizomes of Tupistra chinensis.

PubMed

Xiang, Limin; Wang, Yihai; Yi, Xiaomin; He, Xiangjiu

2016-12-01

Phytochemical investigations of the rhizome of Tupistra chinensis led to the isolation of ten new furostanol saponins along with fourteen known spirostanols. Their chemical structures were elucidated on the basis of spectroscopic and chemical methods, including IR, NMR, MS, and GC analyses. The antiproliferative effects against FaDu and Detroit 562 cell lines and inhibitory activities on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in a macrophage cell line RAW 264.7 were assayed for all the isolated compounds. Compound 14 exhibited significant antiproliferative effects against FaDu and Detroit 562 cells with IC 50 values of 1.1±0.1 and 1.2±0.1μM, respectively. Compounds 1, 2, 6, 13, 16, 19 and 24 exhibited inhibitory effects on NO production with IC 50 values ranging from 15.7 to 46.2μM. Copyright © 2016 Elsevier Inc. All rights reserved.

Cytotoxic and apoptosis-inducing activity of C21 steroids from the roots of Cynanchum atratum.

PubMed

Zhang, Jian; Ma, Lin; Wu, Zheng-Feng; Yu, Shu-Le; Wang, Lei; Ye, Wen-Cai; Zhang, Qing-Wen; Yin, Zhi-Qi

2017-06-01

Two new (1-2) and two known C 21 steroids (3-4) were isolated from the roots of Cynanchum atratum. Their structures were elucidated by detailed 1D and 2D spectroscopic. The MTT assay showed that compounds 1-4 displayed obvious cytotoxic activities against HepG2 cells with IC 50 values ranging from 10.19μM to 76.12μM. Compounds 1-3 also exhibited cytotoxic effects in A549 cells with IC 50 values of 30.87-95.39μM. Compound 3 showed the antiproliferative activity via G0/G1 cell cycle arrest and proapoptosis in HepG2 cells by Flowcytometry analysis. Western blotting analysis revealed that compound 3 could induce HepG2 cell apoptosis via the mitochondrial pathway by downregulating Bcl-2 expression, upregulating Bax protein expression, and activating caspase-9 and caspase-3. Copyright © 2017 Elsevier Inc. All rights reserved.

Polyketides from two Chaetomium species and their biological functions.

PubMed

Li, He; Liao, Zhong-Bin; Tang, Dan; Han, Wen-Bo; Zhang, Qiang; Gao, Jin-Ming

2018-04-16

Four new secondary metabolites, chaetosemins G-J (1-4), along with 11 known ones (5-15) were isolated from the culture of C. seminudum C208 and Chaetomium sp. C521. Their structures were determined by extensive NMR spectroscopic analyses. These metabolites were evaluated in vitro for antifungal, antioxidant, toxicity, and α-glucosidase inhibitory activities. Chaetosemin J (4) and monaschromone (5) significantly inhibited the growth of four plant pathogenic fungi Botrytis cinerea, Alternaria solani, Magnaporthe oryzae, and Gibberella saubinettii with the minimum inhibitory concentrations (MIC) values ranging from 6.25 to 25.0 μM. Moreover, both epicoccone B (11) and flavipin (14) exhibited the DPPH free radical scavenging ability with IC 50 values of 10.8 and 7.2 μM, respectively, and had more potent α-glucosidase inhibition than the drug acarbose with IC 50 values of 27.3 and 33.8 μM, respectively. Monaschromone (5) might act as the lead compound of pesticide.

Facile dimethyl amino group triggered cyclic sulfonamides synthesis and evaluation as alkaline phosphatase inhibitors.

PubMed

Bhatti, Huma Aslam; Khatoon, Memoona; Al-Rashida, Mariya; Bano, Huma; Iqbal, Nafees; Zaib-Un-Nisa; Yousuf, Sammer; Khan, Khalid Mohammed; Hameed, Abdul; Iqbal, Jamshed

2017-04-01

Owing to the biological importance of cyclic sulfonamides (sultams), herein we report a new, facile and cost-effective method for the synthesis of sultams that makes use of a reaction between dansyl amide and easily accessible benzaldehydes under mildly acidic conditions. All compounds were obtained in good yields (69-96%). Consequently a series of cyclic sulfonamides (7a-7n) was synthesized and characterized using FTIR, MS and NMR spectroscopy, crystal structure of compound 7b has also been determined. All compounds were evaluated for their potential to inhibit alkaline phosphatase (bTNAP and bIAP). All compounds were found to be excellent inhibitors of bTNAP with IC 50 values in lower micro-molar range (0.11-6.63μM). Most of the compounds were selective inhibitors of bTNAP over bIAP. Only six compounds were found to be active against bIAP (IC 50 values in the range 0.38-3.48μM). Molecular docking studies were carried out to identify and rationalize the structural elements necessary for efficient AP inhibition. Copyright © 2017 Elsevier Inc. All rights reserved.

Antiparasitic activity of natural and semi-synthetic tirucallane triterpenoids from Schinus terebinthifolius (Anacardiaceae): structure/activity relationships.

PubMed

Morais, Thiago R; da Costa-Silva, Thais A; Tempone, Andre G; Borborema, Samanta Etel T; Scotti, Marcus T; de Sousa, Raquel Maria F; Araujo, Ana Carolina C; de Oliveira, Alberto; de Morais, Sérgio Antônio L; Sartorelli, Patricia; Lago, João Henrique G

2014-05-05

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC50 values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC50 values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees.

Synthesis and in vitro study of benzofuran hydrazone derivatives as novel alpha-amylase inhibitor.

PubMed

Taha, Muhammad; Shah, Syed Adnan Ali; Imran, Syahrul; Afifi, Muhammad; Chigurupati, Sridevi; Selvaraj, Manikandan; Rahim, Fazal; Ullah, Hayat; Zaman, Khalid; Vijayabalan, Shantini

2017-12-01

The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1-25), characterized through different spectroscopic techniques such as 1 HNMR and EI-MS. All screened analog shows good α-amylase inhibitory potentials with IC 50 value ranging between 1.078±0.19 and 2.926±0.05µM when compared with acarbose having IC 50 =0.62±0.22µM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC 50 values 1.644±0.128, 1.078±0.19, 1.245±0.25, 1.843±0.19, 1.350±0.24, 1.629±0.015, 1.353±0.232, 1.359±0.119 and 1.488±0.07µM when compare with standard drug acarbose. All other analogs showed good to moderate α-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of Phenolic Content Variability along with Antioxidant, Antimicrobial, and Cytotoxic Potential of Selected Traditional Medicinal Plants from India.

PubMed

Singh, Garima; Passsari, Ajit K; Leo, Vincent V; Mishra, Vineet K; Subbarayan, Sarathbabu; Singh, Bhim P; Kumar, Brijesh; Kumar, Sunil; Gupta, Vijai K; Lalhlenmawia, Hauzel; Nachimuthu, Senthil K

2016-01-01

Plants have been used since ancient times as an important source of biologically active substances. The aim of the present study was to investigate the phytochemical constituents (flavonoids and phenolics), antioxidant potential, cytotoxicity against HepG2 (human hepato carcinoma) cancer cell lines, and the antimicrobial activity of the methanol extract of selected traditional medicinal plants collected from Mizoram, India. A number of phenolic compounds were detected using HPLC-DAD-ESI-TOF-MS, mainly Luteolin, Kaempferol, Myricetin, Gallic Acid, Quercetin and Rutin, some of which have been described for the first time in the selected plants. The total phenolic and flavonoid contents showed high variation ranging from 4.44 to 181.91 μg of Gallic Acid equivalent per milligram DW (GAE/mg DW) and 3.17 to 102.2 μg of Quercetin/mg, respectively. The antioxidant capacity was determined by DPPH (IC50 values ranges from 34.22 to 131.4 μg/mL), ABTS (IC50 values ranges from 24.08 to 513.4 μg/mL), and reducing power assays. Antimicrobial activity was assayed against gram positive (Staphylococcus aureus), gram negative (Escherichia coli, Pseudomonas aeruginosa), and yeast (Candida albicans) demonstrating that the methanol extracts of some plants were efficacious antimicrobial agents. Additionally, cytotoxicity was assessed on human hepato carcinoma (HepG2) cancer cell lines and found that the extracts of Albizia lebbeck, Dillenia indica, and Bombax ceiba significantly decreased the cell viability at low concentrations with IC50 values of 24.03, 25.09, and 29.66 μg/mL, respectively. This is the first report of detection of phenolic compounds along with antimicrobial, antioxidant and cytotoxic potential of selected medicinal plants from India, which indicates that these plants might be valuable source for human and animal health.

Evaluation of Phenolic Content Variability along with Antioxidant, Antimicrobial, and Cytotoxic Potential of Selected Traditional Medicinal Plants from India

PubMed Central

Singh, Garima; Passsari, Ajit K.; Leo, Vincent V.; Mishra, Vineet K.; Subbarayan, Sarathbabu; Singh, Bhim P.; Kumar, Brijesh; Kumar, Sunil; Gupta, Vijai K.; Lalhlenmawia, Hauzel; Nachimuthu, Senthil K.

2016-01-01

Plants have been used since ancient times as an important source of biologically active substances. The aim of the present study was to investigate the phytochemical constituents (flavonoids and phenolics), antioxidant potential, cytotoxicity against HepG2 (human hepato carcinoma) cancer cell lines, and the antimicrobial activity of the methanol extract of selected traditional medicinal plants collected from Mizoram, India. A number of phenolic compounds were detected using HPLC-DAD-ESI-TOF-MS, mainly Luteolin, Kaempferol, Myricetin, Gallic Acid, Quercetin and Rutin, some of which have been described for the first time in the selected plants. The total phenolic and flavonoid contents showed high variation ranging from 4.44 to 181.91 μg of Gallic Acid equivalent per milligram DW (GAE/mg DW) and 3.17 to 102.2 μg of Quercetin/mg, respectively. The antioxidant capacity was determined by DPPH (IC50 values ranges from 34.22 to 131.4 μg/mL), ABTS (IC50 values ranges from 24.08 to 513.4 μg/mL), and reducing power assays. Antimicrobial activity was assayed against gram positive (Staphylococcus aureus), gram negative (Escherichia coli, Pseudomonas aeruginosa), and yeast (Candida albicans) demonstrating that the methanol extracts of some plants were efficacious antimicrobial agents. Additionally, cytotoxicity was assessed on human hepato carcinoma (HepG2) cancer cell lines and found that the extracts of Albizia lebbeck, Dillenia indica, and Bombax ceiba significantly decreased the cell viability at low concentrations with IC50 values of 24.03, 25.09, and 29.66 μg/mL, respectively. This is the first report of detection of phenolic compounds along with antimicrobial, antioxidant and cytotoxic potential of selected medicinal plants from India, which indicates that these plants might be valuable source for human and animal health. PMID:27066046

An extensive cocktail approach for rapid risk assessment of in vitro CYP450 direct reversible inhibition by xenobiotic exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spaggiari, Dany, E-mail: dany.spaggiari@unige.ch

Acute exposure to environmental factors strongly affects the metabolic activity of cytochrome P450 (P450). As a consequence, the risk of interaction could be increased, modifying the clinical outcomes of a medication. Because toxic agents cannot be administered to humans for ethical reasons, in vitro approaches are therefore essential to evaluate their impact on P450 activities. In this work, an extensive cocktail mixture was developed and validated for in vitro P450 inhibition studies using human liver microsomes (HLM). The cocktail comprised eleven P450-specific probe substrates to simultaneously assess the activities of the following isoforms: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,more » 2E1, 2J2 and subfamily 3A. The high selectivity and sensitivity of the developed UHPLC-MS/MS method were critical for the success of this methodology, whose main advantages are: (i) the use of eleven probe substrates with minimized interactions, (ii) a low HLM concentration, (iii) fast incubation (5 min) and (iv) the use of metabolic ratios as microsomal P450 activities markers. This cocktail approach was successfully validated by comparing the obtained IC{sub 50} values for model inhibitors with those generated with the conventional single probe methods. Accordingly, reliable inhibition values could be generated 10-fold faster using a 10-fold smaller amount of HLM compared to individual assays. This approach was applied to assess the P450 inhibition potential of widespread insecticides, namely, chlorpyrifos, fenitrothion, methylparathion and profenofos. In all cases, P450 2B6 was the most affected with IC{sub 50} values in the nanomolar range. For the first time, mixtures of these four insecticides incubated at low concentrations showed a cumulative inhibitory in vitro effect on P450 2B6. - Highlights: • Ten P450 isoforms activities assessed simultaneously with only one incubation. • P450 activity levels measured using the metabolic ratio approach. • IC{sub 50} values generated 10-fold faster and cheaper compared to individual assays. • P450 2B6 was the most affected by pesticides with IC{sub 50} in the nanomolar range. • Cumulative inhibition of P450 2B6 by mixtures of four low-dosed insecticides.« less

A new pair of enantiomeric lignans from the fruits of Morinda citrifolia and their absolute configuration.

PubMed

Liu, Wen-Jian; Chen, Yue-Juan; Chen, Dan-Na; Wu, Ya-Ping; Gao, Yu-Jie; Li, Jing; Zhong, Wen-Jun; Jiang, Lin

2018-04-01

A new pair of sesamin-type lignan enantiomers (±)-morifolia A (1a/1b) together with eight known analogues (2-9) were isolated from the fruits of Morinda citrifolia. Their structures were established by spectroscopic data and the absolute configurations of 1a/1b were determined by ECD calculation. All compounds were examined for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 macrophages, and compounds 1a, 1b, 2-4 and 7-9 exhibited pronounced inhibition with IC 50 values in the range of 1.97-8.01 (μM, being more active than the positive control, quercetin (IC 50  = 15.32 (M).

Benzyloxynitrostyrene analogues - A novel class of selective and highly potent inhibitors of monoamine oxidase B.

PubMed

Van der Walt, Mietha M; Terre'Blanche, Gisella; Petzer, Jacobus P; Petzer, Anél

2017-01-05

This study examines a series of novel 3-benzyloxy-β-nitrostyrene analogues as a novel class of inhibitors of the monoamine oxidase (MAO) enzymes. MAO inhibitors are considered useful for the treatment of depression and Parkinson's disease, and have recently attracted attention as potential therapeutic agents for a range of disorders including Alzheimer's disease, prostate cancer and certain cardiomyopathies. This study shows that the 3-benzyloxy-β-nitrostyrene analogues are potent inhibitors of the MAO-B isoform with IC 50 values in the nanomolar range (39-565 nM). Significantly, effectiveness towards MAO-B inhibition seems to be governed by the introduction of a 4″-fluoro-substituent on the benzyloxy ring, with compound 2b exhibiting the highest degree of MAO-B inhibition potency (IC 50  = 0.039 μM) and selectivity (SI = 166) among the compounds investigated. Since some of the 3-benzyloxy-β-nitrostyrene analogues possess potencies that are comparable to that of the reversible inhibitor, safinamide (IC 50  = 0.080 μM), it may be concluded that this class may be promising leads for the development of reversible and selective MAO-B inhibitors, that may be useful for the management of Parkinson's disease. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

ITC commentary on the prediction of digoxin clinical drug-drug interactions from in vitro transporter assays.

PubMed

Lee, C A; Kalvass, J C; Galetin, A; Zamek-Gliszczynski, M J

2014-09-01

The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.

Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors.

PubMed

Shelke, Rupesh U; Degani, Mariam S; Raju, Archana; Ray, Mukti Kanta; Rajan, Mysore G R

2016-08-01

Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38-90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5-125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nira acidity and antioxidant activity of Palm sugar in Sumowono Village

NASA Astrophysics Data System (ADS)

Winarni, Sri; Arifan, Fahmi; Wisnu Broto, RTD.; Fuadi, Ariza; Alviche, Lola

2018-05-01

The palm sugar not only has potential as natural sweetener but also has antioxidant. The purpose of this study was to analyze antioxidant and pH of the nira in palm sugar. The sample in this study was palm sugar from 6 different production sites. Test of antioxidant activity used DPPH method (1.1-diphenyl-2-picrylhydrazyl) with a wavelength of 517 nm. The value of absorbance solution was measured using spectrophotometry and the value of effective concentration (IC50) was counted. The pH test was measured using a pH meter. Pearson’s correlation test revealed r=-0.045 with significant value 0.932 (>0.005). There was no correlation between pH value and antioxidant activity of palm sugar. IC50 value of palm sugar in Sumowono village revealed that it had a strong antioxidant activity (50 μg/ml - 100 μg/ml) that is 74,73 μg/ml 83.94 μg/ml 82.31 μg/ml 83.94 μg/ml 86.10 μg/ml 82.13 μg/ml 89.17 μg/ml 89.71 μg/ml 89.17 μg/ml and 84.84 μg/ml). Lower IC50 values indicate higher antioxidant activity. Palm sugar with the best antioxidant activity came from the production sites which had IC50 values of 74.73 μg/ml. Potential antioxidants can be optimized by making improvements to the processing system.

Evaluation of in vitro anti-Leishmanial activity of some brown, green and red algae from the Persian Gulf.

PubMed

Fouladvand, M; Barazesh, A; Farokhzad, F; Malekizadeh, H; Sartavi, K

2011-06-01

Leishmaniasis is a protozoan parasitic disease which is transmitted by the female Phlebotomus sand fly and is prevalent in four continents.The first-choice treatment for the leishmaniasis is pentavalent antimonials, which are potentially toxic and often ineffective and use of them exhibit therapeutic failure. These pharmaceutical problems point towards the need to develop novel chemotherapeutic agents. Seaweeds are considered as source of bioactive metabolites characterized by a broad spectrum of biological activities. In this experimental study, cold and hot water crude extracts of four species of green, brown and red marine algae "Caulerpa sertularioides, Gracilaria corticata, Gracillaria salicornia and Sargassum oligocystum" collected along the Bushehr coast of the Persian Gulf (southwest of Iran), prepared and their in vitro activities against Leishmania major promastigote were evaluated by using the MTT assay test. The cold and hot water crude extracts of four algae species exhibited different anti-Leishmanial activities. The minimum inhibitory concentration of hot water extracts calculated as IC50 was as follows: Caulerpa sertularioides (IC50 < or =85 microg/ml), Gracilaria corticata (IC50 < or =38 microg/ml), Gracillaria salicornia (IC50 < or =46 microg/ml) and Sargassum oligocystum (IC(50)9 < or =78 microg/ml, while these values for cold water extracts were (IC50 >125 microg/ml) for Caulerpa Sertularioides (IC50 >65 microg/ml) for Gracilaria corticata (IC50 >74 microg/ml) for Gracilaria salicornia and (IC50 >105 microg/ml) for Sargassum oligocystum, IC50 values for reference drug (Amphotericin B) was (0.16-0.2 microg/ml). According to the results, inhibitory effects of the crude extracts from these four species algae specially hot water crude extracts from "Gracilaria corticata, Gracillaria salicornia and Sargassum oligocystum" are significant and in accordance with other studies that has been done on different algae species. So these results are sufficiently promising to be followed with further studies on isolation and characterization of pure compounds from these algae species as well as in vivo experiments, a work that is already under way in our laboratory.

Acetylcholinesterase and butyrylcholinesterase inhibitory activity of Pinus species essential oils and their constituents.

PubMed

Bonesi, Marco; Menichini, Federica; Tundis, Rosa; Loizzo, Monica R; Conforti, Filomena; Passalacqua, Nicodemo G; Statti, Giancarlo A; Menichini, Francesco

2010-10-01

This study aimed to investigate the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity of the essential oils from Pinus nigra subsp. nigra, P. nigra var. calabrica, and P. heldreichii subsp. leucodermis. This activity is relevant to the treatment of Alzheimer's disease (AD), since cholinesterase drugs are currently the only drugs available to treat AD. P. heldreichii subsp. leucodermis exhibited the most promising activity, with IC(50) values of 51.1 and 80.6 microg/mL against AChE and BChE, respectively. An interesting activity against AChE was also observed with P. nigra subsp. nigra essential oil, with an IC(50) value of 94.4 microg/mL. Essential oils were analyzed by GC and GC-MS with the purpose of investigating their relationships with the observed activities. Among the identified constituents, terpinolene, beta-phellandrene, linalyl acetate, trans-caryophyllene, and terpinen-4-ol were tested. trans-Caryophyllene and terpinen-4-ol inhibited BChE with IC(50) values of 78.6 and 107.6 microg/mL, respectively. beta-Phellandrene was selective against AChE (IC(50) value of 120.2 microg/mL).

Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET.

PubMed

Singh, Pankaj Kumar; Silakari, Om

2018-04-25

Secondary acquired mutation in EGFR, i.e. EGFR T790M and amplification of c-MET form the two key components of resistant NSCLC. Thus, previously published pharmacophore models of EGFR T790M and c-MET were utilized to screen an in-house database. On the basis of fitness score, indole-pyrimidine scaffold was selected for further evaluation. Derivatives of indole-pyrimidine scaffold with variedly substituted aryl substitutions were sketched and then docked in both the targets. These docked complexes were then subjected to molecular dynamic simulations, to study the stability of the complexes and evaluate orientations of the designed molecules in the catalytic domain of the selected kinases. Afterwards, the complexes were subjected to MM-GBSA calculation, to study the effect of substitutions on binding affinity of double mutant EGFR towards these small molecules. Finally, the designed molecules were synthesized and evaluated for their inhibitory potential against both the kinases using in vitro experiments. Additionally, the compounds were also evaluated against EGFR (L858R) to determine their selectivity towards double mutant, resistant kinase [EGFR (T790M)]. Compound 7a and 7c were found to be possess nanomolar range inhibitory (IC 50 ) potential against EGFR (T790M), 7 h showed good inhibitory potential against c-MET with IC 50 value of 0.101 µM. Overall, this work is one of the earliest report of compounds having significant dual inhibitory potential against secondary acquired EGFR and cMET, with IC 50 values in nanomolar range. Copyright © 2018 Elsevier Inc. All rights reserved.

Biological activities of two macroalgae from Adriatic coast of Montenegro

PubMed Central

Kosanić, Marijana; Ranković, Branislav; Stanojković, Tatjana

2014-01-01

In the present investigation the acetone extracts of macroalgae Ulva lactuca and Enteromorpha intestinalis were tested for antioxidant, antimicrobial and cytotoxic potential. Antioxidant activity was evaluated by measuring the scavenging capacity of tested samples on DPPH and superoxide anion radicals, reducing the power of samples and determination of total phenolic and flavonoid compounds in extracts. As a result of the study, U. lactuca extract was found to have a better free radical scavenging activity (IC50 = 623.58 μg/ml) than E. intestinalis extract (IC50 = 732.12 μg/ml). Moreover, the tested extracts had effective ferric reducing power and superoxide anion radical scavenging. The total content of phenol in extracts of U. lactuca and E. intestinalis was 58.15 and 40.68 μg PE/mg, while concentrations of flavonoids were 39.58 and 21.74 μg RE/mg, respectively. Furthermore, among the tested species, extracts of U. lactuca showed a better antimicrobial activity with minimum inhibitory concentration values ranging from 0.156 to 5 mg/ml, but it was relatively weak in comparison with standard antibiotics. Bacillus mycoides and Bacillus subtilis were the most susceptible to the tested extracts. Contrary to this Aspergillus flavus, Aspergillus fumigatus and Penicillium purpurescens were the most resistant. Finally, cytotoxic activity of tested extracts was evaluated on four human cancer cell lines. Extract of E. intestinalis expressed the stronger cytotoxic activity towards all tested cell lines with IC50 values ranging from 74.73 to 155.39 μg/ml. PMID:26150743

4,6-Diaryl/heteroarylpyrimidin-2(1H)-ones as a new class of xanthine oxidase inhibitors.

PubMed

Shukla, Shiwani; Kumar, Dinesh; Ojha, Ritu; Gupta, Manish K; Nepali, Kunal; Bedi, Preet M S

2014-07-01

A series of 4,6-diaryl/heteroarylpyrimidones was synthesized employing silica-supported fluoroboric acid under solvent-free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesized compounds were evaluated for in vitro xanthine oxidase (XO) inhibitory activity for the first time. Structure-activity relationship analyses are also presented. Among the synthesized compounds, VA-5, -9, -10, -12, -22, -23, and -25 were the active inhibitors with IC50 values ranging from 6.45 to 13.46 µM. Compound VA-25 with a pyridinyl ring as ring A and a thiophenyl ring as ring B emerged as the most potent XO inhibitor (IC50 = 6.45 µM) in comparison to allopurinol (IC50 = 12.24 µM). Some of the important interactions of VA-25 with the amino acid residues of the active site of XO were figured out by molecular modeling studies. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of Antileishmanial Activity of Selected Brazilian Plants and Identification of the Active Principles

PubMed Central

Filho, Valdir Cechinel; Meyre-Silva, Christiane; Niero, Rivaldo; Bolda Mariano, Luisa Nathália; Gomes do Nascimento, Fabiana; Vicente Farias, Ingrid; Gazoni, Vanessa Fátima; dos Santos Silva, Bruna; Giménez, Alberto; Gutierrez-Yapu, David; Salamanca, Efrain; Malheiros, Angela

2013-01-01

This study evaluated extracts, fractions, and isolated compounds from some selected Brazilian medicinal plants against strains of promastigotes of Leishmania amazonensis and L. brasiliensis in vitro. The cell viability was determined, comparing the results with reference standards. The dichloromethane fractions of the roots, stems, and leaves of Allamanda schottii showed IC50 values between 14.0 and 2.0 μg/mL. Plumericin was the main active compound, with IC50 of 0.3 and 0.04 μg/mL against the two species of Leishmania analyzed. The hexane extract of Eugenia umbelliflora fruits showed IC50 of 14.3 and 5.7 μg/mL against L. amazonensis and L. brasiliensis, respectively. The methanolic extracts of the seeds of Garcinia achachairu and guttiferone A presented IC50 values of 35.9 and 10.4 μg/mL, against L. amazonensis, respectively. The ethanolic extracts of the stem barks of Rapanea ferruginea and the isolated compound, myrsinoic acid B, presented activity against L. brasiliensis with IC50 of 24.1 and 6.1 μg/mL. Chloroform fraction of Solanum sisymbriifolium exhibited IC50 of 33.8 and 20.5 μg/mL, and cilistol A was the main active principle, with IC50 of 6.6 and 3.1 μg/mL against L. amazonensis and L. brasiliensis, respectively. It is concluded that the analyzed plants are promising as new and effective antiparasitic agents. PMID:23840252

The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate.

PubMed

O'Connor, Stephen; Szwej, Emilia; Nikodinovic-Runic, Jasmina; O'Connor, Aisling; Byrne, Annette T; Devocelle, Marc; O'Donovan, Norma; Gallagher, William M; Babu, Ramesh; Kenny, Shane T; Zinn, Manfred; Zulian, Qun Ren; O'Connor, Kevin E

2013-04-01

The biodegradable polymer medium chain length polyhydroxyalkanoate (mclPHA), produced by Pseudomonas putida CA-3, was depolymerised and the predominant monomer (R)-3-hydroxydecanoic acid (R10) purified. R10 was conjugated to a d-peptide DP18 and its derivatives. All peptides conjugated with R10 exhibited greater anti-cancer activity compared to the unconjugated peptides. Unconjugated and conjugated peptides were cytocidal for cancer cells. Conjugation of R10 to peptides was essential for enhanced anti-proliferation activity, as unconjugated mixes did not result in enhancement of anti-cancer activity. The conjugation of R10 resulted in more rapid uptake of peptides into HeLa and MiaPaCa cells compared to unconjugated peptide. Both unconjugated and R10 conjugated peptides localized to the mitochondria of HeLa and MiaPaCa cells and induced apoptosis. Peptide conjugated with a terminally hydroxylated decanoic acid (ω-hydroxydecanoic acid) exhibited 3.3 and 6.3 fold higher IC(50) values compared to R10 conjugated peptide indicating a role for the position of the hydroxyl moiety in enhancement of anti-cancer activity. Conjugation of decanoic acid (C10) to peptides resulted in similar or higher IC(50) values compared to R10 conjugates but C10 conjugates did not exhibit any cancer selectivity. Combination studies showed that R10DP18L exhibited synergy with cisplatin, gemcitabine, and taxotere with IC(50) values in the nanomolar range. Copyright © 2013 Elsevier Ltd. All rights reserved.

Phenolic, flavonoid contents, anticholinesterase and antioxidant evaluation of Iris germanica var; florentina.

PubMed

Ullah, Farhat; Ayaz, Muhammad; Sadiq, Abdul; Hussain, Abid; Ahmad, Sajjad; Imran, Muhammad; Zeb, Anwar

2016-06-01

This study was designed to investigate antioxidant and anticholinesterase potential of Iris germanica var; florentina. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential of plant samples were investigated by Ellman's assay. Antioxidant activity was performed using DPPH, H2O2 and ABTS free radical scavenging assays. Total phenolics and flavonoids contents were expressed in mg GAE/g dry weight and mg RTE/g, respectively. In AChE inhibition assay, Ig.Fl, Ig.Sp and Ig.Cf fractions exhibited highest activity with IC50 values of < 0.1, 5.64 and 19 μg/mL, respectively. In BChE inhibitory assay, Ig.Fl, Ig.Sp, Ig.Cf and Ig.Cr were most active with IC50 of < 0.1, < 0.1, 31 and 78 μg/mL, respectively. In DPPH assay, Ig.Fl and Ig.Cf exhibited highest inhibition of free radicals, 80.52% (IC50 = 9 μg/mL) and 78.30% (IC50 = 8 μg/mL), respectively. In ABTS assay Ig.Cr, Ig.Cf, Ig.Fl and Ig.Sp exhibited IC50 values of < 0.1, 2, 2 and 3 μg/mL, respectively.

Biofunctional Properties of Enzymatic Squid Meat Hydrolysate

PubMed Central

Choi, Joon Hyuk; Kim, Kyung-Tae; Kim, Sang Moo

2015-01-01

Squid is one of the most important commercial fishes in the world and is mainly utilized or consumed as sliced raw fish or as processed products. The biofunctional activities of enzymatic squid meat hydrolysate were determined to develop value-added products. Enzymatic squid hydrolysate manufactured by Alcalase effectively quenched 1,1-diphenyl-2-picrylhydrazyl radical, hydroxyl radical, and hydrogen peroxide radical with IC50 values of 311, 3,410, and 111.5 μg/mL, respectively. Angiotensin I-converting enzyme inhibitory activity of squid hydrolysate was strong with an IC50 value of 145.1 μg/mL, while tyrosinase inhibitory activity with an IC50 value of 4.72 mg/mL was moderately low. Overall, squid meat hydrolysate can be used in food or cosmetic industries as a bioactive ingredient and possibly be used in the manufacture of seasoning, bread, noodle, or cosmetics. PMID:25866752

Direct led-fluorescence method for Mao-B inactivation in the treatment of Parkinson's

NASA Astrophysics Data System (ADS)

Castillo, Jimmy A.; Hung, Jannett; Rodriguez, M.; Bastidas, E.; Laboren, I.; Jaimes, A.

2004-10-01

A led-fluorescence spectroscopy method determinate the inhibitory effects of probe compounds on MAO-B activity is described. In this assay, we demonstrate the possibility of determinate the activity of MAO-B efficiently and rapidly without the use of reference substrate. Measuring variations in fluorescence intensity of MAO-B enzyme during the reaction with inhibitors, L-deprenyl and berberine IC50 and KI values were obtained. For L-deprenyl (IC50 = 0.017 μM and KI = 0.019 μM) and berberine (IC50 = 90 μM and KI = 47 μM) were in agreement to the values obtained with a standard method and literature reported.

Hypoxia affects cellular responses to plant extracts.

PubMed

Liew, Sien-Yei; Stanbridge, Eric J; Yusoff, Khatijah; Shafee, Norazizah

2012-11-21

Microenvironmental conditions contribute towards varying cellular responses to plant extract treatments. Hypoxic cancer cells are known to be resistant to radio- and chemo-therapy. New therapeutic strategies specifically targeting these cells are needed. Plant extracts used in Traditional Chinese Medicine (TCM) can offer promising candidates. Despite their widespread usage, information on their effects in hypoxic conditions is still lacking. In this study, we examined the cytotoxicity of a series of known TCM plant extracts under normoxic versus hypoxic conditions. Pereskia grandifolia, Orthosiphon aristatus, Melastoma malabathricum, Carica papaya, Strobilanthes crispus, Gynura procumbens, Hydrocotyle sibthorpioides, Pereskia bleo and Clinacanthus nutans leaves were dried, blended into powder form, extracted in methanol and evaporated to produce crude extracts. Human Saos-2 osteosarcoma cells were treated with various concentrations of the plant extracts under normoxia or hypoxia (0.5% oxygen). 24h after treatment, an MTT assay was performed and the IC(50) values were calculated. Effect of the extracts on hypoxia inducible factor (HIF) activity was evaluated using a hypoxia-driven firefly luciferase reporter assay. The relative cytotoxicity of each plant extract on Saos-2 cells was different in hypoxic versus normoxic conditions. Hypoxia increased the IC(50) values for Pereskia grandifola and Orthosiphon aristatus extracts, but decreased the IC(50) values for Melastoma malabathricum and Carica papaya extracts. Extracts of Strobilanthes crispus, Gynura procumbens, Hydrocotyle sibthorpioides had equivalent cytotoxic effects under both conditions. Pereskia bleo and Clinacanthus nutans extracts were not toxic to cells within the concentration ranges tested. The most interesting result was noted for the Carica papaya extract, where its IC(50) in hypoxia was reduced by 3-fold when compared to the normoxic condition. This reduction was found to be associated with HIF inhibition. Hypoxia variably alters the cytotoxic effects of TCM plant extracts on cancer cells. Carica papaya showed enhanced cytotoxic effect on hypoxic cancer cells by inhibiting HIF activities. These findings provide a plausible approach to killing hypoxic cancer cells in solid tumors. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Kinetic properties of Streptomyces canarius L- Glutaminase and its anticancer efficiency.

PubMed

Reda, Fifi M

2015-01-01

L-glutaminase was produced by Streptomyces canarius FR (KC460654) with an apparent molecular mass of 44 kDa. It has 17.9 purification fold with a final specific activity 132.2 U/mg proteins and 28% yield recovery. The purified L-glutaminase showed a maximal activity against L-glutamine when incubated at pH 8.0 at 40 °C for 30 min. It maintained its stability at wide range of pH from 5.0 11.0 and thermal stable up to 60 °C with Tm value 57.5 °C. It has high affinity and catalytic activity for L-glutamine (Km 0.129 mM, Vmax 2.02 U/mg/min), followed by L-asparagine and L-aspartic acid. In vivo, L-glutaminase showed no observed changes in liver; kidney functions; hematological parameters and slight effect on RBCs and level of platelets after 10 days of rabbit's injection. The anticancer activity of L-glutaminase was also tested against five types of human cancer cell lines using MTT assay in vitro. L-glutaminase has a significant efficiency against Hep-G2 cell (IC50, 6.8 μg/mL) and HeLa cells (IC50, 8.3 μg/mL), while the growth of MCF-7 cells was not affected. L-glutaminase has a moderate cytotoxic effect against HCT-116 cell (IC50, 64.7 μg/mL) and RAW 264.7 cell (IC50, 59.3 μg/mL).

Ultrasensitive Immunochromatographic Strip for Fast Screening of 27 Sulfonamides in Honey and Pork Liver Samples Based on a Monoclonal Antibody.

PubMed

Chen, Yanni; Guo, Lingling; Liu, Liqiang; Song, Shanshan; Kuang, Hua; Xu, Chuanlai

2017-09-20

Group-specific monoclonal antibodies (Mabs) with selectivity for 27 sulfonamides were developed based on new combinations of immunogen and coating antigen. The Mab was able to recognize 27 sulfonamides with 50% inhibition concentration (IC 50 ) values ranging from 0.15 to 15.38 μg/L. In particular, the IC 50 values for five sulfonamides (sulfamethazine, sulfaquinoxaline, sulfamonomethoxine, sulfadimethoxine, and sulfamethoxazole) were 0.51, 0.15, 0.56, 0.54, and 2.14 μg/L, respectively. On the basis of the Mab, an immunochromatographic lateral flow strip test was established for rapid screening of sulfonamides in honey samples. The visual limit of detection of the strip test for most sulfonamides in spiked honey samples was below 10 μg/kg, satisfying the requirements of authorities. Positive honey and pork liver samples, which had been confirmed by high-performance liquid chromatography/mass spectrometry, were used to validate the reliability of the proposed strip test. The immunochromatographic lateral flow strip test provides a rapid and convenient method for fast screening of sulfonamides in honey samples.

New benzoate derivatives and hirsutane type sesquiterpenoids with antimicrobial activity and cytotoxicity from the solid-state fermented rice by the medicinal mushroom Stereum hirsutum.

PubMed

Ma, Ke; Bao, Li; Han, Junjie; Jin, Tao; Yang, Xiaoli; Zhao, Feng; Li, Shaifei; Song, Fuhang; Liu, Miaomiao; Liu, Hongwei

2014-01-15

In addition to the fruiting bodies, mushroom mycelia can be used as functional foods and nutraceutical materials. In this study, two new benzoate derivatives (1 and 2) and three new sesquiterpenoids (3-5) were isolated from the mycelia of Stereum hirsutum. Their chemical structures were elucidated by NMR experiments. The absolute configuration in 3 was assigned by X-ray crystallographic analysis. In bioactivities evaluation, compounds 1 and 2 showed antimicrobial effects against methicillin-resistant Staphylococcusaureus, and S. aureus with the MIC values of 25.0μg/mL; compounds 1 and 3 inhibited the NO overproduction in the LPS-induced macrophages with the IC50 values of 19.17 and 15.44μM, and also displayed cytotoxicity against A549 and HepG2 with IC50 in the range of 10-50μM. These results support the usage of the mycelia of S. hirsutum as a good functional food. Copyright © 2013 Elsevier Ltd. All rights reserved.

Acetyl analogs of combretastatin A-4: synthesis and biological studies.

PubMed

Babu, Balaji; Lee, Megan; Lee, Lauren; Strobel, Raymond; Brockway, Olivia; Nickols, Alexis; Sjoholm, Robert; Tzou, Samuel; Chavda, Sameer; Desta, Dereje; Fraley, Gregory; Siegfried, Adam; Pennington, William; Hartley, Rachel M; Westbrook, Cara; Mooberry, Susan L; Kiakos, Konstantinos; Hartley, John A; Lee, Moses

2011-04-01

The combretastatins have received significant attention because of their simple chemical structures, excellent antitumor efficacy and novel antivascular mechanisms of action. Herein, we report the synthesis of 20 novel acetyl analogs of CA-4 (1), synthesized from 3,4,5-trimethoxyphenylacetone that comprises the A ring of CA-4 with different aromatic aldehydes as the B ring. Molecular modeling studies indicate that these new compounds possess a 'twisted' conformation similar to CA-4. The new analogs effectively inhibit the growth of human and murine cancer cells. The most potent compounds 6k, 6s and 6t, have IC(50) values in the sub-μM range. Analog 6t has an IC(50) of 182 nM in MDA-MB-435 cells and has advantages over earlier analogs due to its enhanced water solubility (456 μM). This compound initiates microtubule depolymerization with an EC(50) value of 1.8 μM in A-10 cells. In a murine L1210 syngeneic tumor model 6t had antitumor activity and no apparent toxicity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Bioactive halogenated dihydroisocoumarins produced by the endophytic fungus Lachnum palmae isolated from Przewalskia tangutica.

PubMed

Zhao, Min; Yuan, Lv-Yi; Guo, Da-Le; Ye, Ye; Da-Wa, Zhuo-Ma; Wang, Xiao-Ling; Ma, Feng-Wei; Chen, Lei; Gu, Yu-Cheng; Ding, Li-Sheng; Zhou, Yan

2018-04-01

Guided by the UPLC-ESIMS profile, seven previously undescribed halogenated dihydroisocoumarins, palmaerones A-G, along with eleven known dihydroisocoumarins, were isolated from Lachnum palmae, an endophytic fungus from Przewalskia tangutica by exposure to a histone deacetylase inhibitor SAHA. Structures of the isolates were elucidated by analysis of their NMR, MS and optical rotation values. The antimicrobial, anti-inflammatory and cytotoxic activities of palmaerones A-G were evaluated. Palmaerones A-G showed antimicrobial activities against the strains (C. neoformans, Penicillium sp., C. albicans, B. subtilis and S. aureus), and palmaerone E exhibited potential antimicrobial activities against all the test strains with the MIC value in the range of 10-55 μg/mL. Palmaerones A and E exhibited moderate inhibitory effects on NO production in LPS-induced RAW 264.7 cells, with the IC 50 values of 26.3 and 38.7 μM, respectively and no obvious toxicities were observed at 50 μM. Palmaerone E showed weak cytotoxicity against HepG2 with the IC 50 value of 42.8 μM. This work provides an effective strategy for expanding natural product resource. Copyright © 2018 Elsevier Ltd. All rights reserved.

Syntheses of 4,6-dihydroxypyrimidine diones, their urease inhibition, in vitro, in silico, and kinetic studies.

PubMed

Muhammad, Munira Taj; Khan, Khalid Mohammed; Arshia; Khan, Ajmal; Arshad, Fiza; Fatima, Bibi; Choudhary, M Iqbal; Syed, Naima; Moin, Syed Tarique

2017-12-01

A library of 4,6-dihydroxypyrimidine diones (1-35) were synthesized and evaluated for their urease inhibitory activity. Structure-activity relationships, and mechanism of inhibition were also studied. All compounds were found to be active with IC 50 values between 22.6±1.14-117.4±0.73µM, in comparison to standard, thiourea (IC 50 =21.2±1.3µM). Kinetics studies on the most active compounds 2-7, 16, 17, 28, and 33 were performed to investigate their modes of inhibition, and dissociation constants K i . Compounds 2, 3, 7, 16, 28, and 33 were found to be mixed-type of inhibitors with K i values in the range of 7.91±0.024-13.03±0.013µM, whereas, compounds 4-6, and 17 were found to be non-competitive inhibitors with K i values in the range of 9.28±0.019-13.05±0.023µM. In silico study was also performed, and a good correlation was observed between experimental and docking studies. This study is continuation of our previously reported urease inhibitory activity of pyrimidine diones, representing potential leads for further research as possible treatment of diseases caused by ureolytic bacteria. Copyright © 2017. Published by Elsevier Inc.

Antitumor and antiangiogenic effects of GA-13315, a gibberellin derivative.

PubMed

Zhang, Yanli; Zhang, Hui; Chen, Jingbo; Zhao, Haixia; Zeng, Xianghui; Zhang, Hongbin; Qing, Chen

2012-02-01

This study showed that 13-chlorine-3,15-dioxy-gibberellic acid methyl ester (GA-13315), a gibberellin derivative, possessed high antitumor and antiangiogenic activity in vitro and in vivo. Cytotoxicity assays showed that GA-13315 was a potential and efficient antitumor compound, with inhibitory concentration 50 (IC(50)) values ranging from 0.13 to 30.28 μg/ml in 12 human tumor cell lines, and it showed moderate toxicity to peripheral blood mononuclear cells with an IC(50) value of 14.2 μg/ml. Administration of 0.5 or 2.5 mg/kg GA-13315 for 23 days significantly inhibited tumor growth of human non-small cell lung tumor (A549) xenografts, with relative growth rates ranging from 29.91% to 35.05%. Acute toxicity was determined in ICR mice, and the lethal dose 50 (LD(50)) was 4.19 g/kg after intragastric administration. The high antitumor potency of GA-13315 occurred in parallel with its antiangiogenic activity. In vitro, GA-13315 inhibited recombinant human epithelial growth factor-induced chemotactic motility and capillary-like tube formation of primary cultured human endothelial cells. Furthermore, GA-13315 decreased the factor VIII(+) microvessel density and vascular endothelial growth factor expression in A549 tumors, indicating its antiangiogenic efficacy in vivo. These results indicate that the antiangiogenic activity of GA-13315 contributes to its anticancer properties. Further studies are needed to investigate the use of GA-13315 as an anticancer drug.

Development of a direct competitive enzyme-linked immunosorbent assay for parathion residue in food samples.

PubMed

Gui, Wen-Jun; Liu, Yi-Hua; Wang, Chun-Mei; Liang, Xiao; Zhu, Guo-Nian

2009-10-01

A heterologous direct competitive enzyme-linked immunosorbent assay (ELISA) for parathion residue determination is described based on a monoclonal antibody and a new competitor. The effects of several physicochemical factors, such as methanol concentration, ionic strength, pH value, and sample matrix, on the performance of the ELISA were optimized for the sake of obtaining a satisfactory assay sensitivity. Results showed that when the assay medium was in the optimized condition (phosphate buffer solution [PBS] containing 10% [v/v] methanol and 0.2 mol/L NaCl at a pH value of 5.0), the sensitivity (estimated as the IC(50) value) and the limit of detection (LOD, estimated as the IC(10) value) were 1.19 and 0.08 ng/ml, respectively. The precision investigation indicated that the intraassay precision values all were below 10% and that the interassay precision values ranged from 4.89 to 19.12%. In addition, the developed ELISA showed a good linear correlation (r(2)=0.9962) to gas chromatography within the analyte's concentration range of 0.1 to 16 ng/ml. When applied to the fortified samples (parathion adding level: 5-15 microg/kg), the developed ELISA presented mean recoveries of 127.46, 122.52, 91.92, 124.01, 129.72, 99.37, and 87.17% for tomato, cucumber, banana, apple, orange, pear, and sugarcane, respectively. Results indicated that the established ELISA is a potential tool for parathion residue determination.

Inhibition of lipoxygenases and cyclooxygenase-2 enzymes by extracts isolated from Bacopa monniera (L.) Wettst.

PubMed

Viji, V; Helen, A

2008-07-23

Bacopa monniera Linn is described in the Ayurvedic Materia Medica, as a therapeutically useful herb for the treatment of inflammation. In the current study, we investigated the anti-inflammatory activity of methanolic extract of Bacopa monniera (BME). For some experiments EtOAc and bacoside fractions were prepared from BME. The effect of these extracts in modulating key mediators of inflammation was evaluated. Carrageenan-induced rat paw edema, rat mononuclear cells and human whole blood assay were employed as in vivo and in vitro models. In carrageenan-induced rat paw edema, BME brought about 82% edema inhibition at a dose of 100mg/kg i.p. when compared to indomethacin (INDO) (3mg/kg) that showed 70% edema inhibition. BME also significantly inhibited 5-lipoxygenase (5-LOX), 15-LOX and cyclooxygenase-2 (COX-2) activities in rat monocytes in vivo. Among the fractions tested in vitro, EtOAc fraction possessed significant 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity with IC(50) value of 30 microg/ml compared to butylated hydroxyl toluene (IC(50) = 13 microg/ml). This fraction also exerted significant hydroxyl radical scavenging activity with IC(50) value of 25 microg/ml in comparison with quercetin (IC(50) = 5 microg/ml). Inhibitory effects of EtOAc and bacoside fractions on LOX and COX activities in Ca-A23187 stimulated rat mononuclear cells were also assessed. 5-LOX IC(50) values were 25 microg/ml for EtOAc, 68 microg/ml for bacosides and 2 microg/ml for nordihydroguaiaretic acid (NDGA) where as COX-2 IC(50) values were 1.32 microg/ml for EtOAc, 1.19 microg/ml for bacoside fraction and 0.23 microg/ml for indomethacin. EtOAc and bacoside fractions also brought about significant decrease in TNF-alpha release ex vivo. Bacopa monniera possesses anti-inflammatory activity through inhibition of COX and LOX and downregulation of TNF-alpha.

Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition.

PubMed

Fawcett, William P; Aracava, Yasco; Adler, Michael; Pereira, Edna F R; Albuquerque, Edson X

2009-02-01

This study was designed to test the hypothesis that the acute toxicity of the nerve agents S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate (VX), O-pinacolyl methylphosphonofluoridate (soman), and O-isopropyl methylphosphonofluoridate (sarin) in guinea pigs is age- and sex-dependent and cannot be fully accounted for by the irreversible inhibition of acetylcholinesterase (AChE). The subcutaneous doses of nerve agents needed to decrease 24-h survival of guinea pigs by 50% (LD(50) values) were estimated by probit analysis. In all animal groups, the rank order of LD(50) values was sarin > soman > VX. The LD(50) value of soman was not influenced by sex or age of the animals. In contrast, the LD(50) values of VX and sarin were lower in adult male than in age-matched female or younger guinea pigs. A colorimetric assay was used to determine the concentrations of nerve agents that inhibit in vitro 50% of AChE activity (IC(50) values) in guinea pig brain extracts, plasma, red blood cells, and whole blood. A positive correlation between LD(50) values and IC(50) values for AChE inhibition would support the hypothesis that AChE inhibition is a major determinant of the acute toxicity of the nerve agents. However, such a positive correlation was found only between LD(50) values and IC(50) values for AChE inhibition in brain extracts from neonatal and prepubertal guinea pigs. These results demonstrate for the first time that the lethal potencies of some nerve agents in guinea pigs are age- and sex-dependent. They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents.

The use of microfluorometric method for activity-guided isolation of antiplasmodial compound from plant extracts.

PubMed

Shuaibu, M N; Wuyep, P A; Yanagi, T; Hirayama, K; Tanaka, T; Kouno, I

2008-05-01

In vitro antiplasmodial activity of methanolic extracts of 16 medicinal plants was evaluated by fluorometric assay using PicoGreen. The IC50s, as determined by parasite DNA concentration, ranged from <11 to >200 and <13 to >200 microg/ml for Plasmodium falciparum 3D7 and K1, respectively; and the most active extracts were those from Anogeissus leiocarpus and Terminalia avicennoides (<11-> or =14 microg/ml). Aqueous, butanolic, ethyl acetate, and methanolic fractions of these two extracts revealed butanolic fraction to have a relatively better activity (IC50, 10-12 microg/ml). Activity-guided chromatographic separation of the butanolic fraction on Sephadex LH-20 followed by nuclear magnetic resonance and correlation high-performance liquid chromatography revealed the presence of known hydrolysable tannins and some related compounds-castalagin, ellagic acid, flavogallonic acid, punicalagin, terchebulin, and two other fractions. The IC50s of all these compounds ranged between 8-21 microg/ml (8-40 microM) against both the strains. Toxicity assay with mouse fibroblasts showed all the extracts and isolated compounds to have IC50 > or = 1500 microg/ml, except for Momordica balsamina with <1500 microg/l. All the extracts and isolated compounds did not affect the integrity of human erythrocyte membrane at the observed IC50s. However, adverse effects manifest in a concentration-dependent fashion (from IC50 > or = 500 microg/ml).

Neopetrosiquinones A and B, Sesquiterpene Benzoquinones Isolated from the Deep-water Sponge Neopetrosia cf. proxima

PubMed Central

Winder, Priscilla L.; Baker, Heather L.; Linley, Patricia; Guzmán, Esther; Pomponi, Shirley A.; Diaz, M. Cristina; Reed, John K.; Wright, Amy E.

2011-01-01

Two new marine-derived sesquiterpene benzoquinones which we designate as neopetrosiquinone A (1) and B (2), have been isolated from a deep-water sponge of the family Petrosiidae. The structures were elucidated on the basis of their spectroscopic data. Compounds 1 and 2 inhibit the in vitro proliferation of the DLD-1 human colorectal adenocarcinoma cell line with IC50 values of 3.7 and 9.8 μM, respectively, and the PANC-1 human pancreatic carcinoma cell line with IC50 values of 6.1 and 13.8 μM, respectively. Neopetrosiquinone A (1) also inhibited the in vitro proliferation of the AsPC-1 human pancreatic carcinoma cell line with an IC50 value of 6.1 μM. The compounds are structurally related to alisiaquinone A, cyclozonarone and xestoquinone. PMID:22014756

Development of an enzyme-linked immunosorbent assay for detection of clopidol residues in chicken tissues.

PubMed

Jiang, Jin-Qing; Zhang, Hai-Tang; Zhang, Hui-Hui; Wang, Zi-Liang; Yang, Xue-Feng; Fan, Guo-Ying

2014-08-01

Clopidol is mainly used for the prevention and treatment of coccidiosis, which poses a serious potential hazard to public health, in veterinary medicine. The aim of this study was to prepare monoclonal antibodies (mAbs) against clopidol (CLOP) and develop an immunoassay for detecting CLOP residues in chicken tissues. After derivation, CLOP hapten was conjugated to carrier proteins to synthesize the artificial antigen, and immunized Balb/C mice were employed to screen mAbs. A sensitive hybridoma named C1G3 was screened out and two indirect competitive enzyme-linked immunosorbent assay (icELISA) standard curves were established. For the traditional two-step assay the linear range was from 0.06 to 98 ng mL(-1) , with half-maximal inhibitory concentration (IC50 ) and limit of detection (LOD) values of 2.76 ng mL(-1) and 0.03 ng mL(-1) respectively, while the rapid one-step icELISA had a working range from 0.08 to 102 ng mL(-1) , with IC50 and LOD values of 3.52 ng mL(-1) and 0.03 ng mL(-1) respectively. It was also indicated that a 10-fold dilution in chicken muscles gave an inhibition curve almost the same as that obtained in phosphate-buffered saline. When applied to spiking tests in chicken samples, the correlation coefficient (R(2) ) between concentrations added and measured was 0.9534. The results of this study suggest that the immunoassay described is a promising alternative for screening CLOP residues in biological matrices and is suitable for routine diagnostics. © 2014 Society of Chemical Industry.

Free radical scavengers and antioxidants from Lemongrass (Cymbopogon citratus (DC.) Stapf.).

PubMed

Cheel, José; Theoduloz, Cristina; Rodríguez, Jaime; Schmeda-Hirschmann, Guillermo

2005-04-06

Methanol, MeOH/water extracts, infusion, and decoction of Cymbopogon citratus were assessed for free radical scavenging effects measured by the bleaching of the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical, scavenging of the superoxide anion, and inhibition of the enzyme xanthine oxidase (XO) and lipid peroxidation in human erythrocytes. The extracts presented effect in the DPPH and superoxide anion assay, with values ranging between 40 and 68% and 15-32% at 33 and 50 microg/mL, respectively, inhibited lipid peroxidation in erythrocytes by 19-71% at 500 microg/mL and were inactive toward the XO at 50 microg/mL. Isoorientin, isoscoparin, swertiajaponin, isoorientin 2' '-O-rhamnoside, orientin, chlorogenic acid, and caffeic acid were isolated and identified by spectroscopic methods. Isoorientin and orientin presented similar activities toward the DPPH (IC(50): 9-10 microM) and inhibited lipid peroxidation by 70% at 100 microg/mL. Caffeic and chlorogenic acid were active superoxide anion scavengers with IC(50) values of 68.8 and 54.2 microM, respectively, and a strong effect toward DPPH. Caffeic acid inhibited lipid peroxidation by 85% at 100 microg/mL.

Chemical Composition and Acetylcholinesterase Inhibitory Activity of Essential Oils from Piper Species.

PubMed

Xiang, Cai-Peng; Han, Jia-Xin; Li, Xing-Cong; Li, Yun-Hui; Zhang, Yi; Chen, Lin; Qu, Yan; Hao, Chao-Yun; Li, Hai-Zhou; Yang, Chong-Ren; Zhao, San-Jun; Xu, Min

2017-05-10

The essential oils (EOs) derived from aromatic plants such as Piper species are considered to play a role in alleviating neuronal ailments that are associated with inhibition of acetylcholinesterase (AChE). The chemical compositions of 23 EOs prepared from 16 Piper spp. were analyzed by both gas chromatography with a flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS). A total of 76 compounds were identified in the EOs from the leaves and stems of 19 samples, while 30 compounds were detected in the EOs from the fruits of four samples. Sesquiterpenes and phenylpropanoids were found to be rich in these EOs, of which asaricin, caryophyllene, caryophyllene oxide, isospathulenol, (+)-spathulenol, and β-bisabolene are the major constituents. The EOs from the leaves and stems of Piper austrosinense, P. puberulum, P. flaviflorum, P. betle, and P. hispidimervium showed strong AChE inhibitory activity with IC 50 values in the range of 1.51 to 13.9 mg/mL. A thin-layer chromatography (TLC) bioautography assay was employed to identify active compound(s) in the most active EO from P. hispidimervium. The active compound was isolated and identified as asaricin, which gave an IC 50 value of 0.44 ± 0.02 mg/mL against AChE, comparable to galantamine with an IC 50 0.15 ± 0.01 mg/mL.

Evaluation of P-Glycoprotein Inhibitory Potential Using a Rhodamine 123 Accumulation Assay

PubMed Central

Jouan, Elodie; Le Vée, Marc; Mayati, Abdullah; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

2016-01-01

In vitro evaluation of P-glycoprotein (P-gp) inhibitory potential is now a regulatory issue during drug development, in order to predict clinical inhibition of P-gp and subsequent drug–drug interactions. Assays for this purpose, commonly based on P-gp-expressing cell lines and digoxin as a reference P-gp substrate probe, unfortunately exhibit high variability, raising thus the question of developing alternative or complementary tests for measuring inhibition of P-gp activity. In this context, the present study was designed to investigate the use of the fluorescent dye rhodamine 123 as a reference P-gp substrate probe for characterizing P-gp inhibitory potential of 16 structurally-unrelated drugs known to interact with P-gp. 14/16 of these P-gp inhibitors were found to increase rhodamine 123 accumulation in P-gp-overexpressing MCF7R cells, thus allowing the determination of their P-gp inhibitory potential, i.e., their half maximal inhibitor concentration (IC50) value towards P-gp-mediated transport of the dye. These IC50 values were in the range of variability of previously reported IC50 for P-gp and can be used for the prediction of clinical P-gp inhibition according to Food and Drug Administration (FDA) criteria, with notable sensitivity (80%). Therefore, the data demonstrated the feasibility of the use of rhodamine 123 for evaluating the P-gp inhibitory potential of drugs. PMID:27077878

AVP-IC50 Pred: Multiple machine learning techniques-based prediction of peptide antiviral activity in terms of half maximal inhibitory concentration (IC50).

PubMed

Qureshi, Abid; Tandon, Himani; Kumar, Manoj

2015-11-01

Peptide-based antiviral therapeutics has gradually paved their way into mainstream drug discovery research. Experimental determination of peptides' antiviral activity as expressed by their IC50 values involves a lot of effort. Therefore, we have developed "AVP-IC50 Pred," a regression-based algorithm to predict the antiviral activity in terms of IC50 values (μM). A total of 759 non-redundant peptides from AVPdb and HIPdb were divided into a training/test set having 683 peptides (T(683)) and a validation set with 76 independent peptides (V(76)) for evaluation. We utilized important peptide sequence features like amino-acid compositions, binary profile of N8-C8 residues, physicochemical properties and their hybrids. Four different machine learning techniques (MLTs) namely Support vector machine, Random Forest, Instance-based classifier, and K-Star were employed. During 10-fold cross validation, we achieved maximum Pearson correlation coefficients (PCCs) of 0.66, 0.64, 0.56, 0.55, respectively, for the above MLTs using the best combination of feature sets. All the predictive models also performed well on the independent validation dataset and achieved maximum PCCs of 0.74, 0.68, 0.59, 0.57, respectively, on the best combination of feature sets. The AVP-IC50 Pred web server is anticipated to assist the researchers working on antiviral therapeutics by enabling them to computationally screen many compounds and focus experimental validation on the most promising set of peptides, thus reducing cost and time efforts. The server is available at http://crdd.osdd.net/servers/ic50avp. © 2015 Wiley Periodicals, Inc.

Development and evaluation of an immunochromatographic strip for rapid screening of sildenafil-type compounds as illegal additives in functional foods.

PubMed

Guo, Jiebiao; Liu, Wangpei; Lan, Xianquan; Chen, Hualong; Xiao, Zijun

2016-07-01

Sildenafil is a phosphodiesterase-5 inhibitor (PDE-5) for the treatment of erectile dysfunction. Undeclared sildenafil and related analogues adulterated in functional foods are a threat to public health. To screen these illegal drugs rapidly in herbal samples, an immunochromatographic (IC) assay was developed based on polyclonal antibodies specific to both sildenafil and its analogues. A group that is pharmacological necessary for sildenafil and its analogues was employed as a representative hapten for the generation antibodies against the target compounds. The desired antisera showed satisfactory specificities to sildenafil and major analogues with IC50 values ranging from 19.3 to 34.6 ng ml(-1) in a referring enzyme-linked immunosorbent assay (ELISA). The optimised IC assay showed detection thresholds in the range 5.0-20 μg g(-1) for sildenafil and major analogues in herbal samples. Sixty herbal food supplements were screened and six were found to be positive using the IC strip. It was confirmed by ELISA and UPLC-PDA-MS/MS that positive samples contain target illegal additives in levels of 10-40 mg g(-1) (1-4%). In this range, sensitivity of the IC strip is adequate to screen sildenafil-type compounds in herbal commodities under a dilution ratio of 1:10(3). Thus, the current IC assay is a suitable tool for screening sildenafil and its analogues as illegal additives in herbal food supplements.

Antioxidant and Anti-Inflammatory Activities of Hydrolysates and Peptide Fractions Obtained by Enzymatic Hydrolysis of Selected Heat-Treated Edible Insects.

PubMed

Zielińska, Ewelina; Baraniak, Barbara; Karaś, Monika

2017-09-02

This study investigated the effect of heat treatment of edible insects on antioxidant and anti-inflammatory activities of peptides obtained by in vitro gastrointestinal digestion and absorption process thereof. The antioxidant potential of edible insect hydrolysates was determined as free radical-scavenging activity, ion chelating activity, and reducing power, whereas the anti-inflammatory activity was expressed as lipoxygenase and cyclooxygenase-2 inhibitory activity. The highest antiradical activity against DPPH • (2,2-diphenyl-1-picrylhydrazyl radical) was noted for a peptide fraction from baked cricket Gryllodes sigillatus hydrolysate (IC 50 value 10.9 µg/mL) and that against ABTS •+ (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical) was the highest for raw mealworm Tenebrio molitor hydrolysate (inhibitory concentration (IC 50 value) 5.3 µg/mL). The peptides obtained from boiled locust Schistocerca gregaria hydrolysate showed the highest Fe 2+ chelation ability (IC 50 value 2.57 µg/mL); furthermore, the highest reducing power was observed for raw G. sigillatus hydrolysate (0.771). The peptide fraction from a protein preparation from the locust S. gregaria exhibited the most significant lipoxygenase and cyclooxygenase-2 inhibitory activity (IC 50 value 3.13 µg/mL and 5.05 µg/mL, respectively).

Antioxidant and Anti-Inflammatory Activities of Hydrolysates and Peptide Fractions Obtained by Enzymatic Hydrolysis of Selected Heat-Treated Edible Insects

PubMed Central

Zielińska, Ewelina; Baraniak, Barbara; Karaś, Monika

2017-01-01

This study investigated the effect of heat treatment of edible insects on antioxidant and anti-inflammatory activities of peptides obtained by in vitro gastrointestinal digestion and absorption process thereof. The antioxidant potential of edible insect hydrolysates was determined as free radical-scavenging activity, ion chelating activity, and reducing power, whereas the anti-inflammatory activity was expressed as lipoxygenase and cyclooxygenase-2 inhibitory activity. The highest antiradical activity against DPPH• (2,2-diphenyl-1-picrylhydrazyl radical) was noted for a peptide fraction from baked cricket Gryllodes sigillatus hydrolysate (IC50 value 10.9 µg/mL) and that against ABTS•+ (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical) was the highest for raw mealworm Tenebrio molitor hydrolysate (inhibitory concentration (IC50 value) 5.3 µg/mL). The peptides obtained from boiled locust Schistocerca gregaria hydrolysate showed the highest Fe2+ chelation ability (IC50 value 2.57 µg/mL); furthermore, the highest reducing power was observed for raw G. sigillatus hydrolysate (0.771). The peptide fraction from a protein preparation from the locust S. gregaria exhibited the most significant lipoxygenase and cyclooxygenase-2 inhibitory activity (IC50 value 3.13 µg/mL and 5.05 µg/mL, respectively). PMID:28869499

Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

PubMed Central

Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

2014-01-01

Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives ▿

PubMed Central

Dardonville, Christophe; Fernández-Fernández, Cristina; Gibbons, Sarah-Louise; Jagerovic, Nadine; Nieto, Lidia; Ryan, Gary; Kaiser, Marcel; Brun, Reto

2009-01-01

A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC50) ranging from 0.12 to 10 μM, and 33 compounds active against the chloroquine- and pyrimethamine-resistant K1 strain of P. falciparum (IC50 range, 0.17 to 5 μM). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC50, 1.97 μM) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton. PMID:19564359

In vitro antitumour activity of orsellinates.

PubMed

Bogo, Danielle; de Matos, Maria Fatima Cepa; Honda, Neli Kika; Pontes, Elenir Curi; Oguma, Patricia Midori; da Santos, Evelyn Cristina Silva; de Carvalho, João Ernesto; Nomizo, Auro

2010-01-01

Lichen phenolic compounds exhibit antioxidant, antimicrobial, antiproliferative, and cytotoxic activities. The purpose of this study was to evaluate the anticancer activity of lecanoric acid, a secondary metabolite of the lichen Parmotrema tinctorum, and its derivatives, orsellinates, obtained by structural modification. A cytotoxicity assay was carried out in vitro with sulforhodamine B (SRB) using HEp-2 larynx carcinoma, MCF7 breast carcinoma, 786-0 kidney carcinoma, and B16-F10 murine melanoma cell lines, in addition to a normal (Vero) cell line in order to calculate the selectivity index of the compounds. n-Butyl orsellinate was the most active compound, with IC50 values (the concentration that inhibits 50% of growth) ranging from 7.2 to 14.0 microg/mL, against all the cell lines tested. The compound was more active (IC50 = 11.4 microg/mL) against B16-F10 cells than was cisplatin (12.5 microg/mL). Conversely, lecanoric acid and methyl orsellinate were less active against all cell lines, having an IC50 value higher than 50 microg/mL. Ethyl orsellinate was more active against HEp-2 than against MCF7, 786-0, or B16-F10 cells. The same pattern was observed for n-propyl and n-butyl orsellinates. n-Pentyl orsellinate was less active than n-propyl or n-butyl orsellinates against HEp-2 cells. The orsellinate activity increased with chain elongation (from methyl to n-butyl), a likely consequence of an increase in lipophilicity. The results revealed that the structural modification of lecanoric acid increases the cytotoxic activity of the derivatives tested.

Structure-based design, synthesis, and biological evaluation of withaferin A-analogues as potent apoptotic inducers.

PubMed

Llanos, Gabriel G; Araujo, Liliana M; Jiménez, Ignacio A; Moujir, Laila M; Rodríguez, Jaime; Jiménez, Carlos; Bazzocchi, Isabel L

2017-11-10

Apoptosis inducers represent an attractive approach for the discovery and development of anticancer agents. Herein, we report on the development by molecular fine tuning of a withaferin A-based library of 63 compounds (2-64), 53 of them reported for the first time. Their antiproliferative evaluation on HeLa, A-549 and MCF-7 human tumor cell lines identified fifteen analogues displaying higher activity (IC 50 values ranging 0.3-4.8 μM) than the lead (IC 50 values ranging 1.3-10.1 μM) either in lag or log growth phases. SAR analysis revealed that acylation enhances cytotoxicity, suggesting the hydrophobic moiety contributes to the activity, presumably by increasing affinity and/or cell membrane permeability. Further investigation clearly indicated that compounds 3, 11, 12, and 18 induce apoptosis evidenced by chromatin condensation, phosphatidylserine externalization, and caspase-3 activation effects on HeLa cells. The potent capacity to induce apoptosis with concomitant cell loss in G2/M highlights the potential of 27-benzyl analogue (18) as an apoptotic inducer drug candidate. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Protein Tyrosine Phosphatase 1B Inhibitors from the Stems of Akebia quinata.

PubMed

An, Jin-Pyo; Ha, Thi Kim Quy; Kim, Jinwoong; Cho, Tae Oh; Oh, Won Keun

2016-08-19

PTP1B deficiency in mouse mammary tumor virus (MMTV)-NeuNT transgenic mice inhibited the onset of MMTV-NeuNT-evoked breast cancer, while its overexpression was observed in breast cancer. Thus, PTP1B inhibitors are considered chemopreventative agents for breast cancer. As part of our program to find PTP1B inhibitors, one new diterpene glycoside (1) and 13 known compounds (2-14) were isolated from the methanol extract of the stems of Akebia quinata. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR and MS. Compounds 2, 3, 6, 8 and 11 showed significant inhibitory effects on the PTP1B enzyme, with IC50 values ranging from 4.08 ± 1.09 to 21.80 ± 4.74 μM. PTP1B inhibitors also had concentration-dependent cytotoxic effects on breast cancer cell lines, such as MCF7, MDA-MB-231 and tamoxifen-resistant MCF7 (MCF7/TAMR) (IC50 values ranging from 0.84 ± 0.04 to 7.91 ± 0.39 μM). These results indicate that compounds 6 and 8 from Akebia quinata may be lead compounds acting as anti-breast cancer agents.

Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups.

PubMed

Gao, Shuai; Zang, Jie; Gao, Qianwen; Liang, Xuewu; Ding, Qinge; Li, Xiaoyang; Xu, Wenfang; Chou, C James; Zhang, Yingjie

2017-06-15

As a hot topic of epigenetic studies, histone deacetylases (HDACs) are related to lots of diseases, especially cancer. Further researches indicated that different HDAC isoforms played various roles in a wide range of tumor types. Herein a novel series of HDAC inhibitors with isatin-based caps and o-phenylenediamine-based zinc binding groups have been designed and synthesized through scaffold hopping strategy. Among these compounds, the most potent compound 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat (MS-275). Additionally, compared with MS-275 (IC 50 values for HDAC1, 2 and 3 were 0.163, 0.396 and 0.605µM, respectively), compound 9n with IC 50 values of 0.032, 0.256 and 0.311µM for HDAC1, 2 and 3 respectively, showed a moderate HDAC1 selectivity. Copyright © 2017. Published by Elsevier Ltd.

Obionin B: An o-pyranonaphthoquinone decaketide from an unidentified fungus (MSX 63619) from the Order Pleosporales.

PubMed

Ayers, Sloan; Graf, Tyler N; Adcock, Audrey F; Kroll, David J; Shen, Qi; Swanson, Steven M; Wani, Mansukh C; Darveaux, Blaise A; Pearce, Cedric J; Oberlies, Nicholas H

2011-10-05

A fungal extract (MSX 63619), from the Mycosynthetix library of over 50,000 fungi, displayed promising cytotoxicity against a human tumor cell panel. Bioactivity-directed fractionation led to the isolation of an o-pyranonaphthoquinone decaketide, which we termed obionin B (1). The structure of 1 was deduced via spectroscopic and spectrometric techniques. The IC(50) value of 1 was moderate, ranging from 3 to 13 μM, depending on the cell line tested.

In vitro anti-plasmodial activity of some traditionally used medicinal plants against Plasmodium falciparum.

PubMed

Venkatesalu, V; Gopalan, N; Pillai, C R; Singh, Vineeta; Chandrasekaran, M; Senthilkumar, A; Chandramouli, N

2012-07-01

The anti-plasmodial activity of different solvent extracts of Adhatoda vasica (root), Caesalpinia pulcherrima (leaf), Carica papaya (pulp), Erythroxylum monogynum (leaf), Lantana camara (whole plant), Ocimum sanctum (root) and Phyllanthus niruri (whole plant) were studied against Plasmodium falciparum. Of the 35 extracts tested, seven extracts showed good anti-plasmodial activity. Methanol extract of C. pulcherrima showed the lowest IC50 value (10.96 μg/mL) followed by methanol extract of A. vasica (IC(50)=11.1 μg/mL), chloroform extract of O. sanctum (IC(50)=11.47 μg/mL), methanol extract of E. monogynum (IC(50)=12.23 μg/mL), acetone extract of C. pulcherrima (IC(50)=12.49 μg/mL), methanol extract of O. sanctum and acetone extract of A. vasica (IC(50)=14.04 μg/mL). The results of the present study justify the use of these medicinal plants in traditional practice, and also, a further study on the isolation of anti-plasmodial molecules from their active crude extracts is in progress.

Inhibition of monoamine oxidase A and B activities by imidazol(ine)/guanidine drugs, nature of the interaction and distinction from I2-imidazoline receptors in rat liver

PubMed Central

Ozaita, Andrés; Olmos, Gabriel; Assumpció Boronat, M; Miguel Lizcano, José; Unzeta, Mercedes; García-Sevilla, Jesús A

1997-01-01

I2-Imidazoline sites ([3H]-idazoxan binding) have been identified on monoamine oxidase (MAO) and proposed to modulate the activity of the enzyme through an allosteric inhibitory mechanism (Tesson et al., 1995). The main aim of this study was to assess the inhibitory effects and nature of the inhibition of imidazol(ine)/guanidine drugs on rat liver MAO-A and MAO-B isoforms and to compare their inhibitory potencies with their affinities for the sites labelled by [3H]-clonidine in the same tissue. Competition for [3H]-clonidine binding in rat liver mitochondrial fractions by imidazol(ine)/guanidine compounds revealed that the pharmacological profile of the interaction (2 - styryl - 2 - imidazoline, LSL 61112>idazoxan>2 - benzofuranyl - 2 - imidazoline, 2-BFI=cirazoline>guanabenz>oxymetazoline>>clonidine) was typical of that for I2-sites. Clonidine inhibited rat liver MAO-A and MAO-B activities with very low potency (IC50s: 700 μM and 6 mM, respectively) and displayed the typical pattern of competitive enzyme inhibition (Lineweaver-Burk plots: increased Km and unchanged Vmax values). Other imidazol(ine)/guanidine drugs also were weak MAO inhibitors with the exception of guanabenz, 2-BFI and cirazoline on MAO-A (IC50s: 4–11 μM) and 2-benzofuranyl-2-imidazol (LSL 60101) on MAO-B (IC50: 16 μM). Idazoxan was a full inhibitor, although with rather low potency, on both MAO-A and MAO-B isoenzymes (IC50s: 280 μM and 624 μM, respectively). Kinetic analyses of MAO-A inhibition by these drugs revealed that the interactions were competitive. For the same drugs acting on MAO-B the interactions were of the mixed type inhibition (increased Km and decreased Vmax values), although the greater inhibitory effects on the apparent value of Vmax/Km than on the Vmax value indicated that the competitive element of the MAO-B inhibition predominated. Competition for [3H]-Ro 41-1049 binding to MAO-A or [3H]-Ro 19-6327 binding to MAO-B in rat liver mitochondrial fractions by imidazol(ine)/guanidine compounds revealed that the drug inhibition constants (Ki values) were similar to the IC50 values displayed for the inhibition of MAO-A or MAO-B activities. In fact, very good correlations were obtained when the affinities of drugs at MAO-A or MAO-B catalytic sites were correlated with their potencies in inhibiting MAO-A (r=0.92) or MAO-B (r=0.99) activity. This further suggested a direct drug interaction with the catalytic sites of MAO-A and MAO-B isoforms. No significant correlations were found when the potencies of imidazol(ine)/guanidine drugs at the high affinity site (pKiH, nanomolar range) or the low-affinity site (pKiL, micromolar range) of I2-imidazoline receptors labelled with [3H]-clonidine were correlated with the pIC50 values of the same drugs for inhibition of MAO-A or MAO-B activity. These discrepancies indicated that I2-imidazoline receptors are not directly related to the site of action of these drugs on MAO activity in rat liver mitochondrial fractions. Although these studies cannot exclude the presence of additional binding sites on MAO that do not affect the activity of the enzyme, they would suggest that I2-imidazoline receptors represent molecular species that are distinct from MAO. PMID:9222546

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors against clinical isolates of the influenza viruses circulating in the 2010-2011 to 2014-2015 Japanese influenza seasons.

PubMed

Ikematsu, Hideyuki; Kawai, Naoki; Iwaki, Norio; Kashiwagi, Seizaburo

2016-09-01

To assess the extent of viral resistance to the four neuraminidase inhibitors (NAIs), we measured their 50% inhibitory concentration (IC50) for influenza virus isolates from the 2014-2015 influenza season for comparison with those circulating in the 2010-2011 to 2013-2014 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. IC50 was measured for 200 influenza A(H3N2) and 19 influenza B in the 2014-2015 season, and no virus with highly reduced sensitivity to the four NAIs was detected. The ratios of the geometric means of the A(H3N2) IC50s of 2014-2015 to those of the 2010-2011, 2011-2012, 2012-2013, and 2013-2014 seasons ranged from 0.72 to 1.05, 0.82 to 1.22, 0.69 to 1.00, and 0.70 to 1.03, respectively. The ratios of the geometric mean of the B IC50s to the previous four seasons ranged from 0.59 to 1.28, 0.66 to 1.34, 0.84 to 1.21, and 1.06 to 1.47, respectively. There was no trend in the change of the IC50s for A(H3N2) or B. Significant differences were found in some seasons, but the differences in the IC50s were all less than two fold. These results show change in the geometric mean IC50 by season but with no trend, which indicates that the influence of viral mutation on the effectiveness of these NAIs was minute for A(H3N2) and B over the past five seasons. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Comparative Study of Erythrina indica Lam. (Febaceae) Leaves Extracts for Antioxidant Activity

PubMed Central

Sakat, SS; Juvekar, AR

2010-01-01

The present study was designed to investigate the antioxidant activity of aqueous and methanol extracts of Erythrina indica Lam leaves by in vitro methods viz. 1, 1-Diphenyl-2-Picrylhydrazyl, nitric oxide radical scavenging activity, and inhibition of lipid peroxidation by thiobarbituric acid reactive substances (TBARS) method on isolated rat liver tissues. Quantitative analysis of antioxidative components like total amount of phenolics, flavonoids, and flavonols were estimated using the spectrophotometric method. Linear regression analysis was used to calculate the IC50 value. Results showed that the aqueous and methanol extracts exhibited significant DPPH radicals scavenging activity with an IC50 value 342.59 ± 19.59, 283.24 ± 12.28 µg/mL respectively. Nitric oxide radicals were significantly scavenged by the aqueous and methanol extracts (IC50 = 250.12 ± 10.66; 328.29 ± 3.74 µg/mL). Lipid peroxidation induced by the Fe2+ was inhibited by the aqueous extract with low IC50 value (97.29 ± 2.05 µg/mL) as compared to methanol extract (IC50 = 283.74 ± 5.70 µg/mL). Both the extracts were exhibited similar quantities of total phenolics. Total flavonoids were found to be in higher quantities than total flavonols in aqueous extract as compared to methanol extract. From the results, it is concluded that the aqueous and methanol extracts of E. indica leaves possesses significant antioxidant activity that may be due to the presence of flavonoids and related polyphenolic compounds. PMID:21331194

Docking analysis targeted to the whole enzyme: an application to the prediction of inhibition of PTP1B by thiomorpholine and thiazolyl derivatives.

PubMed

Ganou, C A; Eleftheriou, P Th; Theodosis-Nobelos, P; Fesatidou, M; Geronikaki, A A; Lialiaris, T; Rekka, E A

2018-02-01

PTP1b is a protein tyrosine phosphatase involved in the inactivation of insulin receptor. Since inhibition of PTP1b may prolong the action of the receptor, PTP1b has become a drug target for the treatment of type II diabetes. In the present study, prediction of inhibition using docking analysis targeted specifically to the active or allosteric site was performed on 87 compounds structurally belonging to 10 different groups. Two groups, consisting of 15 thiomorpholine and 10 thiazolyl derivatives exhibiting the best prediction results, were selected for in vitro evaluation. All thiomorpholines showed inhibitory action (with IC 50 = 4-45 μΜ, Ki = 2-23 μM), while only three thiazolyl derivatives showed low inhibition (best IC 50 = 18 μΜ, Ki = 9 μΜ). However, free binding energy (E) was in accordance with the IC 50 values only for some compounds. Docking analysis targeted to the whole enzyme revealed that the compounds exhibiting IC 50 values higher than expected could bind to other peripheral sites with lower free energy, E o , than when bound to the active/allosteric site. A prediction factor, E- (Σ Eo × 0.16), which takes into account lower energy binding to peripheral sites, was proposed and was found to correlate well with the IC 50 values following an asymmetrical sigmoidal equation with r 2 = 0.9692.

Enhancing the Bioconversion of Azelaic Acid to Its Derivatives by Response Surface Methodology.

PubMed

Khairudin, Nurshafira; Basri, Mahiran; Fard Masoumi, Hamid Reza; Samson, Shazwani; Ashari, Siti Efliza

2018-02-13

Azelaic acid (AzA) and its derivatives have been known to be effective in the treatment of acne and various cutaneous hyperpigmentary disorders. The esterification of azelaic acid with lauryl alcohol (LA) to produce dilaurylazelate using immobilized lipase B from Candida antarctica (Novozym 435) is reported. Response surface methodology was selected to optimize the reaction conditions. A well-fitting quadratic polynomial regression model for the acid conversion was established with regards to several parameters, including reaction time and temperature, enzyme amount, and substrate molar ratios. The regression equation obtained by the central composite design of RSM predicted that the optimal reaction conditions included a reaction time of 360 min, 0.14 g of enzyme, a reaction temperature of 46 °C, and a molar ratio of substrates of 1:4.1. The results from the model were in good agreement with the experimental data and were within the experimental range (R² of 0.9732).The inhibition zone can be seen at dilaurylazelate ester with diameter 9.0±0.1 mm activities against Staphylococcus epidermidis S273. The normal fibroblasts cell line (3T3) was used to assess the cytotoxicity activity of AzA and AzA derivative, which is dilaurylazelate ester. The comparison of the IC 50 (50% inhibition of cell viability) value for AzA and AzA derivative was demonstrated. The IC 50 value for AzA was 85.28 μg/mL, whereas the IC 50 value for AzA derivative was more than 100 μg/mL. The 3T3 cell was still able to survive without any sign of toxicity from the AzA derivative; thus, it was proven to be non-toxic in this MTT assay when compared with AzA.

Bond-based bilinear indices for computational discovery of novel trypanosomicidal drug-like compounds through virtual screening.

PubMed

Castillo-Garit, Juan Alberto; del Toro-Cortés, Oremia; Vega, Maria C; Rolón, Miriam; Rojas de Arias, Antonieta; Casañola-Martin, Gerardo M; Escario, José A; Gómez-Barrio, Alicia; Marrero-Ponce, Yovani; Torrens, Francisco; Abad, Concepción

2015-01-01

Two-dimensional bond-based bilinear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A data set of 440 organic chemicals, 143 with antitrypanosomal activity and 297 having other clinical uses, is used to develop the theoretical models. Two discriminant models, computed using bond-based bilinear indices, are developed and both show accuracies higher than 86% for training and test sets. The stochastic model correctly indentifies nine out of eleven compounds of a set of organic chemicals obtained from our synthetic collaborators. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a good agreement between theoretical predictions and experimental results. Three compounds showed IC50 values for epimastigote elimination (AE) lower than 50 μM, while for the benznidazole the IC50 = 54.7 μM which was used as reference compound. The value of IC50 for cytotoxicity of these compounds is at least 5 times greater than their value of IC50 for AE. Finally, we can say that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new antitrypanosomal compounds. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A Novel Two-Step Hierarchical Quantitative Structure–Activity Relationship Modeling Work Flow for Predicting Acute Toxicity of Chemicals in Rodents

PubMed Central

Zhu, Hao; Ye, Lin; Richard, Ann; Golbraikh, Alexander; Wright, Fred A.; Rusyn, Ivan; Tropsha, Alexander

2009-01-01

Background Accurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public–private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening. Objective A wealth of available biological data requires new computational approaches to link chemical structure, in vitro data, and potential adverse health effects. Methods and results A database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC50) and in vivo rodent median lethal dose (LD50) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments). The application of conventional quantitative structure–activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD50 values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC50 and LD50. However, a linear IC50 versus LD50 correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC50 and LD50 values: One group comprises compounds with linear IC50 versus LD50 relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models to predict the group affiliation based on chemical descriptors only. Third, we developed k-nearest neighbor continuous QSAR models for each subclass to predict LD50 values from chemical descriptors. All models were extensively validated using special protocols. Conclusions The novelty of this modeling approach is that it uses the relationships between in vivo and in vitro data only to inform the initial construction of the hierarchical two-step QSAR models. Models resulting from this approach employ chemical descriptors only for external prediction of acute rodent toxicity. PMID:19672406

A novel two-step hierarchical quantitative structure-activity relationship modeling work flow for predicting acute toxicity of chemicals in rodents.

PubMed

Zhu, Hao; Ye, Lin; Richard, Ann; Golbraikh, Alexander; Wright, Fred A; Rusyn, Ivan; Tropsha, Alexander

2009-08-01

Accurate prediction of in vivo toxicity from in vitro testing is a challenging problem. Large public-private consortia have been formed with the goal of improving chemical safety assessment by the means of high-throughput screening. A wealth of available biological data requires new computational approaches to link chemical structure, in vitro data, and potential adverse health effects. A database containing experimental cytotoxicity values for in vitro half-maximal inhibitory concentration (IC(50)) and in vivo rodent median lethal dose (LD(50)) for more than 300 chemicals was compiled by Zentralstelle zur Erfassung und Bewertung von Ersatz- und Ergaenzungsmethoden zum Tierversuch (ZEBET; National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments). The application of conventional quantitative structure-activity relationship (QSAR) modeling approaches to predict mouse or rat acute LD(50) values from chemical descriptors of ZEBET compounds yielded no statistically significant models. The analysis of these data showed no significant correlation between IC(50) and LD(50). However, a linear IC(50) versus LD(50) correlation could be established for a fraction of compounds. To capitalize on this observation, we developed a novel two-step modeling approach as follows. First, all chemicals are partitioned into two groups based on the relationship between IC(50) and LD(50) values: One group comprises compounds with linear IC(50) versus LD(50) relationships, and another group comprises the remaining compounds. Second, we built conventional binary classification QSAR models to predict the group affiliation based on chemical descriptors only. Third, we developed k-nearest neighbor continuous QSAR models for each subclass to predict LD(50) values from chemical descriptors. All models were extensively validated using special protocols. The novelty of this modeling approach is that it uses the relationships between in vivo and in vitro data only to inform the initial construction of the hierarchical two-step QSAR models. Models resulting from this approach employ chemical descriptors only for external prediction of acute rodent toxicity.

Phytochemical and cytotoxic studies on the roots of Euphorbia fischeriana.

PubMed

Shi, Qun; Sun, Yi-Wei; Meng, Dali

2017-01-15

With the aim of supporting the folk applications of Euphorbia fischeriana, a phytochemical study was performed, which led to the discovery of 9 compounds, including three new ones (1-3) and six known ones (4-9). Their structures were determined by 1D, 2D NMR, and HRESIMS analysis. In the cytotoxic assays on Hep-3B cell line, 2 showed stronger inhibitory effects (IC 50 8.1μmol/L) than that of positive control, and 1, 8 and 9 also gave inhibitory effects in a certain degree with IC 50 values of 12.5, 12.0 and 18.7μmol/L, respectively. While on A549, the cytotoxic activities of 1 (IC 50 11.9μmol/L) and 8 (IC 50 9.4μmol/L) were superior to that of 5-Fu, and those of 4 and 9 were moderate with IC 50 values of 28.2 and 29.8μmol/L, respectively. In addition, both petroleum ether and dichloromethane extracts showed cytotoxic activities with different degree, while n-butanol extracts had no effect. The results clarified that the low-polarity fractions of E. fischeriana, including triterpenoids, abietane and tigliane-type diterpenoids might be the potential bioactive ingredients which will exert strong antitumor effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein.

PubMed

Keogh, John P; Kunta, Jeevan R

2006-04-01

Regulatory interest is increasing for drug transporters generally and P-glycoprotein (Pgp) in particular, primarily in the area of drug-drug interactions. To aid in both identifying and discharging the potential liabilities associated with drug-transporter interactions, the pharmaceutical industry has a growing requirement for routine and robust non-clinical assays. An assay was designed, optimised and validated to determine the in vitro inhibitory potency of new chemical entities (NCEs) towards human Pgp-mediated transport. [3H]-Digoxin was established as a suitable probe substrate by investigating its characteristics in the in vitro system (MDCKII-MDR1 cells grown in 24-multiwell inserts). The inhibitory potencies (apparent IC50) of known Pgp inhibitors astemizole, GF120918, ketoconazole, itraconazole, quinidine, verapamil and quinine were determined over at least a 1000-fold concentration range. Validation was carried out using manual and automatic techniques. [3H]-Digoxin was found to be stable and have good mass balance in the system. In contrast to [A-->B] transport, [3H]-digoxin [B-->A] transport rates were readily measured with good reproducibility. There was no evidence of saturation of transport up to 10 microM digoxin and 30 nM digoxin was selected for routine assay use, reflecting clinical therapeutic concentrations. IC50 values ranged over approximately 100-fold with excellent reproducibility. Results from manual and automated versions were in close agreement. This method is suitable for routine use to assess the in vitro inhibitory potency of NCEs on Pgp-mediated digoxin transport. Comparison of IC50 values against clinical interaction profiles for the probe inhibitors indicated the in vitro assay is predictive of clinical digoxin-drug interactions mediated via Pgp.

Cytotoxic and antibacterial angucycline- and prodigiosin-analogues from the deep-sea derived Streptomyces sp. SCSIO 11594.

PubMed

Song, Yongxiang; Liu, Guangfu; Li, Jie; Huang, Hongbo; Zhang, Xing; Zhang, Hua; Ju, Jianhua

2015-03-16

Two new C-glycoside angucyclines, marangucycline A (1) and marangucycline B (2), along with three known compounds, dehydroxyaquayamycin (3), undecylprodigiosin (4) and metacycloprodigiosin (5), have been identified as products of the deep-sea sediment strain Streptomyces sp. SCSIO 11594. New structures were elucidated on the basis of HRESIMS, 1D and 2D NMR analyses and comparisons to previously reported datasets. Compounds 2 and 4 displayed in vitro cytotoxicity against four cancer cell lines A594, CNE2, HepG2, MCF-7 superior to those obtained with cisplatin, the positive control. Notably, compound 2 bearing a keto-sugar displayed significant cytotoxicity against cancer cell lines with IC50 values ranging from 0.24 to 0.56 μM; An IC50 value of 3.67 μM was found when using non-cancerous hepatic cell line HL7702, demonstrating the cancer cell selectivity of 2. Compounds 1-3 were proved to have weak antibacterial activities against Enterococcus faecalis ATCC29212 with an MIC value of 64.0 μg/mL. Moreover, 3 displayed selective antibacterial activity against methicillin-resistant Staphylococcus epidermidis shhs-E1 with an MIC value of 16.0 μg/mL.

Antimicrobial and antileishmanial activities of diterpenoids isolated from the roots of Salvia deserta

USDA-ARS?s Scientific Manuscript database

Four diterpenes with biological activity were isolated from Salvia deserta roots. Taxodione was considered leishmanicidal, with IC50 value of 0.46 µg/mL against Leishimania donovani and also exhibited antifungal and antimicrobial activities. Ferruginol displayed the greatest activity (24-h IC50 1.29...

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

PubMed Central

Köck, Kathleen; Xie, Ying; Oberlies, Nicholas H.; Brouwer, Kim L. R.

2013-01-01

Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. PMID:23401473

A potent human anti-eotaxin1 antibody, CAT-213: isolation by phage display and in vitro and in vivo efficacy.

PubMed

Main, Sarah; Handy, Rachel; Wilton, Jane; Smith, Stephen; Williams, Liz; Fou, Leila Du; Andrews, John; Conroy, Louise A; May, Richard; Anderson, Ian; Vaughan, Tristan J

2006-12-01

The CC chemokine, eotaxin1 (CCL11) is an important regulator of eosinophil function. A marked accumulation of eosinophils in tissues has been correlated with the up-regulation of eotaxin1 expression in several diseases. The potential therapeutic value of neutralizing the effects of eotaxin1 in inflammatory conditions (including asthma) is under investigation. A human single-chain fragment variable antibody that neutralizes human eotaxin1 (CAT-212) was produced using antibody phage display and converted to whole antibody IgG4 format (CAT-213). A novel approach to lead optimization in which the length of the variable heavy chain complementarity-determining region 3 was reduced by one amino acid resulted in an increase in potency of >1000-fold compared with the parent anti-eotaxin1 antibody. The optimized antibody binds eotaxin1 with high affinity (80.4 pM) and specificity. CAT-213 and CAT-212 do not bind or neutralize a range of other human proteins including human monocyte chemoattractant protein-1, a structurally similar chemokine. CAT-213 neutralizes the ability of eotaxin1 to cause an increase in intracellular calcium signaling (with an IC(50) value of 2.86 nM), migration of CCR3-expressing L1.2 cells (with an IC(50) value of 0.48 nM), and inhibition of the eotaxin1-evoked shape change of human eosinophils in vitro (with an IC(50) of 0.71 nM). Local administration of CAT-213 to mice (1-100 microg kg(-1)) attenuates dermal eosinophilia induced by human eotaxin1, achieving >90% inhibition of eosinophil influx. CAT-213 may therefore be of therapeutic value in inhibiting diseases in which eotaxin1 and eosinophils play a major role, for example, severe asthma.

Antiproliferative Activity of Xanthones Isolated from Artocarpus obtusus

PubMed Central

Hashim, Najihah Mohd; Rahmani, Mawardi; Ee, Gwendoline Cheng Lian; Sukari, Mohd Aspollah; Yahayu, Maizatulakmal; Oktima, Winda; Ali, Abd Manaf; Go, Rusea

2012-01-01

An investigation of the chemical constituents in Artocarpus obtusus species led to the isolation of three new xanthones, pyranocycloartobiloxanthone A (1), dihydroartoindonesianin C (2), and pyranocycloartobiloxanthone B (3). The compounds were subjected to antiproliferative assay against human promyelocytic leukemia (HL60), human chronic myeloid leukemia (K562), and human estrogen receptor (ER+) positive breast cancer (MCF7) cell lines. Pyranocycloartobiloxanthone A (1) consistently showed strong cytotoxic activity against the three cell lines compared to the other two with IC50 values of 0.5, 2.0 and 5.0 μg/mL, respectively. Compound (1) was also observed to exert antiproliferative activity and apoptotic promoter towards HL60 and MCF7 cell lines at respective IC50 values. The compound (1) was not toxic towards normal cell lines human nontumorigenic breast cell line (MCF10A) and human peripheral blood mononuclear cells (PBMCs) with IC50 values of more than 30 μg/mL. PMID:21960741

Neopetrosiquinones A and B, sesquiterpene benzoquinones isolated from the deep-water sponge Neopetrosia cf. proxima.

PubMed

Winder, Priscilla L; Baker, Heather L; Linley, Patricia; Guzmán, Esther A; Pomponi, Shirley A; Diaz, M Cristina; Reed, John K; Wright, Amy E

2011-11-15

Two new marine-derived sesquiterpene benzoquinones which we designate as neopetrosiquinones A (1) and B (2), have been isolated from a deep-water sponge of the family Petrosiidae. The structures were elucidated on the basis of their spectroscopic data. Compounds 1 and 2 inhibit the in vitro proliferation of the DLD-1 human colorectal adenocarcinoma cell line with IC(50) values of 3.7 and 9.8 μM, respectively, and the PANC-1 human pancreatic carcinoma cell line with IC(50) values of 6.1 and 13.8 μM, respectively. Neopetrosiquinone A (1) also inhibited the in vitro proliferation of the AsPC-1 human pancreatic carcinoma cell line with an IC(50) value of 6.1 μM. The compounds are structurally related to alisiaquinone A, cyclozonarone, and xestoquinone. Copyright © 2011 Elsevier Ltd. All rights reserved.

Optimization of cell-based assays to quantify the anti-inflammatory/allergic potential of test substances in 96-well format.

PubMed

Chandrasekaran, C V; Edwin Jothie, R; Kapoor, Preeti; Gupta, Anumita; Agarwal, Amit

2011-06-01

There is an insistent need for robust, reliable, and optimized assays for screening novel drugs targeting the inflammatory/allergic markers. The present study describes about the optimization of eight cell-based assays utilizing mammalian cell lines in 96-well format for quantifying anti-inflammatory/allergic drug candidates. We estimated the inhibitory response of reference compounds: 1400 W dihydrochloride on LPS-induced NO release, celecoxib on LPS-induced PGE(2) production and dexamethasone on LPS-induced pro-inflammatory cytokines IL-1 beta, IL-6, and TNF-alpha production by J774A.1 murine macrophages. Response of acetylsalicylic acid and celecoxib was studied on A23187-induced TXB(2) production; captopril on A23187-stimulated LTB(4) production by HL-60 cells. Effect of ketotifen fumarate was evaluated on A23187-elicited histamine release by RBL-2H3 cells. Each experiment was repeated twice to assess the reproducibility and suitability of the assays by determining appropriate statistical tools viz. %CV, S/B and Z' factor. 1400 W dihydrochloride was capable of inhibiting LPS-induced NO levels (IC(50) = 10.7 μM). Dexamethasone attenuated LPS-induced IL-1 beta (IC(50) = 70 nM), IL-6 (IC(50) = 58 nM) and TNF-alpha (IC(50) = 44 nM) release, whereas celecoxib, a specific COX-2 inhibitor showed marked reduction in LPS-induced PGE(2) (IC(50) = 23 nM) production. Captopril (IC(50) = 48 μM) and ketotifen fumarate (IC(50) = 36.4 μM) demonstrated potent inhibitory effect against A23187-stimulated LTB(4) and histamine levels, respectively. Both acetylsalicylic acid (IC(50) = 5.5 μM) and celecoxib (IC(50) = 7.9 nM) exhibited concentration-dependent decrease in TXB(2) production. Results for all the cell assays from two experiments showed a Z' factor varying from 0.30 to 0.99; the S/B ratio ranged from 2.39 to 24.92; %CV ranged between 1.52 and 20.14. The results proclaim that these cell-based assays can act as ideal tools for screening new anti-inflammatory/anti-allergic compounds.

Quinolinic Carboxylic Acid Derivatives as Potential Multi-target Compounds for Neurodegeneration: Monoamine Oxidase and Cholinesterase Inhibition.

PubMed

Khan, Nehal A; Khan, Imtiaz; Abid, Syed M A; Zaib, Sumera; Ibrar, Aliya; Andleeb, Hina; Hameed, Shahid; Iqbal, Jamshed

2018-01-01

Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds. The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM. The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Potential of Polygonum cuspidatum Root as an Antidiabetic Food: Dual High-Resolution α-Glucosidase and PTP1B Inhibition Profiling Combined with HPLC-HRMS and NMR for Identification of Antidiabetic Constituents.

PubMed

Zhao, Yong; Chen, Martin Xiaoyong; Kongstad, Kenneth Thermann; Jäger, Anna Katharina; Staerk, Dan

2017-06-07

The worldwide increasing incidence of type 2 diabetes has fueled an intensified search for food and herbal remedies with preventive and/or therapeutic properties. Polygonum cuspidatum Siebold & Zucc. (Polygonaceae) is used as a functional food in Japan and South Korea, and it is also a well-known traditional antidiabetic herb used in China. In this study, dual high-resolution α-glucosidase and protein-tyrosine phosphatase 1B (PTP1B) inhibition profiling was used for the identification of individual antidiabetic constituents directly from the crude ethyl acetate extract and fractions of P. cuspidatum. Subsequent preparative-scale HPLC was used to isolate a series of α-glucosidase inhibitors, which after HPLC-HRMS and NMR analysis were identified as procyanidin B2 3,3″-O-digallate (3) and (-)-epicatechin gallate (5) with IC 50 values of 0.42 ± 0.02 and 0.48 ± 0.0004 μM, respectively, as well as a series of stilbene analogues with IC 50 value in the range from 6.05 ± 0.05 to 116.10 ± 2.04 μM. In addition, (trans)-emodin-physcion bianthrone (15b) and (cis)-emodin-physcion bianthrone (15c) were identified as potent PTP1B inhibitors with IC 50 values of 2.77 ± 1.23 and 7.29 ± 2.32 μM, respectively. These findings show that P. cuspidatum is a potential functional food for management of type 2 diabetes.

Inhibitory Effects of Commonly Used Herbal Extracts on UDP-Glucuronosyltransferase 1A4, 1A6, and 1A9 Enzyme Activities

PubMed Central

Mohamed, Mohamed-Eslam F.

2011-01-01

The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC50) and the volume in which the dose could be diluted to generate an IC50-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC50 value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC50 values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC50 values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC50-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions. PMID:21632963

Inhibition of the recombinant cattle tick Rhipicephalus (Boophilus) annulatus glutathione S-transferase.

PubMed

Guneidy, Rasha A; Shahein, Yasser E; Abouelella, Amira M K; Zaki, Eman R; Hamed, Ragaa R

2014-09-01

Rhipicephalus (Boophilus) annulatus is a bloodsucking ectoparasite that causes severe production losses in the cattle industry. This study aims to evaluate the in vitro effects of tannic acid, hematin (GST inhibitors) and different plant extracts (rich in tannic acid) on the activity of the recombinant glutathione S-transferase enzyme of the Egyptian cattle tick R. annulatus (rRaGST), in order to confirm their ability to inhibit the parasitic essential detoxification enzyme glutathione S-transferase. Extraction with 70% ethanol of Hibiscus cannabinus (kenaf flowers), Punica granatum (red and white pomegranate peel), Musa acuminata (banana peel) (Musaceae), Medicago sativa (alfalfa seeds), Tamarindus indicus (seed) and Cuminum cyminum (cumin seed) were used to assess: (i) inhibitory capacities of rRaGST and (ii) their phenolic and flavonoid contents. Ethanol extraction of red pomegranate peel contained the highest content of phenolic compounds (29.95mg gallic acid/g dry tissue) compared to the other studied plant extracts. The highest inhibition activities of rRaGST were obtained with kenaf and red pomegranate peel (P. granatum) extracts with IC50 values of 0.123 and 0.136mg dry tissue/ml, respectively. Tannic acid was the more effective inhibitor of rRaGST with an IC50 value equal to 4.57μM compared to delphinidine-HCl (IC50=14.9±3.1μM). Gossypol had a weak inhibitory effect (IC50=43.7μM), and caffeic acid had almost no effect on tick GST activity. The IC50 values qualify ethacrynic acid as a potent inhibitor of rRaGST activity (IC50=0.034μM). Cibacron blue and hematin showed a considerable inhibition effect on rRaGST activity, and their IC50 values were 0.13μM and 7.5μM, respectively. The activity of rRaGST was highest for CDNB (30.2μmol/min/mg protein). The enzyme had also a peroxidatic activity (the specific activity equals 26.5μmol/min/mg protein). Both tannic acid and hematin inhibited rRaGST activity non-competitively with respect to GSH and competitively with respect to CDNB. While red pomegranate extracts inhibited rRaGST activity competitively with respect to GSH, uncompetitive inhibition was observed with respect to CDNB. Copyright © 2014 Elsevier GmbH. All rights reserved.

Evaluation of the in vitro/in vivo potential of five berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) commonly used as herbal supplements to inhibit uridine diphospho-glucuronosyltransferase.

PubMed

Choi, Eu Jin; Park, Jung Bae; Yoon, Kee Dong; Bae, Soo Kyung

2014-10-01

In this study, we evaluated inhibitory potentials of popularly-consumed berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) as herbal supplements on UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in vitro. We also investigated the potential herb-drug interaction via UGT1A1 inhibition by blueberry in vivo. We demonstrated that these berries had only weak inhibitory effects on the five UGTs. Bilberry and elderberry had no apparent inhibitions. Blueberry weakly inhibited UGT1A1 with an IC50 value of 62.4±4.40 μg/mL and a Ki value of 53.1 μg/mL. Blueberry also weakly inhibited UGT2B7 with an IC50 value of 147±11.1 μg/mL. In addition, cranberry weakly inhibited UGT1A9 activity (IC50=458±49.7 μg/mL) and raspberry ketones weakly inhibited UGT2B7 activity (IC50=248±28.2 μg/mL). Among tested berries, blueberry showed the lowest IC50 value in the inhibition of UGT1A1 in vitro. However, the co-administration of blueberry had no effect on the pharmacokinetics of irinotecan and its active metabolite, SN-38, which was mainly eliminated via UGT1A1, in vivo. Our data suggests that these five berries are unlikely to cause clinically significant herb-drug interactions mediated via inhibition of UGT enzymes involved in drug metabolism. These findings should enable an understanding of herb-drug interactions for the safe use of popularly-consumed berries. Copyright © 2014 Elsevier Ltd. All rights reserved.

Impact of commercial precooking of common bean (Phaseolus vulgaris) on the generation of peptides, after pepsin-pancreatin hydrolysis, capable to inhibit dipeptidyl peptidase-IV.

PubMed

Mojica, Luis; Chen, Karen; de Mejía, Elvira González

2015-01-01

The objective of this research was to determine the bioactive properties of the released peptides from commercially available precook common beans (Phaseolus vulgaris). Bioactive properties and peptide profiles were evaluated in protein hydrolysates of raw and commercially precooked common beans. Five varieties (Black, Pinto, Red, Navy, and Great Northern) were selected for protein extraction, protein and peptide molecular mass profiles, and peptide sequences. Potential bioactivities of hydrolysates, including antioxidant capacity and inhibition of α-amylase, α-glucosidase, dipeptidyl peptidase-IV (DPP-IV), and angiotensin converting enzyme I (ACE) were analyzed after digestion with pepsin/pancreatin. Hydrolysates from Navy beans were the most potent inhibitors of DPP-IV with no statistical differences between precooked and raw (IC50 = 0.093 and 0.095 mg protein/mL, respectively). α-Amylase inhibition was higher for raw Red, Navy and Great Northern beans (36%, 31%, 27% relative to acarbose (rel ac)/mg protein, respectively). α-Glucosidase inhibition among all bean hydrolysates did not show significant differences; however, inhibition values were above 40% rel ac/mg protein. IC50 values for ACE were not significantly different among all bean hydrolysates (range 0.20 to 0.34 mg protein/mL), except for Red bean that presented higher IC50 values. Peptide molecular mass profile ranged from 500 to 3000 Da. A total of 11 and 17 biologically active peptide sequences were identified in raw and precooked beans, respectively. Peptide sequences YAGGS and YAAGS from raw Great Northern and precooked Pinto showed similar amino acid sequences and same potential ACE inhibition activity. Processing did not affect the bioactive properties of released peptides from precooked beans. Commercially precooked beans could contribute to the intake of bioactive peptides and promote health. © 2014 Institute of Food Technologists®

From Vegetable Waste to New Agents for Potential Health Applications: Antioxidant Properties and Effects of Extracts, Fractions and Pinocembrin from Glycyrrhiza glabra L. Aerial Parts on Viability of Five Human Cancer Cell Lines.

PubMed

Aiello, Francesca; Armentano, Biagio; Polerà, Nicoletta; Carullo, Gabriele; Loizzo, Monica Rosa; Bonesi, Marco; Cappello, Maria Stella; Capobianco, Loredana; Tundis, Rosa

2017-09-13

Glycyrrhiza glabra cultivation and harvesting produces substantial quantities of aerial parts as waste. With the aim to prospect an innovative valorization of these byproducts, the aerial parts were harvested in May and October and analyzed for their chemical profile, antioxidant properties, and effects on viability of five cancer cell lines. Pinocembrin was the main constituent. A significant protection of lipid peroxidation was observed with the May total extract (IC 50 of 4.2 ± 0.4 μg/mL at 30 min of incubation). The effects on viability of HeLa, MCF-7, MDA-MB-231, Caco-2, and PC3 human cancer cells were investigated. All samples shown a remarkable activity with IC 50 values below 25 μg/mL. Samples from plants harvested in May exhibited greater activity than those harvested in October. MCF-7 and HeLa were the most sensitive cells with IC 50 in the range 2.73-3.01 and 3.28-5.53 μg/mL, respectively. G. glabra aerial parts represent a good source of valuable products.

Synthesis, in vitro β-glucuronidase inhibitory potential and molecular docking studies of quinolines.

PubMed

Bano, Bilquees; Arshia; Khan, Khalid Mohammed; Kanwal; Fatima, Bibi; Taha, Muhammad; Ismail, Nor Hadiani; Wadood, Abdul; Ghufran, Mehreen; Perveen, Shahnaz

2017-10-20

In this study synthesis and β-glucuronidase inhibitory potential of 3/5/8 sulfonamide and 8-sulfonate derivatives of quinoline (1-40) are discussed. Studies reveal that all the synthetic compounds were found to have good inhibitory activity against β-glucuronidase. Nonetheless, compounds 1, 2, 5, 13, and 22-24 having IC 50 values in the range of 1.60-8.40 μM showed superior activity than the standard saccharic acid 1,4-lactone (IC 50  = 48.4 ± 1.25 μM). Moreover, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites. Structures of all the synthetic compounds were confirmed through 1 H NMR, EI-MS and HREI-MS spectroscopic techniques. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes.

PubMed

Nishimoto, Tomoyuki; Tozawa, Ryuichi; Amano, Yuichiro; Wada, Takeo; Imura, Yoshimi; Sugiyama, Yasuo

2003-12-01

TAK-475 is a squalene synthase inhibitor, rapidly metabolized to T-91485 in vivo. We investigated the myotoxicities of T-91485 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in a human rhabdomyosarcoma cell line, RD, and in human skeletal myocytes. In differentiated RD cells, T-91485, atorvastatin (ATV) and simvastatin acid (SIM) inhibited cholesterol biosynthesis, with IC(50) values of 36, 2.8 and 3.8 nM, respectively. ATV and SIM decreased the intracellular ATP content, with IC(25) values (concentrations giving a 25% decrease in intracellular ATP content) of 0.61 and 0.44 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis in RD cells, the IC(25) value exceeded 100 microM. In human skeletal myocytes, T-91485, ATV and SIM concentration-dependently inhibited cholesterol biosynthesis, with IC(50) values of 45, 8.6 and 8.4 nM, respectively. ATV and SIM decreased intracellular ATP content, with IC(25) values of 2.1 and 0.72 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis, the IC(25) value exceeded 100 microM. Myotoxicity induced by ATV was prevented by mevalonate or geranylgeranyl-PP, but not by squalene in skeletal cells. Furthermore, T-91485 attenuated the myotoxicity of ATV. These findings suggest that TAK-475 and T-91485 may not only be far from myotoxic, they may also decrease statin-induced myotoxicity in lipid-lowering therapy.

Naphthoquinones from the leaves of Rhinacanthus nasutus having acetylcholinesterase inhibitory and cytotoxic activities.

PubMed

Boonyaketgoson, Sirada; Rukachaisirikul, Vatcharin; Phongpaichit, Souwalak; Trisuwan, Kongkiat

2018-01-01

Four new naphthoquinones (1-4), named rhinacanthins S (1), T (2), U (3) and V (4), together with 13 known naphthoquinones were isolated from the leaf extract of Rhinacanthus nasutus. The structures of isolated compounds were elucidated by spectroscopic methods, especially 1D and 2D NMR spectroscopy and mass spectrometry. Rhinacanthin S (1) exhibited acetylcholinesterase inhibition activity with a % inhibition value of 48.04±3.25. The known rhinacanthin A (5) showed cytotoxicity against a MCF-7 cell line with an IC 50 value of 8.79μM, while rhinacanthin N (15) was active against the NCI-H187 cell line with an IC 50 =2.24μM and Vero cells (IC 50 =3.00μM). Copyright © 2017 Elsevier B.V. All rights reserved.

Cancer targeting potential of folate targeted nanocarrier under comparative influence of tretinoin and dexamethasone.

PubMed

Dhakad, Raghvendra Singh; Tekade, Rakesh Kumar; Jain, Narendra Kumar

2013-08-01

The objective of this investigation was aimed to explore the cancer targeting potential of folate conjugated dendrimer (polypropylene imine, PPI) under strategic influence of folate receptor up-regulators (all trans Retinoic acid, ATRA and Dexamethasone, DEXA). The folate conjugated dendrimer nanoconjugate (FPPI) was synthesized and characterized by FTIR, and (1)H-NMR spectroscopy. The cell line studies investigations were performed on MCF-7 cells. ATRA and DEXA caused 2.17 and 1.65 folds selective up-regulation of folate receptor respectively, when compared with untreated control, after 48 h of pretreatment. ATRA caused 50.47±2.11% more up regulation of folate receptor, than DEXA treated cell. Both up regulators showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC50 values of naked docetaxel (DTX) and DTX loaded dendrimer (PPI-DTX) were found to be 678.93±11.99 nM and 663.51±15.23 nM, respectively, while DTX loaded folate-anchored dendrimer (FPPI-DTX) showed a selectively lowered IC50 value of 468.56±20.86 nM. FPPI-DTX further showed a significant reduction in IC50 value in ATRA and DEXA pretreated cells, wherein IC50 values of 184.21 nM and 290.40±14.05 nM, respectively were observed. The study also concludes ATRA to be a superior receptor up-regulator as well as promoter of folate based targeting compared to DEXA.

Development and validation of a sensitive monoclonal antibody-based indirect competitive enzyme-linked immunosorbent assay for the determination of the aflatoxin M1 levels in milk.

PubMed

Peng, Dapeng; Yang, Bijia; Pan, Yuanhu; Wang, Yulian; Chen, Dongmei; Liu, Zhenli; Yang, Wenxiang; Tao, Yanfei; Yuan, Zonghui

2016-04-01

A sensitive monoclonal antibody (mAb) against aflatoxin M1 (AFM1) was generated to quickly monitor the AFM1 residues in milk. Then, a mAb-based indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) was established that utilizes simple sample preparation and clean-up methods. The obtained 3D8 mAb, which is an IgG1 isotype mAb, displayed an IC50 value of 64.75 ng L(-1) for AFM1 and did not exhibit measurable cross-reactivity with other aflatoxins and antibiotics. The decision limit (CCα, α = 1%), detection capability (CCβ, β = 5%), and LOQ value for the AFM1 matrix calibration method were 24 ng L(-1), 27.5 ng L(-1), and 35 ng L(-1) in the milk matrices, respectively. The AFM1 recovery ranged from 85.3% to 107.6%. The CVs were less than 13.8%. A positive correlation (r > 0.99) was observed between the ic-ELISA and HPLC-MS/MS results. This ic-ELISA would be a useful tool for screening the AFM1 residues in milk. Copyright © 2016 Elsevier Ltd. All rights reserved.

DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants

PubMed Central

Kaltenbach, Robert F.; Trainor, George; Getman, Daniel; Harris, Greg; Garber, Sena; Cordova, Beverly; Bacheler, Lee; Jeffrey, Susan; Logue, Kelly; Cawood, Pamela; Klabe, Ronald; Diamond, Sharon; Davies, Marc; Saye, Joanne; Jona, Janan; Erickson-Viitanen, Susan

2001-01-01

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC90). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC90s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC50 values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC50 values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir). PMID:11600351

Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1.

PubMed

Prior, Allan M; Yu, Xufen; Park, Eun-Jung; Kondratyuk, Tamara P; Lin, Yan; Pezzuto, John M; Sun, Dianqing

2017-12-15

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC 50  = 1.61 μM; 21, IC 50  = 3.05 μM; and 27, IC 50  = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC 50 ) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC 50  = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3'-nitrogen coordinating with the heme group. Copyright © 2017 Elsevier Ltd. All rights reserved.

Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells

PubMed Central

2012-01-01

Background Umbelliprenin is a natural compound, belonging to the class of sesquiterpene coumarins. Recently, umbelliprenin has attracted the researchers' attention for its antitumor activities against skin tumors. Its effect on lung cancer is largely unknown. The aim of our study was to investigate the effects of this natural compound, which is expected to have low adverse effects, on lung cancer. Methods The QU-DB large cell and A549 adenocarcinoma lung cancer cell lines were treated with umbelliprenin. IC50 values were estimated using methyl thiazolely diphenyl-tetrazolium bromide (MTT) assay, in which a decrease in MTT reduction can occur as a result of cell death or cell proliferation inhibition. To quantify the rate of cell death at IC50 values, flow cytometry using Annexin V-FITC (for apoptotic cells), and propidium iodide (for necrotic cells) dyes were employed. Results Data from three independent MTT experiments in triplicate revealed that IC50 values for QU-DB and A549 were 47 ± 5.3 μM and 52 ± 1.97 μM, respectively. Annexin V/PI staining demonstrated that umbelliprenin treatment at IC50 induced 50% cell death in QU-DB cells, but produced no significant death in A549 cells until increasing the umbelliprenin concentration to IC80. The pattern of cell death was predominantly apoptosis in both cell lines. When peripheral blood mononuclear cells were treated with 50 μM and less concentrations of umbelliprenin, no suppressive effect was observed. Conclusions We found cytotoxic/anti-proliferative effects of umbelliprenin against two different types of lung cancer cell lines. PMID:23351548

Casein Fermentate of Lactobacillus animalis DPC6134 Contains a Range of Novel Propeptide Angiotensin-Converting Enzyme Inhibitors▿

PubMed Central

Hayes, M.; Stanton, C.; Slattery, H.; O'Sullivan, O.; Hill, C.; Fitzgerald, G. F.; Ross, R. P.

2007-01-01

This work evaluated the angiotensin-converting-enzyme (ACE)-inhibitory activities of a bovine sodium caseinate fermentate generated using the proteolytic capabilities of the porcine small intestinal isolate Lactobacillus animalis DPC6134 (NCIMB deposit 41355). The crude 10-kDa L. animalis DPC6134 fermentate exhibited ACE-inhibitory activity of 85.51% (±15%) and had a 50% inhibitory concentration (IC50) of 0.8 mg protein/ml compared to captopril, which had an IC50 value of 0.005 mg/ml. Fractionation of the crude L. animalis DPC6134 fermentate by membrane filtration and reversed-phase high-performance liquid chromatography (HPLC) generated three bioactive fractions from a total of 72 fractions. Fractions 10, 19, and 43 displayed ACE-inhibitory activity percentages of 67.53 (±15), 83.71 (±19), and 42.36 (±11), respectively, where ACE inhibition was determined with 80 μl of the fractions with protein concentrations of 0.5 mg/ml. HPLC and mass spectrometry analysis identified 25 distinct peptide sequences derived from α-, β-, and κ-caseins. In silico predictions, based on the C-terminal tetrapeptide sequences, suggested that peptide NIPPLTQTPVVVPPFIQ, corresponding to β-casein f(73-89); peptide IGSENSEKTTMP, corresponding to αs1-casein f(201212); peptide SQSKVLPVPQ, corresponding to β-casein f(166-175); peptide MPFPKYPVEP, corresponding to β-casein f(124133); and peptide EPVLGPVRGPFP, corresponding to β-casein f(210-221), contained ACE-inhibitory activities. These peptides were chosen for chemical synthesis to confirm the ACE-inhibitory activity of the fractions. Chemically synthesized peptides displayed IC50 values in the range of 92 μM to 790 μM. Additionally, a simulated gastrointestinal digestion confirmed that the ACE-inhibitory 10-kDa L. animalis DPC6134 fermentation was resistant to a cocktail of digestive enzymes found in the gastrointestinal tract. PMID:17483275

Effects of alkylphenols on CYP1A and CYP3A expression in first spawning Atlantic cod (Gadus morhua).

PubMed

Hasselberg, Linda; Meier, Sonnich; Svardal, Asbjørn; Hegelund, Tove; Celander, Malin C

2004-05-12

Alkylphenols are continuously released into the ocean as a result of offshore oil production. Alkylphenols, including 4-tert-butylphenol (C4), 4n-pentylphenol (C5), 4n-hexylphenol (C6), and 4n-heptylphenol (C7), up to 237 ppb concentrations, have been detected in produced water from oil platforms. Previous studies have shown that alkylphenols induce vitellogenesis in fish. Atlantic cod (Gadus morhua) of both sexes were force-fed with various doses ranging between 0.02 and 80 ppm of a mixture of alkylphenols (C4:C5:C6:C7 ratio 1:1:1:1) or 5 ppm 17 beta-estradiol. We investigated effects on hepatic CYP1A and CYP3A protein expression in protein blots, using antibodies against scup (Stenotomus chrysops) CYP1A1 and rainbow trout (Oncorhynchus mykiss) CYP3A. There was a sexually dimorphic expression of CYP1A and CYP3A protein levels, with females expressing higher levels than males. Treatment of male Atlantic cod with 17 beta-estradiol resulted in increased CYP1A and CYP3A protein levels. Exposure to alkylphenols resulted in a dose-dependent increase of CYP1A and CYP3A protein expression in males, but not in females. However, this increase of CYP1A protein levels was not reflected on the CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activity, implying that alkylphenols inhibited the CYP1A enzyme activity in vivo. In vitro inhibition studies with pooled liver microsomes from Atlantic cod confirmed that the alkylphenols mixture efficiently inhibited the CYP1A activity (IC50=10 microM), although the inhibitory effect of each individual alkylphenol varied. The IC50 values for each individual alkylphenol on the CYP1A activity were, in a descending order of magnitude: [C7>C6>C5>C4], ranging from 12 to 300 microM with decreased length of the 4-alkyl chain. The effect of alkylphenols on the CYP3A activity in vitro in liver microsomes also was investigated, using the fluorescent 7-benzyloxy-4-[trifluoromethyl]-coumarin (BFC) as a diagnostic CYP3A substrate. The alkylphenol mixture inhibited CYP3A activity with IC50 value at 100 microM. The IC50 values for each individual alkylphenol on CYP3A activity were, in a descending order of magnitude: [C5>C6>C7>C4], ranging between 60 and 250 microM. Taken together, our results show that the alkylphenol mixture and 17 beta-estradiol resulted in elevated hepatic CYP1A and CYP3A expression in male Atlantic cod. The alkylphenol mixture strongly inhibited CYP1A activities, whereas it weakly inhibited CYP3A activity in Atlantic cod liver microsomes in vitro. In addition, 17 beta-estradiol was a weak inhibitor of CYP3A activity (IC50=75 microM) and did not notably inhibit the CYP1A activity in vitro.

In vitro antiplasmodial activity, macronutrients and trace metals in the medicinal plants: Phyllanthus spp. and Alpinia conchigera Griff.

PubMed

Haslinda, M S; Aiyub, Z; Bakar, N K A; Tohar, N; Musa, Y; Abdullah, N R; Ibrahim, H; Awang, K

2015-03-01

An antiplasmodial screening of Phyllanthus debilis and Phyllanthus urinaria was carried out. The medicinal plants were extracted and evaluated for in vitro antiplasmodial activity against D10 (chloroquine-sensitive, CQS) and Gombak A (chloroquine-resistant, CQR) strains of Plasmodium falciparum. The methanolic crudes from the soxhlet extraction were active against both strains however, P. urinaria (IC50 8.9 μg/ml with CQR strain) exhibited better anti-malarial activity compared to P. debilis (IC50 12.2 μg/ml with CQR strain). Furthermore, the methanolic crude of P. urinaria obtained by the cold extraction has good anti-malarial activity towards CQS (IC50 4.1 μg/ml). The concentration of macronutrients (calcium and magnesium) and trace metals (copper, manganese, iron and zinc) from three Phyllanthus species i.e. P. debilis Klein ex Wild., Phyllanthus niruri L., P. urinaria L. and Alpinia conchigera Griff. were determined using microwave digestion method and analyzed by Flame Atomic Absorption Spectroscopy. Standard Reference Material 1547 (peach leaves) was used to validate the method throughout this study. The recovery values were in the range of 80% to 120% which were in very good agreement with the certified values. The three Phyllanthus species and leaves of A. conchigera showed the highest concentration of calcium compared to other metals and macronutrients studied. The significant presence of all the important macronutrients and trace metals which are essential for human health and well-being substantiate their use medicinally in traditional practices.

8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase.

PubMed

Strydom, Belinda; Bergh, Jacobus J; Petzer, Jacobus P

2011-08-01

Recently it was reported that a series of 8-benzyloxycaffeine analogues are potent reversible inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to discover additional C8 oxy substituents of caffeine that lead to potent MAO inhibition, a series of related 8-aryl- and alkyloxycaffeine analogues were synthesized and their MAO-A and -B inhibition potencies were compared to those of the 8-benzyloxycaffeines. The results document that while the 8-substituted-oxycaffeine analogues inhibited both human MAO isoforms, they displayed a high degree of selectivity for MAO-B. 8-(3-Phenylpropoxy)caffeine, 8-(2-phenoxyethoxy)caffeine and 8-[(5-methylhexyl)oxy]caffeine were found to be the especially potent MAO-B inhibitors with IC(50) values ranging from 0.38 to 0.62 μM. These inhibitors are therefore 2.5-4.6 fold more potent MAO-B inhibitors than is 8-benzyloxycaffeine (IC(50) = 1.77 μM). It is also demonstrated that, analogous to 8-benzyloxycaffeine, halogen substitution on the phenyl ring of the C8 substituent significantly enhances MAO binding affinity. For example, the most potent MAO-B inhibitor of the present series is 8-[2-(4-bromophenoxy)ethoxy]caffeine with an IC(50) value of 0.166 μM. This study also reports possible binding orientations of selected oxy caffeines within the active site cavities of MAO-A and MAO-B. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Synthesis of 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone as a candidate anticancer against cervical (WiDr), colon (HeLa), and breast (T47d) cancer cell lines in vitro

NASA Astrophysics Data System (ADS)

Matsjeh, Sabirin; Swasono, Respati Tri; Anwar, Chairil; Solikhah, Eti Nurwening; Lestari, Endang

2017-03-01

The compound 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone have been synthesized through Claisen-Schmidt reaction from 2-hydroxyacetophenone and 2,4-dihydroxyacetophenone with 4-hydroxy-3-methoxy benzaldehida (vanillin) in aqueous KOH 40% and KSF montmorillonite as catalyst in methanol. All these products were characterized by FT-IR, TLC Scanner, GC-MS, MS-Direct, and 1H-NMR and 13C-NMR spectrometer. Both of these compounds were tested citotoxycity activity as an anticancer against cervical, colon, and breast cancer cells (Hela, WiDr, and T47D cell lines) using MTT assay in vitro. Dose series given test solution concentration on Hela, WiDr, and T47D cells started from 6,25; 25; 50 and 100 µg/mL with incubation treatment for 24 hours. The result of study showed that the 2',4-dihydroxy-3-methoxychalcone as bright yellow crystal with the melting point of 114-115 °C and the yield of 13.77% and the 2',4',4-trihydroxy-3-methoxychalcone as bright yellow crystals with the melting point of 195-197 °C and the yield of 6%. Other 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone also exhibited cytotoxic activity against the cancer cell lines, with the 2',4',4-trihydroxy-3-methoxychalcone showed greater activities than the 2',4-dihydroxy-3-methoxychalcone in WiDr cell lines. The 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone exhibited strong anticancer activities with IC50 value below 20 µg/mL. The activity of 2',4',4-trihydroxy-3-methoxychalcone showed the most active against Hela and WiDr cell lines with IC50 value 8.53 and 2.66 µg/mL respectively, than T47D cell lines with IC50 value 24.61 µg/mL. The test results cytotoxic of 2',4-dihydroxy-3-methoxychalcone showed the most active against Hela and WiDr cell lines with IC50 value 12.80, 19.57 µg/mL than T47D cell lines with IC50 value of 20.73 µg/mL. IC50 value indicated that 2',4-dihydroxy-3-methoxychalcone and 2',4',4-trihydroxy-3-methoxychalcone potential as inhibitors in Hela, WiDr and T47D cell lines.

Antiparasitic activity and effect of casearins isolated from Casearia sylvestris on Leishmania and Trypanosoma cruzi plasma membrane.

PubMed

Bou, Diego Dinis; Tempone, André G; Pinto, Érika G; Lago, João Henrique G; Sartorelli, Patricia

2014-04-15

Leishmaniasis and Chagas disease are infectious diseases caused by parasite Leishmania sp. and Trypanosoma cruzi, respectively, and are included among the most neglected diseases in several underdeveloped and developing countries, with an urgent demand for new drugs. Considering the antiparasitic potential of MeOH extract from leaves of Casearia sylvestris Sw. (Salicaceae), a bioguided fractionation was conducted and afforded four active clerodane diterpenes (casearins A, B, G, and J). The obtained results indicated a superior efficacy of tested casearins against trypomastigotes of T. cruzi, with IC50 values ranging from 0.53 to 2.77 μg/ml. Leishmania infantum promastigotes were also susceptible to casearins, with IC50 values in a range between 4.45 and 9.48 μg/ml. These substances were also evaluated for mammalian cytotoxicity against NCTC cells resulting in 50% cytotoxic concentrations (CC50) ranging from 1.46 to 13.76 μg/ml. Additionally, the action of casearins on parasite membranes was investigated using the fluorescent probe SYTOX Green. The obtained results demonstrated a strong interaction of casearins A and B to the plasma membrane of T. cruzi parasites, corroborating their higher efficacy against these parasites. In contrast, the tested casearins induced no alteration in the permeability of plasma membrane of Leishmania parasites, suggesting that biochemical differences between Leishmania and T. cruzi plasma membrane might have contributed to the target effect of casearins on trypomastigotes. Thus, considering the importance of studying novel and selective drug candidates against protozoans, casearins A, B, G, and J could be used as tools to future drug design studies. Copyright © 2014 Elsevier GmbH. All rights reserved.

EI-2128-1, a novel interleukin-1beta converting enzyme inhibitor produced by Penicillium sp. E-2128.

PubMed

Koizumi, Fumito; Agatsuma, Tsutomu; Ando, Katsuhiko; Kondo, Hidemasa; Saitoh, Yutaka; Matsuda, Yuzuru; Nakanishi, Satoshi

2003-11-01

EI-2128-1, a novel interleukin-1beta converting enzyme (ICE) inhibitor, was isolated from the culture broths of Penicillium sp. E-2128. EI-2128-1 selectively inhibited human recombinant ICE activity with IC50 value of 0.59 microM, without inhibiting elastase and cathepsin B. EI-2128-1 also inhibited mature interleukin-1beta secretion from THP-1 cells induced by LPS with IC50 value of 0.28 microM.

MMB-4 Inhibition of Aceylcholinesterase Is Similar across Species

DTIC Science & Technology

2014-11-01

version 5.4). An IC50 value was determined for AChE from each animal species by fitting the percent of AChE activity with respect to MMB 4 concentration...in GraphPad Prism (version 5) using a nonlinear regression dose response model for inhibition (normalized response with variable slope). Assessing the...Therefore, AChE activity and inhibition studies were carried out at 435 nm to reduce interference from MMB 4. Comparison of IC50 Values for MMB 4 with AChE

The anti-arthritic, anti-inflammatory, antioxidant activity and relationships with total phenolics and total flavonoids of nine South African plants used traditionally to treat arthritis.

PubMed

Elisha, Ishaku Leo; Dzoyem, Jean-Paul; McGaw, Lyndy Joy; Botha, Francien S; Eloff, Jacobus Nicolaas

2016-08-23

Oxidative stress predisposes the human and animal body to diseases like cancer, diabetes, arthritis, rheumatoid arthritis, atherosclerosis and chronic inflammatory disorders. Hence, this study seeks to determine the antioxidant, anti-inflammatory and anti-arthritic activities of acetone leaf extracts of nine South African medicinal plants that have been used traditionally to treat arthritis and inflammation. The anti-inflammatory activity of the extracts was determined by investigating inhibition of nitric oxide production in lipopolysaccharide activated RAW 264.7 macrophages as well as 15-lipoxygenase enzyme inhibition. An anti-protein denaturation assay was used to determine the anti-arthritic properties of the extracts. The antioxidant activity was determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethyl-benzthiazoline-6-sulfonic acid) (ABTS) radical scavenging assays and ferric reducing antioxidant power (FRAP). The total phenolic and total flavonoid concentration of extracts were determined by using standard methods. All extracts inhibited nitric oxide production in a dose-dependent manner in the LPS-stimulated RAW 264.7 macrophages. Extracts of Maesa lanceolata and Heteromorpha arborescens inhibited NO production by 99.16 % and 89.48 % at a concentration of 30 μg/ml respectively. Elaeodendron croceum and Calpurnia aurea extracts had strong activity against 15-lipoxygenase activity with IC50 values of 26.23 and 34.70 μg/ml respectively. Morus mesozygia and Heteromorpha arborescens extracts had good in vitro anti-arthritic activity with IC50 values of 11.89 and 53.78 μg/ml, the positive control diclofenac sodium had IC50 value of 32.37 μg/ml. The free radical scavenging activity of the extracts in DPPH assays ranged between 7.72 and 154.77 μg/ml. Trolox equivalent antioxidant capacity (TEAC) and FRAP values ranged from 0.06 to 1.32 and 0.06 to 0.99 respectively. Results from this study support the traditional use of the selected medicinal plants in the management of arthritis and other inflammatory conditions. The free radical scavenging capacity of the extracts may be related to an immune boosting potential.

Monoalkylated barbiturate derivatives: X-ray crystal structure, theoretical studies, and biological activities

NASA Astrophysics Data System (ADS)

Barakat, Assem; Al-Majid, Abdullah Mohammed; Soliman, Saied M.; Islam, Mohammad Shahidul; Ghawas, Hussain Mansur; Yousuf, Sammer; Choudhary, M. Iqbal; Wadood, Abdul

2017-08-01

Barbiturate derivatives are privileged structures with a broad range of pharmaceutical applications. We prepared a series of 5-monoalkylated barbiturate derivatives (3a-l) and evaluated, in vitro, their antioxidant (DPPH assay), and α-glucosidase inhibitory activities. Compounds 3a-l were synthesized via Michael addition. The structure of compound 3k was determined using X-ray single-crystal diffraction, and geometric parameters were calculated using density functional theory at the B3LYP/6-311G(d,p) level of theory. Further, the structural analysis of 3k were also investigated. Biological studies revealed that compounds 3b (IC50 = 133.1 ± 3.2 μM), 3d (IC50 = 305 ± 7.7 μM), and 3e (IC50 = 184 ± 2.3 μM) have potent α-glucosidase enzyme inhibitors and showed greater activity than the standard drug acarbose (IC50 = 841 ± 1.73 μM). Compounds 3a-3i were found to show weak antioxidant activity against 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals (IC50 = 91 ± 0.75 to 122 ± 1.0 μM) when tested against a standard antioxidant, gallic acid (IC50 = 23 ± 0.43 μM).

The activity of aminoglycoside antibiotics against Trypanosoma brucei.

PubMed

Maina, N W; Kinyanjui, B; Onyango, J D; Auma, J E; Croj, S

1998-01-01

The trypanocidal activity of four aminoglycosides was determined against Trypanosoma brucei in vitro. The drug activity in descending order, was as follows; paromomycin kanamycin>gentamycin > neomycin. Paromomycin bad the highest activity and the concentration that inhibited 50% of trypanosome growth (IC50) was 11.4microM. The effect of paromomycin on the causative agents of the East African form of sleeping sickness - T.b. rhodesiense KETRI 265, 2285, 2545, 2562 and EATRO 110,112, 1152 was subsequently assessed. Variations sensitivities between the trypanosome populations were observed and IC50 values ranging from 13.01 to 43.06 microM recorded. However, when paromomycin was administered intraperitoneally (i.p) at 500 mg/kg, it was not effective in curing mice infected with T. b. rhodesienseKETRI 2545 the most drug-sensitive isolate in vitro. Lack of in vivo activity may be because the trypanosome is an extracellular parasite. The pharmacokinetics of paromomycin in the mouse model need to be determined.

In Vitro Test for Potential Inhibitors of Plasmepsin II and IV as Anti-malarial Agents

NASA Astrophysics Data System (ADS)

Kang, Hee-Kyoung; Hwang, Soon-Wook; Kim, Do-Won; Breton, Vincent; Kim, Doman

Plasmepsins (PMs) are involved in the degradation of host cell hemoglobin during malaria infection. PM II and IV initiate the degradative process, and have been suggested as attractive targets for treatment of malaria. Previously, 30 compounds were identified by post-processing the results of a large docking screen of commercially available compounds using an automated procedure based on molecular dynamics refinement and binding free-energy estimation using MM-PBSA and MM-GBSA (Degliesposti et al., 2009). Presently, these were experimentally validated using an inhibition assay based on fluorescence resonance energy transfer (FRET) and hemoglobin substrate degradation. Remarkably, 26 of the 30 tested compounds were active as PM II inhibitors, with FRET IC50 values ranging from 4.3 nM to 1.8 μM. Also, IC50 value for PM IV inhibition ranged from 9.34 nM to 83 μM and the best inhibitor among the 30 compounds was compound 7. Hemoglobin degradation by recombinant PM II and IV was completely inhibited by 100 μM of compound 7. The newly identified compounds, and one in particular (compound 7), can inhibit PM II and IV activity and hemoglobin degradation in vitro. These experiments suggest an overall approach in the design of powerful and selective PM II and IV inhibitors.

In vitro antiplasmodial activity of benzophenones and xanthones from edible fruits of Garcinia species.

PubMed

Lyles, James T; Negrin, Adam; Khan, Shabana I; He, Kan; Kennelly, Edward J

2014-06-01

Species of Garcinia have been used to combat malaria in traditional African and Asian medicines, including Ayurveda. In the current study, we have identified antiplasmodial benzophenone and xanthone compounds from edible Garcinia species by testing for in vitro inhibitory activity against Plasmodium falciparum. Whole fruits of Garcinia xanthochymus, G. mangostana, G. spicata, and G. livingstonei were extracted and tested for antiplasmodial activity. Garcinia xanthochymus was subjected to bioactivity-guided fractionation to identify active partitions. Purified benzophenones (1-9) and xanthones (10-18) were then screened in the plasmodial lactate dehydrogenase assay and tested for cytotoxicity against mammalian (Vero) cells. The benzophenones guttiferone E (4), isoxanthochymol (5), and guttiferone H (6), isolated from G. xanthochymus, and the xanthones α-mangostin (15), β-mangostin (16), and 3-isomangostin (17), known from G. mangostana, showed antiplasmodial activity with IC50 values in the range of 4.71-11.40 µM. Artemisinin and chloroquine were used as positive controls and exhibited IC50 values in the range of 0.01-0.24 µM. The identification of antiplasmodial benzophenone and xanthone compounds from G. xanthochymus and G. mangostana provides evidence for the antiplasmodial activity of Garcinia species and warrants further investigation of these fruits as dietary sources of chemopreventive compounds. Georg Thieme Verlag KG Stuttgart · New York.

Inhibitory effects of psychotropic drugs on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes.

PubMed

Okada, Muneyoshi; Watanabe, Shinya; Matada, Takashi; Asao, Yoko; Hamatani, Ramu; Yamawaki, Hideyuki; Hara, Yukio

2013-01-01

Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTPγS). To elucidate mechanism for anticholinergic action, IC50 ratio, the ratio of IC50 for GTPγS-activated IK.ACh to CCh-induced IK.ACh, was calculated. Antipsychotics and antidepressants inhibited CCh-induced IK.ACh in a concentration-dependent manner. The IC50 values were as follows; chlorpromazine 0.53 μM, clozapine 0.06 μM, fluphenazine 2.69 μM, haloperidol 2.66 μM, sulpiride 42.3 μM, thioridazine 0.07 μM, amitriptyline 0.03 μM, imipramine 0.22 μM and maprotiline 1.81 μM. The drugs, except for sulpiride, inhibited GTPγS-activated IK.ACh with following IC50 values; chlorpromazine 1.71 μM, clozapine 14.9 μM, fluphenazine 3.55 μM, haloperidol 2.73 μM, thioridazine 1.90 μM, amitriptyline 7.55 μM, imipramine 7.09 μM and maprotiline 5.93 μM. The IC50 ratio for fluphenazine and haloperidol was close to unity. The IC50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress IK.ACh. Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel.

Inhibition of Procarcinogen Activating Enzyme CYP1A2 Activity and Free Radical Formation by Caffeic Acid and its Amide Analogues.

PubMed

Narongchai, Paitoon; Niwatananun, Kanokporn; Narongchai, Siripun; Kusirisin, Winthana; Jaikang, Churdsak

2016-01-01

Caffeic acid (CAF) and its amide analogues, ethyl 1-(3',4'-dihydroxyphenyl) propen amide (EDPA), phenethyl 1-(3',4'-dihydroxyphenyl) propen amide (PEDPA), phenmethyl 1- (3',4'-dihydroxyphenyl) propen amide (PMDPA) and octyl 1-(3',4'-dihydroxyphenyl) propen amide (ODPA) were investigated for the inhibition of procarcinogen activating enzyme. CYP1A2 and scavenging activity on formation of nitric oxide, superoxide anion, DPPH radical and hydroxyl radical. It was found that they inhibited CYP1A2 enzyme by uncompetitive inhibition. Apparent Ki values of CAF, EDPA, PEDPA, PMDPA and ODPA were 0.59, 0.39, 0.45, 0.75 and 0.80 µM, respectively suggesting potent inhibitors of CYP1A2. Moreover, they potentially scavenged nitric oxide radical with IC 50 values of 0.12, 0.22, 0.28, 0.22 and 0.51 mM, respectively. The IC50 values of superoxide anion scavenging were 0.20, 0.22, 0.44, 2.18 and 2.50 mM, respectively. 1, 1- diphenyl-2- picrylhydrazyl (DPPH) radical-scavenging ability, shown as IC50 values, were 0.41, 0.29, 0.30, 0.89 and 0.84 mM, respectively. Moreover, the hydroxyl radical scavenging in vitro model was shown as IC50 values of 23.22, 21.06, 17.10, 17.21 and 15.81 µM, respectively. From our results, caffeic acid and its amide analogues are in vitro inhibitors of human CYP1A2 catalytic activity and free radical formation. They may be useful to be developed as potential chemopreventive agents that block CYP1A2-mediated chemical carcinogenesis.

Synthesis of 4-thiazolidinone analogs as potent in vitro anti-urease agents.

PubMed

Rahim, Fazal; Zaman, Khalid; Ullah, Hayat; Taha, Muhammad; Wadood, Abdul; Javed, Muhammad Tariq; Rehman, Wajid; Ashraf, Muhammad; Uddin, Reaz; Uddin, Imad; Asghar, Humna; Khan, Aftab Ahmad; Khan, Khalid M

2015-12-01

4-Thiazolidinone analogs 1-20 were synthesized, characterized by (1)H NMR and EI-MS and investigated for urease inhibitory activity. All twenty (20) analogs exhibited varied degree of urease inhibitory potential with IC50 values 1.73-69.65μM, if compared with standard thiourea having IC50 value of 21.25±0.15μM. Among the series, eight derivatives 3, 6, 8, 10, 15, 17, 19, and 20 showed outstanding urease inhibitory potential with IC50 values of 9.34±0.02, 14.62±0.03, 8.43±0.01, 7.3±0.04, 2.31±0.002, 5.75±0.003, 8.81±0.005, and 1.73±0.001μM, respectively, which is better than the standard thiourea. The remaining analogs showed good to excellent urease inhibition. The binding interactions of these compounds were confirmed through molecular docking studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Bioactive compounds from Stuhlmannia moavi from the Madagascar dry forest.

PubMed

Liu, Yixi; Harinantenaina, Liva; Brodie, Peggy J; Bowman, Jessica D; Cassera, Maria B; Slebodnick, Carla; Callmander, Martin W; Randrianaivo, Richard; Rakotobe, Etienne; Rasamison, Vincent E; Applequist, Wendy; Birkinshaw, Chris; Lewis, Gwilym P; Kingston, David G I

2013-12-15

Bioassay-directed fractionation of the leaf and root extracts of the antiproliferative Madagascar plant Stuhlmannia moavi afforded 6-acetyl-5,8-dihydroxy-2-methoxy-7-methyl-1,4-naphthoquinone (stuhlmoavin, 1) as the most active compound, with an IC50 value of 8.1 μM against the A2780 human ovarian cancer cell line, as well as the known homoisoflavonoid bonducellin (2) and the stilbenoids 3,4,5'-trihydroxy-3'-methoxy-trans-stilbene (3), piceatannol (4), resveratrol (5), rhapontigenin (6), and isorhapontigenin (7). The structure elucidation of all compounds was based on NMR and mass spectroscopic data, and the structure of 1 was confirmed by a single crystal X-ray analysis. Compounds 2-5 showed weak A2780 activities, with IC50 values of 10.6, 54.0, 41.0, and 74.0 μM, respectively. Compounds 1-3 also showed weak antimalarial activity against Plasmodium falciparum with IC50 values of 23, 26, and 27 μM, respectively. Copyright © 2013 Elsevier Ltd. All rights reserved.

Novel Marine Phenazines as Potential Cancer Chemopreventive and Anti-Inflammatory Agents

PubMed Central

Kondratyuk, Tamara P.; Park, Eun-Jung; Yu, Rui; van Breemen, Richard B.; Asolkar, Ratnakar N.; Murphy, Brian T.; Fenical, William; Pezzuto, John M.

2012-01-01

Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects. PMID:22412812

Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities.

PubMed

Verlinden, Bianca K; Niemand, Jandeli; Snyman, Janette; Sharma, Shiv K; Beattie, Ross J; Woster, Patrick M; Birkholtz, Lyn-Marie

2011-10-13

A series of alkylated (bis)urea and (bis)thiourea polyamine analogues were synthesized and screened for antimalarial activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. All analogues showed growth inhibitory activity against P. falciparum at less than 3 μM, with the majority having effective IC(50) values in the 100-650 nM range. Analogues arrested parasitic growth within 24 h of exposure due to a block in nuclear division and therefore asexual development. Moreover, this effect appears to be cytotoxic and highly selective to malaria parasites (>7000-fold lower IC(50) against P. falciparum) and is not reversible by the exogenous addition of polyamines. With this first report of potent antimalarial activity of polyamine analogues containing 3-7-3 or 3-6-3 carbon backbones and substituted terminal urea- or thiourea moieties, we propose that these compounds represent a structurally novel class of antimalarial agents.

Isolation, Structural Modification, and HIV Inhibition of Pentacyclic Lupane-Type Triterpenoids from Cassine xylocarpa and Maytenus cuzcoina.

PubMed

Callies, Oliver; Bedoya, Luis M; Beltrán, Manuela; Muñoz, Alejandro; Calderón, Patricia Obregón; Osorio, Alex A; Jiménez, Ignacio A; Alcamí, José; Bazzocchi, Isabel L

2015-05-22

As a part of our investigation into new anti-HIV agents, we report herein the isolation, structure elucidation, and biological activity of six new (1-6) and 20 known (7-26) pentacyclic lupane-type triterpenoids from the stem of Cassine xylocarpa and root bark of Maytenus cuzcoina. Their stereostructures were elucidated on the basis of spectroscopic and spectrometric methods, including 1D and 2D NMR techniques. To gain a more complete understanding of the structural requirements for anti-HIV activity, derivatives 27-48 were prepared by chemical modification of the main secondary metabolites. Sixteen compounds from this series displayed inhibitory effects of human immunodeficiency virus type 1 replication with IC50 values in the micromolar range, highlighting compounds 12, 38, and 42 (IC50 4.08, 4.18, and 1.70 μM, respectively) as the most promising anti-HIV agents.

Aspergillus ficuum phytase activity is inhibited by cereal grain components.

PubMed

Bekalu, Zelalem Eshetu; Madsen, Claus Krogh; Dionisio, Giuseppe; Brinch-Pedersen, Henrik

2017-01-01

In the current study, we report for the first time that grain components of barley, rice, wheat and maize can inhibit the activity of Aspergillus ficuum phytase. The phytase inhibition is dose dependent and varies significantly between cereal species, between cultivars of barley and cultivars of wheat and between Fusarium graminearum infected and non-infected wheat grains. The highest endpoint level of phytase activity inhibition was 90%, observed with grain protein extracts (GPE) from F. graminearum infected wheat. Wheat GPE from grains infected with F. graminearum inhibits phytase activity significantly more than GPE from non-infected grains. For four barley cultivars studied, the IC50 value ranged from 0.978 ± 0.271 to 3.616 ± 0.087 mg×ml-1. For two non-infected wheat cultivars investigated, the IC50 values were varying from 2.478 ± 0.114 to 3.038 ± 0.097 mg×ml-1. The maize and rice cultivars tested gaveIC50 values on 0.983 ± 0.205 and 1.972 ± 0.019 mg×ml-1, respectively. After purifying the inhibitor from barley grains via Superdex G200, an approximately 30-35 kDa protein was identified. No clear trend for the mechanism of inhibition could be identified via Michaelis-Menten kinetics and Lineweaver-Burk plots. However, testing of the purified phytase inhibitor together with the A. ficuum phytase and the specific protease inhibitors pepstatin A, E64, EDTA and PMSF revealed that pepstatin A repealed the phytase inhibition. This indicates that the observed inhibition of A. ficuum phytase by cereal grain extracts is caused by protease activity of the aspartic proteinase type.

Aspergillus ficuum phytase activity is inhibited by cereal grain components

PubMed Central

Bekalu, Zelalem Eshetu; Madsen, Claus Krogh; Dionisio, Giuseppe

2017-01-01

In the current study, we report for the first time that grain components of barley, rice, wheat and maize can inhibit the activity of Aspergillus ficuum phytase. The phytase inhibition is dose dependent and varies significantly between cereal species, between cultivars of barley and cultivars of wheat and between Fusarium graminearum infected and non-infected wheat grains. The highest endpoint level of phytase activity inhibition was 90%, observed with grain protein extracts (GPE) from F. graminearum infected wheat. Wheat GPE from grains infected with F. graminearum inhibits phytase activity significantly more than GPE from non-infected grains. For four barley cultivars studied, the IC50 value ranged from 0.978 ± 0.271 to 3.616 ± 0.087 mg×ml-1. For two non-infected wheat cultivars investigated, the IC50 values were varying from 2.478 ± 0.114 to 3.038 ± 0.097 mg×ml-1. The maize and rice cultivars tested gaveIC50 values on 0.983 ± 0.205 and 1.972 ± 0.019 mg×ml-1, respectively. After purifying the inhibitor from barley grains via Superdex G200, an approximately 30–35 kDa protein was identified. No clear trend for the mechanism of inhibition could be identified via Michaelis-Menten kinetics and Lineweaver-Burk plots. However, testing of the purified phytase inhibitor together with the A. ficuum phytase and the specific protease inhibitors pepstatin A, E64, EDTA and PMSF revealed that pepstatin A repealed the phytase inhibition. This indicates that the observed inhibition of A. ficuum phytase by cereal grain extracts is caused by protease activity of the aspartic proteinase type. PMID:28472144

Synthesis and study of the α-amylase inhibitory potential of thiadiazole quinoline derivatives.

PubMed

Taha, Muhammad; Tariq Javid, Muhammad; Imran, Syahrul; Selvaraj, Manikandan; Chigurupati, Sridevi; Ullah, Hayat; Rahim, Fazal; Khan, Fahad; Islam Mohammad, Jahidul; Mohammed Khan, Khalid

2017-10-01

α-Amylase is a target for type-2 diabetes mellitus treatment. However, small molecule inhibitors of α-amylase are currently scarce. In the course of developing small molecule α-amylase inhibitors, we designed and synthesized thiadiazole quinoline analogs (1-30), characterized by different spectroscopic techniques such as 1 HNMR and EI-MS and screened for α-amylase inhibitory potential. Thirteen analogs 1, 2, 3, 4, 5, 6, 22, 23, 25, 26, 27, 28 and 30 showed outstanding α-amylase inhibitory potential with IC 50 values ranges between 0.002±0.60 and 42.31±0.17μM which is many folds better than standard acarbose having IC 50 value 53.02±0.12μM. Eleven analogs 7, 9, 10, 11, 12, 14, 15, 17, 18, 19 and 24 showed good to moderate inhibitory potential while seven analogs 8, 13, 16, 20, 21 and 29 were found inactive. Our study identifies novel series of potent α-amylase inhibitors for further investigation. Structure activity relationship has been established. Copyright © 2017 Elsevier Inc. All rights reserved.

Extraction, characterization and biological studies of phytochemicals from Mammea suriga.

PubMed

Poojary, Mahesha M; Vishnumurthy, Kanivebagilu A; Vasudeva Adhikari, Airody

2015-06-01

The present work involves extraction of phytochemicals from the root bark of a well-known Indian traditional medicinal plant, viz. Mammea suriga , with various solvents and evaluation of their in vitro antimicrobial and antioxidant activities using standard methods. The phytochemical analysis indicates the presence of some interesting secondary metabolites like flavonoids, cardiac glycosides, alkaloids, saponins and tannins in the extracts. Also, the solvent extracts displayed promising antimicrobial activity against Staphylococcus aureus , Bacillus subtilis and Cryptococcus neoformans with inhibition zone in a range of 20-33 mm. Further, results of their antioxidant screening revealed that aqueous extract (with IC 50 values of 111.51±1.03 and 31.05±0.92 μg/mL in total reducing power assay and DPHH radical scavenging assay, respectively) and ethanolic extract (with IC 50 values of 128.00±1.01 and 33.25±0.89 μg/mL in total reducing power assay and DPHH radical scavenging assay, respectively) were better antioxidants than standard ascorbic acid. Interestingly, FT-IR analysis of each extract established the presence of various biologically active functional groups in it.

Antimicrobial and antiparasitic activities of three algae from the northwest coast of Algeria.

PubMed

Ghania, Aissaoui; Nabila, Belyagoubi-Benhammou; Larbi, Belyagoubi; Elisabeth, Mouray; Philippe, Grellier; Mariem, Benmahdjoub; Khadidja, Kerzabi-Kanoun; Wacila, Benguedda-Rahal; Fawzia, Atik-Bekkara

2017-11-22

The objective of this study was to investigate the biological activities of Algerian algae, Sargassum vulgare, Cladostephus hirsutus and Rissoella verruculosa. Antimicrobial activity of the crude extracts and their fractions was assessed using the disc diffusion assay, the minimum inhibitory concentration and the minimum bactericidal concentration. Antiparasitic activity was studied in vitro against the blood stream forms of Trypanosoma brucei brucei and the intraerythrocytic stages of Plasmodium falciparum. Ethyl acetate (EA) fractions of the three tested algae showed more potent antimicrobial activity against S. aureus (7-14.5 mm) and B. cereus (7-10.75 mm), MIC values ranged from 0.9375 to 7.5 mg mL -1 and MBC values > 15 mg mL -1 . Concerning the antiparasitic activity, EA factions of S. vulgare (IC 50  = 9.3 μg mL -1 ) and R. verruculosa (IC 50  = 11.0 μg mL -1 ) were found to be more effective against T. brucei brucei, whereas the three EA fractions were little active against P. falciparum.

Discovery of antitumor ursolic acid long-chain diamine derivatives as potent inhibitors of NF-κB.

PubMed

Jiang, Wei; Huang, Ri-Zhen; Zhang, Jing; Guo, Tong; Zhang, Meng-Ting; Huang, Xiao-Chao; Zhang, Bin; Liao, Zhi-Xin; Sun, Jing; Wang, Heng-Shan

2018-05-08

A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing long-chain diamine moieties were designed and synthesized as well as evaluated the antitumor effects. These compounds exhibited significant inhibitory activity to the NF-κB with IC 50 values at micromolar concentrations in A549 lung cancer cell line. Among them, compound 8c exerted potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC 50 values ranged from 5.22 to 8.95 μM. Moreover, compound 8c successfully suppressed the migration of A549 cells. Related mechanism study indicated compound 8c caused cell cycle arrest at G1 phase and triggered apoptosis in A549 cells through blockage of NF-κB signalling pathway. Molecular docking study revealed that key interactions between 8c and the active site of NF-κB in which the bulky and strongly electrophilic group of long-chain diamine moieties were important for improving activity. Copyright © 2018 Elsevier Inc. All rights reserved.

Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors.

PubMed

Ravez, Séverine; Arsenlis, Stéphane; Barczyk, Amélie; Dupont, Anthony; Frédérick, Raphaël; Hesse, Stéphanie; Kirsch, Gilbert; Depreux, Patrick; Goossens, Laurence

2015-11-15

Inhibition of receptor tyrosine kinases (RTKs) continued to be a successful approach for the treatment of many types of human cancers and many potent small molecules kinase inhibitors have been discovered the last decade. In the present study, we describe the synthesis of thienopyrimidine derivatives and their pharmacological evaluation against nine kinases (EGFR, PDGFR-ß, c-Kit, c-Met, Src, Raf, VEGFR-1, -2 and -3). Most of the synthesized compounds showed from moderate to potent activities against c-Kit with IC50 values in the nanomolar range. Among them, 4-anilino(urea)thienopyrimidine analogs showed selectivity and potent c-Kit inhibition with IC50 values less than 6 nM. Docking simulation was performed for the most promising compound 9 into the c-Kit active site to determine the potential binding mode. This study reveal that the 4-anilino(urea)thienopyrimidine is an interesting scaffold to design novel potent and selective c-Kit inhibitors which may make promising candidates for cancers where c-Kit receptors are overexpressed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Food Polyphenol Apigenin Inhibits the Cytochrome P450 Monoxygenase Branch of the Arachidonic Acid Cascade.

PubMed

Steuck, Maryvonne; Hellhake, Stefan; Schebb, Nils Helge

2016-11-30

The product of cytochrome P450 monooxygenase (P450) ω-hydroxylation of arachidonic acid (AA), 20- hydroxyeicosatetraenoic acid (HETE), is a potent vasoconstrictor. Utilizing microsomes as well as individual CYP4 isoforms we demonstrate here that flavonoids can block 20-HETE formation. Apigenin inhibits CYP4F2 with an IC 50 value of 4.6 μM and 20-HETE formation in human liver and kidney microsomes at 2.4-9.8 μM. Interestingly, the structurally similar naringenin shows no relevant effect on the formation of 20-HETE. Based on these in vitro data, it is impossible to evaluate if a relevant blockade of 20-HETE formation can result in humans from intake of polyphenols with the diet. However, the potency of apigenin is comparable to those of P450 inhibitors such as ketoconazole. Moreover, an IC 50 value in the micromolar range is also described for the inhibition of CYP-mediated drug metabolism leading to food-drug interactions. The modulation of the arachidonic acid cascade by food polyphenols therefore warrants further investigation.

Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization

PubMed Central

Kong, Xiangqian; Qin, Jie; Li, Zeng; Vultur, Adina; Tong, Linjiang; Feng, Enguang; Rajan, Geena; Liu, Shien; Lu, Junyan; Liang, Zhongjie; Zheng, Mingyue; Zhu, Weiliang; Jiang, Hualiang; Herlyn, Meenhard; Liu, Hong; Marmorstein, Ronen; Luo, Cheng

2012-01-01

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-RafV600E mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we described the development of novel B-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC50 values were identified as B-RafV600E inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC50 values with selectivity for B-RafV600E in vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells. PMID:22875039

Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization.

PubMed

Kong, Xiangqian; Qin, Jie; Li, Zeng; Vultur, Adina; Tong, Linjiang; Feng, Enguang; Rajan, Geena; Liu, Shien; Lu, Junyan; Liang, Zhongjie; Zheng, Mingyue; Zhu, Weiliang; Jiang, Hualiang; Herlyn, Meenhard; Liu, Hong; Marmorstein, Ronen; Luo, Cheng

2012-09-28

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-Raf(V600E) mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we describe the development of novel B-Raf(V600E) selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC(50) values were identified as B-Raf(V600E) inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC(50) values with selectivity for B-Raf(V600E)in vitro and exclusive cytotoxicity against B-Raf(V600E) harboring cancer cells.

Studies on the secondary metabolites of a Pseudoalteromonas sp. isolated from sediments collected at the northeastern coast of Brazil.

PubMed

Arthaud, Isabelle D B; Rodrigues, Felipe A R; Jimenez, Paula C; Montenegro, Raquel C; Angelim, Alysson L; Maciel, Vânia M M; Silveira, Edilberto R; Freitas, Hozana P S; Sousa, Thiciana S; Pessoa, Otília D L; Lotufo, Tito M C; Costa-Lotufo, Letícia V

2012-02-01

Continuing search for anticancer compounds from the marine environment, we have studied microorganisms that inhabit intertidal sediments of the northeastern Brazilian coast. Of the 32 strains isolated, 13 were selected for biological evaluation of their crude extracts. The acetate extract obtained from a Gram-negative bacterium was strongly active against cancer cell lines with IC(50) values that ranged from 0.04 (HL60 leukemia cells) to 0.26 μg/ml (MDA MB-435 melanoma cells). The bacterium was identified as a Pseudoalteromonas sp. based on 16S rRNA gene sequencing. A bioassay-guided fractionation of the active extract led to the isolation of prodigiosin, a well-known tripyrrole red pigment with immunosuppressive and anticancer activities. Further experiments with ErbB-2 overexpressing cell lines, including HB4a-C3.6 (moderate overexpression), HB4a-C5.2 (high overexpression), and the parental HB4a cell line, were performed. Prodigiosin was moderately active toward HB4a cells with an IC(50) of 4.6 μg/ml, while it was 115 and 18 times more active toward HB4a-C3.6 cells (IC(50) of 0.04 μg/ml) and HB4a-C5.2 (IC(50) of 0.26 μg/ml) cells, respectively. These data suggest that, in spite of its previously described apoptosis-inducing properties, prodigiosin can selectively recognize cells overexpressing ErbB-2, which could be highly appealing in human breast cancer therapy. Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich.

Protective effect of unsymmetrical dichalcogenide, a novel antioxidant agent, in vitro and an in vivo model of brain oxidative damage.

PubMed

Prigol, Marina; Wilhelm, Ethel A; Schneider, Caroline C; Nogueira, Cristina W

2008-11-25

Unsymmetrical dichalcogenides, a class of organoselenium compounds, were screened for antioxidant activity in rat brain homogenates in vitro. Unsymmetrical dichalcogenides (1-3) were tested against lipid peroxidation induced by sodium nitroprusside (SNP) or malonate, and reactive species (RS) production induced by sodium azide in rat brain homogenates. Compounds 1 (without a substituent at the phenyl group), 2 (chloro substituent at the phenyl group bounded to the sulfur atom) and 3 (chloro substituent at the phenyl group bounded to the selenium atom) protected against lipid peroxidation induced by SNP. The IC50 values followed the order 3<2<1. Lipid peroxidation induced by malonate was also reduced by dichalcogenides 1, 2 and 3. The IC50 values were 3

Reversal of in vitro cellular MRP1 and MRP2 mediated vincristine resistance by the flavonoid myricetin.

PubMed

van Zanden, Jelmer J; de Mul, Anika; Wortelboer, Heleen M; Usta, Mustafa; van Bladeren, Peter J; Rietjens, Ivonne M C M; Cnubben, Nicole H P

2005-06-01

In the present study, the effects of myricetin on either MRP1 or MRP2 mediated vincristine resistance in transfected MDCKII cells were examined. The results obtained show that myricetin can inhibit both MRP1 and MRP2 mediated vincristine efflux in a concentration dependent manner. The IC50 values for cellular vincristine transport inhibition by myricetin were 30.5+/-1.7 microM for MRP1 and 24.6+/-1.3 microM for MRP2 containing MDCKII cells. Cell proliferation analysis showed that the MDCKII control cells are very sensitive towards vincristine toxicity with an IC50 value of 1.1+/-0.1 microM. The MDCKII MRP1 and MRP2 cells are less sensitive towards vincristine toxicity with IC50 values of 33.1+/-1.9 and 22.2+/-1.4 microM, respectively. In both the MRP1 and MRP2 cells, exposure to 25 microM myricetin enhances the sensitivity of the cells towards vincristine toxicity to IC50 values of 7.6+/-0.5 and 5.8+/-0.5 microM, respectively. The increase of sensitivity represents a reversal of the resistance towards vincristine as a result of MRP1 and MRP2 inhibition. Thus, the present study demonstrates the ability of the flavonoid myricetin to modulate MRP1 and MRP2 mediated resistance to the anticancer drug vincristine in transfected cells, indicating that flavonoids might be a valuable adjunct to chemotherapy to block MRP mediated resistance.

Compounds from Sedum caeruleum with antioxidant, anticholinesterase, and antibacterial activities.

PubMed

Bensouici, Chawki; Kabouche, Ahmed; Karioti, Anastasia; Öztürk, Mehmet; Duru, Mehmet Emin; Bilia, Anna Rita; Kabouche, Zahia

2016-01-01

This is the first study on the phytochemistry, antioxidant, anticholinesterase, and antibacterial activities of Sedum caeruleum L. (Crassulaceae). The objective of this study is to isolate the secondary metabolites and determine the antioxidant, anticholinesterase, and antibacterial activities of S. caeruleum. Six compounds (1-6) were isolated from the extracts of S. caeruleum and elucidated using UV, 1D-, 2D-NMR, and MS techniques. Antioxidant activity was investigated using DPPH(•), CUPRAC, and ferrous-ions chelating assays. Anticholinesterase activity was determined against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes using the Ellman method. Antibacterial activity was performed according to disc diffusion and minimum inhibitory concentration (MIC) methods. Isolated compounds were elucidated as ursolic acid (1), daucosterol (2), β-sitosterol-3-O-β-D-galactopyranoside (3), apigenin (4), apigetrin (5), and apiin (6). The butanol extract exhibited highest antioxidant activity in all tests (IC50 value: 28.35 ± 1.22 µg/mL in DPPH assay, IC50 value: 40.83 ± 2.24 µg/L in metal chelating activity, and IC50 value: 23.52 ± 0.44 µg/L in CUPRAC), and the highest BChE inhibitory activity (IC50 value: 36.89 ± 0.15 µg/L). Moreover, the chloroform extract mildly inhibited (MIC value: 80 µg/mL) the growth of all the tested bacterial strains. Ursolic acid (1), daucosterol (2), β-sitosterol-3-O-β-D-galactopyranoside (3), apigenin (4), apigetrin (5), and apiin (6) were isolated from Sedum caeruleum for the first time. In addition, a correlation was observed between antioxidant and anticholinesterase activities of bioactive ingredients of this plant.

Cytotoxic and Antibacterial Angucycline- and Prodigiosin- Analogues from the Deep-Sea Derived Streptomyces sp. SCSIO 11594

PubMed Central

Song, Yongxiang; Liu, Guangfu; Li, Jie; Huang, Hongbo; Zhang, Xing; Zhang, Hua; Ju, Jianhua

2015-01-01

Two new C-glycoside angucyclines, marangucycline A (1) and marangucycline B (2), along with three known compounds, dehydroxyaquayamycin (3), undecylprodigiosin (4) and metacycloprodigiosin (5), have been identified as products of the deep-sea sediment strain Streptomyces sp. SCSIO 11594. New structures were elucidated on the basis of HRESIMS, 1D and 2D NMR analyses and comparisons to previously reported datasets. Compounds 2 and 4 displayed in vitro cytotoxicity against four cancer cell lines A594, CNE2, HepG2, MCF-7 superior to those obtained with cisplatin, the positive control. Notably, compound 2 bearing a keto-sugar displayed significant cytotoxicity against cancer cell lines with IC50 values ranging from 0.24 to 0.56 μM; An IC50 value of 3.67 μM was found when using non-cancerous hepatic cell line HL7702, demonstrating the cancer cell selectivity of 2. Compounds 1–3 were proved to have weak antibacterial activities against Enterococcus faecalis ATCC29212 with an MIC value of 64.0 μg/mL. Moreover, 3 displayed selective antibacterial activity against methicillin-resistant Staphylococcus epidermidis shhs-E1 with an MIC value of 16.0 μg/mL. PMID:25786061

Potentiation by adrenaline of human platelet activation and the inhibition by the alpha-adrenergic antagonist nicergoline of platelet adhesion, secretion and aggregation.

PubMed

Lanza, F; Cazenave, J P; Beretz, A; Sutter-Bay, A; Kretz, J G; Kieny, R

1986-08-01

Adrenaline (1 to 10 microM) can induce the aggregation of human platelets suspended in citrated plasma but does not induce the aggregation of washed human platelets at doses as high as 1 mM, although these platelets respond normally to ADP, PAF-acether, collagen, arachidonic acid, thrombin, the endoperoxide analog U-46619 and the Ca2+ ionophore A23187. Adrenaline (0.5 microM) potentiates the aggregation and secretion induced by all the previous agonists in citrated platelet-rich plasma (cPRP) or in washed platelets. The activation by adrenaline of human platelets is mediated by alpha 2-adrenergic receptors, as demonstrated by inhibition with a series of adrenergic antagonists. The alpha-adrenergic antagonist nicergoline inhibits the activation of human platelets by adrenaline in the following situations: nicergoline inhibits the aggregation and secretion caused by adrenaline in cPRP (IC50 0.22 microM and 0.28 microM respectively); nicergoline inhibits the aggregation and secretion induced by the combination of adrenaline and each aggregating agent listed above in cPRP (IC50 ranging from 0.1 to 2.5 microM) or in washed platelets (IC50 ranging from 0.1 to 0.8 microM); nicergoline inhibits the binding of 3H-yohimbine to washed human platelets (IC50 0.26 microM); the intravenous administration of nicergoline (0.5 mg/kg per day) to patients inhibits significantly the ex vivo response of their platelets to adrenaline in cPRP. High concentrations of nicergoline also inhibit the aggregation and secretion induced by the aggregating agents listed above in cPRP (IC50 range 108 to 670 microM) and in washed platelets (IC50 range 27 to 140 microM) and the adhesion of platelets to collagen-coated surfaces. This latter effect is not mediated through blockade of alpha-adrenoceptors. A possible role of adrenaline in platelet activation in vivo could justify the use of nicergoline (Sermion), an alpha-adrenergic antagonist in combination therapy to prevent arterial thrombosis.

Cytotoxicity of fucosterol containing fraction of marine algae against breast and colon carcinoma cell line

PubMed Central

Khanavi, Mahnaz; Gheidarloo, Razieh; Sadati, Nargess; Ardekani, Mohammad Reza Shams; Nabavi, Seyed Mohammad Bagher; Tavajohi, Shohreh; Ostad, Seyed Nasser

2012-01-01

Context: Marine algae produce different secondary metabolites with a wide range of biological activities. Many studies have been achieved on the screening of biological effects of marine organisms and a lot of active compounds were isolated and characterized. Aims: In an attempt to find cytotoxic compound of hexane fraction, isolation, identification, and cytotoxicity of active compound of this fraction were performed. Materials and Methods: In this study, total methanolic (70%) extract and partition fractions of hexane, chloroform (CHCl3), ethyl acetate (EtOAc), and MeOH–H2O of Sargassum angustifolium, Chondria dasyphylla, and Ulva flexuosa, collected from coastlines of the Persian Gulf in south of Iran, were studied against colon carcinoma (HT-29), colorectal adenocarcinoma (Caco-2), breast ductal carcinoma (T47D), and Swiss mouse embryo fibroblast (NIH 3T3) cell lines by MTT assay. Statistical Analysis Used: IC50 (median growth inhibitory concentration) values were calculated by Sigmaplot (10) software. Results: Hexane fraction of Chondria dasyphylla (IC50 82.26 ± 4.09 μg/ml) and MeOH-H2O fraction of Ulva flexuosa (IC50 116.92 ± 8.58 μg/ml) showed cytotoxic activity against proliferation of T47D cells. Hexane fraction of Sargassum angustifolium was also observed for cytotoxicity against T47D and HT-29 cell lines (IC50 166.42 ± 26.7 and 190.24 ± 52.8 μg/ml), respectively. An investigation of a component from the hexane fraction of Sargassum angustifolium yielded a steroidal metabolite, fucosterol, with cytotoxicity in T47D and HT29 (IC50 27.94 ± 9.3 and 70.41 ± 7.5 μg/ml). Conclusions: These results indicated that fucosterol, the most abundant phytosterol in brown algae, is responsible for cytotoxic effect of this extract against breast and colon carcinoma cell lines. PMID:22438665

Toxicity evaluation and prediction of toxic chemicals on activated sludge system.

PubMed

Cai, Bijing; Xie, Li; Yang, Dianhai; Arcangeli, Jean-Pierre

2010-05-15

The gaps of data for evaluating toxicity of new or overloaded organic chemicals on activated sludge system resulted in the requirements for methodology of toxicity estimation. In this study, 24 aromatic chemicals typically existed in the industrial wastewater were selected and classified into three groups of benzenes, phenols and anilines. Their toxicity on activated sludge was then investigated. Two indexes of IC(50-M) and IC(50-S) were determined respectively from the respiration rates of activated sludge with different toxicant concentration at mid-term (24h) and short-term (30min) time intervals. Experimental results showed that the group of benzenes was the most toxic, followed by the groups of phenols and anilines. The values of IC(50-M) of the tested chemicals were higher than those of IC(50-S). In addition, quantitative structure-activity relationships (QSARs) models developed from IC(50-M) were more stable and accurate than those of IC(50-S). The multiple linear models based on molecular descriptors and K(ow) presented better reliability than single linear models based on K(ow). Among these molecular descriptors, E(lumo) was the most important impact factor for evaluation of mid-term toxicity. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors.

PubMed

Li, Yingjun; Yu, Yang; Jin, Kun; Gao, Lixin; Luo, Tongchuan; Sheng, Li; Shao, Xin; Li, Jia

2014-09-01

A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC50=1.18-8.01 μg/mL) and PTP1B (IC50=0.85-8.75 μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC50 values of 1.18 and 0.85 μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na3VO4 (IC50=0.93 μg/mL) and oleanolic acid (IC50=0.85 μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor. Copyright © 2014 Elsevier Ltd. All rights reserved.

Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug-Induced Torsades de Pointes: A Meta-Analysis.

PubMed

Lehmann, David F; Eggleston, William D; Wang, Dongliang

2018-03-01

Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (C max ) is used during drug development to screen out chemical entities likely to cause TdP. To validate the use of the hERG IC50:C max ratio to predict TdP risk from a culprit drug by its correlation with TdP incidence. Medline (between 1966 and March 2017) was accessed for hERG IC50 and C max values from the antihistamine, fluoroquinolone, and antipsychotic classes to identify cases of drug-induced TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer. Inclusion criteria for TdP cases were provision of an ECG tracing that demonstrated QTc prolongation with TdP and normal serum values of potassium, calcium, and magnesium. Cases reported in patients with a prior rhythm disturbance and those involving a drug interaction were excluded. The Meta-Analysis of Observational Studies in Epidemiology checklist was used for epidemiological data extraction by two authors. Negligible risk drugs were defined by an hERG IC50:C max ratio that correlated with less than a 5% chance of one TdP event for every 100 million exposures (relative risk [RR] 1.0). The hERG IC50:C max ratio correlated with TdP risk (0.312; 95% confidence interval 0.205-0.476, p<0.0001), a ratio of 80 (RR 1.0). The RR from olanzapine is on par with loratadine; ziprasidone is comparable with ciprofloxacin. Drugs with an RR greater than 50 include astemizole, risperidone, haloperidol, and thioridazine. The hERG IC50:C max ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:C max ratio for clinical decision making in instances of drug selection where TdP risk is a concern. © 2018 Pharmacotherapy Publications, Inc.

Phytochemical profile and biological activities of Deverra tortuosa (Desf.)DC.: a desert aromatic shrub widespread in Northern Region of Saudi Arabia.

PubMed

Guetat, Arbi; Boulila, Abdennacer; Boussaid, Mohamed

2018-04-16

The present study describes the chemical composition of the essential oil of different plant parts of Devrra tortuosa; in vivo and in vitro biological activities of plant extract and essential oils. Apiol was found to be the major component of the oil (between 65.73% and 74.41%). The best antioxidant activities were observed for the oil of flowers (IC50 = 175 μg/ml). The samples of stems and roots exhibit lower antioxidant activity (IC50 = 201 μg/ml and 182 μg/ml, respectively). The values of IC50 showed that the extracts of methanol exhibit the highest antioxidants activities (IC50 = 64.8 102 μg/ml). EOs showed excellent antifungal activity against yeasts with low azole susceptibilities (i.e. Malassezia spp. and Candida krusei). The MIC values of oils varied between 2.85 mg/mL and 27 mg/mL. The obtained results also showed that the plant extracts inhibited the germination and the shoot and root growth of Triticum æstivum seedlings.

Chemical and biological analyses of the essential oils and main constituents of Piper species.

PubMed

Moura do Carmo, Dominique F; Amaral, Ana Cláudia Fernandes; Machado, Gérzia M C; Leon, Leonor Laura; Silva, Jefferson Rocha de Andrade

2012-02-13

The essential oils obtained from leaves of Piper duckei and Piper demeraranum by hydrodistillation were analyzed by gas chromatography-mass spectrometry. The main constituents found in P. demeraranum oil were limonene (19.3%) and β-elemene (33.1%) and in P. duckei oil the major components found were germacrene D (14.7%) and trans-caryophyllene (27.1%). P. demeraranum and P. duckei oils exhibited biological activity, with IC(50) values between 15 to 76 μg mL(-1) against two Leishmania species, P. duckei oil being the most active. The cytotoxicity of the essential oils on mice peritoneal macrophage cells was insignificant, compared with the toxicity of pentamidine. The main mono- and sesquiterpene, limonene (IC(50) = 278 μM) and caryophyllene (IC(50) = 96 μM), were tested against the strains of Leishmania amazonensis, and the IC(50) values of these compounds were lower than those found for the essential oils of the Piper species. The HET-CAM test was used to evaluate the irritation potential of these oils as topical products, showing that these oils can be used as auxiliary medication in cases of cutaneous leishmaniasis, with less side effects and lower costs.

Synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory potential of hydrazide based Schiff bases.

PubMed

Rahim, Fazal; Ullah, Hayat; Taha, Muhammad; Wadood, Abdul; Javed, Muhammad Tariq; Rehman, Wajid; Nawaz, Mohsan; Ashraf, Muhammad; Ali, Muhammad; Sajid, Muhammad; Ali, Farman; Khan, Muhammad Naseem; Khan, Khalid Mohammed

2016-10-01

To discover multifunctional agents for the treatment of Alzheimer's disease, a series of hydrazide based Schiff bases were designed and synthesized based on multitarget-directed strategy. We have synthesized twenty-eight analogs of hydrazide based Schiff bases, characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase and butyrylcholinesterase inhibition. All compounds showed varied degree of acetylcholinesterase and butyrylcholinesterase inhibition when compared with standard Eserine. Among the series, compounds 10, 3 and 24 having IC50 values 4.12±0.01, 8.12±0.01 and 8.41±0.06μM respectively showed potent acetylcholinesterase inhibition when compared with Eserine (IC50=0.85±0.0001μM). Three compounds 13, 24 and 3 having IC50 values 6.51±0.01, 9.22±0.07 and 37.82±0.14μM respectively showed potent butyrylcholinesterase inhibition by comparing with eserine (IC50=0.04±0.0001μM). The remaining compounds also exhibited moderate to weak inhibitory potential. Structure activity relationship has been established. Through molecular docking studies the binding interaction was confirmed. Copyright © 2016 Elsevier Inc. All rights reserved.

In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients.

PubMed

Engdal, Silje; Nilsen, Odd Georg

2009-07-01

The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P-450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c-DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6-beta-OH-testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC(50): 73 microg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 microg/mL, respectively). All IC(50) values were high compared with those determined for crude extracts of other herbal remedies. The IC(50)/IC(25) ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non-inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. Copyright 2009 John Wiley & Sons, Ltd.

Microbial toxicity of the insensitive munitions compound, 2,4-dinitroanisole (DNAN), and its aromatic amine metabolites.

PubMed

Liang, Jidong; Olivares, Christopher; Field, Jim A; Sierra-Alvarez, Reyes

2013-11-15

2,4-Dinitroanisole (DNAN) is an insensitive munitions compound considered to replace conventional explosives such as 2,4,6-trinitrotoluene (TNT). DNAN undergoes facile microbial reduction to 2-methoxy-5-nitroaniline (MENA) and 2,4-diaminoanisole (DAAN). This study investigated the inhibitory effect of DNAN, MENA, and DAAN toward various microbial targets in anaerobic (acetoclastic methanogens) and aerobic (heterotrophs and nitrifiers) sludge, and the bioluminescent bacterium, Aliivibrio fischeri, used in the Microtox assay. Aerobic heterotrophic and nitrifying batch experiments with DAAN could not be performed because the compound underwent extensive autooxidation in these assays. DNAN severely inhibited methanogens, nitrifying bacteria, and A. fischeri (50% inhibitory concentrations (IC50) ranging 41-57μM), but was notably less inhibitory to aerobic heterotrophs (IC50>390 μM). Reduction of DNAN to MENA and DAAN lead to a marked decrease in methanogenic inhibition (i.e., DNAN>MENA≈DAAN). Reduction of all nitro groups in DNAN also resulted in partial detoxification in assays with A. fischeri. In contrast, reduction of a single nitro group did not alter the inhibitory impact of DNAN toward A. fischeri and nitrifying bacteria given the similar IC50 values determined for MENA and DNAN in these assays. These results indicate that reductive biotransformation could reduce the inhibitory potential of DNAN. Copyright © 2013 Elsevier B.V. All rights reserved.

Antileishmanial and antitrypanosomal activities of the 8-aminoquinoline tafenoquine.

PubMed

Yardley, Vanessa; Gamarro, Francisco; Croft, Simon L

2010-12-01

The 8-aminoquinoline tafenoquine showed significant in vitro activity against Leishmania species, including L. donovani amastigotes in macrophages, with 50% inhibitory concentrations (IC(50)s) between 0.1 and 4.0 μM for both pentavalent antimony (SbV)-sensitive and SbV-resistant strains and by oral administration in BALB/c mice, with 50% effective dose (ED(50)) values of 1.2 to 3.5 mg/kg for 5 days. Tafenoquine was less active against intracellular Trypanosoma cruzi amastigotes, with an IC(50) of 21.9 μM.

Antileishmanial and Antitrypanosomal Activities of the 8-Aminoquinoline Tafenoquine ▿

PubMed Central

Yardley, Vanessa; Gamarro, Francisco; Croft, Simon L.

2010-01-01

The 8-aminoquinoline tafenoquine showed significant in vitro activity against Leishmania species, including L. donovani amastigotes in macrophages, with 50% inhibitory concentrations (IC50s) between 0.1 and 4.0 μM for both pentavalent antimony (SbV)-sensitive and SbV-resistant strains and by oral administration in BALB/c mice, with 50% effective dose (ED50) values of 1.2 to 3.5 mg/kg for 5 days. Tafenoquine was less active against intracellular Trypanosoma cruzi amastigotes, with an IC50 of 21.9 μM. PMID:20837750

Biological activities of aqueous extract from Cinnamomum porrectum

NASA Astrophysics Data System (ADS)

Farah, H. Siti; Nazlina, I.; Yaacob, W. A.

2013-11-01

A study was carried out to evaluate biological activities of an extract obtained from Cinnamomum porrectum under reflux using water. Aqueous extract of Cinnamomum porrectum was tested for antibacterial activity against six Gram-positive and eight Gram-negative bacteria as well as MRSA. The results confirmed that the aqueous extract of Cinnamomum porrectum was bactericidal. Cytotoxic tests on Vero cell culture revealed that Cinnamomum porrectum was non-toxic which IC50 value higher than 0.02 mg/mL. Antiviral activity was tested based on the above IC50 values together with the measured EC50 values to obtain Therapeutic Index. The result showed that Cinnamomum porrectum has the ability to inhibit viral replication of HSV-1 in Vero cells.

Chemical Constituents of Muehlenbeckia tamnifolia (Kunth) Meisn (Polygonaceae) and Its In Vitro α-Amilase and α-Glucosidase Inhibitory Activities.

PubMed

Torres-Naranjo, María; Suárez, Alirica; Gilardoni, Gianluca; Cartuche, Luis; Flores, Paola; Morocho, Vladimir

2016-11-02

The phytochemical investigation of Muehlenbeckia tamnifolia , collected in Loja-Ecuador, led to the isolation of nine known compounds identified as: lupeol acetate ( 1 ); cis - p -coumaric acid ( 2 ); lupeol ( 3 ); β-sitosterol ( 4 ) trans - p -coumaric acid ( 5 ); linoleic acid ( 6 ) (+)-catechin ( 7 ); afzelin ( 8 ) and quercitrin ( 9 ). The structures of the isolated compounds were determined based on analysis of NMR and MS data, as well as comparison with the literature. The hypoglycemic activity of crude extracts and isolated compounds was assessed by the ability to inhibit α-amylase and α-glucosidase enzymes. The hexane extract showed weak inhibitory activity on α-amylase, with an IC 50 value of 625 µg·mL -1 , while the other extracts and isolated compounds were inactive at the maximum dose tested. The results on α-glucosidase showed more favorable effects; the hexanic and methanolic extracts exhibited a strong inhibitory activity with IC 50 values of 48.22 µg·mL -1 and 19.22 µg·mL -1 , respectively. Four of the nine isolated compounds exhibited strong inhibitory activity with IC 50 values below 8 µM, much higher than acarbose (377 uM). Linoleic acid was the most potent compound (IC 50 = 0.42 µM) followed by afzelin, (+)-catechin and quercitrin.

In vitro metabolic interactions between black cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450 2D6 and 3A4

PubMed Central

Li, Jinghu; Gödecke, Tanja; Chen, Shao-Nong; Imai, Ayano; Lankin, David; Farnsworth, Norman R.; Pauli, Guido F.; van Breemen, Richard B.; Nikolić, Dejan

2012-01-01

Women who experience hot flashes as a side effect of tamoxifen therapy often try botanical remedies such as black cohosh to alleviate these symptoms. Since pharmacological activity of tamoxifen is dependent on the metabolic conversion into active metabolites by the action of cytochromes P450 2D6 and 3A4, the objective of this study was to evaluate whether black cohosh extracts can inhibit formation of active tamoxifen metabolites and possibly reduce its clinical efficacy.At 50 µg/ml, a 75% ethanolic extract of black cohosh inhibited formation of 4-hydroxy-tamoxifen by 66.3%, N-desmethyl tamoxifen by 74.6% and α-hydroxy tamoxifen by 80.3%. In addition, using midazolam and dextromethorphan as probe substrates, this extract inhibited CYP3A4 and CYP2D6 with IC50 values of 16.5 and 50.1 µg/ml, respectively.Eight triterpene glycosides were identified as competitive CYP3A4 inhibitors with IC50 values ranging from 2.3–5.1 µM, while the alkaloids protopine and allocryptopine were identified as competitive CYP2D6 inhibitors with Ki values of 78 and 122 nM, respectively.The results of this study suggests that co-administration of black cohosh with tamoxifen might interfere with the clinical efficacy of this drug. However, additional clinical studies are needed to determine the clinical significance of these in vitro results. PMID:21827327

Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies.

PubMed

Cao, Lei; Kwara, Awewura; Greenblatt, David J

2017-12-01

Excessive exposure to acetaminophen (APAP, paracetamol) can cause liver injury through formation of a reactive metabolite that depletes hepatic glutathione and causes hepatocellular oxidative stress and damage. Generation of this metabolite is mediated by Cytochrome-P450 (CYP) isoforms, mainly CYP2E1. A number of naturally occurring flavonoids can mitigate APAP-induced hepatotoxicity in experimental animal models. Our objective was to determine the mechanism of these protective effects and to evaluate possible human applicability. Two flavonoids, luteolin and quercetin, were evaluated as potential inhibitors of eight human CYP isoforms, of six UDP-glucuronosyltransferase (UGT) isoforms and of APAP glucuronidation and sulfation. The experimental model was based on in-vitro metabolism by human liver microsomes, using isoform-specific substrates. Luteolin and quercetin inhibited human CYP isoforms to varying degrees, with greatest potency towards CYP1A2 and CYP2C8. However, 50% inhibitory concentrations (IC 50 values) were generally in the micromolar range. UGT isoforms were minimally inhibited. Both luteolin and quercetin inhibited APAP sulfation but not glucuronidation. Inhibition of human CYP activity by luteolin and quercetin occurred with IC 50 values exceeding customary in-vivo human exposure with tolerable supplemental doses of these compounds. The findings indicate that luteolin and quercetin are not likely to be of clinical value for preventing or treating APAP-induced hepatotoxicity. © 2017 Royal Pharmaceutical Society.

Three new triterpenoids from Ganoderma theaecolum.

PubMed

Liu, Li-Ying; Yan, Zheng; Kang, Jie; Chen, Ruo-Yun; Yu, De-Quan

2017-09-01

Three new triterpenoids (1-3), together with four known triterpenoids (4-7), were isolated from the fruiting bodies of Ganoderma theaecolum. Their structures were elucidated on the basis of their spectroscopic data and chemical evidence. Compounds 4 and 6 exhibited antitumor activities against H460 cells with IC 50 values of 22.4 and 43.1 μM, respectively. And the cytotoxic activities of compounds 4 and 5 against MDA-MB-231 cancer cell lines were assayed with IC 50 values of 49.1 and 75.8 μM, respectively.

Two new triterpenoid saponins from the aerial parts of Anemone taipaiensis.

PubMed

Li, Hui; Wang, Xiao-Yang; Wang, Xia-Yin; Hua, Dong; Liu, Yang; Tang, Hai-Feng

2015-05-01

Phytochemical study on the aerial parts of Anemone taipaiensis for the first time led to the isolation of two new oleanane-type triterpenoid saponins 1 and 2, together with four known saponins (3-6). Their structures were elucidated by extensive spectroscopic analysis and chemical evidences. Saponins 2-4 exhibited cytotoxicity against human glioblastoma U251MG cell line with IC50 values ranging from 1.56 to 80.62 μM.

5-Bromo-2-aryl benzimidazole derivatives as non-cytotoxic potential dual inhibitors of α-glucosidase and urease enzymes.

PubMed

Arshad, Tanzila; Khan, Khalid Mohammed; Rasool, Najma; Salar, Uzma; Hussain, Shafqat; Asghar, Humna; Ashraf, Mohammed; Wadood, Abdul; Riaz, Muhammad; Perveen, Shahnaz; Taha, Muhammad; Ismail, Nor Hadiani

2017-06-01

On the basis of previous report on promising α-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC 50 =8.15±0.03-354.67±0.19μM) as compared to standard thiourea (IC 50 =21.25±0.15μM). It is worth mentioning that derivatives 7 (IC 50 =12.07±0.05μM), 8 (IC 50 =10.57±0.12μM), 11 (IC 50 =13.76±0.02μM), 14 (IC 50 =15.70±0.12μM) and 22 (IC 50 =8.15±0.03μM) were found to be more potent inhibitors than standard. All compounds were also evaluated for cytotoxicity towards 3T3 mouse fibroblast cell line and found to be completely non-toxic. Previously benzimidazole 1-25 were also showed α-glucosidase inhibitory potential. In silico studies were performed on the lead molecules i.e.2, 7, 8, 11, 14, and 22, in order to rationalize the binding interaction of compounds with the active site of urease enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

Different Culture Metabolites of the Red Sea Fungus Fusarium equiseti Optimize the Inhibition of Hepatitis C Virus NS3/4A Protease (HCV PR).

PubMed

Hawas, Usama W; Al-Farawati, Radwan; Abou El-Kassem, Lamia T; Turki, Adnan J

2016-10-20

The endophytic fungus Fusarium equiseti was isolated from the brown alga Padina pavonica , collected from the Red Sea. The fungus was identified by its morphology and 18S rDNA. Cultivation of this fungal strain in biomalt-peptone medium led to isolation of 12 known metabolites of diketopeprazines and anthraquinones. The organic extract and isolated compounds were screened for their inhibition of hepatitis C virus NS3/4A protease (HCV PR). As a result, the fungal metabolites showed inhibition of HCV protease (IC 50 from 19 to 77 μM), and the fungus was subjected to culture on Czapek's (Cz) media, with a yield of nine metabolites with potent HCV protease inhibition ranging from IC 50 10 to 37 μM. The Cz culture extract exhibited high-level inhibition of HCV protease (IC 50 27.6 μg/mL) compared to the biomalt culture extract (IC 50 56 μg/mL), and the most potent HCV PR isolated compound (Griseoxanthone C, IC 50 19.8 μM) from the bio-malt culture extract showed less of an inhibitory effect compared to isolated ω-hydroxyemodin (IC 50 10.7 μM) from the optimized Cz culture extract. Both HCV PR active inhibitors ω-hydroxyemodin and griseoxanthone C were considered as the lowest selective safe constituents against Trypsin inhibitory effect with IC 50 48.5 and 51.3 μM, respectively.

The in-vitro evaluation of antibacterial, antifungal and cytotoxic properties of Marrubium vulgare L. essential oil grown in Tunisia

PubMed Central

2011-01-01

Background In order to validate its antiseptic and anticancer properties with respect to traditional uses, we have screened for the first time the antimicrobial activity of aerial parts of M. vulgare L. essential oil against different pathogenic microorganisms and the cytotoxic activity against HeLa cell lines. Methods The agar disk diffusion method was used to study the antibacterial activity of M. vulgare essential oil against 12 bacterial and 4 fungi strains. The disc diameters of zone of inhibition (DD), the minimum inhibitory concentrations (MIC) and the concentration inhibiting 50% (IC50) were investigated to characterize the antimicrobial activities of this essential oil. The in vitro cytotoxicity of M. vulgare essential oil was examined using a modified MTT assay; the viability and the IC50 were used to evaluate this test. Results The antimicrobial activity of the essential oil was investigated in order to evaluate its efficacy against the different tested microorganisms. The present results results showed a significant activity against microorganisms especially Gram (+) bacteria with inhibition zones and minimal inhibitory concentration values in the range of 6.6-25.2 mm and 1120-2600 μg/ml, respectively, whereas Gram (-) bacteria exhibited a higher resistance. As far as the antifungal activity, among four strains tested, Botrytis cinerea exhibited the strongest activity with inhibition zones of 12.6 mm. However, Fusarium solani, Penicillium digitatum and Aspergillus niger were less sensitive to M. vulgare essential oil. About the citotoxicity assay, this finding indicate the capability of this essential oil to inhibited the proliferation of HeLa cell lines under some conditions with IC50 value of 0.258 μg/ml. Conclusion This investigation showed that the M. vulgare essential oil has a potent antimicrobial activity against some Gram (+) pathogenic bacteria and Botrytis cinerea fungi. The present studies confirm the use of this essential oil as anticancer agent. Further research is required to evaluate the practical values of therapeutic applications. PMID:21936887

The in-vitro evaluation of antibacterial, antifungal and cytotoxic properties of Marrubium vulgare L. essential oil grown in Tunisia.

PubMed

Zarai, Zied; Kadri, Adel; Ben Chobba, Ines; Ben Mansour, Riadh; Bekir, Ahmed; Mejdoub, Hafedh; Gharsallah, Néji

2011-09-21

In order to validate its antiseptic and anticancer properties with respect to traditional uses, we have screened for the first time the antimicrobial activity of aerial parts of M. vulgare L. essential oil against different pathogenic microorganisms and the cytotoxic activity against HeLa cell lines. The agar disk diffusion method was used to study the antibacterial activity of M. vulgare essential oil against 12 bacterial and 4 fungi strains. The disc diameters of zone of inhibition (DD), the minimum inhibitory concentrations (MIC) and the concentration inhibiting 50% (IC50) were investigated to characterize the antimicrobial activities of this essential oil. The in vitro cytotoxicity of M. vulgare essential oil was examined using a modified MTT assay; the viability and the IC50 were used to evaluate this test. The antimicrobial activity of the essential oil was investigated in order to evaluate its efficacy against the different tested microorganisms. The present results results showed a significant activity against microorganisms especially Gram (+) bacteria with inhibition zones and minimal inhibitory concentration values in the range of 6.6-25.2 mm and 1120-2600 μg/ml, respectively, whereas Gram (-) bacteria exhibited a higher resistance. As far as the antifungal activity, among four strains tested, Botrytis cinerea exhibited the strongest activity with inhibition zones of 12.6 mm. However, Fusarium solani, Penicillium digitatum and Aspergillus niger were less sensitive to M. vulgare essential oil. About the citotoxicity assay, this finding indicate the capability of this essential oil to inhibited the proliferation of HeLa cell lines under some conditions with IC50 value of 0.258 μg/ml. This investigation showed that the M. vulgare essential oil has a potent antimicrobial activity against some Gram (+) pathogenic bacteria and Botrytis cinerea fungi. The present studies confirm the use of this essential oil as anticancer agent. Further research is required to evaluate the practical values of therapeutic applications.

Metal transport capabilities of anticancer copper chelators.

PubMed

Gaál, Anikó; Orgován, Gábor; Mihucz, Victor G; Pape, Ian; Ingerle, Dieter; Streli, Christina; Szoboszlai, Norbert

2018-05-01

In the present study, several Cu chelators [2,2'-biquinoline, 8-hydroxiquinoline (oxine), ammonium pyrrolidinedithiocarbamate (APDTC), Dp44mT, dithizone, neocuproine] were used to study Cu uptake, depletion and localization in different cancer cell lines. To better understand the concentration dependent fluctuations in the Cu intracellular metal content and Cu-dependent in vitro antiproliferative data, the conditional stability constants of the Cu complex species of the investigated ligands were calculated. Each investigated chelator increased the intracellular Cu content on HT-29 cells causing Cu accumulation depending on the amount of the free Cu(II). Copper accumulation was 159 times higher for Dp44mT compared to the control. Investigating a number of other transition metals, intracellular accumulation of Cd was observed only for two chelators. Intracellular Zn content slightly decreased (cca. 10%) for MCF-7 cells, while a dramatic decrease was observed on MDA-MB-231 ones (cca. 50%). A similar decrease was observed for HCT-116, while Zn depletion for HT-29 corresponded to cca. 20%. The IC 50 values were registered for the investigated four cell lines at increasing external Cu(II) concentration, namely, MDA-MB-231 cells had the lowest IC 50 values for Dp44mT ranging between 7 and 35 nM. Thus, Zn depletion could be associated with lower IC 50 values. Copper depletion was observed for all ligands being less pronounced for Dp44mT and neocuproine. Copper localization and its colocalization with Zn were determined by μ-XRF imaging. Loose correlation (0.57) was observed for the MCF-7 cells independently of the applied chelator. Similarly, a weak correlation (0.47) was observed for HT-29 cells treated with Cu(II) and oxine. Colocalization of Cu and Zn in the nucleus of HT-29 cells was observed for Dp44mT (correlation coefficient of 0.85). Copyright © 2018 Elsevier GmbH. All rights reserved.

A SYBR Green 1-based in vitro test of susceptibility of Ghanaian Plasmodium falciparum clinical isolates to a panel of anti-malarial drugs.

PubMed

Quashie, Neils B; Duah, Nancy O; Abuaku, Benjamin; Quaye, Lydia; Ayanful-Torgby, Ruth; Akwoviah, George A; Kweku, Margaret; Johnson, Jacob D; Lucchi, Naomi W; Udhayakumar, Venkatachalam; Duplessis, Christopher; Kronmann, Karl C; Koram, Kwadwo A

2013-12-17

Based on report of declining efficacy of chloroquine, Ghana shifted to the use of artemisinin-based combination therapy (ACT) in 2005 as the first-line anti-malarial drug. Since then, there has not been any major evaluation of the efficacy of anti-malarial drugs in Ghana in vitro. The sensitivity of Ghanaian Plasmodium falciparum isolates to anti-malarial drugs was, therefore, assessed and the data compared with that obtained prior to the change in the malaria treatment policy. A SYBR Green 1 fluorescent-based in vitro drug sensitivity assay was used to assess the susceptibility of clinical isolates of P. falciparum to a panel of 12 anti-malarial drugs in three distinct eco-epidemiological zones in Ghana. The isolates were obtained from children visiting health facilities in sentinel sites located in Hohoe, Navrongo and Cape Coast municipalities. The concentration of anti-malarial drug inhibiting parasite growth by 50% (IC50) for each drug was estimated using the online program, ICEstimator. Pooled results from all the sentinel sites indicated geometric mean IC50 values of 1.60, 3.80, 4.00, 4.56, 5.20, 6.11, 10.12, 28.32, 31.56, 93.60, 107.20, and 8952.50 nM for atovaquone, artesunate, dihydroartemisin, artemether, lumefantrine, amodiaquine, mefloquine, piperaquine, chloroquine, tafenoquine, quinine, and doxycycline, respectively. With reference to the literature threshold value indicative of resistance, the parasites showed resistance to all the test drugs except the artemisinin derivatives, atovaquone and to a lesser extent, lumefantrine. There was nearly a two-fold decrease in the IC50 value determined for chloroquine in this study compared to that determined in 2004 (57.56 nM). This observation is important, since it suggests a significant improvement in the efficacy of chloroquine, probably as a direct consequence of reduced drug pressure after cessation of its use. Compared to that measured prior to the change in treatment policy, significant elevation of artesunate IC50 value was observed. The results also suggest the existence of possible cross-resistance among some of the test drugs. Ghanaian P. falciparum isolates, to some extent, have become susceptible to chloroquine in vitro, however the increasing trend in artesunate IC50 value observed should be of concern. Continuous monitoring of ACT in Ghana is recommended.

Evaluation of metal concentration and antioxidant, antimicrobial, and anticancer potentials of two edible mushrooms Lactarius deliciosus and Macrolepiota procera.

PubMed

Kosanić, Marijana; Ranković, Branislav; Rančić, Aleksandar; Stanojković, Tatjana

2016-07-01

This study is designed for the determination of metal concentrations, antioxidant, antimicrobial, and anticancer potential of two edible mushrooms Lactarius deliciosus and Macrolepiota procera. Concentrations of nine metals are determined and all metals are present in the allowable concentrations in the tested mushrooms except Cd in M. procera. Antioxidant activity was evaluated by free radical scavenging and reducing power. M. procera extract had more potent free radical scavenging activity (IC 50 =311.40 μg/mL) than L. deliciosus extract. Moreover, the tested extracts had effective reducing power. The total content of phenol in the extracts was examined using Folin-Ciocalteu reagent and obtained values expressed as pyrocatechol equivalents. Further, the antimicrobial potential was determined with a microdilution method on 15 microorganisms. Among the tested species, extract of L. deliciosus showed a better antimicrobial activity with minimum inhibitory concentration values ranging from 2.5 mg/mL to 20 mg/mL. Finally, the cytotoxic activity was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method on human epithelial carcinoma HeLa cells, human lung carcinoma A549 cells, and human colon carcinoma LS174 cells. Extract of both mushrooms expressed similar cytotoxic activity with IC 50 values ranging from 19.01 μg/mL to 80.27 μg/mL. Copyright © 2016. Published by Elsevier B.V.

Antimicrobial peptides isolated from Phyllomedusa nordestina (Amphibia) alter the permeability of plasma membrane of Leishmania and Trypanosoma cruzi.

PubMed

Pinto, Erika Gracielle; Pimenta, Daniel C; Antoniazzi, Marta Maria; Jared, Carlos; Tempone, Andre Gustavo

2013-12-01

Nature has provided inspiration for Drug Discovery studies and amphibian secretions have been used as a promising source of effective peptides which could be explored as novel drug prototypes for neglected parasitic diseases as Leishmaniasis and Chagas disease. In this study, we isolated four antimicrobial peptides (AMPs) from Phyllomedusa nordestina secretion, and studied their effectiveness against Leishmania (L.) infantum and Trypanosoma cruzi. The antiparasitic fractions were characterized by mass spectrometry and Edman degradation, leading to the identification of dermaseptins 1 and 4 and phylloseptins 7 and 8. T. cruzi trypomastigotes were susceptible to peptides, showing IC50 values in the range concentration of 0.25-0.68 μM. Leishmania (L.) infantum showed susceptibility to phylloseptin 7, presenting an IC50 value of 10 μM. Except for phylloseptin 7 which moderate showed cytotoxicity (IC50=34 μM), the peptides induced no cellular damage to mammalian cells. The lack of mitochondrial oxidative activity of parasites detected by the MTT assay, suggested that peptides were leishmanicidal and trypanocidal. By using the fluorescent probe SYTOX(®) Green, dermaseptins 1 and 4 and phylloseptins 7 and 8 showed time-dependent plasma membrane permeabilization of T. cruzi; phylloseptin 7 also showed a similar effect in Leishmania parasites. The present study demonstrates for the first time that AMPs target the plasma membrane of Leishmania and T. cruzi, leading to cellular death. Considering the potential of amphibian peptides against protozoan parasites and the reduced mammalian toxicity, they may contribute as scaffolds for drug design studies. Copyright © 2013 Elsevier Inc. All rights reserved.

In vitro cytotoxicity testing of 30 reference chemicals to predict acute human and animal toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barile, F.A.; Arjun, S.; Borges, L.

1991-03-11

This study was conducted in cooperation with the Scandinavian Society of Cell Toxicology, as part of the Multicenter Evaluation for In Vitro Cytotoxicity (MEIC), and was designed to develop an in vitro model for predicting acute human and animal toxicity. The technique relies on the ability of cultured transformed rat lung epithelial cells (L2) to incorporate radiolabled amino acids into newly synthesized proteins in the absence or presence of increasing doses of the test chemical, during a 24-hr incubation. IC50 values were extrapolated from the dose-response curves after linear regression analysis. Human toxic blood concentrations estimated from rodent LD50 valuesmore » suggest that our experimental IC50's are in close correlation with the former. Validation of the data by the MEIC committee shows that our IC50 values predicted human lethal dosage as efficient as rodent LD50's. It is anticipated that this and related procedures may supplement or replace currently used animal protocols for predicting human toxicity.« less

Synthesis and study of thiocarbonate derivatives of choline as potential inhibitors of acetylcholinesterase.

PubMed

Boyle, N A; Talesa, V; Giovannini, E; Rosi, G; Norton, S J

1997-09-12

Fourteen alkyl and aryl thiocarbonate derivatives of choline were synthesized and studied as potential inhibitors of acetylcholinesterase (AChE). Twelve of the compounds inhibited AChEs derived from calf forebrain, human red blood cells, and octopus brain ranging from low to moderately high inhibition potency. The concentration of each inhibitory compound giving 50% inhibition of enzyme activity (IC50 values, which ranged from 1 x 10(-2) to 8 x 10(-7) M) was determined and is reported; inhibitor constants (Ki values) for the most inhibitory compounds, (1-pentylthiocarbonyl)choline chloride and (1-heptylthiocarbonyl)choline chloride, were calculated from kinetic data and are also reported. The inhibitors are competitive with substrate, and they are not hydrolyzed by the AChE activities. Certain of these new compounds may provide direction for the development of new drugs that have anticholinesterase activity and may be used for the treatment of Alzheimer's disease.

Antimicrobial and cytotoxic constituents from native Cameroonian medicinal plant Hypericum riparium.

PubMed

Tala, Michel Feussi; Talontsi, Ferdinand Mouafo; Zeng, Guang-Zhi; Wabo, Hippolyte Kamdem; Tan, Ning-Hua; Spiteller, Michael; Tane, Pierre

2015-04-01

Bioassay guided fractionation of Hypericum riparium leaves extract has resulted in the isolation and characterization of three new compounds namely chipericumin E (1), hyperenone C (3), and hyperixanthone (5), together with twenty known compounds. Their structures were elucidated based on comprehensive interpretation of spectroscopic and spectrometric data. Compounds 1-4, and 6-8 displayed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and cytotoxic effects on the human gastric cell line BGC-823 with IC50 values ranging from 6.54 to 18.50μM. Copyright © 2015 Elsevier B.V. All rights reserved.

Report: Comparison of qualitative, quantitative analysis and antioxidant potential between wild and cultivated Borago officinalis leaves from palestine.

PubMed

Abu-Qaoud, Hassan; Shawarb, Nuha; Hussen, Fatima; Jaradat, Nidal; Shtaya, Munqez

2018-05-01

Borago officinalis plant is an important plant of high medicinal and nutritional values. This study designed to evaluate antioxidant activity, screen the existence of phytogenic chemical compounds and to determine the total flavonoid and phenol contents of wild and cultivated Borago officinalis. Total flavonoid contents of the wild and cultivated Borago officinalis were determined by using rutin reference standard method and total phenols determined by using Folin Ciocalteu's method while antioxidant activity evaluated by using 2, 2-diphenyl-1-picryl-hydrazyl-hydrate assay. Phytochemical analyses indicated the presence of carbohydrate, phenols, flavonoids, phytosteroids tannins and volatile oil. The total flavonoid content of the methanolic extract from the wild borage plant was 22.4mg RU/g this value was reduced to 13.1mg RU/g for the cultivated methanolic extract as well as the total phenols contents was dropped from 5.21mg GA/g to 2.37mg GA/g methanolic extracts. Total tannins content of the wild growing borage plant was 13.7mg GA/g methanolic extract. This value was higher in the cultivated borage with 21.33mg GA/g methanolic extract. The wild leaves extract had IC 50 =6.3μg/mL for wild leaves extract was closer to IC 50 value of Trolox (standard reference with high antioxidant activity), while the cultivated leaves extract had higher IC 50 = 8.7μg/mL which mean lower antioxidant activity than the wild growing one. The data of this study showed that the extracts of Borago officinalis possess antioxidant and free radical scavenging activities. Variation was clear between wild and cultivated species, these findings propose that such plant extract could have a wide range of applications in both food and pharmaceutical industries. Therefore, more research is necessary to investigate different cultural practices on the efficiency of borage plant.

Inhibition properties of propolis extracts to some clinically important enzymes.

PubMed

Baltas, Nimet; Yildiz, Oktay; Kolayli, Sevgi

2016-01-01

The present study was conducted to envisage inhibition effects of propolis on the crucial enzymes, urease, xanthine oxidase (XO) and acetylcholinesterase (AChE). Some of the antioxidant properties of the propolis samples were determined using the total phenolic content (TPE) and total flavonoids in the eight different ethanolic propolis extracts (EPE) samples. Inhibition values of the enzymes were expressed as inhibition concentration (IC 50 ; mg/mL or μg/mL) causing 50% inhibition of the enzymes with donepezil, acetohydroxamic acid and allopurinol as reference inhibitors. All the propolis extracts exhibited variable inhibition effects on these enzymes, but the higher the phenolic contents the lower the inhibitions values (IC 50 = 0.074 to 1.560 mg/mL). IC 50 values of the P5 propolis sample having the highest TPE, obtained from Zonguldak, for AChE, urease and XO were 0.081 ± 0.009, 0.080 ± 0.006 and 0.074 ± 0.011 μg/mL, respectively. The EPE proved to be a good source of inhibitor agents that can be used as natural inhibitors to serve human health.

Large scale screening of commonly used Iranian traditional medicinal plants against urease activity

PubMed Central

2012-01-01

Background and purpose of the study H. pylori infection is an important etiologic impetus usually leading to gastric disease and urease enzyme is the most crucial role is to protect the bacteria in the acidic environment of the stomach. Then urease inhibitors would increase sensitivity of the bacteria in acidic medium. Methods 137 Iranian traditional medicinal plants were examined against Jack bean urease activity by Berthelot reaction. Each herb was extracted using 50% aqueous methanol. The more effective extracts were further tested and their IC50 values were determined. Results 37 plants out of the 137 crude extracts revealed strong urease inhibitory activity (more than 70% inhibition against urease activity at 10 mg/ml concentration). Nine of the whole studied plants crude extracts were found as the most effective with IC50 values less than 500 μg/ml including; Rheum ribes, Sambucus ebulus, Pistachia lentiscus, Myrtus communis, Areca catechu, Citrus aurantifolia, Myristica fragrans, Cinnamomum zeylanicum and Nicotiana tabacum. Conclusions The most potent urease inhibitory was observed for Sambucus ebulus and Rheum ribes extracts with IC50 values of 57 and 92 μg/ml, respectively. PMID:23351780

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2015-16 season: Comparison with the 2010-11 to 2014-15 seasons.

PubMed

Ikematsu, Hideyuki; Kawai, Naoki; Iwaki, Norio; Kashiwagi, Seizaburo

2017-09-01

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2015-2016 influenza season in Japan, we measured the 50% inhibitory concentration (IC 50 ) of NAIs for influenza virus isolates and compared them with the results from the 2010-11 to 2014-15 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. Influenza viruses were isolated: 210 influenza A(H1N1)pdm09 (67.3%), 20 A(H3N2) (6.4%), and 82 B (26.3%), and for the Victoria and Yamagata lineages the numbers were 53 (64.6%) and 28 (34.1%), respectively, with one unknown. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM). No isolate showed a very high IC50 for A(H3N2) or B. The ratios of geometric mean IC50 of the 2015-2016 influenza season to those of the 2010-2011 to 2014-2015 influenza seasons ranged from 0.62 to 1.78 for A(H1N1) pdm09. The range was 0.73-1.35 for A(H3N2) and 0.48-1.12 for B. No significant trend of increase or decrease in IC50 was found for any of the four NAIs. Although some isolates showed highly reduced sensitivity to oseltamivir among the A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2), and B viruses are susceptible to all four NAIs, with no trend toward decreased sensitivity. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Antioxidant, anti-inflammatory, and enzyme inhibitory activity of natural plant flavonoids and their synthesized derivatives.

PubMed

Nile, Shivraj Hariram; Keum, Young Soo; Nile, Arti Shivraj; Jalde, Shivkumar S; Patel, Rahul V

2018-01-01

The synthesized flavonoid derivatives were examined for their antioxidant, anti-inflammatory, xanthine oxidase (XO), urease inhibitory activity, and cytotoxicity. Except few, all the flavonoids under this study showed significant antioxidant activity (45.6%-85.5%, 32.6%-70.6%, and 24.9%-65.5% inhibition by DPPH, ferric reducing/antioxidant power, and oxygen radical absorption capacity assays) with promising TNF-α inhibitory activity (42%-73% at 10 μM) and IL-6 inhibitory activity (54%-81% at 10 μM) compared with that of control dexamethasone. The flavonoids luteolin, apigenin, diosmetin, chrysin, O 3Ꞌ , O 7 -dihexyl diosmetin, O 4Ꞌ , O 7 -dihexyl apigenin, and O 7 -hexyl chrysin, showed an inhibition with IC 50 values (4.5-8.1 μg/mL), more than allopurinol (8.5 μg/mL) at 5 μM against XO and showing more than 50% inhibition at a final concentration (5 mM) with an IC 50 value of ranging from 4.8 to 7.2 (μg/mL) in comparison with the positive control thiourea (5.8 μg/mL) for urease inhibition. Thus, the flavonoid derivatives may be considered as potential antioxidant and antigout agents. © 2017 Wiley Periodicals, Inc.

Antileishmanial, antimalarial and antimicrobial activities of the extract and isolated compounds from Austroplenckia populnea (Celastraceae).

PubMed

Andrade, Sérgio F; da Silva Filho, Ademar A; de O Resende, Dimas; Silva, Márcio L A; Cunha, Wilson R; Nanayakkara, N P Dhammika; Bastos, Jairo Kenupp

2008-01-01

Austroplenckia populnea (Celastraceae), known as "marmelinho do campo", is used in Brazilian folk medicine as antimicrobial, anti-inflammatory, and antitumoural agent. The aim of the present work was to evaluate the antimicrobial, antileishmanial and antimalarial activities of the crude hydroalcoholic extract of A. populnea (CHE) and some of its isolated compounds. The phytochemical study of the CHE was carried out affording the isolation of methyl populnoate (1), populnoic acid (2), and stigmast-5-en-3-O-beta-(D-glucopyranoside) (3). This is the first time that the presence of compound 3 in A. populnea is reported. The results showed that the CHE presents antifungal and antibacterial activities, especially against Candida glabrata and Candida albicans, for which the CHE showed IC50 values of 0.7 microg mL(-1) and 5.5 microg mL(-1), respectively, while amphotericin B showed an IC50 value of 0.1 microg mL(-1) against both microorganisms. Compounds 1-3 were inactive against all tested microorganisms. In the antileishmanial activity test against Leishmania donovani, the CHE showed an IC50 value of 52 microg mL(-1), while compounds 2 and 3 displayed an IC50 value of 18 microg mL(-1) In the antimalarial assay against Plasmodium falciparum (D6 and W2 clones), it was observed that all evaluated samples were inactive. In order to compare the effect on the parasites with the toxicity to mammalian cells, the cytotoxicity activity of the isolated compounds was evaluated against Vero cells, showing that all evaluated samples exhibited no cytotoxicity at the maximum dose tested.

Classification of drug molecules considering their IC50 values using mixed-integer linear programming based hyper-boxes method.

PubMed

Armutlu, Pelin; Ozdemir, Muhittin E; Uney-Yuksektepe, Fadime; Kavakli, I Halil; Turkay, Metin

2008-10-03

A priori analysis of the activity of drugs on the target protein by computational approaches can be useful in narrowing down drug candidates for further experimental tests. Currently, there are a large number of computational methods that predict the activity of drugs on proteins. In this study, we approach the activity prediction problem as a classification problem and, we aim to improve the classification accuracy by introducing an algorithm that combines partial least squares regression with mixed-integer programming based hyper-boxes classification method, where drug molecules are classified as low active or high active regarding their binding activity (IC50 values) on target proteins. We also aim to determine the most significant molecular descriptors for the drug molecules. We first apply our approach by analyzing the activities of widely known inhibitor datasets including Acetylcholinesterase (ACHE), Benzodiazepine Receptor (BZR), Dihydrofolate Reductase (DHFR), Cyclooxygenase-2 (COX-2) with known IC50 values. The results at this stage proved that our approach consistently gives better classification accuracies compared to 63 other reported classification methods such as SVM, Naïve Bayes, where we were able to predict the experimentally determined IC50 values with a worst case accuracy of 96%. To further test applicability of this approach we first created dataset for Cytochrome P450 C17 inhibitors and then predicted their activities with 100% accuracy. Our results indicate that this approach can be utilized to predict the inhibitory effects of inhibitors based on their molecular descriptors. This approach will not only enhance drug discovery process, but also save time and resources committed.

Synthesis and biological evaluation of a series of dithiocarbamates as new cholinesterase inhibitors.

PubMed

Altıntop, Mehlika D; Gurkan-Alp, A Selen; Ozkay, Yusuf; Kaplancıklı, Zafer A

2013-08-01

In the present paper, a novel series of dithiocarbamates was synthesized via the treatment of 4-(trifluoromethyl)benzyl chloride with appropriate sodium salts of N,N-disubstituted dithiocarbamic acids. The chemical structures of the compounds were elucidated by (1) H NMR, mass spectral data, and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The most potent AChE inhibitor was found as compound 2g (IC50  = 0.53 ± 0.001 µM) followed by compounds 2f (IC50  = 0.74 ± 0.001 µM) and 2j (IC50  = 0.89 ± 0.002 µM) when compared with donepezil (IC50  = 0.048 ± 0.001 µM). Compounds 2f and 2g were more effective than donepezil (IC50  = 7.88 ± 0.52 µM) on BuChE inhibition. Compounds 2f and 2g exhibited the inhibitory effect on BuChE with IC50 values of 1.39 ± 0.041 and 3.64 ± 0.072 µM, respectively. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and evaluation of novel triazolyl quinoline derivatives as potential antileishmanial agents.

PubMed

Upadhyay, Akanksha; Kushwaha, Pragati; Gupta, Sampa; Dodda, Ranga Prasad; Ramalingam, Karthik; Kant, Ruchir; Goyal, Neena; Sashidhara, Koneni V

2018-05-12

The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover novel series of 25 compounds for the development of new antileishmanial agents. A series of triazolyl 2-methyl-4-phenylquinoline-3-carboxylate derivatives has been synthesized via click chemistry inspired molecular hybridization approach and evaluated against Leishmania donovani. Most of the screened derivatives exhibited significant in vitro anti-leishmanial activity against promastigote (IC 50 ranging from 2.43 to 45.75 μM) and intracellular amastigotes (IC 50 ranging from 7.06 to 34.9 μM) than the control, miltefosine (IC 50  = 8.4 μM), with less cytotoxicity in comparison to the standard drugs. Overall results revealed that prototype signify a new structural lead for antileishmanial chemotherapy. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Potential of rare actinomycetes in the production of metabolites against multiple oxidant agents.

PubMed

Mohammadipanah, Fatemeh; Momenilandi, Mana

2018-12-01

Actinobacteria are a precious source of novel bioactive metabolites with potential pharmaceutical applications. Representatives of 11 genera of rare Actinobacteria were selected for the evaluation of antioxidant activity. Fermentation broths of the Actinobacteria were extracted and dosage of 10 to 2000 µg/mL were applied for in vitro antioxidant-related bioassays. Cytotoxicity was assessed at the concentration of 2.5-20 µg/mL. In the DPPH scavenging activity, 15 out of 52 extracts showed 17.0-26.8% activity in quantitative evaluation. Metabolites of five prominent antioxidant producing strains protected the DNA (pUC19) against UV-induced photolyzed H 2 O 2 -oxidative degradation. The potent antioxidant extracts inhibited two oxidative enzymes of xanthine oxidase in the range of 17.5-45.2% (three extracts had IC 50 less than allopurinol) and lipoxygenase in the range of 36-55% (all five extracts had IC 50 values less than daidzein). All these extracts could also protect eythrocytes from iron-induced hemolysis with ED 50 values in a range of 0.014-1.25 mg/mL. Growth restoration of the yeast cells lacking the sod1 gene was observed by the antioxidant metabolite of Saccharothrix ecbatanensis UTMC 537 at the concentration of 1 mg/mL. The presence of nonidentical metabolites might be responsible for antioxidant and enzyme inhibitory activities of S. ecbatanensis, newly described actinobacterium in family Pseudonocardiaceae. The scavenging of the free electrons, protection of DNA and model yeast cells against oxidative stress, in addition to the inhibition of the oxidating enzymes are the main mechanisms of the antioxidant effect of the introduced resource in this study.

Abietane-Type Diterpenoid Amides with Highly Potent and Selective Activity against Leishmania donovani and Trypanosoma cruzi.

PubMed

Pirttimaa, Minni; Nasereddin, Abedelmajeed; Kopelyanskiy, Dmitry; Kaiser, Marcel; Yli-Kauhaluoma, Jari; Oksman-Caldentey, Kirsi-Marja; Brun, Reto; Jaffe, Charles L; Moreira, Vânia M; Alakurtti, Sami

2016-02-26

Dehydroabietylamine (1) was used as a starting material to synthesize a small library of dehydroabietyl amides by simple and facile methods, and their activities against two disease-causing trypanosomatids, namely, Leishmania donovani and Trypanosoma cruzi, were assayed. The most potent compound, 10, an amide of dehydroabietylamine and acrylic acid, was found to be highly potent against these parasites, displaying an IC50 value of 0.37 μM against L. donovani axenic amastigotes and an outstanding selectivity index of 63. Moreover, compound 10 fully inhibited the growth of intracellular amastigotes in Leishmania donovani-infected human macrophages with a low IC50 value of 0.06 μM. This compound was also highly effective against T. cruzi amastigotes residing in L6 cells with an IC50 value of 0.6 μM and high selectivity index of 58, being 3.5 times more potent than the reference compound benznidazole. The potent activity of this compound and its relatively low cytotoxicity make it attractive for further development in pursuit of better drugs for patients suffering from leishmaniasis and Chagas disease.

Detecting quinoxaline-2-carboxylic acid in animal tissues by using sensitive rapid enzyme-linked immunosorbent assay and time-resolved fluoroimmunoassay.

PubMed

Le, Tao; Yu, Huan; Niu, Xiaodong

2015-05-15

An indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) and time-resolved fluoroimmunoassay (TR-FIA) based on an anti-N-butylquinoxaline-2-carboxamide (BQCA) monoclonal antibody were standardized and validated for quinoxaline-2-carboxylic acid (QCA) screening in animal tissues and its performance were compared to HPLC. The sensitivities obtained for edible tissue extracts were 1.62 and 1.12 ng ml(-1) for ic-ELISA and TR-FIA detection, respectively. Two samples were spiked with QCA and analyzed by both methods. The recovery values ranged from 92.6% to 112.2% and the coefficients of variation were less than 15% for QCA spiking into swine tissue samples at concentrations of 2.5-50.0 μg kg(-1). Excellent correlations (r(2)=0.987-0.996) of the ic-ELISA/HPLC and TR-FIA/HPLC data were observed for processed samples. The results demonstrated that the ic-ELISA and TR-FIA methods were rapid and accurate for the residue detection of QCA in animal tissues. Copyright © 2014 Elsevier Ltd. All rights reserved.

Rapid toxicity assessment using an in vivo enzyme test for Brachionus plicatilis (Rotifera).

PubMed

Moffat, B D; Snell, T W

1995-02-01

A 1-hr in vivo enzyme inhibition assay based on esterase activity has good potential for marine toxicity assessment. A test was developed for the rotifer Brachionus plicatilis based on the nonfluorescent substrate fluorescein diacetate (FDA), which is metabolized by esterases to a fluorescent product. Enzyme inhibition, as determined by reduced fluorescence, can be scored visually or quantified using a fluorometer. Quantification of fluorescence permits the calculation of NOEC, LOEC, chronic value, and IC20. The 1-hr esterase inhibition test has sensitivity comparable to that of 24-hr rotifer acute tests for several compounds. The toxicity of six compounds was examined using the quantified assay. The resulting IC20s were within a factor of 3 of the 24-hour LC50s. IC20 values ranged from 0.017 mg/l for tributyltin to 3.1 mg/l for zinc, with an average coefficient of variation of 17.8%. Electrophoretic analysis of rotifer homogenates suggested that a single C esterase (acetylesterase) was responsible for FDA metabolism in B. plicatilis. Several other aquatic species are capable of metabolizing FDA, including Brachionus calyciflorus, Mysidopsis bahia, Menidia beryllina, Pimephales promelas, Ceriodaphnia dubia, Daphnia pulex, Artemia salina, and Ophryotrocha sp. The esterase inhibition test is an attractive tool for assessing aquatic toxicity because of its speed, simplicity, sensitivity, and applicability to a broad range of aquatic species.

Protein adsorption to poly(ethylenimine)-modified Sepharose FF: I. a critical ionic capacity for drastically enhanced capacity and uptake kinetics.

PubMed

Yu, Lin-Ling; Tao, Shi-Peng; Dong, Xiao-Yan; Sun, Yan

2013-08-30

To explore the details of protein uptake to polymer-grafted ion exchangers, Sepharose FF was modified with poly(ethylenimine) (PEI) to prepare anion exchanger of 10 different ionic capacities (ICs, 100-1220mmol/L). Adsorption equilibria and kinetics of bovine serum albumin (BSA) were then studied. It is found that ionic capacity, i.e., the coupling density of PEI, had significant effect on both adsorption capacity (qm) and effective protein diffusivity (De). With increasing ionic capacity, the qm value increased rapidly at IC<260mmol/L and then increased slowly till reaching a plateau at IC=600mmol/L. In the IC range of 100-600mmol/L, however, the De values kept at a low level (De/D0<0.07); it first decreased from 0.05±0.01 at IC=100mmol/L to 0.01±0.01 at IC=260mmol/L and then increased to 0.06±0.01 at IC=600mmol/L. Thereafter, sharp increases of the qm and De values [36% (from 201 to 273mg/mL) and 670% (from 0.06±0.01 to 0.49±0.04), respectively] were observed in the narrow range of IC from 600 to 740mmol/L. Finally, at IC>740mmol/L, the qm value decreased significantly while the De value increased moderately with increasing the IC. The results indicate that PEI chains played an important role in protein adsorption and transport. In brief, there was a critical IC (cIC) or PEI chain density, above which protein adsorption and transport behaviors changed drastically. The cIC was identified to be about 600mmol/L. Estimation of PEI grafting-layer thickness suggests that PEI chains formed an extended three-dimensional grafting-layer at IC>cIC, which provided high flexibility as well as accessibility of the chains for protein binding. Therefore, at IC>cIC, the adjacent PEI chains became close and flexible enough, leading to facilitated transport of adsorbed protein molecules by the interactions of neighboring chains mediated by the bound molecules. It is regarded as "chain delivery" effect. At the same time, improved accessibility of binding sites led the significant increase of binding capacity. The decrease of qm value at IC>740mmol/L is considered due to the decrease of effective porosity. The research has thus provided new insight into protein adsorption and transport in polymer-grafted ion-exchange media. Copyright © 2013 Elsevier B.V. All rights reserved.

Preparation and characterization of novel bioactive peptides responsible for angiotensin I-converting enzyme inhibition from wheat germ.

PubMed

Matsui, T; Li, C H; Osajima, Y

1999-07-01

Reported is the preparation of wheat germ (WG) hydrolyzate with potent angiotensin I-converting enzyme (ACE) inhibitory activity, and the characterization of peptides responsible for ACE inhibition. Successful hydrolyzate with the most potent ACE inhibitory activity was obtained by 0.5 wt.%-8 h Bacillus licheniformis alkaline protease hydrolysis after 3.0 wt.%-3 h alpha-amylase treatment of defatted WG (IC50; 0.37 mg protein ml(-1)). The activity of WG hydrolyzate was markedly increased by ODS and subsequent AG50W purifications (IC50; 0.018 mg protein ml(-1)). As a result of isolations by high performance liquid chromatographies, 16 peptides with the IC50 value of less than 20 microM, composed of 2-7 amino acid residues were identified from the WG hydrolyzate. Judging from the high content (260 mg in 100 g of AG50W fraction) and powerful ACE inhibitory activity (IC50; 0.48 microM), Ile-Val-Tyr was identified as a main contributor to the ACE inhibition of the hydrolyzate.

Novel synthetic kojic acid-methimazole derivatives inhibit mushroom tyrosinase and melanogenesis.

PubMed

Chen, Ming-Jen; Hung, Chih-Chuan; Chen, Yan-Ru; Lai, Shih-Ting; Chan, Chin-Feng

2016-12-01

In this study, two kojic acid-methimazole (2-mercapto-1-methylimidazole, MMI, 1) derivatives, 5-hydroxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 4) and 5-methoxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 5), were synthesized to examine their inhibitory kinetics on mushroom tyrosinase. Compound 4 exhibited a potent inhibitory effect on monophenolase activity in a dose-dependent manner, with an IC 50 value of 0.03 mM. On diphenolase activity, compound 4 exhibited a less inhibitory effect (IC 50  = 1.29 mM) but was stronger than kojic acid (IC 50  = 1.80 mM). Kinetic analysis indicated that compound 4 was both as a noncompetitive monophenolase and diphenolase inhibitor. By contrast, compound 5 exhibited no inhibitory effects on mushroom tyrosinase activity. The IC 50 value of compound 4 for the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was 4.09 mM, being much higher than the IC 50 of compound 4 for inhibiting the tyrosinase activity. The results indicated that the antioxidant activity of compound 4 may be partly related to the potent inhibitory effect on mushroom tyrosinase. Compound 4 also exerted a potent inhibitory effect on intracellular melanin formation in B16/F10 murine melanoma cells, and caused no cytotoxicity. Furthermore, compound 4 induced no adverse effects on the Hen's egg test-chorioallantoic membrane (HET-CAM). Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Synthesis of Cryptophycin Affinity Labels and Tubulin Labeling

DTIC Science & Technology

2004-05-01

isolated from blue-green algae ( Nostoc sp.), are a new and potent tumor-selective class of tubulin-binding antimitotic agents that show excellent activity... Nostoc sp.3𔃾 and displays IC 50 values in the pM range. Of special importance is the reduced susceptibility of the cryptophycins to P-glycoprotein...also named arenastatin A), isolated from the Okinawan marine sponge Dysidea arenaria5 and later from Nostoc sp. strain GSV 224,6 is also a potent

Correlation of polyphenolic content with radical-scavenging capacity and anthelmintic effects of Rubus ulmifolius (Rosaceae) against Haemonchus contortus.

PubMed

Akkari, Hafidh; Hajaji, Soumaya; B'chir, Fatma; Rekik, Mourad; Gharbi, Mohamed

2016-05-15

Phenolic content, antioxidant and anthelmintic activities of herbal extracts are of particular interest to drug industry; plant extracts with significant anthelmintic activity have the potential to be used as alternatives to conventional chemical drugs. In the present study, Rubus ulmifolius fruit extracts obtained using solvents of increasing polarity (water, methanol, chloroform and hexane) were examined for their antioxidant and anthelmintic activities in correlation with their polyphenolic content. In vitro antioxidant activity of all extracts was carried out using free radical-scavenging activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethilenebenzotiazolin)-6-sulfonic acid (ABTS) radical cation. In vitro anthelmintic activities were investigated on the egg and adult worms of Haemonchus contortus from sheep in comparison to albendazole. Total polyphenol content of R. ulmifolius was higher in more polar extract, ranging from 64.5 in aqueous extract to 1.57 mg gallic acid equivalents per gram of dry weight (GAE/g DW) in hexanic extract. Likewise, highest amounts of flavonoids and condensed tannins were found in aqueous extract (28.06 mg QE/g and 7.42 mg CE/g DW, respectively) compared to hexanic extract (0.71 mg QE/g and 0.29 mg CE/g DW, respectively) (p<0.05). Both DPPH and ABTS antioxidant assays showed that all tested extracts possess free radical scavenging activity, while the inhibitory concentration 50% (IC50) range values were similar for both assays (2.13-45.54 μg/mL and 1.2-43.82 μg/mL, respectively). All plant extracts showed ovicidal activity at all tested concentrations. Fruit methanolic (IC50=2.76mg/mL) and aqueous (IC50=2.08 mg/mL) extracts showed higher inhibitory effects than chloroformic (IC50=7.62 mg/mL) and hexanic (IC50=12.93 mg/mL) extracts on egg hatching (p<0.05). There was a significant correlation of total polyphenol, flavonoids and tannins content with scavenging of either DPPH (r=0.722, 0.764 and 0.752, p<0.01, respectively) or ABTS radicals (r=0.893, 0.765 and 0.722, p<0.01, respectively) and with inhibition of egg hatching (r=0.874, 0.883 and 0.862, p<0.01, respectively). Highest inhibition of motility (100%) of worms was observed 8h post-exposure in aqueous and methanolic extract at 8 mg/mL. To our knowledge, these results depict for the first time that R. ulmifolius possesses in vitro anthelmintic properties. Published by Elsevier B.V.

In vitro inhibitory activities of selected Australian medicinal plant extracts against protein glycation, angiotensin converting enzyme (ACE) and digestive enzymes linked to type II diabetes.

PubMed

Deo, Permal; Hewawasam, Erandi; Karakoulakis, Aris; Claudie, David J; Nelson, Robert; Simpson, Bradley S; Smith, Nicholas M; Semple, Susan J

2016-11-04

There is a need to develop potential new therapies for the management of diabetes and hypertension. Australian medicinal plants collected from the Kuuku I'yu (Northern Kaanju) homelands, Cape York Peninsula, Queensland, Australia were investigated to determine their therapeutic potential. Extracts were tested for inhibition of protein glycation and key enzymes relevant to the management of hyperglycaemia and hypertension. The inhibitory activities were further correlated with the antioxidant activities. Extracts of five selected plant species were investigated: Petalostigma pubescens, Petalostigma banksii, Memecylon pauciflorum, Millettia pinnata and Grewia mesomischa. Enzyme inhibitory activity of the plant extracts was assessed against α-amylase, α-glucosidase and angiotensin converting enzyme (ACE). Antiglycation activity was determined using glucose-induced protein glycation models and formation of protein-bound fluorescent advanced glycation endproducts (AGEs). Antioxidant activity was determined by measuring the scavenging effect of plant extracts against 1, 1-diphenyl-2-picryl hydrazyl (DPPH) and using the ferric reducing anti-oxidant potential assay (FRAP). Total phenolic and flavonoid contents were also determined. Extracts of the leaves of Petalostigma banksii and P. pubescens showed the strongest inhibition of α-amylase with IC 50 values of 166.50 ± 5.50 μg/mL and 160.20 ± 27.92 μg/mL, respectively. The P. pubescens leaf extract was also the strongest inhibitor of α-glucosidase with an IC 50 of 167.83 ± 23.82 μg/mL. Testing for the antiglycation potential of the extracts, measured as inhibition of formation of protein-bound fluorescent AGEs, showed that P. banksii root and fruit extracts had IC 50 values of 34.49 ± 4.31 μg/mL and 47.72 ± 1.65 μg/mL, respectively, which were significantly lower (p < 0.05) than other extracts. The inhibitory effect on α-amylase, α-glucosidase and the antiglycation potential of the extracts did not correlate with the total phenolic, total flavonoid, FRAP or DPPH. For ACE inhibition, IC 50 values ranged between 266.27 ± 6.91 to 695.17 ± 15.38 μg/mL. The tested Australian medicinal plant extracts inhibit glucose-induced fluorescent AGEs, α-amylase, α-glucosidase and ACE with extracts of Petalostigma species showing the most promising activity. These medicinal plants could potentially be further developed as therapeutic agents in the treatment of hyperglycaemia and hypertension.

Endocrine disruptive effects of chemicals eluted from nitrile-butadiene rubber gloves using reporter gene assay systems.

PubMed

Satoh, Kanako; Nonaka, Ryouichi; Ohyama, Ken-ichi; Nagai, Fumiko; Ogata, Akio; Iida, Mitsuru

2008-03-01

Disposable gloves made of nitrile-butadiene rubber (NBR) are used for contact with foodstuffs rather than polyvinyl chloride gloves containing di(2-ethylhexyl)phthalate (DEHP), because endocrine-disruptive effects are suspected for phthalate diesters including DEHP. However, 4,4'-butylidenebis(6-t-butyl-m-cresol) (BBBC), 2,4-di-t-butylphenol, and 2,2,4-trimetyl-1,3-pentanediol diisobutyrate can be eluted from NBR gloves, and possibly also detected in food. In this study, we examined the endocrine-disrupting effects of these chemicals via androgen receptor (AR) and estrogen receptor (ER)-mediated pathways using stably transfected reporter gene cell lines expressing AR (AR-EcoScreen system) and ER (MVLN cells), respectively. We also examined the binding activities of these chemicals to AR and ER. The IC50 value of BBBC for antagonistic androgen was in the range of 10(-6)M. The strength of inhibition was about 5 times that of a known androgen antagonist, 1,1'-(2,2-dichloroethylidene)bis[4-chlorobenzene] (p,p'-DDE), and similar to that of bisphenol A. The IC50 value of BBBC for antagonistic estrogen was in the range of 10(-6)M. These results suggest that BBBC and its structural homologue, 4,4'-thiobis(6-t-butyl-m-cresol) are androgen and estrogen antagonists. It is therefore necessary to study these chemicals in vivo, and clarify their effect on the endocrine system.

Novel 1, 3-N, O-Spiroheterocyclic compounds inhibit heparanase activity and enhance nedaplatin-induced cytotoxicity in cervical cancer cells.

PubMed

Song, Yanan; Hu, Bin; Qu, Hongjie; Wang, Lu; Zhang, Yunxiao; Tao, Jinchao; Cui, Jinquan

2016-06-14

Heparanase (HPA) is an enzyme that plays an important role in cancer metastasis and angiogenesis and is a potential target for molecular treatment of tumors. We previously found that abnormally high HPA expression in cervical cancer tissues is associated with poor survival and increased lymph node metastasis. The present study was conducted to assess the utility of inhibiting HPA enzyme activity in cervical cancer treatment. Two series of 13 novel HPA inhibitors were synthesized and optimized. All tested inhibitors reduced HPA enzyme activity (IC50 values ranged from 4.47 μM to 47.19 μM) and inhibited the growth of HeLa cells (IC50 values ranged from 48.16 μM to 96.64 μM). The No. 16 inhibitor inhibited the migration and growth of HeLa and Siha cells in a dose- and time-dependent manner, and increased cell apoptosis and cell cycle G0/G1 and G2/M phase arrest, while decreasing the S phase cell population. More importantly, No. 16 sensitized cervical cancer cells to low concentrations of nedaplatin, decreased HPA, c-Myc and h-TERT levels, and increased p53 levels in HeLa and Siha cells. These results suggest that this HPA inhibitor reduced proliferation and HPA expression in cervical cancer cells by restoring p53 activity and downregulating h-TERT and c-Myc expression.

Alkylphosphocholines and curcumin induce programmed cell death in cutaneous T-cell lymphoma cell lines.

PubMed

Yosifov, Deyan Y; Kaloyanov, Kaloyan A; Guenova, Margarita L; Prisadashka, Kamelia; Balabanova, Maria B; Berger, Martin R; Konstantinov, Spiro M

2014-01-01

While most patients with early-stage cutaneous T-cell lymphomas (CTCL) have a very good prognosis, the survival of patients with extensive tumour stage and visceral involvement remains extremely poor and necessitates the development of more effective treatment modalities. In this study, we evaluated the in vitro effects of two alkylphosphocholines (APCs, miltefosine and erufosine) and the polyphenolic compound curcumin on 5 human CTCL cell lines (Hut-78, HH, MJ, My-La CD4+ and My-La CD8+). All tested drugs showed considerable cytotoxic activity, as determined by the MTT dye reduction assay. The IC50 values of both APCs ranged from the low micromolar level (Hut-78 cells) to 60-80μM (HH cells). The IC50 values of curcumin ranged from 12 to 24μM. All tested drugs induced apoptosis, as ascertained by morphological changes, DNA fragmentation and activation of caspase cascades. Miltefosine and erufosine induced dephosphorylation of Akt in My-La CD8+ cells and phosphorylation of JNK in Hut-78 and My-La CD8+ cells. APCs increased the level of the autophagic marker LC3B in Hut-78 and MJ cells. Results from co-treatment with autophagy modulators suggested that the cytotoxicity of APCs in CTCL cells is mediated, at least in part, by induction of autophagy. Copyright © 2013 Elsevier Ltd. All rights reserved.

New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4-trioxane-ferrocene hybrids.

PubMed

Reiter, Christoph; Fröhlich, Tony; Zeino, Maen; Marschall, Manfred; Bahsi, Hanife; Leidenberger, Maria; Friedrich, Oliver; Kappes, Barbara; Hampel, Frank; Efferth, Thomas; Tsogoeva, Svetlana B

2015-06-05

In our ongoing search for highly active hybrid molecules exceeding their parent compounds in anticancer, antimalaria as well as antiviral activity and being an alternative to the standard drugs, we present the synthesis and biological investigations of 2nd generation 1,2,4-trioxane-ferrocene hybrids. In vitro tests against the CCRF-CEM leukemia cell line revealed di-1,2,4-trioxane-ferrocene hybrid 7 as the most active compound (IC50 of 0.01 μM). Regarding the activity against the multidrug resistant subline CEM/ADR5000, 1,2,4-trioxane-ferrocene hybrid 5 showed a remarkable activity (IC50 of 0.53 μM). Contrary to the antimalaria activity of hybrids 4-8 against Plasmodium falciparum 3D7 strain with slightly higher IC50 values (between 7.2 and 30.2 nM) than that of their parent compound DHA, hybrids 5-7 possessed very promising activity (IC50 values lower than 0.5 μM) against human cytomegalovirus (HCMV). The application of 1,2,4-trioxane-ferrocene hybrids against HCMV is unprecedented and demonstrated here for the first time. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Differential modulation of microglia superoxide anion and thromboxane B2 generation by the marine manzamines

PubMed Central

Mayer, Alejandro MS; Hall, Mary L; Lynch, Sean M; Gunasekera, Sarath P; Sennett, Susan H; Pomponi, Shirley A

2005-01-01

Background Thromboxane B2 (TXB2) and superoxide anion (O2-) are neuroinflammatory mediators that appear to be involved in the pathogenesis of several neurodegenerative diseases. Because activated-microglia are the main source of TXB2 and O2- in these disorders, modulation of their synthesis has been hypothesized as a potential therapeutic approach for neuroinflammatory disorders. Marine natural products have become a source of novel agents that modulate eicosanoids and O2- generation from activated murine and human leukocytes. With the exception of manzamine C, all other manzamines tested are characterized by a complex pentacyclic diamine linked to C-1 of the β-carboline moiety. These marine-derived alkaloids have been reported to possess a diverse range of bioactivities including anticancer, immunostimulatory, insecticidal, antibacterial, antimalarial and antituberculosis activities. The purpose of this investigation was to conduct a structure-activity relationship study with manzamines (MZ) A, B, C, D, E and F on agonist-stimulated release of TXB2 and O2- from E. coli LPS-activated rat neonatal microglia in vitro. Results The manzamines differentially attenuated PMA (phorbol 12-myristate 13-acetate)-stimulated TXB2 generation in the following order of decreasing potency: MZA (IC50 <0.016 μM) >MZD (IC50 = 0.23 μM) >MZB (IC50 = 1.6 μM) >MZC (IC50 = 2.98 μM) >MZE and F (IC50 >10 μM). In contrast, there was less effect on OPZ (opsonized zymosan)-stimulated TXB2 generation: MZB (IC50 = 1.44 μM) >MZA (IC50 = 3.16 μM) >MZC (IC50 = 3.34 μM) >MZD, MZE and MZF (IC50 >10 μM). Similarly, PMA-stimulated O2- generation was affected differentially as follows: MZD (apparent IC50<0.1 μM) >MZA (IC50 = 0.1 μM) >MZB (IC50 = 3.16 μM) >MZC (IC50 = 3.43 μM) >MZE and MZF (IC50 >10 μM). In contrast, OPZ-stimulated O2- generation was minimally affected: MZB (IC50 = 4.17 μM) >MZC (IC50 = 9.3 μM) >MZA, MZD, MZE and MZF (IC50 > 10 μM). From the structure-activity relationship perspective, contributing factors to the observed differential bioactivity on TXB2 and O2- generation are the solubility or ionic forms of MZA and D as well as changes such as saturation or oxidation of the β carboline or 8-membered amine ring. In contrast, the fused 13-membered macrocyclic and isoquinoline ring system, and any substitutions in these rings would not appear to be factors contributing to bioactivity. Conclusion To our knowledge, this is the first experimental study that demonstrates that MZA, at in vitro concentrations that are non toxic to E. coli LPS-activated rat neonatal microglia, potently modulates PMA-stimulated TXB2 and O2- generation. MZA may thus be a lead candidate for the development of novel therapeutic agents for the modulation of TXB2 and O2- release in neuroinflammatory diseases. Marine natural products provide a novel and rich source of chemical diversity that can contribute to the design and development of new and potentially useful anti-inflammatory agents to treat neurodegenerative diseases. PMID:15762999

Hypolipidemic and Antioxidant Properties of Hot Pepper Flower (Capsicum annuum L.).

PubMed

Marrelli, Mariangela; Menichini, Francesco; Conforti, Filomena

2016-09-01

At present, the various medical treatments of obesity involve side effects. The aim of the research is therefore to find natural compounds that have anti-obesity activity with minimum disadvantages. In this study, the hypolipidemic effect of hydroalcoholic extract of flowers from Capsicum annuum L. was examined through the evaluation of inhibition of pancreatic lipase. Antioxidant activity was assessed using different tests: 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (˙NO) and lipid peroxidation inhibition assays. Phytochemical analysis indicated that total phenolic and flavonoid content in the extract was 128.7 ± 4.5 mg chlorogenic acid equivalent/g of crude extract and 17.66 ± 0.11 mg of quercetin equivalent/g of crude extract, respectively. The extract inhibited pancreatic lipase with IC50 value equal to 3.54 ± 0.18 mg/ml. It also inhibited lipid peroxidation with IC50 value of 27.61 ± 2.25 μg/ml after 30 min of incubation and 41.69 ± 1.13 μg/ml after 60 min of incubation. The IC50 value of radical scavenging activity was 51.90 ± 2.03 μg/ml. The extract was also able to inhibit NO production (IC50 = of 264.3 ± 7.98 μg/ml) without showing any cytotoxic effect.

Ecotoxicological responses of three ornamental herb species to cadmium.

PubMed

Liu, Zhouli; He, Xingyuan; Chen, Wei; Zhao, Mingzhu

2013-08-01

Cadmium is one of the most toxic elements. The ideal vegetal cover should be ensured by the selection of appropriate plant species for successful phytoremediation. In the present study, the ecotoxicological effects of Cd on the following 3 ornamental herbs were investigated: Italian ryegrass (Lolium multiflorum Lam.), white clover (Trifolium repens L.), and alfalfa (Medicago sativa L.). Based on the inhibition rate of seed germination, root and shoot elongation, early seedling growth, median inhibition concentration (IC50) values, and index of tolerance (IT) values, ecotoxicological indicators were determined. The results showed that 10 μM to 50 μM Cd had little effect on seed germination or root and shoot elongation of the 3 ornamental herbs (p > 0.01). With an increase in Cd concentrations, alfalfa (M. sativa) was the most sensitive to Cd toxicity in terms of seed germination and root elongation. Based on the IC50 of root elongation, Italian ryegrass (L. multiflorum) was the least sensitive to Cd. Based on the IC50 of seed germination and shoot elongation, white clover had the least sensitivity to Cd. Among the 3 ornamental herbs, based on the IC50 of seed germination and root and shoot elongation, alfalfa (M. sativa) was all the most sensitive plant. According to the index of tolerance, Italian ryegrass (L. multiflorum) was the most tolerant plant. Copyright © 2013 SETAC.

Ion recombination and polarity correction factors for a plane-parallel ionization chamber in a proton scanning beam.

PubMed

Liszka, Małgorzata; Stolarczyk, Liliana; Kłodowska, Magdalena; Kozera, Anna; Krzempek, Dawid; Mojżeszek, Natalia; Pędracka, Anna; Waligórski, Michael Patrick Russell; Olko, Paweł

2018-01-01

To evaluate the effect on charge collection in the ionization chamber (IC) in proton pencil beam scanning (PBS), where the local dose rate may exceed the dose rates encountered in conventional MV therapy by up to three orders of magnitude. We measured values of the ion recombination (k s ) and polarity (k pol ) correction factors in water, for a plane-parallel Markus TM23343 IC, using the cyclotron-based Proteus-235 therapy system with an active proton PBS of energies 30-230 MeV. Values of k s were determined from extrapolation of the saturation curve and the Two-Voltage Method (TVM), for planar fields. We compared our experimental results with those obtained from theoretical calculations. The PBS dose rates were estimated by combining direct IC measurements with results of simulations performed using the FLUKA MC code. Values of k s were also determined by the TVM for uniformly irradiated volumes over different ranges and modulation depths of the proton PBS, with or without range shifter. By measuring charge collection efficiency versus applied IC voltage, we confirmed that, with respect to ion recombination, our proton PBS represents a continuous beam. For a given chamber parameter, e.g., nominal voltage, the value of k s depends on the energy and the dose rate of the proton PBS, reaching c. 0.5% for the TVM, at the dose rate of 13.4 Gy/s. For uniformly irradiated regular volumes, the k s value was significantly smaller, within 0.2% or 0.3% for irradiations with or without range shifter, respectively. Within measurement uncertainty, the average value of k pol , for the Markus TM23343 IC, was close to unity over the whole investigated range of clinical proton beam energies. While no polarity effect was observed for the Markus TM23343 IC in our pencil scanning proton beam system, the effect of volume recombination cannot be ignored. © 2017 American Association of Physicists in Medicine.

CYTOTOXIC, α-CHYMOTRYPSIN AND UREASE INHIBITION ACTIVITIES OF THE PLANT Heliotropium dasycarpum L.

PubMed

Ghaffari, Muhammad Abuzar; Chaudhary, Bashir Ahmed; Uzair, Muhammad; Ashfaq, Khuram

2016-01-01

The aim of this study was to investigate Cytotoxic, α-Chymotrypsin and Urease inhibition activities of the plant Heliotropium dasycarpum . Dichloromethane and methanol extracts of the plant were evaluated for cytotoxic, α-Chymotrypsin and Urease inhibition by using in vivo Brine Shrimp lethality bioassay and in vitro enzymatic inhibition assays respectively. The methanol extract of the plant exhibited significant cytotoxic activity. Out of 30 brine shrimp larvae, 2 (6%), 26 (86%) and 28 (93%) larvae were survived at concentration of 1000μg/ml, 100μg/ml and 10μg/ml respectively with LD50; 215.837. Similarly 21 (70%), 25 (83%), 29 (96%) larvae were survived of dichloromethane plant extract with LD50; 6170.64. The methanol and dichloromethane extract exhibited 10.50±0.18% and 41.51±0.15% α-chymotrypsin enzyme inhibition respectively with IC 50 values of greater than 500 μmol. The methanol extract showed 24.39±0.21% Urease enzyme inhibition with IC 50 values of greater than 400 μmol While dichloromethane extract has 11.46±0.09% enzyme inhibition with IC 50 values of greater than 500 μmol. The results clearly indicated that Heliotropium dasycarpum has cytotoxic potential and enzyme inhibition properties. Further study is needed to screen out antitumor and anti-ulcerative agents.

CYTOTOXIC, α-CHYMOTRYPSIN AND UREASE INHIBITION ACTIVITIES OF THE PLANT Heliotropium dasycarpum L.

PubMed Central

Ghaffari, Muhammad Abuzar; Chaudhary, Bashir Ahmed; Uzair, Muhammad; Ashfaq, Khuram

2016-01-01

Background: The aim of this study was to investigate Cytotoxic, α-Chymotrypsin and Urease inhibition activities of the plant Heliotropium dasycarpum. Materials & Methods: Dichloromethane and methanol extracts of the plant were evaluated for cytotoxic, α-Chymotrypsin and Urease inhibition by using in vivo Brine Shrimp lethality bioassay and in vitro enzymatic inhibition assays respectively. Results: The methanol extract of the plant exhibited significant cytotoxic activity. Out of 30 brine shrimp larvae, 2 (6%), 26 (86%) and 28 (93%) larvae were survived at concentration of 1000μg/ml, 100μg/ml and 10μg/ml respectively with LD50; 215.837. Similarly 21 (70%), 25 (83%), 29 (96%) larvae were survived of dichloromethane plant extract with LD50; 6170.64. The methanol and dichloromethane extract exhibited 10.50±0.18% and 41.51±0.15% α-chymotrypsin enzyme inhibition respectively with IC50 values of greater than 500 μmol. The methanol extract showed 24.39±0.21% Urease enzyme inhibition with IC50 values of greater than 400 μmol While dichloromethane extract has 11.46±0.09% enzyme inhibition with IC50 values of greater than 500 μmol Conclusion: The results clearly indicated that Heliotropium dasycarpum has cytotoxic potential and enzyme inhibition properties. Further study is needed to screen out antitumor and anti-ulcerative agents. PMID:28480379

Design, synthesis and biological evaluation of diaziridinyl quinone isoxazole hybrids.

PubMed

Swapnaja, K Jones M; Yennam, Satyanarayana; Chavali, Murthy; Poornachandra, Y; Kumar, C Ganesh; Muthusamy, Krubakaran; Jayaraman, Venkatesh Babu; Arumugam, Premkumar; Balasubramanian, Sridhar; Sriram, Kiran Kumar

2016-07-19

A series of novel diaziridinyl quinone isoxazole hybrids (9a-9j) were synthesized starting from 2, 5-dimethoxy acetophenone 1 via Claisen reaction, cyclisation, alkoxy carbonylation, hydrolysis, oxidation and aziridine insertion. All the compounds were screened for antimicrobial, anti-biofilm and cytotoxic activities. Among the screened compounds, the compound 9h showed good antibacterial and anti-biofilm activities with MIC value of 3.9, 3.9, 3.9 and 7.8 μg/mL, respectively, and IC50 values of 1.9, 2.5, 2.8 and 5.1 μM, respectively, against Staphylococcus aureus MTCC 96, S. aureus MLS-16 MTCC 2940, Bacillus subtilis MTCC 121 and Klebsiella planticola MTCC 530, and also exhibited potent antifungal activity against Candida albicans MTCC 227, C. albicans MTCC 854 and Candida krusei MTCC 3020 equipotent to standard miconazole (MIC value 7.8 μg/mL). All the synthesized compounds exhibited promising cytotoxicity against A549 and PC3 cell lines (IC50 values between 1 and 4 μM). Compounds 9b and 9j exhibited IC50 value of 0.5 μM which was similar to that of Mitomycin C against PC3 cell line. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

α-Pyrone derivatives with cytotoxic activities, from the endophytic fungus Phoma sp. YN02-P-3.

PubMed

Sang, Xia-Nan; Chen, Shao-Fei; Tang, Ming-Xu; Wang, Hai-Feng; An, Xiao; Lu, Xiao-Jie; Zhao, Dan; Wang, Yu-Bo; Bai, Jiao; Hua, Hui-Ming; Chen, Gang; Pei, Yue-Hu

2017-08-15

Four new α-pyrone derivatives phomones C-F (1-4) together with four known compounds (5-8) were isolated from the endophytic fungus Phoma sp. YN02-P-3. Compound 1 is the first example of 6-α,β-unsaturated ester-2-pyrone dimers via intermolecular symmetrical [2+2] cycloaddition. The chemical structures of these compounds were determined from spectroscopic data (1D/2D NMR, MS and IR). The acetylated product (9) of 1 along with compounds 1-8 were then tested for their cytotoxicity against HL-60, PC-3 and HCT-116 cell lines. Compounds 2, 3, 5 and 9 with acetyl groups showed significant inhibitory activities against the three cell lines with IC 50 values in the range 0.52-9.85μM. while compounds 1, 4 and 6-8 that possess no acetyl group showed no inhibitory activity (IC 50 >50μM), indicating that the acetyl group at 10- or 12- are essential for their cytotoxic activities. The structure-activity relationships of these phomones were also reported. Copyright © 2017 Elsevier Ltd. All rights reserved.

Urease and serine protease inhibitory alkaloids from Isatis tinctoria.

PubMed

Ahmad, Ijaz; Fatima, Itrat; Afza, Nighat; Malik, Abdul; Lodhi, Muhammad Arif; Choudhary, Muhammad Iqbal

2008-12-01

Phytochemical investigations on the alkaloidal fraction of the whole plant of the Isatis tinctoria led to the isolation of the alkaloids 1-6., 3'-Hydroxyepiglucoisatisin (3), Epiglucoisatisin (2) were found to be potent urease inhibitors in a concentration-dependent manner with IC(50) values 25.63 +/- 0.74, 37.01 +/- 0.41 and 31.72 +/- 0.93, 47.33 +/- 0.31 microM against Bacillus pasteurii & Jack bean urease, respectively. Compounds 3 and 2 also showed potent inhibitory potential against alpha-chymotrypsin with IC(50) values of 23.40 +/- 0.21 and 27.45 +/- 0.23 microM, respectively.

In vitro anti-influenza viral activities of constituents from Caesalpinia sappan.

PubMed

Liu, Ai-Lin; Shu, Shi-Hui; Qin, Hai-Lin; Lee, Simon Ming Yuen; Wang, Yi-Tao; Du, Guan-Hua

2009-03-01

Six constituents with neuraminidase (NA) inhibitory activity, namely brazilein, brazilin, protosappanin A, 3-deoxysappanchalcone, sappanchalcone and rhamnetin, were isolated from the hearthwood of Caesalpinia sappan (Leguminosae). Their in vitro anti-influenza virus activities were evaluated with the cytopathic effect (CPE) reduction method. The results showed that 3-deoxysappanchalcone and sappanchalcone exhibited the highest activity against influenza virus (H3N2) with IC50 values of 1.06 and 2.06 microg/mL, respectively, in comparison to the positive control oseltamivir acid and ribavirin with IC50 values of 0.065 and 9.17 microg/mL, respectively.

Phytochemical investigations and antioxidant potential of roots of Leea macrophylla (Roxb.).

PubMed

Mahmud, Zobaer Al; Bachar, Sitesh C; Hasan, Choudhury Mahmood; Emran, Talha Bin; Qais, Nazmul; Uddin, Mir Muhammad Nasir

2017-07-06

Oleanolic acid (NZ-15), 7 α, 28-olean diol (NZ-38) and Stigmasterol (NZ-14) were isolated from the ethanolic extracts of the roots of Leea macrophylla (Family: Leeaceae) by using chromatographic analysis. This is the first report of isolation of these compounds from this plant. Their structures were constructed by spectroscopic analysis and by comparing the data with the published one. Subsequently the ethanolic extract was fractionated with two organic solvents and all the fractions were studied to evaluate their in vitro antioxidant property. The ethanolic extract was fractionated with two organic solvents and all the fractions were studied to evaluate their in vitro antioxidant property by DPPH free radical scavenging assay, superoxide anion radical scavenging assay, nitric oxide radical scavenging assay, and reducing power assay. In the DPPH free radical scavenging assay and superoxide radical scavenging assay, the ethyl acetate soluble fraction of ethanolic extract revealed the highest free radical scavenging activity with IC 50 value of 2.65 and 155.62 μg/ml, respectively as compared to standard ascorbic acid (IC 50 value of 5.8 and 99.66 μg/ml). Ethyl acetate fraction also possessed highest reducing power activity with an EC50 value of 15.27 μg/ml compared to ascorbic acid (EC 50 0.91 μg/ml). On the other hand, the carbon tetrachloride fraction exhibited most significant NO scavenging activity with IC 50 value of 277.8 μg/ml that was even higher than that of standard ascorbic acid (IC 50 value 356.04 μg/ml). In addition, the total phenolic contents of these extract and fractions were evaluated using Folin-Ciocalteu reagent and varied from 7.93 to 50.21 mg/g dry weight expressed as gallic acid equivalents (GAE). This study showed that different extracts of roots of L. macrophylla possess potential DPPH, superoxide, and NO free radical scavenging activities. The antioxidant activities of the plant extracts might be due to the presence of oleanolic acid, oleanolic acid derivative 7 α, 28-olean diol and stigmasterol.

A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities.

PubMed

Bharkavi, Chelliah; Vivek Kumar, Sundaravel; Ashraf Ali, Mohamed; Osman, Hasnah; Muthusubramanian, Shanmugam; Perumal, Subbu

2016-11-15

A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC 50 1.07μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC 50 <1.56μM) and 6l (IC 50 =2.87μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC 50 values of 1.10 and 1.16μmol/L respectively. Copyright © 2016 Elsevier Ltd. All rights reserved.

The antiviral effects of RSV fusion inhibitor, MDT-637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin.

PubMed

Kim, Young-In; Pareek, Rajat; Murphy, Ryan; Harrison, Lisa; Farrell, Eric; Cook, Robert; DeVincenzo, John

2017-11-01

Respiratory syncytial virus (RSV) viral load and disease severity associate, and the timing of viral load and disease run in parallel. An antiviral must be broadly effective against the natural spectrum of RSV genotypes and must attain concentrations capable of inhibiting viral replication within the human respiratory tract. We evaluated a novel RSV fusion inhibitor, MDT-637, and compared it with ribavirin for therapeutic effect in vitro to identify relative therapeutic doses achievable in humans. MDT-637 and ribavirin were co-incubated with RSV in HEp-2 cells. Quantitative PCR assessed viral concentrations; 50% inhibitory concentrations (IC 50 ) were compared to achievable human MDT-637 and ribavirin peak and trough concentrations. The IC 50 for MDT-637 and ribavirin (against RSV-A Long) was 1.42 and 16 973 ng/mL, respectively. The ratio of achievable peak respiratory secretion concentration to IC 50 was 6041-fold for MDT-637 and 25-fold for aerosolized ribavirin. The ratio of trough concentration to IC 50 was 1481-fold for MDT-637 and 3.29-fold for aerosolized ribavirin. Maximal peak and trough levels of oral or intravenous ribavirin were significantly lower than their IC 50 s. We also measured MDT-637 IC 50 s in 3 lab strains and 4 clinical strains. The IC 50 s ranged from 0.36 to 3.4 ng/mL. Achievable human MDT-637 concentrations in respiratory secretions exceed the IC 50 s by factors from hundreds to thousands of times greater than does ribavirin. Furthermore, MDT-637 has broad in vitro antiviral activity on clinical strains of different RSV genotypes and clades. Together, these data imply that MDT-637 may produce a superior clinical effect compared to ribavirin on natural RSV infections. © 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Quadruple high-resolution α-glucosidase/α-amylase/PTP1B/radical scavenging profiling combined with high-performance liquid chromatography-high-resolution mass spectrometry-solid-phase extraction-nuclear magnetic resonance spectroscopy for identification of antidiabetic constituents in crude root bark of Morus alba L.

PubMed

Zhao, Yong; Kongstad, Kenneth Thermann; Jäger, Anna Katharina; Nielsen, John; Staerk, Dan

2018-06-29

In this paper, quadruple high-resolution α-glucosidase/α-amylase/PTP1B/radical scavenging profiling combined with HPLC-HRMS-SPE-NMR were used for studying the polypharmacological properties of crude root bark extract of Morus alba L. This species is used as an anti-diabetic principle in many traditional treatment systems around the world, and the crude ethyl acetate extract of M. alba root bark was found to inhibit α-glucosidase, α-amylase and protein-tyrosine phosphatase 1B (PTP1B) with IC 50 values of 1.70 ± 0.72, 5.16 ± 0.69, and 5.07 ± 0.68 μg/mL as well as showing radical scavenging activity equaling a TEAC value of (3.82 ± 0.14) × 10 4  mM per gram extract. Subsequent investigation of the crude extract using quadruple high-resolution α-glucosidase/α-amylase/PTP1B/radical scavenging profiling provided a quadruple biochromatogram that allowed direct correlation of the HPLC peaks with one or more of the tested bioactivities. This was used to target subsequent HPLC-HRMS-SPE-NMR analysis towards peaks representing bioactive analytes, and led to identification of a new Diels-Alder adduct named Moracenin E as well as a series of Diels-Alder adducts and isoprenylated flavonoids as potent α-glucosidase and α-amylase inhibitors with IC 50 values in the range of 0.60-27.15 μM and 1.22-69.38 μM, respectively. In addition, these compounds and two 2-arylbenzofurans were found to be potent PTP1B inhibitors with IC 50 values ranging from 4.04 to 21.67 μM. The high-resolution radical scavenging profile also revealed that almost all of the compounds possess radical scavenging activity. In conclusion the quadruple high-resolution profiling method presented here allowed a detailed profiling of individual constituents in crude root bark extract of M. alba, and the method provides a general tool for detailed mapping of bioactive constituents in polypharmacological herbal remedies. Copyright © 2018 Elsevier B.V. All rights reserved.

Potent Inhibitory Effect of Chinese Dietary Spices on Fatty Acid Synthase.

PubMed

Jiang, Bing; Liang, Yan; Sun, Xuebing; Liu, Xiaoxin; Tian, Weixi; Ma, Xiaofeng

2015-09-01

Dietary spices have been adopted in cooking since ancient times to enhance flavor and also as food preservatives and disease remedies. In China, the use of spices and other aromatic plants as food flavoring is an integral part of dietary behavior, but relatively little is known about their functions. Fatty acid synthase (FAS) has been recognized as a remedy target, and its inhibitors might be applied in disease treatment. The present work was designed to assess the inhibitory activities on FAS of spices extracts in Chinese menu. The in vitro inhibitory activities on FAS of 22 extracts of spices were assessed by spectrophotometrically monitoring oxidation of NADPH at 340 nm. Results showed that 20 spices extracts (90.9 %) exhibited inhibitory activities on FAS, with half inhibition concentration (IC(50)) values ranging from 1.72 to 810.7 μg/ml. Among them, seven spices showed strong inhibitory effect with IC(50) values lower than 10 μg/ml. These findings suggest that a large proportion of the dietary spices studied possess promising inhibitory activities on FAS, and subsequently might be applied in the treatment of obesity and obesity-related human diseases.

New synthesis and antiparasitic activity of model 5-aryl-1-methyl-4-nitroimidazoles.

PubMed

Saadeh, Haythem A; Mosleh, Ibrahim M; El-Abadelah, Mustafa M

2009-07-27

A number of 5-aryl-1-methyl-4-nitroimidazoles 5a-f have been synthesized in good yields by the Suzuki coupling reaction between 5-chloro-1-methyl-4-nitroimidazole (3) and arylboronic acids 4a-f, aided by dichlorobis-(triphenylphosphine)palladium(II), K(2)CO(3, )and tetrabutylammonium bromide in water at 70-80 degrees C. Compounds 5a-f were characterized by elemental analysis, NMR and MS spectral data. On the basis of in vitro screening data, 5-(3-chlorophenyl)-1-methyl-4-nitro-1H-imidazole (5f) exhibited potent lethal activity against Entamoeba histolytica and Giardia intestinalis with IC(50) = 1.47 microM/mL, a value lower by a factor of two than that of the standard drug, metronidazole. The boosted activity of 5f was not accompanied by any increased cytotoxicity.The rest of the series also exhibited potent antiparasitic activity with IC(50 ) values in the 1.72-4.43 microM/mL range. The cytotoxicity of the derivatives 5c and 5e was increased compared to the precursor compound, metronidazole, although they remain non-cytotoxic at concentrations much higher than the antiparasitic concentration of the two derivatives.

Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies.

PubMed

Kumar, Bhupinder; Sharma, Praveen; Gupta, Vivek Prakash; Khullar, Madhu; Singh, Sandeep; Dogra, Nilambra; Kumar, Vinod

2018-08-01

A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC 50 values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC 50 values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket. Copyright © 2018 Elsevier Inc. All rights reserved.

Rapid screening of flonicamid residues in environmental and agricultural samples by a sensitive enzyme immunoassay.

PubMed

Liu, Zhenjiang; Zhang, Zhen; Zhu, Gangbing; Sun, Jianfan; Zou, Bin; Li, Ming; Wang, Jiagao

2016-05-01

A fast and sensitive polyclonal antibody-based enzyme-linked immunosorbent assay (ELISA) was developed for the analysis of flonicamid in environmental and agricultural samples. Two haptens of flonicamid differing in spacer arm length were synthesized and conjugated to proteins to be used as immunogens for the production of polyclonal antibodies. To obtain most sensitive combination of antibody/coating antigen, two antibodies were separately screened by homologous and heterologous assays. After optimization, the flonicamid ELISA showed that the 50% inhibitory concentration (IC50 value) was 3.86mgL(-1), and the limit of detection (IC20 value) was 0.032mgL(-1). There was no cross-reactivity to similar tested compounds. The recoveries obtained after the addition of standard flonicamid to the samples, including water, soil, carrot, apple and tomato, ranged from 79.3% to 116.4%. Moreover, the results of the ELISA for the spiked samples were largely consistent with the gas chromatography (R(2)=0.9891). The data showed that the proposed ELISA is an alternative tool for rapid, sensitive and accurate monitoring of flonicamid in environmental and agricultural samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Antioxidant and antibacterial activities on foodborne pathogens of Artocarpus heterophyllus Lam. (Moraceae) leaves extracts.

PubMed

Loizzo, M R; Tundis, R; Chandrika, U G; Abeysekera, A M; Menichini, F; Frega, N G

2010-06-01

Total water extract, ethyl acetate, and aqueous fractions from the leaves of Artocarpus heterophyllus were evaluated for phenolic content, antioxidant, and antibacterial activities against some foodborne pathogens such as E. coli, Listeria monocytogenes, Salmonella typhimurium, Salmonella enterica, Bacillus cereus, Enterococcus faecalis, and Staphylococcus aureus. The minimum inhibitory concentration (MICs) of extract and fractions determined by the agar dilution method were ranged from 221.9 microg/mL for ethyl acetate fraction to 488.1 microg/mL for total extract. In the agar diffusion method the diameters of inhibition were 12.2 for the total extract, 10.7 and 11.5 for ethyl acetate and aqueous fractions, respectively. A. heterophyllus showed significant antioxidant activity tested in different in vitro systems (DPPH, ABTS, FRAP, and Fe(2+) chelating activity assay). In particular, in DPPH assay A. heterophyllus total extract exhibited a strong antiradical activity with an IC(50) value of 73.5 microg/mL while aqueous fraction exerted the highest activity in FRAP assay (IC(50) value of 72.0 microg/mL). The total phenols content by Folin-Ciocalteau method was determined with the purpose of testing its relationship with the antioxidant and antibacterial activities.

Indanones as high-potency reversible inhibitors of monoamine oxidase.

PubMed

Mostert, Samantha; Petzer, Anél; Petzer, Jacobus P

2015-05-01

Recent reports document that α-tetralone (3,4-dihydro-2H-naphthalen-1-one) is an appropriate scaffold for the design of high-potency monoamine oxidase (MAO) inhibitors. Based on the structural similarity between α-tetralone and 1-indanone, the present study involved synthesis of 34 1-indanone and related indane derivatives as potential inhibitors of recombinant human MAO-A and MAO-B. The results show that C6-substituted indanones are particularly potent and selective MAO-B inhibitors, with IC50 values ranging from 0.001 to 0.030 μM. C5-Substituted indanone and indane derivatives are comparatively weaker MAO-B inhibitors. Although the 1-indanone and indane derivatives are selective inhibitors of the MAO-B isoform, a number of homologues are also potent MAO-A inhibitors, with three homologues possessing IC50 values <0.1 μM. Dialysis of enzyme-inhibitor mixtures further established a selected 1-indanone as a reversible MAO inhibitor with a competitive mode of inhibition. It may be concluded that 1-indanones are promising leads for the design of therapies for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

New isopimarane diterpenes and nortriterpene with cytotoxic activity from Ephorbia alatavica Boiss.

PubMed

Rozimamat, Rushangul; Hu, Rui; Aisa, Haji Akber

2018-06-01

Three new isopimarane diterpenes and one new nor-triterpenes, along with five known diterpenes were isolated from the whole areal part of Ephorbia alatavica Boiss. The structures of the new compounds (1-4) were determined based on extensive spectroscopic analysis, including HR-ESIMS, 1D and 2D NMR data. A plausible biosynthetic pathway for new compounds (1-4) were hypothesized. All isolated compounds were screen for cytotoxicity activity against MCF-8, HeLa and A549 cell lines in vitro by MTT assay. New compound 1 and known 9 showed potential cytotoxic activities with IC 50 values of 15.327 μg/mL, 23.066 μg/mL against MCF-8 cell lines, compound1 showed noteworthy cytotoxic activity with IC 50 13.033 μg/mL against A549 cancer cell line. New compounds 2, 4 and 4 showed moderate cytotoxic activities three human cancer lines with IC 50 value around 50 μg/mL, which compared with positive control doxorubicin (DOX). Copyright © 2018 Elsevier B.V. All rights reserved.

Synthesis, Characterization, and Anti-Cancer Activity of Some New N'-(2-Oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazones Derivatives.

PubMed

El-Faham, Ayman; Farooq, Muhammad; Khattab, Sherine N; Abutaha, Nael; Wadaan, Mohammad A; Ghabbour, Hazem A; Fun, Hoong-Kun

2015-08-13

Eight novel N'-(2-oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazone derivatives 4a-h were synthesized and fully characterized by IR, NMR ((1)H-NMR and (13)C-NMR), elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2) and leukaemia (Jurkat), as well as in normal cell lines derived from human embryonic kidney (HEK293) using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC50 values between 3 and 7 μM) as compared to the known anti-cancer drug 5-Fluorouracil (IC50 32-50 μM). Among the tested compounds, 4a showed specificity against leukaemia (Jurkat) cells, with an IC50 value of 3.14 μM, but this compound was inactive in liver cancer and normal cell lines.

In vitro susceptibility of Trypanosoma brucei brucei to selected essential oils and their major components.

PubMed

Costa, Sonya; Cavadas, Cláudia; Cavaleiro, Carlos; Salgueiro, Lígia; do Céu Sousa, Maria

2018-07-01

Aiming for discovering effective and harmless antitrypanosomal agents, 17 essential oils and nine major components were screened for their effects on T. b. brucei. The essential oils were obtained by hydrodistillation from fresh plant material and analyzed by GC and GC-MS. The trypanocidal activity was assessed using blood stream trypomastigotes cultures of T. b. brucei and the colorimetric resazurin method. The MTT test was used to assess the cytotoxicity of essential oils on macrophage cells and Selectivity Indexes were calculated. Of the 17 essential oils screened three showed high trypanocidal activity (IC 50  < 10 μg/mL): Juniperus oxycedrus (IC 50 of 0.9 μg/mL), Cymbopogon citratus (IC 50 of 3.2 μg/mL) and Lavandula luisieri (IC 50 of 5.7 μg/mL). These oils had no cytotoxic effects on macrophage cells showing the highest values of Selectivity Index (63.4, 9.0 and 11.8, respectively). The oils of Distichoselinum tenuifolium, Lavandula viridis, Origanum virens, Seseli tortuosom, Syzygium aromaticum, and Thymbra capitata also exhibited activity (IC 50 of 10-25 μg/mL) but showed cytotoxicity on macrophages. Of the nine compounds tested, α-pinene (IC 50 of 2.9 μg/mL) and citral (IC 50 of 18.9 μg/mL) exhibited the highest anti-trypanosomal activities. Citral is likely the active component of C. citratus and α-pinene is responsible for the antitrypanosomal effects of J. oxycedrus. The present work leads us to propose the J. oxycedrus, C. citratus and L. luisieri oils as valuable sources of new molecules for African Sleeping Sickness treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1.

PubMed

Vaidyanathan, Jayabharathi; Yoshida, Kenta; Arya, Vikram; Zhang, Lei

2016-07-01

Evaluation of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an integral part of drug development and is recommended by regulatory agencies. In this study we compared various prediction methods and cutoff criteria based on in vitro inhibition data to assess the potential of a new molecular entity to inhibit OATP1B1 in vivo. In vitro (eg, IC50 , fu,p ) and in vivo (eg, dose, Cmax , change in area under the curve [AUC]) data for 11 substrates and 61 inhibitors for OATP1B1 were obtained from literature and Drugs@FDA, which include 107 clinical (in vivo) DDI studies. Substrate dependency and variability of IC50 values were noted. In addition to the ratio of unbound or total systemic concentration (Imax,u and Imax ) to IC50 , maximum unbound inhibitor concentration at the inlet to the liver (Iu,in,max ) was used for the estimation of "R value" where R = 1 + Iu,in,max /IC50 . Based on our analyses, Imax /Ki ≥ 0.1, R ≥ 1.04, or R ≥ 1.1 seem to be appropriate for reducing the false-negative (FN) predictions. However, as compared with R ≥ 1.1, Imax /Ki ≥ 0.1 and R ≥ 1.04 resulted in higher false positives (FPs) and lower true negatives (TNs). R ≥ 1.1, Imax,u /Ki ≥ 0.02, and R ≥ 1.25 alone, or combined criterion of Imax /Ki ≥ 0.1 and R ≥ 1.25, were reasonable to determine the need to perform clinical DDI studies with OATP1B1 substrates with similar positive and negative predictive values. Possible reasons of FP or FN from different decision criteria should be considered when interpreting prediction results, and the variability in IC50 determination needs to be understood and minimized. © 2016, The American College of Clinical Pharmacology.

Effects of pyrogallol, hydroquinone and duroquinone on responses to nitrergic nerve stimulation and NO in the rat anococcygeus muscle

PubMed Central

La, Mylinh; Rand, Michael J

1999-01-01

The hypothesis that endogenous superoxide dismutase (SOD) protects the nitrergic transmitter from inactivation by superoxide and that this explains the lack of sensitivity of the transmitter to superoxide generators was tested in the rat isolated anococcygeus muscle.Responses to nitrergic nerve stimulation or to NO were not significantly affected by exogenous SOD or by the Cu/Zn SOD inhibitor diethyldithiocarbamic acid (DETCA).Hydroquinone produced a concentration-dependent reduction of responses to NO with an IC50 of 27 μM, and higher concentrations reduced relaxant responses to nitrergic nerve stimulation with an IC50 of 612 μM. The effects of hydroquinone were only slightly reversed by SOD, so it does not appear to be acting as a superoxide generator.Pyrogallol produced a concentration-dependent reduction in responses to NO with an IC50 value of 39 μM and this effect was reversed by SOD (100–1000 u ml−1). Pyrogallol did not affect responses to nitrergic nerve stimulation. Treatment with DETCA did not alter the differentiating action of pyrogallol.Duroquinone produced a concentration-dependent reduction of relaxations to NO with an IC50 value of 240 μM and 100 μM slightly decreased nitrergic relaxations. After treatment with DETCA, duroquinone produced greater reductions of relaxant responses to NO and to nitrergic stimulation, the IC50 values being 8.5 μM for NO and 40 μM for nitrergic nerve stimulation: these reductions were reversed by SOD.The findings do not support the hypothesis that the presence of Cu/Zn SOD explains the greater susceptibility of NO than the nitrergic transmitter to the superoxide generator pyrogallol, but suggest that it may play a role in the effects of duroquinone. PMID:10051154

Cholinesterase enzymes inhibitors from the leaves of Rauvolfia reflexa and their molecular docking study.

PubMed

Fadaeinasab, Mehran; Hadi, A Hamid A; Kia, Yalda; Basiri, Alireza; Murugaiyah, Vikneswaran

2013-03-25

Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1), (E)-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl) acrylate (2), 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3) and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4). The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM) and BChE (IC50 = 61.72 µM), respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.

Screening of α-Glucosidase Inhibitory Activity from Some Plants of Apocynaceae, Clusiaceae, Euphorbiaceae, and Rubiaceae

PubMed Central

Elya, Berna; Basah, Katrin; Mun'im, Abdul; Yuliastuti, Wulan; Bangun, Anastasia; Septiana, Eva Kurnia

2012-01-01

Diabetes mellitus (DM) is recognized as a serious global health problem that is characterized by high blood sugar levels. Type 2 DM is more common in diabetic populations. In this type of DM, inhibition of α-glucosidase is a useful treatment to delay the absorption of glucose after meals. As a megabiodiversity country, Indonesia still has a lot of potential unexploited forests to be developed as a medicine source, including as the α-glucosidase inhibitor. In this study, we determine the α-glucosidase inhibitory activity of 80% ethanol extracts of leaves and twigs of some plants from the Apocynaceae, Clusiaceae, Euphorbiaceae, and Rubiaceae. Inhibitory activity test of the α-glucosidase was performed in vitro using spectrophotometric methods. Compared with the control acarbose (IC50 117.20 μg/mL), thirty-seven samples of forty-five were shown to be more potent α-glucosidase inhibitors with IC50 values in the range 2.33–112.02 μg/mL. PMID:22187534

The antioxidant and cytotoxic activities of Sonchus oleraceus L. extracts

PubMed Central

Yin, Jie; Kwon, Gu-Joong

2007-01-01

This study investigated in vitro antioxidant activity of Sonchus oleraceus L. by extraction solvent, which were examined by reducing power, hydroxyl radical-scavenging activity(HRSA) and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assays. 70% MeOH extract had the greatest reducing power while EtOH extract had the greatest HRSA. The antioxidant activity of S. oleraceus extracts was concentration dependent and its IC50 values ranged from 47.1 to 210.5 µg/ml and IC50 of 70% MeOH, boiling water and 70% EtOH extracts were 47.1, 52.7 and 56.5 µg/ml, respectively. 70% MeOH extract of S. oleraceus contained the greatest amount of both phenolic and flavonoid contents. The extracts tested had greater nitrite scavenging effects at lower pH conditions. The cytotoxic activity showed that EtOH extract had the best activity against the growth of stomach cancer cell. These results suggest that S. oleraceus extract could be used as a potential source of natural antioxidants. PMID:20368937

The antioxidant and cytotoxic activities of Sonchus oleraceus L. extracts.

PubMed

Yin, Jie; Kwon, Gu-Joong; Wang, Myeong-Hyeon

2007-01-01

This study investigated in vitro antioxidant activity of Sonchus oleraceus L. by extraction solvent, which were examined by reducing power, hydroxyl radical-scavenging activity(HRSA) and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assays. 70% MeOH extract had the greatest reducing power while EtOH extract had the greatest HRSA. The antioxidant activity of S. oleraceus extracts was concentration dependent and its IC(50) values ranged from 47.1 to 210.5 microg/ml and IC(50) of 70% MeOH, boiling water and 70% EtOH extracts were 47.1, 52.7 and 56.5 microg/ml, respectively. 70% MeOH extract of S. oleraceus contained the greatest amount of both phenolic and flavonoid contents. The extracts tested had greater nitrite scavenging effects at lower pH conditions. The cytotoxic activity showed that EtOH extract had the best activity against the growth of stomach cancer cell. These results suggest that S. oleraceus extract could be used as a potential source of natural antioxidants.

In vitro antiplasmodial activity of crude extracts from Togolese medicinal plants.

PubMed

Koudouvo, Koffi; Karou, Simplice D; Ilboudo, Denise P; Kokou, Kouami; Essien, Kodjo; Aklikokou, Kodjo; de Souza, Comlan; Simpore, Jacques; Gbéassor, Mensavi

2011-02-01

To investigate the antimalarial effect of a few plants in Togo folk medicine. After ethnobotanical survey, Opilia celtidifolia, Pavetta corymbosa (P. corymbosa) and Tamarindus indica (T. indica) were selected for screening. In vitro antimalarial tests were performed on crude extracts against fresh clinical isolates of Plasmodium falciparum using the semi microtest. Different IC(50) values of the extracts ranged from 2.042 to 100.000 μg/mL. According to the results, the methanol extract of aerial part of P. corymbosa followed by aqueous extract of fruit of T. indica were the most active (IC(50) of 2.042 and 4.786 μg/mL, respectively). Qualitative test revealed the presence of alkaloids in the leaves of P. corymbosa that may be responsible for the activity of the plant. Our study provides scientific evidence for usage of plant in the folk medicine, and further studies are needed for identification and purification of the active principles. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Identification of homemade inorganic explosives by ion chromatographic analysis of post-blast residues.

PubMed

Johns, Cameron; Shellie, Robert A; Potter, Oscar G; O'Reilly, John W; Hutchinson, Joseph P; Guijt, Rosanne M; Breadmore, Michael C; Hilder, Emily F; Dicinoski, Greg W; Haddad, Paul R

2008-02-29

Anions and cations of interest for the post-blast identification of homemade inorganic explosives were separated and detected by ion chromatographic (IC) methods. The ionic analytes used for identification of explosives in this study comprised 18 anions (acetate, benzoate, bromate, carbonate, chlorate, chloride, chlorite, chromate, cyanate, fluoride, formate, nitrate, nitrite, perchlorate, phosphate, sulfate, thiocyanate and thiosulfate) and 12 cations (ammonium, barium(II), calcium(II), chromium(III), ethylammonium, magnesium(II), manganese(II), methylammonium, potassium(I), sodium(I), strontium(II), and zinc(II)). Two IC separations are presented, using suppressed IC on a Dionex AS20 column with potassium hydroxide as eluent for anions, and non-suppressed IC for cations using a Dionex SCS 1 column with oxalic acid/acetonitrile as eluent. Conductivity detection was used in both cases. Detection limits for anions were in the range 2-27.4ppb, and for cations were in the range 13-115ppb. These methods allowed the explosive residue ions to be identified and separated from background ions likely to be present in the environment. Linearity (over a calibration range of 0.05-50ppm) was evaluated for both methods, with r(2) values ranging from 0.9889 to 1.000. Reproducibility over 10 consecutive injections of a 5ppm standard ranged from 0.01 to 0.22% relative standard deviation (RSD) for retention time and 0.29 to 2.16%RSD for peak area. The anion and cation separations were performed simultaneously by using two Dionex ICS-2000 chromatographs served by a single autoinjector. The efficacy of the developed methods was demonstrated by analysis of residue samples taken from witness plates and soils collected following the controlled detonation of a series of different inorganic homemade explosives. The results obtained were also confirmed by parallel analysis of the same samples by capillary electrophoresis (CE) with excellent agreement being obtained.

Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative

PubMed Central

Cupello, Mauricio Peixoto; Saraiva, Francis Monique; Ippolito, Pedro; Fernandes, Andréia da Silva; Costa, Debora de Sousa dos Santos; Paula, Jessica Isis Oliveira; Costa, Paulo Roberto Ribeiro; Dias, Ayres Guimarães

2017-01-01

The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl-tert-butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi forms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC50 = 259.4 ± 6.1 μM) and intracellular amastigotes infecting peritoneal macrophages (IC50 = 188.2 ± 47.5 μM), with no harmful effects upon the mammalian cells (CC50 values greater than 4 mM), resulting in a high selectivity index (CC50/IC50 > 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC50 of about 191.8 ± 10.5 μM and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC50 of 255.1 ± 3.6 μM. Finally, we investigated the mutagenic potential of the nitrone by the Salmonella/microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000 μM. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms of T. cruzi, offering new insights into CD treatment suggesting additional in vivo tests. PMID:28316976

Mutagenic and Cytotoxicity LQB 123 Profile: Safety and Tripanocidal Effect of a Phenyl-t-Butylnitrone Derivative.

PubMed

Cupello, Mauricio Peixoto; Saraiva, Francis Monique; Ippolito, Pedro; Fernandes, Andréia da Silva; Menna-Barreto, Rubem Figueiredo Sadoko; Costa, Debora de Sousa Dos Santos; Paula, Jessica Isis Oliveira; Costa, Paulo Roberto Ribeiro; Nogueira, Natália Pereira; Felzenswalb, Israel; Dias, Ayres Guimarães; Paes, Marcia Cristina

2017-01-01

The therapeutic options for Chagas disease are limited and its treatment presents a number of drawbacks including toxicity, drug resistance, and insufficient effectiveness against the chronic stage of the disease. Therefore, new therapeutical options are mandatory. In the present work, we evaluated the effect of a phenyl- tert -butylnitrone (PBN) derivate, LQB 123, against Trypanosoma cruzi forms. LQB 123 presented a trypanocidal effect against bloodstream trypomastigotes (IC 50 = 259.4 ± 6.1  μ M) and intracellular amastigotes infecting peritoneal macrophages (IC 50 = 188.2 ± 47.5  μ M), with no harmful effects upon the mammalian cells (CC 50 values greater than 4 mM), resulting in a high selectivity index (CC 50 /IC 50 > 20). Additionally, metacyclic trypomastigotes submitted to LQB 123 presented an IC 50 of about 191.8 ± 10.5  μ M and epimastigotes forms incubated with different concentrations of LQB 123 presented an inhibition of parasite growth with an IC 50 of 255.1 ± 3.6  μ M. Finally, we investigated the mutagenic potential of the nitrone by the Salmonella /microsome assay and observed no induction of mutagenicity even in concentrations as high as 33000  μ M. Taken together, these results present a nonmutagenic compound, with trypanocidal activity against all relevant forms of T. cruzi , offering new insights into CD treatment suggesting additional in vivo tests.

Diterpenoids from Azorella compacta (Umbelliferae) active on Trypanosoma cruzi.

PubMed

Araya, Jorge E; Neira, Iván; da Silva, Solange; Mortara, Renato A; Manque, Patricio; Cordero, Esteban; Sagua, Hernán; Loyola, Alberto; Bórquez, Jorge; Morales, Glauco; González, Jorge

2003-04-01

The anti-Trypanosoma cruzi activity of natural products isolated from Azorella compacta was evaluated, with particular emphasis on their effect against intracellular amastigotes. Five diterpenoids from A. compacta derived from mulinane and azorellane were isolated and identified. Only two products, named azorellanol (Y-2) and mulin-11,3-dien-20-oic acid (Y-5), showed trypanocidal activity against all stages of T. cruzi including intracellular amastigotes. At 10 M, these compounds displayed a strong lytic activity. It ranged from 88.4 0.6 to 99.0 1 % for all strains and stages evaluate, with an IC50 /18 h values of 20-84 M and 41-87 M, respectively. The development of intracellular amastigotes was also inhibited by nearly 60% at 25 M. The trypanocidal molecules Y-2 and Y-5 did show different degrees of cytotoxicity depending on the cell line tested, with an IC50 /24 h ranging from 33.2 to 161.2 M. We evaluated the effect of diterpenoids against intracellular T. cruzi forms by immunofluorescent identification of a specific membrane molecular marker (Ssp-4 antigen) of the T. cruzi amastigote forms. The accuracy and reproducibility of the measurements were found to be outstanding when examined by confocal microscopy.

New hydrazine and hydrazide quinoxaline 1,4-di-N-oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity.

PubMed

Quiliano, Miguel; Pabón, Adriana; Ramirez-Calderon, Gustavo; Barea, Carlos; Deharo, Eric; Galiano, Silvia; Aldana, Ignacio

2017-04-15

We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC 50 =1.40μM, FCR-3 IC 50 =2.56μM) and 19 (3D7 IC 50 =0.24μM, FCR-3 IC 50 =2.8μM) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC 50 -values>241μM) and most selective (SI>86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system. Copyright © 2017 Elsevier Ltd. All rights reserved.

4,5-Substituted 3-Isoxazolols with Insecticidal Activity Act as Competitive Antagonists of Housefly GABA Receptors.

PubMed

Liu, Genyan; Ozoe, Fumiyo; Furuta, Kenjiro; Ozoe, Yoshihisa

2015-07-22

The insect GABA receptor (GABAR), which is composed of five RDL subunits, represents an important target for insecticides. A series of 4,5-disubstituted 3-isoxazolols, including muscimol analogues, were synthesized and examined for their activities against four splice variants (ac, ad, bc, and bd) of housefly GABARs expressed in Xenopus oocytes. Muscimol was a more potent agonist than GABA in all four splice variants, whereas synthesized analogues did not exhibit agonism but rather antagonism in housefly GABARs. The introduction of bicyclic aromatic groups at the 4-position of muscimol and the simultaneous replacement of the aminomethyl group with a carbamoyl group at the 5-position to afford six 4-aryl-5-carbamoyl-3-isoxazolols resulted in compounds that exhibited significantly enhanced antagonism with IC50 values in the low micromolar range in the ac variant. The inhibition of GABA-induced currents by 100 μM analogues was approximately 1.5-4-fold greater in the ac and bc variants than in the ad and bd variants. 4-(3-Biphenylyl)-5-carbamoyl-3-isoxazolol displayed competitive antagonism, with IC50 values of 30, 34, 107, and 96 μM in the ac, bc, ad, and bd variants, respectively, and exhibited moderate insecticidal activity against houseflies, with an LD50 value of 5.6 nmol/fly. These findings suggest that these 3-isoxazolol analogues are novel lead compounds for the design and development of insecticides that target the orthosteric site of housefly GABARs.

In vitro effect of important herbal active constituents on human cytochrome P450 1A2 (CYP1A2) activity.

PubMed

Pan, Yan; Tiong, Kai Hung; Abd-Rashid, Badrul Amini; Ismail, Zakiah; Ismail, Rusli; Mak, Joon Wah; Ong, Chin Eng

2014-10-15

This study was designed to investigate eight herbal active constituents (andrographolide, asiaticoside, asiatic acid, madecassic acid, eupatorin, sinensetin, caffeic acid, and rosmarinic acid) on their potential inhibitory effects on human cytochrome P450 1A2 (CYP1A2) activity. A fluorescence-based enzyme assay was performed by co-incubating human cDNA-expressed CYP1A2 with its selective probe substrate, 3-cyano-7-ethoxycoumarin (CEC), in the absence or presence of various concentrations of herbal active constituents. The metabolite (cyano-hydroxycoumarin) formed was subsequently measured in order to obtain IC50 values. The results indicated that only eupatorin and sinensetin moderately inhibited CYP1A2 with IC50 values of 50.8 and 40.2 μM, while the other active compounds did not significantly affect CYP1A2 activity with IC50 values more than 100 μM. Ki values further determined for eupatorin and sinensetin were 46.4 and 35.2 μM, respectively. Our data indicated that most of the investigated herbal constituents have negligible CYP1A2 inhibitory effect. In vivo studies however may be warranted to ascertain the inhibitory effect of eupatorin and sinensetin on CYP1A2 activity in clinical situations. Copyright © 2014 Elsevier GmbH. All rights reserved.

Effects of Fungicides on Rat's Neurosteroid Synthetic Enzymes

PubMed Central

Shen, Xiuwei; Chen, Fan; Chen, Lanlan; Su, Ying; Huang, Ping

2017-01-01

Exposure to environmental endocrine disruptors may interfere with nervous system's activity. Fungicides such as tebuconazole, triadimefon, and vinclozolin have antifungal activities and are used to prevent fungal infections in agricultural plants. In the present study, we studied effects of tebuconazole, triadimefon, and vinclozolin on rat's neurosteroidogenic 5α-reductase 1 (5α-Red1), 3α-hydroxysteroid dehydrogenase (3α-HSD), and retinol dehydrogenase 2 (RDH2). Rat's 5α-Red1, 3α-HSD, and RDH2 were cloned and expressed in COS-1 cells, and effects of these fungicides on them were measured. Tebuconazole and triadimefon competitively inhibited 5α-Red1, with IC50 values of 8.670 ± 0.771 × 10−6 M and 17.390 ± 0.079 × 10−6 M, respectively, while vinclozolin did not inhibit the enzyme at 100 × 10−6 M. Triadimefon competitively inhibited 3α-HSD, with IC50 value of 26.493 ± 0.076 × 10−6 M. Tebuconazole and vinclozolin weakly inhibited 3α-HSD, with IC50 values about 100 × 10−6 M, while vinclozolin did not inhibit the enzyme even at 100 × 10−6 M. Tebuconazole and triadimefon weakly inhibited RDH2 with IC50 values over 100 × 10−6 M and vinclozolin did not inhibit this enzyme at 100 × 10−6 M. Docking study showed that tebuconazole, triadimefon, and vinclozolin bound to the steroid-binding pocket of 3α-HSD. In conclusion, triadimefon potently inhibited rat's neurosteroidogenic enzymes, 5α-Red1 and 3α-HSD. PMID:28812018

In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks.

PubMed

Wagmann, Lea; Brandt, Simon D; Kavanagh, Pierce V; Maurer, Hans H; Meyer, Markus R

2017-04-15

Tryptamines have emerged as new psychoactive substances (NPS), which are distributed and consumed recreationally without preclinical studies or safety tests. Within the alpha-methylated tryptamines, some of the psychoactive effects of the prototypical alpha-methyltryptamine (AMT) have been described decades ago and a contributing factor of its acute toxicity appears to involve the inhibition of monoamine oxidase (MAO). However, detailed information about analogs is scarce. Therefore, thirteen AMT analogs were investigated for their potential to inhibit MAO. An in vitro assay analyzed using hydrophilic interaction liquid chromatography-high resolution-tandem mass spectrometry was developed and validated. The AMT analogs were incubated with recombinant human MAO-A or B and kynuramine, a non-selective MAO substrate to determine the IC 50 values. The known MAO-A inhibitors 5-(2-aminopropyl)indole (5-IT), harmine, harmaline, yohimbine, and the MAO-B inhibitor selegiline were tested for comparison. AMT and all analogs showed MAO-A inhibition properties with IC 50 values between 0.049 and 166μM, whereas four analogs inhibited also MAO-B with IC 50 values between 82 and 376μM. 7-Me-AMT provided the lowest IC 50 value against MAO-A comparable to harmine and harmaline and was identified as a competitive MAO-A inhibitor. Furthermore, AMT, 7-Me-AMT, and nine further analogs inhibited MAO activity in human hepatic S9 fraction used as model for the human liver which expresses both isoforms. The obtained results suggested that MAO inhibition induced by alpha-methylated tryptamines might be clinically relevant concerning possible serotonergic and adrenergic effects and interactions with drugs (of abuse) particularly acting as monoamine reuptake inhibitors. However, as in vitro assays have only limited conclusiveness, further studies are needed. Copyright © 2017 Elsevier B.V. All rights reserved.

Study of cytotoxic activity, podophyllotoxin, and deoxypodophyllotoxin content in selected Juniperus species cultivated in Poland.

PubMed

Och, Marek; Och, Anna; Cieśla, Łukasz; Kubrak, Tomasz; Pecio, Łukasz; Stochmal, Anna; Kocki, Janusz; Bogucka-Kocka, Anna

2015-06-01

The demand for podophyllotoxin and deoxypodophyllotoxin is still increasing and commercially exploitable sources are few and one of them, Podophyllum hexandrum Royle (Berberidaceae), is a "critically endangered" species. The first aim was to quantify the amount of podophyllotoxin and deoxypodophyllotoxin in 61 Juniperus (Cupressaceae) samples. Cytotoxic activity of podophyllotoxin and ethanolic leaf extracts of Juniperus scopulorum Sarg. "Blue Pacific" and Juniperus communis L. "Depressa Aurea" was examined against different leukemia cell lines. Ultra-performance liquid chromatography (UPLC) analysis was performed with the use of a Waters ACQUITY UPLC(TM) system (Waters Corp., Milford, MA). The peaks of podophyllotoxin and deoxypodophyllotoxin were assigned on the basis of their retention data and mass-to-charge ratio (m/z). Trypan blue assay was performed to obtain IC50 cytotoxicity values against selected leukemia cell lines. Juniperus scopulorum was characterized with the highest level of podophyllotoxin (486.7 mg/100 g DW) while Juniperus davurica Pall. contained the highest amount of deoxypodophyllotoxin (726.8 mg/100 g DW). Podophyllotoxin IC50 cytotoxicity values against J45.01 and CEM/C1 leukemia cell lines were 0.0040 and 0.0286 µg/mL, respectively. Juniperus scopulorum extract examined against J45.01 and HL-60/MX2 leukemia cell lines gave the respective IC50 values: 0.369-9.225 µg/mL. Juniperus communis extract was characterized with the following IC50 cytotoxity values against J45.01 and U-266B1 cell lines: 3.310-24.825 µg/mL. Juniperus sp. can be considered as an alternative source of podophyllotoxin and deoxypodophyllotoxin. Cytotoxic activity of podophyllotoxin and selected leaf extracts of Juniperus sp. against a set of leukemia cell lines was demonstrated.

Identification of novel isoform-selective inhibitors within class I histone deacetylases.

PubMed

Hu, Erding; Dul, Edward; Sung, Chiu-Mei; Chen, Zunxuan; Kirkpatrick, Robert; Zhang, Gui-Feng; Johanson, Kyung; Liu, Ronggang; Lago, Amparo; Hofmann, Glenn; Macarron, Ricardo; de los Frailes, Maite; Perez, Paloma; Krawiec, John; Winkler, James; Jaye, Michael

2003-11-01

Histone deacetylases (HDACs) represent an expanding family of protein modifying-enzymes that play important roles in cell proliferation, chromosome remodeling, and gene transcription. We have previously shown that recombinant human HDAC8 can be expressed in bacteria and retain its catalytic activity. To further explore the catalytic activity of HDACs, we expressed two additional human class I HDACs, HDAC1 and HDAC3, in baculovirus. Recombinant HDAC1 and HDAC3 fusion proteins remained soluble and catalytically active and were purified to near homogeneity. Interestingly, trichostatin (TSA) was found to be a potent inhibitor for all three HDACs (IC50 value of approximately 0.1-0.3 microM), whereas another HDAC inhibitor MS-27-275 (N-(2-aminophenyl)-4-[N-(pyridin-3-methyloxycarbonyl)-aminomethyl]benzamide) preferentially inhibited HDAC1 (IC50 value of approximately 0.3 microM) versus HDAC3 (IC50 value of approximately 8 microM) and had no inhibitory activity toward HDAC8 (IC50 value >100 microM). MS-27-275 as well as TSA increased histone H4 acetylation, induced apoptosis in the human colon cancer cell line SW620, and activated the simian virus 40 early promoter. HDAC1 protein was more abundantly expressed in SW620 cells compared with that of HDAC3 and HDAC8. Using purified recombinant HDAC proteins, we identified several novel HDAC inhibitors that preferentially inhibit HDAC1 or HDAC8. These inhibitors displayed distinct properties in inducing histone acetylation and reporter gene expression. These results suggest selective HDAC inhibitors could be identified using recombinantly expressed HDACs and that HDAC1 may be a promising therapeutic target for designing HDAC inhibitors for proliferative diseases such as cancer.

Potent selective monoamine oxidase B inhibition by maackiain, a pterocarpan from the roots of Sophora flavescens.

PubMed

Lee, Hyun Woo; Ryu, Hyung Won; Kang, Myung-Gyun; Park, Daeui; Oh, Sei-Ryang; Kim, Hoon

2016-10-01

Monoamine oxidase (MAO) catalyzes the oxidation of monoamines and its two isoforms, MAO-A and MAO-B, break down neurotransmitter amines. Of the compounds isolated from the roots of Sophora flavescens, (-)-maackiain (4), a pterocarpan, was found to potently and selectively inhibit human MAO-B, with an IC50 of 0.68μM, and to have a selectivity index of 126.2 for MAO-B. As compared with other herbal natural products, the IC50 value of 4 for MAO-B is one of the lowest reported to date. Genistein (1) highly, effectively and non-selectively inhibited MAO-A and MAO-B with IC50 values of 3.9μM and 4.1μM, respectively. (-)-4-Hydroxy-3-methoxy-8,9-methylenedioxypterocarpan (2) effectively and non-selectively inhibited MAO-A and MAO-B with IC50 values of 20.3μM and 10.3μM, respectively. In addition, compound 4 reversibly and competitively inhibited MAO-B with a Ki value of 0.054μM. Molecular docking simulation revealed that the binding affinity of 4 for MAO-B (-26.6kcal/mol) was greater than its affinity for MAO-A (-8.3kcal/mol), which was in-line with our inhibitory activity findings. Furthermore, Cys172 of MAO-B was found to be a key residue for hydrogen bonding with compound 4. The findings of this study suggest compound 4 be viewed as a new potent, selective, and reversible MAO-B inhibitor, and that compounds 1 and 2 be considered useful lead compounds for the developments of nonselective and reversible MAO inhibitors for the treatment of disorders like Parkinson's disease, Alzheimer disease, and depression. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacologically relevant receptor binding characteristics and 5alpha-reductase inhibitory activity of free Fatty acids contained in saw palmetto extract.

PubMed

Abe, Masayuki; Ito, Yoshihiko; Oyunzul, Luvsandorj; Oki-Fujino, Tomomi; Yamada, Shizuo

2009-04-01

Saw palmetto extract (SPE), used widely for the treatment of benign prostatic hyperplasia (BPH) has been shown to bind alpha(1)-adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors. Major constituents of SPE are lauric acid, oleic acid, myristic acid, palmitic acid and linoleic acid. The aim of this study was to investigate binding affinities of these fatty acids for pharmacologically relevant (alpha(1)-adrenergic, muscarinic and 1,4-DHP) receptors. The fatty acids inhibited specific [(3)H]prazosin binding in rat brain in a concentration-dependent manner with IC(50) values of 23.8 to 136 microg/ml, and specific (+)-[(3)H]PN 200-110 binding with IC(50) values of 24.5 to 79.5 microg/ml. Also, lauric acid, oleic acid, myristic acid and linoleic acid inhibited specific [(3)H]N-methylscopolamine ([(3)H]NMS) binding in rat brain with IC(50) values of 56.4 to 169 microg/ml. Palmitic acid had no effect on specific [(3)H]NMS binding. The affinity of oleic acid, myristic acid and linoleic acid for each receptor was greater than the affinity of SPE. Scatchard analysis revealed that oleic acid and lauric acid caused a significant decrease in the maximal number of binding sites (B(max)) for [(3)H]prazosin, [(3)H]NMS and (+)-[(3)H]PN 200-110. The results suggest that lauric acid and oleic acid bind noncompetitively to alpha(1)-adrenergic, muscarinic and 1,4-DHP calcium channel antagonist receptors. We developed a novel and convenient method of determining 5alpha-reductase activity using LC/MS. With this method, SPE was shown to inhibit 5alpha-reductase activity in rat liver with an IC(50) of 101 microg/ml. Similarly, all the fatty acids except palmitic acid inhibited 5alpha-reductase activity, with IC(50) values of 42.1 to 67.6 microg/ml. In conclusion, lauric acid, oleic acid, myristic acid, and linoleic acid, major constituents of SPE, exerted binding activities of alpha(1)-adrenergic, muscarinic and 1,4-DHP receptors and inhibited 5alpha-reductase activity.

Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives.

PubMed

Aremu, Oluwole S; Gopaul, Kaalin; Kadam, Pramod; Singh, Moganavelli; Mocktar, Chunderika; Singh, Parvesh; Koorbanally, Neil A

2017-01-01

Pyrimidines have widespread activity and have shown potent antibacterial and anticancer activity. To synthesise a range of pyrimidine diones and test them for their antibacterial and anticancer activity. The pyranopyrimidin-2,4-dione derivatives (1-7) were synthesized in a one-pot reaction by reacting malononitrile and barbituric acid with several aromatic aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in aqueous medium. The compounds were tested for their antibacterial activity using the broth microdilution method and for their cytotoxicity against three cell lines, HeLa (cervical cancer), Caco-2 (human colon adenocarcinoma) and HEK 293 (human embryonic kidney cells) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Compounds 1-7 were successfully synthesized in yields of >90%. The 3,4-dihydroxyaryl (3) and the 2,5- dimethoxyaryl (7) derivatives were novel. Compounds 3, 5 (4'-methoxy derivative) and 6 (2',3'-dimethoxy derivative) showed antibacterial activity comparable to or better than the standard ampicillin. All the test compounds 1-7 showed good anticancer activity. The IC50 values ranged from 3.46 to 37.13 μM (HeLa); 136.78 to 297.05 μM (Caco-2) and 137.84 to 333.81 μM (HEK293). The best activity was seen in the HeLa cell line when compared to the standard 5FU (5-Fluorouracil IC50 of 41.85 μM), with 1, 2, 5 and 7 having IC50 values of 10.64, 3.46, 4.36 and 4.44 μM respectively. Additionally, two representative compounds (1 and 7) found to be potent against the two cell lines (HeLa and HEK 293) were docked into the binding site of human kinesin Eg5 with the aim of predicting their binding propensities and to establish their mechanism of action. The Lipinski parameters of these compounds were also computed and analysed for their drug-likeness. Compound 6 is an excellent candidate for a broad spectrum antibiotic with MBCs of 45.6-365.2 μM, while both 3 and 6 have the potential to be developed into an antibiotic against MRSA, with MBCs of 183-199 μM. Since all synthesized compounds showed IC50 values of 10 μM or less especially against the HeLa cells, they can be considered good lead compounds for anticancer agents. Additionally, the docking simulations suggested a good binding affinity of the compounds with Eg5 and indicated their anti-cancer action, at least partially, through its inhibition. The predicted Lipinski descriptors also indicated the potential of these compounds as an orally active drug. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pre-incubation with cyclosporine A potentiates its inhibitory effects on pitavastatin uptake mediated by recombinantly expressed cynomolgus monkey hepatic organic anion transporting polypeptide.

PubMed

Takahashi, Tsuyoshi; Ohtsuka, Tatsuyuki; Uno, Yasuhiro; Utoh, Masahiro; Yamazaki, Hiroshi; Kume, Toshiyuki

2016-11-01

Cyclosporine A, an inhibitor of hepatic organic anion transporting polypeptides (OATPs), reportedly increased plasma concentrations of probe substrates, although its maximum unbound blood concentrations were lower than the experimental half-maximal inhibitory (IC 50 ) concentrations. Pre-incubation with cyclosporine A in vitro before simultaneous incubation with probes has been reported to potentiate its inhibitory effects on recombinant human OATP-mediated probe uptake. In the present study, the effects of cyclosporine A and rifampicin on recombinant cynomolgus monkey OATP-mediated pitavastatin uptake were investigated in pre- and simultaneous incubation systems. Pre-incubation with cyclosporine A, but not with rifampicin, decreased the apparent IC 50 values on recombinant cynomolgus monkey OATP1B1- and OATP1B3-mediated pitavastatin uptake. Application of the co-incubated IC 50 values toward R values (1 + [unbound inhibitor] inlet to the liver, theoretically maximum /inhibition constant) in static models, 1.1 in monkeys and 1.3 in humans, for recombinant cynomolgus monkey and human OATP1B1-mediated pitavastatin uptake might result in the poor prediction of drug interaction magnitudes. In contrast, the lowered IC 50 values after pre-incubation with cyclosporine A provided better prediction with R values of 3.9 for monkeys and 2.7 for humans when the estimated maximum cyclosporine A concentrations at the inlet to the liver were used. These results suggest that the enhanced inhibitory potential of perpetrator medicines by pre-incubation on cynomolgus monkey OATP-mediated pitavastatin uptake in vitro could be of value for the precise estimation of drug interaction magnitudes in silico, in accordance with the findings from pre-administration of inhibitors on pitavastatin pharmacokinetics validated in monkeys. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Development of a monoclonal antibody-based indirect competitive enzyme-linked immunosorbent assay for nitroimidazoles in edible animal tissues and feeds.

PubMed

Han, Wei; Pan, Yuanhu; Wang, Yulian; Chen, Dongmei; Liu, Zhenli; Zhou, Qi; Feng, Liang; Peng, Dapeng; Yuan, Zonghui

2016-02-20

The misuse of nitroimidazoles (NDZs) can lead to NDZs residues in edible animal tissues, which would be harmful to consumer health. To quickly monitor NDZs residues in edible animal tissues and feed, a monoclonal antibody-based indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) with a simple sample preparation method and clean-up was developed in the present study. At first, a broad-specificity monoclonal antibody, 1D5, against NDZs has been produced, which the IC50 values of the NDZs, dimetridazole, ipronidazole, ronidazole hydroxydimetridazole, and hydroxyipronidazole, were 4.79μgL(-1), 0.47μgL(-1), 5.97μgL(-1), 23.48μgL(-1), and 15.03μgL(-1), respectively. The limit of detection of the method for the NDZ matrix calibration ranged from 4.2μgkg(-1) to 50.3μgkg(-1) in the feed matrices and from 0.11μgkg(-1) to 4.11μgkg(-1) in the edible animal tissues matrices. The recoveries of the NDZs were in the range of 75.5-111.8%. The CVs were less than 14.4%. A good correlation (r=0.9905) between the ELISA and HPLC-MS results of the tissues demonstrated the reliability of the developed ic-ELISA, which makes it a useful tool for screening of NDZs in animal edible tissue and feed. Copyright © 2015 Elsevier B.V. All rights reserved.

New polyacetylenes glycoside from Eclipta prostrate with DGAT inhibitory activity.

PubMed

Meng, Xiao; Li, Ban-Ban; Lin, Xin; Jiang, Yi-Yu; Zhang, Le; Li, Hao-Ze; Cui, Long

2018-06-08

One new polyacetylene glycoside eprostrata Ⅰ (1), together with seven known compounds (2-8), were isolated from Eclipta prostrata. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated inhibitory activity on DGAT in an in vitro assay. Compounds 1-8 were found to exhibit inhibitory activity of DGAT1 with IC 50 values ranging from 74.4 ± 1.3 to 101.1 ± 1.1 μM.

Polyketides with Immunosuppressive Activities from Mangrove Endophytic Fungus Penicillium sp. ZJ-SY₂.

PubMed

Liu, Hongju; Chen, Senhua; Liu, Weiyang; Liu, Yayue; Huang, Xishan; She, Zhigang

2016-11-25

Nine polyketides, including two new benzophenone derivatives, peniphenone ( 1 ) and methyl peniphenone ( 2 ), along with seven known xanthones ( 3 - 9 ) were obtained from mangrove endophytic fungus Penicillium sp. ZJ-SY₂ isolated from the leaves of Sonneratia apetala . Their structures were elucidated on the basis of MS, 1D, and 2D NMR data. Compounds 1 , 3 , 5 , and 7 showed potent immunosuppressive activity with IC 50 values ranging from 5.9 to 9.3 μg/mL.

Three new aaptamine derivatives from the South China Sea sponge Aaptos aaptos.

PubMed

Gan, Jian-Hong; Hu, Wen-Zhen; Yu, Hao-Bing; Yang, Fan; Cao, Meng-Xue; Shi, Hua-Jin; Kang, Yong-Feng; Han, Bing-Nan

2015-01-01

Three new aaptamine derivatives (1-3), together with six known related compounds (4-9), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated on the basis of spectroscopic analyses. Compounds 1, 4, 5, 7, and 9 showed cytotoxic activities against HeLa, K562, MCF-7, and U937 cell lines with IC50 values in the range of 0.90-12.32 μM.

Collaborative Model for Acceleration of Individualized Therapy of Colon Cancer

DTIC Science & Technology

2013-10-01

Methods: The anti-proliferative effects of TAK-960 as a single agent and in combination with irinotecan (SN38) or cetuximab were assessed using an assay...following treatment with TAK-960 alone or in combination with standard agents (irinotecan or cetuximab ). Results: CRC cell lines were quite...sensitive to TAK-960 with IC50 values ranging from 0.007 to 1 umol/L. While no synergy was observed in the KRAS WT CRC cell lines in the cetuximab

Ex Vivo Drug Sensitivity Profiles of Plasmodium falciparum Field Isolates from Cambodia and Thailand, 2005 to 2010, Determined by a Histidine-Rich Protein-2 Assay

DTIC Science & Technology

2012-06-13

References 1. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD: Quantitative assessment of antimalarial activity in vitro by a semiautomated...potentially concerning. As before, un- regulated availability of antimalarial medications during that period may have been a contributing factor. Not- ably...et al. observed a similar dip in IC50 values for a range of antimalarial drugs in 2006, and attributed the observa- tion to sampling bias since most

Antigiardial activity of glycoproteins and glycopeptides from Ziziphus honey.

PubMed

Mohammed, Seif Eldin A; Kabashi, Ahmed S; Koko, Waleed S; Azim, M Kamran

2015-01-01

Natural honey contains an array of glycoproteins, proteoglycans and glycopeptides. Size-exclusion chromatography fractionated Ziziphus honey proteins into five peaks with molecular masses in the range from 10 to >200 kDa. The fractionated proteins exhibited in vitro activities against Giardia lamblia with IC50 values ≤ 25 μg/mL. Results indicated that honey proteins were more active as antiprotozoal agents than metronidazole. This study indicated the potential of honey proteins and peptides as novel antigiardial agents.

New antioxidants from the culture broth of Hericium coralloides.

PubMed

Kim, Ji-Yul; Woo, E-Eum; Lee, In-Kyoung; Yun, Bong-Sik

2018-05-17

In our effort to find antioxidants from the higher fungi, we isolated three new compounds (1-3) with a known compound, spirobenzofuran (4), from the culture broth of Hericium coralloides. Bioassay-guided fractionation led to the isolation of these compounds, and we determined the chemical structures through spectroscopic methods. These compounds exhibited antioxidant activity in the range of IC 50 values of 29-66 μM in the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging assay.

Tyrosine-like condensed derivatives as tyrosinase inhibitors.

PubMed

Matos, Maria João; Santana, Lourdes; Uriarte, Eugenio; Serra, Silvia; Corda, Marcella; Fadda, Maria Benedetta; Era, Benedetta; Fais, Antonella

2012-05-01

We report the pharmacological evaluation of a new series of 3-aminocoumarins differently substituted with hydroxyl groups, which have been synthesized because they include in their structures the tyrosine fragment (tyrosine-like compounds), with the aim of discovering structural features necessary for tyrosinase inhibitory activity. The synthesized compounds 4 and 7-9 were evaluated in vitro as mushroom tyrosinase inhibitors. Two of the described compounds showed lower IC50 (concentration giving 50% inhibition of tyrosinase activity) than umbelliferone, used as a reference compound. Compound 7 (IC50=53µm) was the best tyrosinase inhibitor of this small series, having an IC50 value 10-fold lower than umbelliferone. Compound 7 (3-amino-7-hydroxycoumarin) had amino and hydroxyl groups precisely mimicking the same positions that both groups occupy on the tyrosine molecule. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

The effect of brominated flame retardants on neurotransmitter uptake into rat brain synaptosomes and vesicles.

PubMed

Mariussen, Espen; Fonnum, Frode

2003-01-01

The environmental levels of brominated flame retardants (BFRs) are increasing, but little is known about their toxic effects. In this paper, we show that some of the most important BFRs in commercial use today, have a neurotoxicological potential. Hexabromocyclododecane (HBCD) and tetrabromobisphenol-A (TBBPA) inhibit plasma membrane uptake of the neurotransmitters dopamine, glutamate and gamma-amino-n-butyric acid (GABA) at a concentration level similar to what previously found for polychlorinated biphenyls (PCBs) and even for ecstasy. The IC(50) value for HBCD on dopamine uptake was 4 microM, and the IC(50) values for TBBPA were 9, 6 and 16 microM for dopamine, glutamate and GABA, respectively. HBCD also inhibited glutamate uptake at low concentrations, but never achieved more than 50% inhibition. The inhibition was primarily due to their effect on the membrane potential, measured by the membrane potential marker tetraphenylphosphonium bromide (TPP(+)). Other brominated flame retardants such as octaBDE and decaBDE did not have any effects on uptake. TBBPA, HBCD and even the pentabrominated diphenylether mixture (pentaBDE, DE-71, Great Lakes) also inhibited the vesicular uptake of dopamine with an IC(50) value of 3, 3 and 8 microM, respectively. The neurotoxicological consequences of these findings for environmental contaminants such as BFRs and PCBs are discussed.

The melanin synthesis inhibition and radical scavenging activities of compounds isolated from the aerial part of Lespedeza cyrtobotrya.

PubMed

Lee, Mi Yeon; Kim, Jin Hee; Choi, Jung Nam; Kim, Jiyoung; Hwang, Geum Sook; Lee, Choonghwan

2010-06-01

The EtOAc fraction of Lespedeza cyrtobotrya showed mushroom tyrosinase inhibitory and radical scavenging activity. Four active compounds were isolated based on LH-20 chromatography and HPLC, and the structures were elucidated on the basis of their LC-MS and NMR spectral data, as 2-(2,4-Dihydroxyphenyl)-6-hydroxybenzofuran (1), eriodictyol-7-O-glucopyranoside (2), haginin A (3), and dalbergioidin (4), respectively. 2-(2,4-Dihydroxyphenyl)-6-hydroxybenzofuran (1) showed mushroom tyrosinase inhibitory activity with an IC50 value of 5.2 micronM and acted as a competitive inhibitor. Furthermore, 37.3 micronM of compound 1 reduced 50 % of the melanin content on a human melanoma (MNT-1) cells. The radical scavenging activity of 2-(2,4-dihydroxyphenyl)-6-hydroxybenzofuran (1), eriodictyol-7-O-glucopyranoside (2), haginin A (3), and dalbergioidin (4) was shown with IC50 values of 11.0, 24.5, 9.0 and 36.5 micronM in an ABTS system and with IC50 values of 42.7, 36.0, 37.7 and 61.7 micronM in a DPPH system, respectively. The mushroom tyrosinase inhibitory activity of EtOAc fraction of Lespedeza cyrtobotrya was contributed by compound 1, 3 and 4, and radical scavenging activity of it was contributed by compound 1-4.

Protective effects of a standard extract of Mangifera indica L. (VIMANG) against mouse ear edemas and its inhibition of eicosanoid production in J774 murine macrophages.

PubMed

Garrido, G; González, D; Lemus, Y; Delporte, C; Delgado, R

2006-06-01

A standard aqueous extract of Mangifera indica L., used in Cuba as antioxidant under the brand name VIMANG, was tested in vivo for its anti-inflammatory activity, using commonly accepted assays. The standard extract of M. indica, administered orally (50-200mg/kg body wt.), reduced ear edema induced by arachidonic acid (AA) and phorbol myristate acetate (PMA) in mice. In the PMA model, M. indica extract also reduced myeloperoxidase (MPO) activity. In vitro studies were performed using macrophage cell line J774 stimulated with pro-inflammatory stimuli lipopolysaccharide-interferon gamma (LPS-IFNgamma) or calcium ionophore A23187 to determine prostaglandin PGE(2) or leukotriene LTB(4) release, respectively. The extract inhibited the induction of PGE(2) and LTB(4) with IC(50) values of 21.7 and 26.0microg/ml, respectively. Mangiferin (a glucosylxanthone isolated from the extract) also inhibited these AA metabolites (PGE(2), IC(50) value=17.2microg/ml and LTB(4), IC(50) value=2.1microg/ml). These results represent an important contribution to the elucidation of the mechanism involved in the anti-inflammatory and anti-nociceptive effects reported for the standard extract of M. indica VIMANG.

Antiplasmodial activity of plant extracts used in west African traditional medicine.

PubMed

Mustofa; Valentin, A; Benoit-Vical, F; Pélissier, Y; Koné-Bamba, D; Mallié, M

2000-11-01

Five plants originating from Ivory Coast were selected after an ethnobotanical survey, Alchornea cordifolia, Mitragyna inermis, Nauclea diderrichii, Pterocarpus santalinoides, and Terminalia glaucescens. Traditional healers for the treatment of malaria commonly used these plants. Extracts of these plants were tested on three strains of Plasmodium falciparum, FcB1-Colombia and FcM29-Cameroon (chloroquine-resistant strains) and a Nigerian chloroquine-sensitive strain. Extracts were obtained by preparing decoction in water of the powdered plant, the technique used by most of the traditional healers. A radioactive micromethod allowed the evaluation of the in vitro activity of the extracts on P. falciparum. Concentrations inhibiting 50% of the parasite growth (IC(50)) ranged from 2.34 to more than 500 microg/ml according to the plant. For the most active plants (A. cordifolia and T. glaucescens) ethanol and pentane extracts were made and tested. The IC(50) values obtained for these extracts ranged from 0.35 to 43.40 microg/ml. The stage specificity of the ethanol extracts of A. cordifolia and T. glaucescens and pentane extract of T. glaucescens on the parasite erythrocytic cycle were determined. The ethanol extract of T. glaucescens showed its highest activity at the transition from the trophozoite to the schizont stages. Cytotoxicity was estimated on human fibroblasts (HeLa) cells and a cytotoxicity/antiplasmodial index was calculated, it ranged between 5 and 21, and the best antiplasmodial extract (T. glaucescens ethanol extract) had the higher index (>20).

Quinazolin-4-one derivatives as selective histone deacetylase-6 inhibitors for the treatment of Alzheimer's disease.

PubMed

Yu, Chao-Wu; Chang, Pei-Teh; Hsin, Ling-Wei; Chern, Ji-Wang

2013-09-12

Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4b, is the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of α-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated β-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydro-quinazolin-7-yl)-acrylamide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50, 29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 μM) or cytochrome P450 activity (IC50 >6.5 μM) in vitro, and significantly improves learning-based performances of mice with β-amyloid-induced hippocampal lesions.

Traditional medicines used by Q'eqchi' Maya to treat diabetic symptoms and their antiglycation potential.

PubMed

Ferrier, J; Saleem, A; Carter Ramirez, A; Liu, R; Chen, Eric; Pesek, T; Cal, V; Balick, M; Arnason, J T

2018-06-21

Because of the recent increase in type 2 diabetes and the need for complementary treatments in remote communities in many parts of the world, we undertook a study of treatments for diabetic symptoms used by traditional Q'eqchi' Maya healers of Belize. We used quantitative ethnobotany to rank culturally important taxa and subsequent pharmacological and phytochemical studies to assess bioactivity. Antidiabetic plants identified in field interviews with traditional healers were ranked by syndromic importance value (SIV) based on 15 symptoms of diabetes.. Species ranked with high SIV were tested in an assay relevant to many diabetes complications, the advanced glycation endproduct (AGE) inhibition assay. Active principles were identified by phytochemical analysis and bioassay. We collected over 70 plant species having a promising SIV score. The plants represented a broad range of neotropical taxa. Selected Q'eqchi' antidiabetic plants with high SIV were collected in bulk and tested in the advanced glycation endproduct (AGE) inhibition assay. All plant extracts showed AGE inhibition and the half maximal inhibitory concentration (IC 50 ) ranged from 40.8 to 733µg/mL, while the most active species was Tynanthus guatemalensis Donn (Bignoniaceae). A linear regression showed a significant relationship between 1/ IC 50 and SIV. Phytochemical analysis revealed the presence of verbascoside, as a major component and active principle of the T guatemalensis which had an IC 50 = 5.1µg/mL, comparable to the positive control quercetin. The results reveal a rich botanical tradition of antidiabetic symptom treatments among the Q'eqchi'. Study of highly ranked plants revealed their activity in AGE inhibition correlated with SIV. T. guatemalensis was identified as a promising species for further evaluation and local use. Copyright © 2018. Published by Elsevier B.V.

Extracts of Morus nigra L. Leaves Standardized in Chlorogenic Acid, Rutin and Isoquercitrin: Tyrosinase Inhibition and Cytotoxicity

PubMed Central

Fontes, Pedro Ribeiro; Souza, Paula Monteiro; William Fagg, Christopher; Neves Silva Guerra, Eliete; de Medeiros Nóbrega, Yanna Karla; Silveira, Damaris; Fonseca-Bazzo, Yris; Simeoni, Luiz Alberto; Homem-de-Mello, Maurício; Oliveira Magalhães, Pérola

2016-01-01

Melanogenesis is a process responsible for melanin production, which is stored in melanocytes containing tyrosinase. Inhibition of this enzyme is a target in the cosmetics industry, since it controls undesirable skin conditions such as hyperpigmentation due to the overproduction of melanin. Species of the Morus genus are known for the beneficial uses offered in different parts of its plants, including tyrosinase inhibition. Thus, this project aimed to study the inhibitory activity of tyrosinase by extracts from Morus nigra leaves as well as the characterization of its chromatographic profile and cytotoxicity in order to become a new therapeutic option from a natural source. M. nigra leaves were collected, pulverized, equally divided into five batches and the standardized extract was obtained by passive maceration. There was no significant difference between batches for total solids content, yield and moisture content, which shows good reproducibility of the extraction process. Tyrosinase enzymatic activity was determined for each batch, providing the percentage of enzyme inhibition and IC50 values obtained by constructing dose-response curves and compared to kojic acid, a well-known tyrosinase inhibitor. High inhibition of tyrosinase activity was observed (above 90% at 15.625 μg/mL). The obtained IC50 values ranged from 5.00 μg/mL ± 0.23 to 8.49 μg/mL ± 0.59 and were compared to kojic acid (3.37 μg/mL ± 0.65). High Performance Liquid Chromatography analysis revealed the presence of chlorogenic acid, rutin and, its major compound, isoquercitrin. The chromatographic method employed was validated according to ICH guidelines and the extract was standardized using these polyphenols as markers. Cytotoxicity, assessed by MTT assay, was not observed on murine melanomas, human keratinocytes and mouse fibroblasts in tyrosinase IC50 values. This study demonstrated the potential of M. nigra leaf extract as a promising whitening agent of natural source against skin hyperpigmentation. PMID:27655047

Anti-Proliferative Effect and Phytochemical Analysis of Cymbopogon citratus Extract

PubMed Central

Halabi, Mohammed F.; Sheikh, Bassem Y.

2014-01-01

The antiproliferative and antioxidant potential of Cymbopogon citratus (Lemon grass) extracts were investigated. The extracts were isolated by solvent maceration method and thereafter subjected to antiproliferative activity test on five different cancer cells: human colon carcinoma (HCT-116), breast carcinoma (MCF-7 and MDA-MB 231), ovarian carcinoma (SKOV-3 and COAV), and a normal liver cell line (WRL 68). The cell viability was determined using MTT assay. The DPPH radical scavenging assay revealed a concentration dependent trend. A maximum percentage inhibition of 45% and an IC50 of 278 μg/mL were observed when aqueous extract was evaluated. In contrast, 48.3% and IC50 of 258.9 μg/mL were observed when 50% ethanolic extract was evaluated. Both extracts at concentration of 50 to 800 μg/mL showed appreciative metal chelating activity with IC50 value of 172.2 ± 31 μg/mL to 456.5 ± 30 μg/mL. Depending on extraction solvent content, extract obtained from 50% ethanolic solvent proved to be more potent on breast cancer MCF-7 cell line (IC50 = 68 μg/mL). On the other hand, 90% ethanolic extract showed a moderate potency on the ovarian cancer (COAV) and MCF-7 cells having an IC50 of 104.6 μg/mL each. These results suggested antiproliferative efficacy of C. citratus ethanolic extract against human cancer cell lines. PMID:24791006

Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats

PubMed Central

Gao, Na; Qi, Bing; Liu, Fang-jun; Fang, Yan; Zhou, Jun; Jia, Lin-jing; Qiao, Hai-ling

2014-01-01

Baicalin has been used as mainly bioactive constituent of about 100 kinds of traditional Chinese medicines in Chinese pharmacopoeia. The effect of baicalin on cytochrome P450 should be paid more attention because baicalin was used widely. The aim of this study was to investigate whether baicalin could inhibit CYP1A2 in pooled human liver microsomes (HLMs) and in rats in vivo and the gene polymorphisms could affect inter-individual variation in IC50 in 28 human livers. Phenacetin was used as probe of CYP1A2. Kinetic parameter of CYP1A2 and IC50 of baicalin on CYP1A2 to each sample were measured and the common CYP1A2 polymorphisms (−3860G>A and −163C>A) were genotyped. The results showed that baicalin exhibited a mixed-type inhibition in pooled HLMs, with a Ki value of 25.4 µM. There was substantial variation in Km, Vmax, CLint of CYP1A2 and IC50 of baicalin on CYP1A2 (3∼10-fold). The range was from 26.6 to 114.8 µM for Km, from 333 to 1330 pmol·min−1·mg−1protein for Vmax and from 3.8 to 45.3 µL·min−1·mg−1 protein for CLint in HLMs (n = 28). The Mean (range) value of IC50 in 28 HLMs was 36.3 (18.9 to 56.1) µM. The genotypes of −3860G>A and −163C>A had no significant effect on the inhibition of baicalin on CYP1A2. The animal experiment results showed that baicalin (450 mg/kg, i.v.) significantly decreased the Cmax and CL of phenacetin, and increased C60 min, t1/2, Vd and AUC (P<0.05). There were significant correlations between percentage of control in C60 min, t1/2, CL, AUC of phenacetin and Cmax of baicalin in 11 rats (P<0.05). Protein binding experiments in vitro showed that baicalin (0–2000 mg/L) increased the unbound phenacetin from 14.5% to 28.3%. In conclusion, baicalin can inhibit the activity of CYP1A2 in HLMs and exhibit large inter-individual variation that has no relationship with gene polymorphism. Baicalin can change the pharmacokinetics of phenacetin in rats. PMID:24587011

Anti-oxidant and anti-inflammatory activity of leaf extracts and fractions of Mangifera indica.

PubMed

Mohan, C G; Deepak, M; Viswanatha, G L; Savinay, G; Hanumantharaju, V; Rajendra, C E; Halemani, Praveen D

2013-04-13

To evaluate the anti-oxidant and anti-inflammatory activity of leaf extracts and fractions of Mangifera indica in in vitro conditions. In vitro DPPH radical scavenging activity and lipoxygenase (LOX) inhibition assays were used to evaluate the anti-oxidant and anti-inflammatory activities respectively. Methanolic extract (MEMI), successive water extract (SWMI) and ethyl acetate fraction (EMEMI), n-butanol fraction (BMEMI) and water soluble fraction (WMEMI) of methanolic extract were evaluated along with respective reference standards. In in vitro DPPH radical scavenging activity, the MEMI, EMEMI and BMEMI have offered significant antioxidant activity with IC(50) values of 13.37, 3.55 and 14.19 μg/mL respectively. Gallic acid, a reference standard showed significant antioxidant activity with IC(50) value of 1.88 and found to be more potent compared to all the extracts and fractions. In in vitro LOX inhibition assay, the MEMI, EMEMI and BMEMI have showed significant inhibition of LOX enzyme activity with IC(50) values of 96.71, 63.21 and 107.44 μg/mL respectively. While, reference drug Indomethacin also offered significant inhibition against LOX enzyme activity with IC(50) of 57.75. Furthermore, MEMI was found to more potent than SWMI and among the fractions EMEMI was found to possess more potent antioxidant and anti-inflammatory activity. These findings suggest that the MEMI and EMEMI possess potent anti-oxidant and anti-inflammatory activities in in vitro conditions. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Inhibitory activity of phenolic-rich pistachio green hull extract-enriched pasta on key type 2 diabetes relevant enzymes and glycemic index.

PubMed

Lalegani, Sajjad; Ahmadi Gavlighi, Hassan; Azizi, Mohammad Hossein; Amini Sarteshnizi, Roghayeh

2018-03-01

Phenolic compounds as agro-industrial by-products have been associated with health benefits since they exhibit high antioxidant activity and anti-diabetic properties. In this study, polyphenol-rich extract from pistachio green hull (PGH) was evaluated for antioxidant activity and its ability to inhibit α-amylase and α-glucosidase activity in vitro. The effect of PGH extract powder on in vitro starch digestibility was also evaluated. The results showed that PGH had stronger antioxidant activity than Trolox. The inhibitory effect of PGH extract against α-amylase from porcine pancreas was dose dependent and the IC 50 value was ~174μgGAE/mL. The crude PGH extract was eight times more potent on baker yeast α-glucosidase activity (IC 50 ~6μgGAE/mL) when compared to acarbose, whereas the IC 50 value of PGH extract against rat intestinal maltase activity obtained ~2.6mgGAE/mL. The non-tannin fraction of PGH extract was more effective against α-glucosidase than tannin fraction whereas the α-amylase inhibitor was concentrated in the tannin fraction. In vitro starch digestibility and glycemic index (GI) of pasta sample supplemented with PGH extract powder (1.5%) was significantly lower than the control pasta. The IC 50 value of PGH extract obtained from cooked pasta against α-amylase and α-glucosidase was increased. These results have important implications for the processing of PGH for food industry application and therefore could comply with glucose control diets. Copyright © 2017 Elsevier Ltd. All rights reserved.

A new inositol triester from Taraxacum mongolicum.

PubMed

Liu, Jifeng; Zhang, Nenling; Liu, Mengqi

2014-01-01

One new inositol triester, 4,5,6-tri-O-p-hydroxyphenylacetyl-chiro-inositol (1), was isolated from the ethanolic extract of Taraxacum mongolicum, along with two known compounds, 11β,13-dihydrotaraxinic acid (2) and taraxinic acid β-d-glucopyranosyl ester (3). The isolates were tested for their anti-hepatitis B virus (HBV) activities; 11β,13-dihydrotaraxinic acid (2) exhibited an IC50 value of 0.91 mM inhibiting the secretion of the HBV surface antigen and an IC50 value of 0.34 mM inhibiting the secretion of the HBV e antigen using HBV transfected Hep G2.2.15 cell line.

Chemistry and biological activity of coumarins at molecular level.

PubMed

Garro, Hugo A; García, Celina; Martín, Víctor S; Tonn, Carlos E; Pungitore, Carlos R

2014-08-01

Synthetic coumarins were prepared in high yields using ionic liquids as an environmental friendly alternative. 3,4-Dimethyl-7-hydroxycoumarin (3ab) and 3-isopropyl-4-methyl-5,7-dihydroxycoumarin (3bc) showed interesting activity against Taq DNA polymerase with IC50 values of 115.7 microM and 82.2 microM, respectively. Also, 4-methyl-7-hydroxycoumarin (3aa) and 4-methyl-5,7-dihydroxycoumarin (3ba) exhibited inhibitory activity against MMLV-RT with IC50 values of 23.5 microM and 18.3 microM, respectively. These inhibitors could have importance as antiretroviral chemotherapeutic agents and also for the development of antitumor drugs.

Colletotrilactam A-D, novel lactams from Colletotrichum gloeosporioides GT-7, a fungal endophyte of Uncaria rhynchophylla.

PubMed

Wei, Bo; Yang, Zhong-Duo; Chen, Xiao-Wei; Zhou, Shuang-Yan; Yu, Hai-Tao; Sun, Jing-Yun; Yao, Xiao-Jun; Wang, Yong-Gang; Xue, Hong-Yan

2016-09-01

Four novel lactams, colletotrilactam A-D (1-4), along with six known compounds (5-10) were isolated from the culture broth of Colletotrichum gloeosporioides GT-7, a fungal endophyte of Uncaria rhynchophylla. The structures of these compounds were elucidated by comprehensive NMR spectroscopy. Isolates were tested for monoamine oxidase (MAO) inhibitory activity and compound 9 showed potent MAO inhibitory activity with IC50 value of 8.93±0.34μg/mL, when the IC50 value of iproniazid as a standard was 1.80±0.5μg/mL. Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibition of phospholipase cgamma1 and cancer cell proliferation by triterpene esters from Uncaria rhynchophylla.

PubMed

Lee, J S; Kim, J; Kim, B Y; Lee, H S; Ahn, J S; Chang, Y S

2000-06-01

Investigation of the hooks of Uncaria rhynchophylla resulted in isolation of six phospholipase Cgamma1 (PLCgamma1) inhibitors (1-6). The structures of these compounds were elucidated as pentacyclic triterpene esters by spectroscopic and chemical analysis. Three of them, namely uncarinic acids C (1), D (2), and E (3), are newly reported as natural products. All the compounds showed dose-dependent inhibitory activities against PLCgamma1 in vitro with IC(50) values of 9.5-44.6 microM and inhibited the proliferation of human cancer cells with IC(50) values of 0.5-6.5 microg/mL.

Antidiabetic potential of Caesalpinia sumatrana, a medicinal herbs traditionally used by local tribe in East Kalimantan

NASA Astrophysics Data System (ADS)

Wicaksono, D. A.; Rosamah, E.; Kusuma, I. W.

2018-04-01

The aims of the research was to analyze the content of phytochemicals, to examine the antioxidant and antidiabeticpotentials of n-hexane, chloroform, ethyl acetate, and ethanol extracts of Caesalpinia sumatrana. Method to measure antioxidant capacity of sample involves the use of the free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH) which is widely used to test the ability of compounds to act as free radical. Analysis the potential of antidiabeticactivity of the extracts was determined by α-glucosidase and α-amylase inhibitory assay. Of all extracts obtained by successive maceration, ethanol maceration gave the highest extract by 2.63% of extract on the dry weigh basis. The result of phytochemicals showed that all extracts contain alkaloid and flavonoid. The highest antioxidant activity was 82.32% with IC50 value of 5.00 µg/ml obtained by ethanol extract. The results of enzyme inhibitory assay of α-glucosidase showed that ethanol extract of C. sumatrana had IC50 value 17.16 µg/mL to inhibit ɑ-glucosidase activity and IC50 value 16.78 µg/mL for ɑ-amylase. The present result displayed potential of the plant to be developed as natural antidiabetic and antioxidant agents.

Cyclopentenone derivatives and polyhydroxylated steroids from the soft coral Sinularia acuta.

PubMed

Zhang, Nai-Xia; Tang, Xu-Li; van Ofwegen, Leen; Xue, Lei; Song, Wen-Juan; Li, Ping-Lin; Li, Guo-Qiang

2015-02-01

Four new polyhydroxylated steroids, 1-4, and the racemic form of cyclopentenone 9, together with four known steroids, 5-8, one known cyclopentenone derivative, 10, and one known butenolide derivative, 11, were isolated from the soft coral Sinularia acuta collected from Weizhou Island of Guangxi Province, P. R. China. Their structures were elucidated on the basis of spectroscopic analyses and by comparison of the corresponding data with those previously reported. The cytotoxicities of the isolates 1-11 in vitro against the selected tumor cell lines HL-60, HeLa, and K562 were evaluated. Compounds 2 and 5 showed potent cytotoxicities against HL-60 cell lines with IC50 values of 7.3 and 9.9 μM, respectively. Compounds 5 and 6 showed moderate activities against K562 cell lines with IC50 values of 10.9 and 11.7 μM, respectively, while compounds 1, 2, and 6 showed weak activities against HeLa cell lines with respective IC50 values of 44.8, 27.1, and 18.2 μM. This is the first report on chemical and bioactivity research of S. acuta. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

Purification, characterization, and biological activities of broccolini lectin.

PubMed

Xu, Pingping; Zhang, Ting; Guo, Xiaolei; Ma, Chungwah; Zhang, Xuewu

2015-01-01

Plant lectins have displayed a variety of biological activities. In this study, for the first time, a 27 kDa arabinose- and mannose-specific lectin from Broccolini (Brassica oleracea Italica × Alboglabra), named as BL (Broccolini lectin), was purified by an activity-driven protocol. Mass spectrometry analysis and database search indicated that no matches with any plant lectin were found, but BL contained some peptide fragments (QQQGQQGQQLQQVISR, QQGQQQGQQGQQLQQVISR and VCNIPQVSVCPF QK). BL exhibited hemagglutinating activity against chicken erythrocytes at 4 µg/mL. BL retained full hemagglutinating activity at pH 7-8 and temperature 30-40°C, and had an optimal activity in Ca(2+) solution. Bioactivity assay revealed that BL exhibited dose-dependent inhibition activity on 5 bacterial species with IC50 values of 143.95-486.33 μg/mL, and on 3 cancer cells with IC50 values of 178.82-350.93 μg/mL. Notably, 5-fold reduction in IC50 values was observed on normal L-O2 vs cancerous HepG-2 cells (924.35 vs. 178.82 μg/mL). This suggests that BL should be promising in food and medicine. © 2015 American Institute of Chemical Engineers.

Urease inhibitory profile of extracts and chemical constituents of Pistacia atlantica ssp. cabulica Stocks.

PubMed

Uddin, Ghias; Ismail; Rauf, Abdur; Raza, Muslim; Khan, Haroon; Nasruddin; Khan, Majid; Farooq, Umar; Khan, Ajmal; Arifullah

2016-06-01

The current study was designed to evaluate the urease inhibitory profile of extract and fractions of Pistacia atlantica ssp. cabulica Stocks followed by bioactivity-guided isolated compounds. The crude extract was found significantly active with urease inhibitor (95.40% at 0.2 mg/mL) with IC50 values of 32.0 ± 0.28 μg/mL. Upon fractionation, ethyl acetate fraction displayed 100% urease inhibition with IC50 values of 19.9 ± 0.51 μg/mL at 0.2 mg/mL. However, n-hexane and chloroform fractions exhibited insignificant urease inhibition. Similarly, the isolated compound, transilitin (1) and dihydro luteolin (2) demonstrated marked urease attenuation with 95 and 98% respectively, at 0.15 mg/mL. Both the isolated compounds showed marked potency with IC50 values of 8.54 ± 0.54 and 9.58 ± 2.22 μg/mL, respectively. In short, both the extract and fractions and isolated compounds showed marked urease inhibition and thus a useful natural source of urease inhibition.

Antitumor, Antioxidant, and Nitrite Scavenging Effects of Chinese Water Chestnut (Eleocharis dulcis) Peel Flavonoids.

PubMed

Zhan, Ge; Pan, Leiqing; Tu, Kang; Jiao, Shunshan

2016-10-01

The preparation, quantification, and characterization of flavonoid compounds from Chinese water chestnut peel (CWCP) flavonoid extract and ethyl acetate fraction (EF), n-butanol fraction, and water fraction were studied. Among these, EF showed the maximum free radical levels (IC 50 values of 0.36, 0.40, and 0.37 mg/mL for DPPH•, ABTS• + , and •OH, respectively), nitrite scavenging effects (IC 50 = 1.89 mg/mL), and A549 cell inhibitory activities (IC 50 = 776.12 μg/mL) with the highest value of total flavonoid content (TFC, 421.32 mg/g). Moreover, the contents of 8 flavonoids in this fraction were quantified using high-performance liquid chromatography, and fisetin, diosmetin, luteolin, and tectorigenin were the 4 major flavonoids with levels of 31.66, 29.91, 13.69, and 12.41 mg/g, respectively. Luteolin produced a greater inhibition of human lung cancer A549 cells (IC 50 = 59.60 μg/mL) than did fisetin, diosmetin, and tectorigenin. Flow cytometry revealed that the cellular mechanisms of luteolin inhibition of A549 cells were achieved via the induction of cell proliferation arrest at G 1 phase and apoptosis/necrosis. Our findings suggest that flavonoids are closely associated with antitumor, antioxidant, and nitrite scavenging effects of CWCP. © 2016 Institute of Food Technologists®.

Dihydropyrimidones: As novel class of β-glucuronidase inhibitors.

PubMed

Ali, Farman; Khan, Khalid Mohammed; Salar, Uzma; Iqbal, Sarosh; Taha, Muhammad; Ismail, Nor Hadiani; Perveen, Shahnaz; Wadood, Abdul; Ghufran, Mehreen; Ali, Basharat

2016-08-15

Dihydropyrimidones 1-37 were synthesized via a 'one-pot' three component reaction according to well-known Biginelli reaction by utilizing Cu(NO3)2·3H2O as catalyst, and screened for their in vitro β-glucuronidase inhibitory activity. It is worth mentioning that amongst the active molecules, compounds 8 (IC50=28.16±.056μM), 9 (IC50=18.16±0.41μM), 10 (IC50=22.14±0.43μM), 13 (IC50=34.16±0.65μM), 14 (IC50=17.60±0.35μM), 15 (IC50=15.19±0.30μM), 16 (IC50=27.16±0.48μM), 17 (IC50=48.16±1.06μM), 22 (IC50=40.16±0.85μM), 23 (IC50=44.16±0.86μM), 24 (IC50=47.16±0.92μM), 25 (IC50=18.19±0.34μM), 26 (IC50=33.14±0.68μM), 27 (IC50=44.16±0.94μM), 28 (IC50=24.16±0.50μM), 29 (IC50=34.24±0.47μM), 31 (IC50=14.11±0.21μM) and 32 (IC50=9.38±0.15μM) found to be more potent than the standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25μM). Molecular docking study was conducted to establish the structure-activity relationship (SAR) which demonstrated that a number of structural features of dihydropyrimidone derivatives were involved to exhibit the inhibitory potential. All compounds were characterized by spectroscopic techniques such as (1)H, (13)C NMR, EIMS and HREI-MS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hyoscine butylbromide potently blocks human nicotinic acetylcholine receptors in SH-SY5Y cells.

PubMed

Weiser, Thomas; Just, Stefan

2009-02-06

Hyoscine butylbromide (HBB; tradenames: Buscopan/Buscapina is an antispasmodic drug for the treatment of abdominal pain associated with gastrointestinal cramping. As a hyoscine derivative, this compound competitively inhibits muscarinic acetylcholine (ACh) receptors on smooth muscle cells in the gastrointestinal tract. Preliminary investigations suggested that it might also inhibit nicotinic ACh receptors. This study investigated the effect of HBB on nicotinic ACh receptor-mediated membrane currents in SH-SY5Y cells. ACh and nicotine application-induced comparable membrane currents with EC(50) values of 25.9+/-0.6 and 40.1+/-0.4microM, respectively. When coapplied with 100microM ACh, HBB concentration-dependently suppressed currents with an IC(50) value of 0.19+/-0.04microM, and was approximately seven-times more potent than the ganglionic blocker, hexamethonium (IC(50)=1.3+/-0.3microM). Increasing the agonist concentration to 5mM did not affect the amount of block by HBB, which suggests a non-competitive mode of action. These functional in vitro data demonstrate for the first time that HBB blocks neuronal nicotinic ACh receptors in the same concentration range as it inhibits muscarinic ACh receptors. If one hypothesizes that HBB might also affect nicotinic receptors in autonomic neurons in vivo (e. g. in the enteric nervous system), this effect could contribute to its spasmolytic activity.

In vitro antiprotozoan activity and mechanisms of action of selected Ghanaian medicinal plants against Trypanosoma, Leishmania, and Plasmodium parasites.

PubMed

Ohashi, Mitsuko; Amoa-Bosompem, Michael; Kwofie, Kofi Dadzie; Agyapong, Jefferey; Adegle, Richard; Sakyiamah, Maxwell Mamfe; Ayertey, Frederick; Owusu, Kofi Baffuor-Awuah; Tuffour, Isaac; Atchoglo, Philip; Tung, Nguyen Huu; Uto, Takuhiro; Aboagye, Frederick; Appiah, Alfred Ampomah; Appiah-Opong, Regina; Nyarko, Alexander K; Anyan, William Kofi; Ayi, Irene; Boakye, Daniel Adjei; Koram, Kwadwo Ansah; Edoh, Dominic; Yamaoka, Shoji; Shoyama, Yukihiro; Ohta, Nobuo

2018-05-07

Trypanosomiasis, leishmaniasis, and malaria are protozoan infections of public health importance with thousands of new cases recorded annually. Control of these infection(s) with existing chemotherapy is limited by drug toxicity, lengthy parenteral treatment, affordability, and/or the emergence of resistant strains. Medicinal plants on the other hand are used in the treatment of various infectious diseases although their chemical properties are not fully evaluated. In this study, we screened 112 crude extracts from 72 selected Ghanaian medicinal plants for anti-Trypanosoma, anti-Leishmania, and anti-Plasmodium activities in vitro and investigated their mechanisms of action. Twenty-three extracts from 20 plants showed significant antiprotozoan activity against at least 1 of 3 protozoan parasites screened with IC 50 values less than 20 μg/ml. Eleven extracts showed high anti-Trypanosoma activity with Bidens pilosa whole plant and Morinda lucida leaf extracts recording the highest activities. Their IC 50 (selectivity index [SI]) values were 5.51 μg/ml (35.00) and 5.96 μg/ml (13.09), respectively. Nine extracts had high anti-Leishmania activity with Annona senegalensis and Cassia alata leaf extracts as the most active. Their IC 50 (SI) values were 10.8 μg/ml (1.50) and 10.1 μg/ml (0.37), respectively. Six extracts had high anti-Plasmodium activity with the leaf and stem-bark extracts of Terminalia ivorensis recording the highest activity. Their IC 50 (SI) values were 7.26 μg/ml (129.36) and 17.45 μg/ml (17.17), respectively. Only M. lucida at 25 μg/ml induced significant apoptosis-like cell death in Trypanosoma parasites. Anti-Leishmania active extracts induced varying morphological changes in Leishmania parasites such as multiple nuclei and/or kinetoplast, incomplete flagella division, or nuclear fragmentation. Active extracts may be potential sources for developing new chemotherapy against these infections. Copyright © 2018 John Wiley & Sons, Ltd.

Phytochemical and cytotoxic studies on the leaves of Calotropis gigantea.

PubMed

Nguyen, Khang D H; Dang, Phu H; Nguyen, Hai X; Nguyen, Mai T T; Awale, Suresh; Nguyen, Nhan T

2017-07-01

A new lignan, 9'-methoxypinoresinol (1), and two new glycosylated 5-hydroxymethylfurfurals, calofurfuralside A (2), and calofurfuralside B (3), together with nine known compounds (4-12) have been isolated from the active fractions, CHCl 3 (IC 50 , 0.32μgmL -1 ) and EtOAc (IC 50 , 0.55μgmL -1 ) fractions of the leaves of Calotropis gigantea. Their structures were elucidated based on NMR and MS data. Among the isolated compounds, compounds 1 and 9 exhibited potent cytotoxicity against PANC-1 human pancreatic cancer cell line under the normoglycemic condition with IC 50 values of 3.7 and 3.3μM, respectively. 9'-Methoxypinoresinol (1) significantly inhibited the colony formation of PANC-1 cells in a concentration-dependent manner. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro.

PubMed

Chen, Huan-Huan; Zhou, Hui-Jun; Fang, Xin

2003-09-01

Artemisinin derivatives artesunate (ART) and dihydroartemisinin are remarkable anti-malarial drugs with low toxicity to humans. In the present investigation, we find they also inhibited tumor cell growth and suppressed angiogenesis in vitro. The anti-cancer activity was demonstrated by inhibition (IC(50)) of four human cancer cell lines: cervical cancer Hela, uterus chorion cancer JAR, embryo transversal cancer RD and ovarian cancer HO-8910 cell lines growth by the MTT assay. IC(50) values ranged from 15.4 to 49.7 microM or from 8.5 to 32.9 microM after treatment with ART or dihydroartemisinin for 48 h, indicating that dihydroartemisinin was more effective than ART in inhibiting cancer cell lines. The anti-angiogenic activities were tested on in vitro models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial (HUVE) cells. We investigated the inhibitory effects of ART and dihydroartemisinin on HUVE cells proliferation by cell counting, migration into the scratch wounded area in HUVE cell monolayers and microvessel tube-like formation on collagen gel. The results showed ART and dihydroartemisinin significantly inhibited angiogenisis in a dose-dependent form in range of 12.5-50 microM and 2.5-50 microM, respectively. They indicated that dihydroartemisinin was more effective than ART in inhibiting angiogenesis either. These results and the known low toxicity are clues that ART and dihydroartemisinin may be promising novel candidates for cancer chemotherapy.

Phenoxyacetohydrazide Schiff bases: β-glucuronidase inhibitors.

PubMed

Jamil, Waqas; Perveen, Shagufta; Shah, Syed Adnan Ali; Taha, Muhammad; Ismail, Nor Hadiani; Perveen, Shahnaz; Ambreen, Nida; Khan, Khalid M; Choudhary, Muhammad I

2014-06-25

Phenoxyacetohydrazide Schiff base analogs 1-28 have been synthesized and their in vitro β-glucouoronidase inhibition potential studied. Compounds 1 (IC50=9.20±0.32 µM), 5 (IC50=9.47±0.16 µM), 7 (IC50=14.7±0.19 µM), 8 (IC50=15.4±1.56 µM), 11 (IC50=19.6±0.62 µM), 12 (IC50=30.7±1.49 µM), 15 (IC50=12.0±0.16 µM), 21 (IC50=13.7±0.40 µM) and 22 (IC50=22.0±0.14 µM) showed promising β-glucuronidase inhibition activity, better than the standard (D-saccharic acid-1,4-lactone, IC50=48.4±1.25 µM).

Drug Synergy of Tenofovir and Nanoparticle-Based Antiretrovirals for HIV Prophylaxis

PubMed Central

Chaowanachan, Thanyanan; Krogstad, Emily; Ball, Cameron; Woodrow, Kim A.

2013-01-01

Background The use of drug combinations has revolutionized the treatment of HIV but there is no equivalent combination product that exists for prevention, particularly for topical HIV prevention. Strategies to combine chemically incompatible agents may facilitate the discovery of unique drug-drug activities, particularly unexplored combination drug synergy. We fabricated two types of nanoparticles, each loaded with a single antiretroviral (ARV) that acts on a specific step of the viral replication cycle. Here we show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV). Methodology/Principal Findings Biodegradable poly(lactide-co-glycolide) nanoparticles loaded with efavirenz (NP-EFV) or saquinavir (NP-SQV) were individually prepared by emulsion or nanoprecipitation techniques. Nanoparticles had reproducible size (d ∼200 nm) and zeta potential (-25 mV). The drug loading of the nanoparticles was approximately 7% (w/w). NP-EFV and NP-SQV were nontoxic to TZM-bl cells and ectocervical explants. Both NP-EFV and NP-SQV exhibited potent protection against HIV-1 BaL infection in vitro. The HIV inhibitory effect of nanoparticle formulated ARVs showed up to a 50-fold reduction in the 50% inhibitory concentration (IC50) compared to free drug. To quantify the activity arising from delivery of drug combinations, we calculated combination indices (CI) according to the median-effect principle. NP-EFV combined with free TFV demonstrated strong synergistic effects (CI50 = 0.07) at a 1∶50 ratio of IC50 values and additive effects (CI50 = 1.05) at a 1∶1 ratio of IC50 values. TFV combined with NP-SQV at a 1∶1 ratio of IC50 values also showed strong synergy (CI50 = 0.07). Conclusions ARVs with different physicochemical properties can be encapsulated individually into nanoparticles to potently inhibit HIV. Our findings demonstrate for the first time that combining TFV with either NP-EFV or NP-SQV results in pronounced combination drug effects, and emphasize the potential of nanoparticles for the realization of unique drug-drug activities. PMID:23630586

Synthesis of 6-chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives: Antidiabetic, antioxidant, β-glucuronidase inhibiton and their molecular docking studies.

PubMed

Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Rashwan, Hesham; Jamil, Waqas; Ali, Sajjad; Kashif, Syed Muhammad; Rahim, Fazal; Salar, Uzma; Khan, Khalid Mohammed

2016-04-01

6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1-26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and β-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC50=240.10±2.50μM) and 4 (IC50=240.30±2.90μM) was found to be most active compound of this series, while compounds 3 (IC50=260.10±2.50μM), 6 (IC50=290.60±3.60μM), 13 (IC50=288.20±3.00μM) and 26 (IC50=292.10±3.20μM) also showed better activities than the standard rutin (IC50=294.50±1.50μM). In antioxidant assay, compound 1 (IC50=69.45±0.25μM), 2 (IC50=58.10±2.50μM), 3 (IC50=74.25±1.10μM), and 4 (IC50=72.50±3.30μM) showed good activities. In β-glucuronidase activity, compounds 3 (IC50=29.25±0.50μM), compound 1 (IC50=30.10±0.60μM) and compound 4 (IC50=46.10±1.10μM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC50=48.50±1.25μM) and their interaction with the enzyme was confirm by docking studies. Copyright © 2016 Elsevier Inc. All rights reserved.

New Metabolites and Bioactive Chlorinated Benzophenone Derivatives Produced by a Marine-Derived Fungus Pestalotiopsis heterocornis.

PubMed

Lei, Hui; Lin, Xiuping; Han, Li; Ma, Jian; Ma, Qingjuan; Zhong, Jialiang; Liu, Yonghong; Sun, Tiemin; Wang, Jinhui; Huang, Xueshi

2017-03-13

Four new compounds, including two isocoumarins, pestaloisocoumarins A and B ( 1 , 2 ), one sesquiterpenoid degradation, isopolisin B ( 4 ), and one furan derivative, pestalotiol A ( 5 ), together with one known isocoumarin, gamahorin ( 3 ), and three chlorinated benzophenone derivatives, pestalachloride B ( 6 ), pestalachloride E ( 7 ) and a mixture of pestalalactone atropisomers ( 8a/8b ), were isolated from a culture of the fungus Pestalotiopsis heterocornis associated with sponge Phakellia fusca . These new chemical structures were established using NMR and MS spectroscopic data, as well as single-crystal X-ray crystallographic analysis and CD Cotton effects. All of the isolated compounds were evaluated for their antimicrobial and cytotoxic activities. Isocoumarins 1 - 3 , showed antibacterial activities against Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis with MIC values ranging from 25 to 100 μg/mL and weak antifungal activities. Chlorinated benzophenone derivatives 6 - 8 exhibited antibacterial activities against S. aureus and B. subtilis with MIC values ranging from 3.0 to 50 μg/mL and cytotoxicities against four human cancer cell lines with IC 50 values of 6.8-87.8 μM.

Rapid determination of phenylethanolamine A in biological samples by enzyme-linked immunosorbent assay and lateral-flow immunoassay.

PubMed

Li, Xiangmei; Wang, Wenjun; Wang, Limiao; Wang, Qi; Pei, Xingyao; Jiang, Haiyang

2015-10-01

Phenylethanolamine A (PA) is a β-adrenergic agonist, which was first used in animal husbandry as a growth promoter in China in 2010. In this study, a monoclonal-antibody (mAb)-based indirect competitive enzyme-linked immunosorbent assay (icELISA) and lateral-flow immunoassay (LFA) for the detection of PA in swine urine and pork were developed. The immunogen was prepared by linking PA hapten with carrier protein via a diazotization method. The IC50 value of the optimized icELISA was 0.44 ng mL(-1). The limits of detection of the icELISA for PA in swine urine and pork were 0.13 ng mL(-1) and 0.39 ng g(-1), respectively. The recoveries of PA from spiked swine urine and pork were in the range 82.0-107.4 % and 81.8-113.3%, respectively, with the coefficients of variation in the range 4.1-16.2% and 1.2-6.3%, respectively. The mAbs had negligible cross reactivity with 10 other β-agonists. In contrast, the LFA had a cut-off level of 5 ng mL(-1) (g) in swine urine and pork, and the results could be achieved within 5 min. Ten blind samples of swine urine were analyzed simultaneously by icELISA, LFA, and ultra-high-performance liquid chromatography-tandem mass spectrometry, and the results of the three methods agreed well. Therefore, the combination of two immunoassays provides an effective and rapid screening method for detection of PA residues in biological samples.

Synthesis and Free Radical Scavenging Activity of New Hydroxybenzylidene Hydrazines.

PubMed

Sersen, Frantisek; Gregan, Fridrich; Kotora, Peter; Kmetova, Jarmila; Filo, Juraj; Loos, Dusan; Gregan, Juraj

2017-05-29

Hydroxybenzylidene hydrazines exhibit a wide spectrum of biological activities. Here, we report synthesis and free radical scavenging activity of nine new N-(hydroxybenzylidene)-N'-[2,6-dinitro-4-(trifluoromethyl)]phenylhydrazines. The chemical structures of these compounds were confirmed by 1H-NMR, 13C-NMR, 19F-NMR, IR spectroscopy, LC-MS, and elemental analysis. The prepared compounds were tested for their activity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical (GOR), and 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) radicals. The free radical scavenging activity expressed as SC50 values of these compounds varied in a wide range, from a strong to no radical scavenging effect. The most effective radical scavengers were hydroxybenzylidene hydrazines containing three hydroxyl groups in the benzylidene part of their molecules. The prepared compounds were also tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts. IC50 values of these compounds varied in wide range, from an intermediate to no inhibitory effect.

Biochemistry and Chemotherapy of Leishmaniasis and Malaria

DTIC Science & Technology

1995-12-01

Allium cepa) and licorice ( Glycyrrhiza glabra). Growth of cells of Leishmania chagasi 13 and Leishmania mexicana 227 was monitored after 72 hr at 590...Leishmania chagasi. Protein Conc. Percent Range Inhibition IC25 IC50 Natural Product Solvent (4g/ml) Range (4g/ml) (0g/ml) Glycyrrhiza AQ 15-150 7.3...jig/ml) Range (jg/ml) (jIg/ml) Glycyrrhiza AQ 15-150 26.4-41.7 6* none glabra ETOH 0.26-268 No Inhibition none none (licorice) Hydrastis AQ 5-15 0.0

Transferrin-conjugated lipid-coated PLGA nanoparticles for targeted delivery of aromatase inhibitor 7alpha-APTADD to breast cancer cells.

PubMed

Zheng, Yu; Yu, Bo; Weecharangsan, Wanlop; Piao, Longzhu; Darby, Michael; Mao, Yicheng; Koynova, Rumiana; Yang, Xiaojuan; Li, Hong; Xu, Songlin; Lee, L James; Sugimoto, Yasuro; Brueggemeier, Robert W; Lee, Robert J

2010-05-10

Transferrin (Tf)-conjugated lipid-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles carrying the aromatase inhibitor, 7alpha-(4'-amino)phenylthio-1,4-androstadiene-3,17-dione (7alpha-APTADD), were synthesized by a solvent injection method. Formulation parameters including PLGA-to-lipid, egg PC-to-TPGS, and drug-to-PLGA ratios and aqueous-to-organic phase ratio at the point of synthesis were optimized to obtain nanoparticles with desired sizes and drug loading efficiency. The optimal formulation had a drug loading efficiency of 36.3+/-3.4%, mean diameter of 170.3+/-7.6nm and zeta potential of -18.9+/-1.5mV. The aromatase inhibition activity of the nanoparticles was evaluated in SKBR-3 breast cancer cells. IC(50) value of the Tf-nanoparticles was ranging from 0.77 to 1.21nM, and IC(50) value of the nanoparticles was ranging from 1.90 to 3.41nM (n=3). The former is significantly lower than the latter (p<0.05). These results suggested that the aromatase inhibition activity of the Tf-nanoparticles was enhanced relative to that of the non-targeted nanoparticles, which was attributable to Tf receptor (TfR) mediated uptake. In conclusion, Tf-conjugated lipid-coated PLGA nanoparticles are potential vehicles for improving the efficiency and specificity of therapeutic delivery of aromatase inhibitors. Copyright 2010 Elsevier B.V. All rights reserved.

A new 5-alkylresorcinol glucoside derivative from Cybianthus magnus.

PubMed

Cabanillas, B; Vásquez-Ocmín, P; Zebiri, I; Rengifo, E; Sauvain, M; Le, H L; Vaisberg, A; Voutquenne-Nazabadioko, L; Haddad, M

2016-01-01

One new 5-alkylresorcinol glucoside (1) was isolated from leaves of Cybianthus magnus, along with 12 known compounds (2-13), isolated from four plants belonging to Myrsinaceae family. Their structures were determined on the basis of spectroscopic analysis and by comparison of their spectral data with those reported in the literature. Among the tested molecules, only compound 2 displayed a strong cytotoxic activity with IC50 values ranging between 22 and 100 μM for all cell lines tested. One new 5-alkylresorcinol glucoside (1) was isolated from leaves of Cybianthus magnus, along with 12 known compounds, isolated from four plants belonging to Myrsinaceae family (2, 3 isolated from C. magnus; 4-7, 10 and 11 isolated from Myrsine latifolia; 4, 8 and 9 isolated from Myrsine sessiflora; 6, 7, 10, 12 and 13 isolated from Myrsine congesta). Their structures were determined on the basis of spectroscopic analysis and by comparison of their spectral data with those reported in the literature. So far, only nine 5-alkylresorcinol glucosides were isolated from leaves of Grevillea robusta. Since resorcinols are known to exhibit strong cytotoxic activity, compounds 1 and 2 were tested against cell lines 3T3, H460, DU145 and MCF-7 for cytotoxicity in vitro and compounds 3-13 were tested for their antileishmanial activity. Compound 2 displayed a strong cytotoxic activity with IC50 values ranging between 22 and 100 μM for all tested cell lines. Compounds 3-13 were not active against Leishmania amazonensis amastigotes.

1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)

PubMed Central

He, Xin; Reeve, Anne McElwee; Desai, Umesh R.; Kellogg, Glen E.; Reynolds, Kevin A.

2004-01-01

The enzyme FabH catalyzes the initial step of fatty acid biosynthesis via a type II dissociated fatty acid synthase. The pivotal role of this essential enzyme, combined with its unique structural features and ubiquitous occurrence in bacteria, has made it an attractive new target for the development of antibacterial and antiparasitic compounds. We have searched the National Cancer Institute database for compounds bearing structural similarities to thiolactomycin, a natural product which exhibits a weak activity against FabH. This search has yielded several substituted 1,2-dithiole-3-ones that are potent inhibitors of FabH from both Escherichia coli (ecFabH) and Staphylococcus aureus (saFabH). The most potent inhibitor was 4,5-dichloro-1,2-dithiole-3-one, which had 50% inhibitory concentration (IC50) values of 2 μM (ecFabH) and 0.16 μM (saFabH). The corresponding 3-thione analog exhibited comparable activities. Analogs in which the 4-chloro substituent was replaced with a phenyl group were also potent inhibitors, albeit somewhat less effectively (IC50 values of 5.7 and 0.98 μM for ecFabH and saFabH, respectively). All of the 5-chlorinated inhibitors were most effective when they were preincubated with FabH in the absence of substrates. The resulting enzyme-inhibitor complex did not readily regain activity after excess inhibitor was removed, suggesting that a slow dissociation occurs. In stark contrast, a series of inhibitors in which the 5-chloro substituent was replaced with the isosteric and isoelectronic trifluoromethyl group were poorer inhibitors (IC50 values typically ranging from 25 to >100 μM for both ecFabH and saFabH), did not require a preincubation period for maximal activity, and generated an enzyme-inhibitor complex which readily dissociated. Possible modes of binding of 5-chloro-1,2-dithiole-3-ones and 5-chloro-1,2-dithiole-3-thiones with FabH which account for the role of the 5-chloro substituent were considered. PMID:15273125

In vitro antiplasmodial and cytotoxic properties of some medicinal plants from western Burkina Faso.

PubMed

Sanon, Souleymane; Gansane, Adama; Ouattara, Lamoussa P; Traore, Abdoulaye; Ouedraogo, Issa N; Tiono, Alfred; Taramelli, Donatella; Basilico, Nicoletta; Sirima, Sodiomon B

2013-01-01

Resistance of malaria parasites to existing drugs complicates treatment, but an antimalarial vaccine that could protect against this disease is not yet available. It is therefore necessary to find new effective and affordable medicines. Medicinal plants could be a potential source of antimalarial agents. Some medicinal plants from Burkina Faso were evaluated for their antiplasmodial and cytotoxic properties in vitro . Crude dichloromethane, methanol, water-methanol, aqueous and alkaloids extracts were prepared for 12 parts of 10 plants. Chloroquine-resistant malaria strain K1 was used for the in vitro sensibility assay. The Plasmodium lactacte dehydrogenase technique was used to determine the 50% inhibitory concentration of parasites activity (IC 50 ). The cytotoxic effects were determined with HepG2 cells, using the tetrazolium-based colorimetric technique, and the selectivity index (SI) was calculated. Sixty crude extracts were prepared. Seven extracts from Terminalia avicenoides showed IC 50 < 5 µg/mL. The IC 50 of dichloromethane, methanol, aqueous and alkaloids extracts ranged between 1.6 µg/mL and 4.5 µg/mL. Three crude extracts from Combretum collinum and three from Ficus capraefolia had an IC 50 ranging between 0.2 µg/mL and 2.5 µg/mL. Crude extracts from these three plants had no cytotoxic effect, with SI > 1. The other plants have mostly moderate or no antimalarial effects. Some extracts from Cordia myxa , Ficus capraefolia and Opilia celtidifolia showed cytotoxicity, with an SI ranging between 0.4 and 0.9. Our study showed a good antiplasmodial in vitro activity of Terminalia avicenoides, Combretum collinum and Ficus capraefolia . These three plants may contain antiplasmodial molecules that could be isolated by bio-guided phytochemical studies.

In vitro antiplasmodial and cytotoxic properties of some medicinal plants from western Burkina Faso

PubMed Central

Gansane, Adama; Ouattara, Lamoussa P.; Traore, Abdoulaye; Ouedraogo, Issa N.; Tiono, Alfred; Taramelli, Donatella; Basilico, Nicoletta; Sirima, Sodiomon B.

2013-01-01

Background Resistance of malaria parasites to existing drugs complicates treatment, but an antimalarial vaccine that could protect against this disease is not yet available. It is therefore necessary to find new effective and affordable medicines. Medicinal plants could be a potential source of antimalarial agents. Some medicinal plants from Burkina Faso were evaluated for their antiplasmodial and cytotoxic properties in vitro. Methods Crude dichloromethane, methanol, water-methanol, aqueous and alkaloids extracts were prepared for 12 parts of 10 plants. Chloroquine-resistant malaria strain K1 was used for the in vitro sensibility assay. The Plasmodium lactacte dehydrogenase technique was used to determine the 50% inhibitory concentration of parasites activity (IC50). The cytotoxic effects were determined with HepG2 cells, using the tetrazolium-based colorimetric technique, and the selectivity index (SI) was calculated. Results Sixty crude extracts were prepared. Seven extracts from Terminalia avicenoides showed IC50 < 5 µg/mL. The IC50 of dichloromethane, methanol, aqueous and alkaloids extracts ranged between 1.6 µg/mL and 4.5 µg/mL. Three crude extracts from Combretum collinum and three from Ficus capraefolia had an IC50 ranging between 0.2 µg/mL and 2.5 µg/mL. Crude extracts from these three plants had no cytotoxic effect, with SI > 1. The other plants have mostly moderate or no antimalarial effects. Some extracts from Cordia myxa, Ficus capraefolia and Opilia celtidifolia showed cytotoxicity, with an SI ranging between 0.4 and 0.9. Conclusion Our study showed a good antiplasmodial in vitro activity of Terminalia avicenoides, Combretum collinum and Ficus capraefolia. These three plants may contain antiplasmodial molecules that could be isolated by bio-guided phytochemical studies. PMID:29043169

Prediction of kinase-inhibitor binding affinity using energetic parameters

PubMed Central

Usha, Singaravelu; Selvaraj, Samuel

2016-01-01

The combination of physicochemical properties and energetic parameters derived from protein-ligand complexes play a vital role in determining the biological activity of a molecule. In the present work, protein-ligand interaction energy along with logP values was used to predict the experimental log (IC50) values of 25 different kinase-inhibitors using multiple regressions which gave a correlation coefficient of 0.93. The regression equation obtained was tested on 93 kinase-inhibitor complexes and an average deviation of 0.92 from the experimental log IC50 values was shown. The same set of descriptors was used to predict binding affinities for a test set of five individual kinase families, with correlation values > 0.9. We show that the protein-ligand interaction energies and partition coefficient values form the major deterministic factors for binding affinity of the ligand for its receptor. PMID:28149052

Desacetylmatricarin, an anti-allergic component from Taraxacum platycarpum.

PubMed

Cheong, H; Choi, E J; Yoo, G S; Kim, K M; Ryu, S Y; Ho, C

1998-08-01

The bioassay-guided fractionation of Taraxacum platycarpum (Compositae) extract led to the isolation of a desacetylmatricarin (1) as an active principle responsible for the anti-allergic property. It showed a potent inhibitory activity upon the beta-hexosaminidase release from RBL-2H3 cells in a dose-dependent manner and the IC50 was 7.5 microM. Two structurally related guaianolide sesquiterpenes, achillin and leucodin, were also examined and their IC50 values were determined as 100 microM and 80 microM, respectively.

Inhibition of tyrosinase activity and melanine pigmentation by 2-hydroxytyrosol

PubMed Central

Uchida, Ryuji; Ishikawa, Seiko; Tomoda, Hiroshi

2014-01-01

2-Hydroxytyrosol (2-HT), originally reported as a synthetic compound, was isolated for the first time as a fungal metabolite. 2-HT was found to inhibit mushroom tyrosinase with an IC50 value of 13.0 µmol/L. Furthermore, 2-HT dose-dependently inhibited tyrosinase activity (IC50, 32.5 µmol/L) in the cell-free extract of B16 melanoma cells and α-melanocyte stimulating hormone (α-MSH)-stimulated melanin formation in intact B16 melanoma cells. PMID:26579376

Inhibition of tyrosinase activity and melanine pigmentation by 2-hydroxytyrosol.

PubMed

Uchida, Ryuji; Ishikawa, Seiko; Tomoda, Hiroshi

2014-04-01

2-Hydroxytyrosol (2-HT), originally reported as a synthetic compound, was isolated for the first time as a fungal metabolite. 2-HT was found to inhibit mushroom tyrosinase with an IC50 value of 13.0 µmol/L. Furthermore, 2-HT dose-dependently inhibited tyrosinase activity (IC50, 32.5 µmol/L) in the cell-free extract of B16 melanoma cells and α-melanocyte stimulating hormone (α-MSH)-stimulated melanin formation in intact B16 melanoma cells.

Simplified molecular input line entry system-based: QSAR modelling for MAP kinase-interacting protein kinase (MNK1).

PubMed

Begum, S; Achary, P Ganga Raju

2015-01-01

Quantitative structure-activity relationship (QSAR) models were built for the prediction of inhibition (pIC50, i.e. negative logarithm of the 50% effective concentration) of MAP kinase-interacting protein kinase (MNK1) by 43 potent inhibitors. The pIC50 values were modelled with five random splits, with the representations of the molecular structures by simplified molecular input line entry system (SMILES). QSAR model building was performed by the Monte Carlo optimisation using three methods: classic scheme; balance of correlations; and balance correlation with ideal slopes. The robustness of these models were checked by parameters as rm(2), r(*)m(2), [Formula: see text] and randomisation technique. The best QSAR model based on single optimal descriptors was applied to study in vitro structure-activity relationships of 6-(4-(2-(piperidin-1-yl) ethoxy) phenyl)-3-(pyridin-4-yl) pyrazolo [1,5-a] pyrimidine derivatives as a screening tool for the development of novel potent MNK1 inhibitors. The effects of alkyl group, -OH, -NO2, F, Cl, Br, I, etc. on the IC50 values towards the inhibition of MNK1 were also reported.

Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status.

PubMed

Wehbe, Mohamed; Lo, Cody; Leung, Ada W Y; Dragowska, Wieslawa H; Ryan, Gemma M; Bally, Marcel B

2017-12-01

Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC 50  ~ 1 μM platinum) and insensitive (IC 50  > 5 μM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC) 2 , Cu(Pyr) 2 , Cu(Plum) 2 and Cu(8-HQ) 2 ) showed IC 50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC) 2 ) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC) 2 ) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p < 0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs.

In Vitro Antioxidant and Antiproliferative Activities of Novel Orange Peel Extract and It's Fractions on Leukemia HL-60 Cells.

PubMed

Diab, Kawthar A E; Shafik, Reham Ezzat; Yasuda, Shin

2015-01-01

In the present work, novel orange peel was extracted with 100%EtOH (ethanol) and fractionated into four fractions namely F1, F2, F3, F4 which were eluted from paper chromatographs using 100%EtOH, 80%EtOH, 50%EtOH and pure water respectively. The crude extract and its four fractions were evaluated for their total polyphenol content (TPC), total flavonoid content (TFC) and radical scavenging activity using DPPH (1,1-diphenyl-2-picrylhydrazyl) assay. Their cytotoxic activity using WST assay and DNA damage by agarose gel electrophoresis were also evaluated in a human leukemia HL-60 cell line. The findings revealed that F4 had the highest TPC followed by crude extract, F2, F3 and F1. However, the crude extract had the highest TFC followed by F4, F3, F2, and F1. Depending on the values of EC50 and trolox equivalent antioxidant capacity, F4 possessed the strongest antioxidant activity while F1 and F2 displayed weak antioxidant activity. Further, incubation HL-60 cells with extract/fractions for 24h caused an inhibition of cell viability in a concentration- dependent manner. F3 and F4 exhibited a high antiproliferative activity with a narrow range of IC50 values (45.9 - 48.9 μg/ml). Crude extract exhibited the weakest antiproliferative activity with an IC50 value of 314.89 μg/ml. Analysis of DNA fragmentation displayed DNA degradation in the form of a smear-type pattern upon agarose gel after incubation of HL-60 cells with F3 and F4 for 6 h. Overall, F3 and F4 appear to be good sources of phytochemicals with antioxidant and potential anticancer activities.

Antioxidant capacity and phenolics content of apricot (Prunus armeniaca L.) kernel as a function of genotype.

PubMed

Korekar, Girish; Stobdan, Tsering; Arora, Richa; Yadav, Ashish; Singh, Shashi Bala

2011-11-01

Fourteen apricot genotypes grown under similar cultural practices in Trans-Himalayan Ladakh region were studied to find out the influence of genotype on antioxidant capacity and total phenolic content (TPC) of apricot kernel. The kernels were found to be rich in TPC ranging from 92.2 to 162.1 mg gallic acid equivalent/100 g. The free radical-scavenging activity in terms of inhibitory concentration (IC(50)) ranged from 43.8 to 123.4 mg/ml and ferric reducing antioxidant potential (FRAP) from 154.1 to 243.6 FeSO(4).7H(2)O μg/ml. A variation of 1-1.7 fold in total phenolic content, 1-2.8 fold in IC(50) by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and 1-1.6 fold in ferric reducing antioxidant potential among the examined kernels underlines the important role played by genetic background for determining the phenolic content and antioxidant potential of apricot kernel. A positive significant correlation between TPC and FRAP (r=0.671) was found. No significant correlation was found between TPC and IC(50); FRAP and IC(50); TPC and physical properties of kernel. Principal component analysis demonstrated that genotypic effect is more pronounced towards TPC and total antioxidant capacity (TAC) content in apricot kernel while the contribution of seed and kernel physical properties are not highly significant.

Thionin-like peptide from Capsicum annuum fruits: mechanism of action and synergism with fluconazole against Candida species.

PubMed

Taveira, Gabriel B; Carvalho, André O; Rodrigues, Rosana; Trindade, Fernanda G; Da Cunha, Maura; Gomes, Valdirene M

2016-01-27

Thionins are a family of plant antimicrobial peptides (AMPs), which participate in plant defense system against pathogens. Here we describe some aspects of the CaThi thionin-like action mechanism, previously isolated from Capsicum annuum fruits. Thionin-like peptide was submitted to antimicrobial activity assays against Candida species for IC50 determination and synergism with fluconazole evaluation. Viability and plasma membrane permeabilization assays, induction of intracellular ROS production analysis and CaThi localization in yeast cells were also investigated. CaThi had strong antimicrobial activity against six tested pathogenic Candida species, with IC50 ranging from 10 to 40 μg.mL(-1). CaThi antimicrobial activity on Candida species was candidacidal. Moreover, CaThi caused plasma membrane permeabilization in all yeasts tested and induces oxidative stresses only in Candida tropicalis. CaThi was intracellularly localized in C. albicans and C. tropicalis, however localized in nuclei in C. tropicalis, suggesting a possible nuclear target. CaThi performed synergistically with fluconazole inhibiting all tested yeasts, reaching 100% inhibition in C. parapsilosis. The inhibiting concentrations for the synergic pair ranged from 1.3 to 4.0 times below CaThi IC50 and from zero to 2.0 times below fluconazole IC50. The results reported herein may ultimately contribute to future efforts aiming to employ this plant-derived AMP as a new therapeutic substance against yeasts.

The Plasmodium falciparum chloroquine resistance transporter is associated with the ex vivo P. falciparum African parasite response to pyronaridine.

PubMed

Madamet, Marylin; Briolant, Sébastien; Amalvict, Rémy; Benoit, Nicolas; Bouchiba, Housem; Cren, Julien; Pradines, Bruno

2016-02-09

The pyronaridine-artesunate combination is one of the most recent oral artemisinin-based therapeutic combinations (ACTs) recommended for the treatment of uncomplicated P. falciparum malaria. The emergence of P. falciparum resistance to artemisinin has recently developed in Southeast Asia. Little data are available on the association between pyronaridine susceptibility and polymorphisms in genes involved in antimalarial drug resistance. The objective of the present study was to investigate the association between ex vivo responses to pyronaridine and the K76T mutation in the pfcrt gene in P. falciparum isolates. The assessment of ex vivo susceptibility to pyronaridine was performed on 296 P. falciparum isolates using a standard 42-h 3H-hypoxanthine uptake inhibition method. The K76T mutation was also investigated. The pyronaridine IC50 (inhibitory concentration 50 %) ranged from 0.55 to 80.0 nM. Ex vivo responses to pyronaridine were significantly associated with the K76T mutation (p-value = 0.020). The reduced susceptibility to pyronaridine, defined as IC50 > 60 nM, was significantly associated with the K76T mutation (p-value = 0.004). Using a Bayesian mixture modelling approach, the pyronaridine IC50 were classified into three components: component A (IC50 median 15.9 nM), component B (IC50 median 34.2 nM) and component C (IC50 median 63.3 nM). The K76T mutation was represented in 46.3% of the isolates in component A, 47.2% of the isolates in component B and 73.3% of the isolates in component C (p-value = 0.021). These results showed the ex vivo reduced susceptibility to pyronaridine, i.e., IC50 > 60 nM, associated with the K76T mutation.

Toxicity testing of sediment collected in the vicinity of effluent discharges from seafood processing plants in the maritimes.

PubMed

Lalonde, Benoit A; Jackman, Paula; Doe, Ken; Garron, Christine; Aubé, Jamie

2009-04-01

There are over 1100 fish-processing plants in Canada and the majority of them discharge untreated effluents directly to marine or estuarine receiving environments. The purpose of this study was to evaluate chemical and toxicological characteristics of sediments near fish-processing plant effluent discharges to assess potential impacts of seafood-processing effluents on receiving environments. Eighteen sediment samples were collected near effluent discharges of six seafood-processing plant outfalls in New Brunswick, Canada in the winter of 2006. Ammonia levels ranged from <0.2 to 3480 microg/g, sulfide levels ranged from <0.4 to 6970 microg/g, and redox ranged from -255 to 443 mV. Only one sample had a Microtox Solid-Phase Test IC(50) value below 1000 mg/kg, whereas three samples caused greater than 30% reduction to amphipod survival. Redox, sulfide, and ammonia concentrations were all found to be significantly related to both Eohaustorius estuarius survival and Microto (Vibrio fischeri) IC(50). An increase in sulfide (R (2) = 0.584; 0.750) and ammonia (R (2) = 0.478; 0.552) and a decrease in redox (R (2) = 0.485; 0.651) were associated with an increase in toxicity to E. estuarius and Microtox, respectively. The highest toxicity to both test organisms, and the most contaminated sediments based on physical/chemical characteristics measured, was observed in samples from Blacks Harbour.

Antiparasitic activity of diallyl trisulfide (Dasuansu) on human and animal pathogenic protozoa (Trypanosoma sp., Entamoeba histolytica and Giardia lamblia) in vitro.

PubMed

Lun, Z R; Burri, C; Menzinger, M; Kaminsky, R

1994-03-01

Garlic (Allium sativum L.) and one of its major components, allicin, have been known to have antibacterial and antifungal activity for a long time. Diallyl trisulfide is a chemically stable final transformation product of allicin which was synthesized in 1981 in China and used for treatment of bacterial, fungal and parasitic infections in man. The activity of diallyl trisulfide was investigated in several important protozoan parasites in vitro. The IC50 (concentration which inhibits metabolism or growth of parasites by 50%) for Trypanosoma brucei brucei, T.b. rhodesiense, T.b. gambiense, T. evansi, T. congolense and T. equiperdum was in the range of 0.8-5.5 micrograms/ml. IC50 values were 59 micrograms/ml for Entamoeba histolytica and 14 micrograms/ml for Giardia lamblia. The cytotoxicity of the compound was evaluated on two fibroblast cell lines (MASEF, Mastomys natalensis embryo fibroblast and HEFL-12, human embryo fibroblast) in vitro. The maximum tolerated concentration for both cell lines was 25 micrograms/ml. The results indicate that the compound has potential to be used for treatment of several human and animal parasitic diseases.

In-vitro antiviral efficacy of ribavirin and interferon-alpha against canine distemper virus.

PubMed

Carvalho, Otávio V; Saraiva, Giuliana L; Ferreira, Caroline G T; Felix, Daniele M; Fietto, Juliana L R; Bressan, Gustavo C; Almeida, Márcia R; Silva Júnior, Abelardo

2014-10-01

Canine distemper is a highly contagious disease with high incidence and lethality in the canine population. The objective of this study was to evaluate the efficacy of antiviral action with ribavirin (RBV), interferon-alpha (IFNα), and combinations of RBV and IFNα against canine distemper virus (CDV). Vero cells inoculated with CDV were treated with RBV, IFNα, and combinations of these drugs. The efficacy to inhibit viral replication was evaluated by adding the compounds at different times to determine which step of the viral replicative process was affected. Both drugs were effective against CDV in vitro. The IFNα was the most active compound, with an average IC50 (50% inhibitory concentration) value lower than the IC50 of the RBV. Ribavirin (RBV) was more selective than IFNα, however, and neither drug showed extracellular antiviral activity. The combination of RBV and IFNα exhibited antiviral activity for the intra- and extracellular stages of the replicative cycle of CDV, although the intracellular viral inhibition was higher. Both RBV and IFNα showed high antiviral efficacy against CDV, and furthermore, RBV + IFNα combinations have shown greater interference range in viral infectivity. These compounds could potentially be used to treat clinical disease associated with CDV infection.

In-vitro antiviral efficacy of ribavirin and interferon-alpha against canine distemper virus

PubMed Central

Carvalho, Otávio V.; Saraiva, Giuliana L.; Ferreira, Caroline G.T.; Felix, Daniele M.; Fietto, Juliana L.R.; Bressan, Gustavo C.; Almeida, Márcia R.; Silva Júnior, Abelardo

2014-01-01

Canine distemper is a highly contagious disease with high incidence and lethality in the canine population. The objective of this study was to evaluate the efficacy of antiviral action with ribavirin (RBV), interferon-alpha (IFNα), and combinations of RBV and IFNα against canine distemper virus (CDV). Vero cells inoculated with CDV were treated with RBV, IFNα, and combinations of these drugs. The efficacy to inhibit viral replication was evaluated by adding the compounds at different times to determine which step of the viral replicative process was affected. Both drugs were effective against CDV in vitro. The IFNα was the most active compound, with an average IC50 (50% inhibitory concentration) value lower than the IC50 of the RBV. Ribavirin (RBV) was more selective than IFNα, however, and neither drug showed extracellular antiviral activity. The combination of RBV and IFNα exhibited antiviral activity for the intra- and extracellular stages of the replicative cycle of CDV, although the intracellular viral inhibition was higher. Both RBV and IFNα showed high antiviral efficacy against CDV, and furthermore, RBV + IFNα combinations have shown greater interference range in viral infectivity. These compounds could potentially be used to treat clinical disease associated with CDV infection. PMID:25355997

Bioactive compounds from Peperomia pellucida.

PubMed

Xu, Su; Li, Na; Ning, Meng-Meng; Zhou, Cai-Hong; Yang, Qiao-Rong; Wang, Ming-Wei

2006-02-01

Five new compounds (1-5), including two secolignans, two tetrahydrofuran lignans, and one highly methoxylated dihydronaphthalenone, were isolated from the whole plant of Peperomia pellucida. These compounds were accompanied by the known peperomins A, B, C, and E, 7,8-trans-8,8'-trans-7',8'-cis-7,7'-bis(5-methoxy-3,4-methylenedioxyphenyl)-8-acetoxymethyl-8'-hydroxymethyltetrahydrofuran, 7,8-trans-8,8'-trans-7',8'-cis-7-(5-methoxy-3,4-methylenedioxyphenyl)-7'-(4-hydroxy-3,5-dimethoxyphenyl)-8,8'-diacetoxymethyltetrahydrofuran, sesamin, and isoswertisin. New structures were elucidated mainly by NMR and MS techniques, and anticancer activities evaluated in HL-60, MCF-7, and HeLa cell lines. Compound 1 and peperomin E show growth inhibitory effects on the three cancer cell lines with IC(50) values ranging between 1.4 and 9.1 and between 1.8 and 11.1 microM, respectively. Compound 2 has a weak suppressive activity on HL-60 cells (IC(50) = 10.8 microM), while 7,8-trans-8,8'-trans-7',8'-cis-7,7'-bis(5-methoxy-3,4-methylenedioxyphenyl)-8-acetoxymethyl-8'-hydroxymethyltetrahydrofuran exhibits estrogen-like properties (EC(50) = 3.1 microM) in CV-1 cells transfected with human estrogen receptor (ERalpha).

Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site.

PubMed

Hou, Zhuang; Lin, Bin; Bao, Yu; Yan, Hai-Ning; Zhang, Miao; Chang, Xiao-Wei; Zhang, Xin-Xin; Wang, Zi-Jie; Wei, Gao-Fei; Cheng, Mao-Sheng; Liu, Yang; Guo, Chun

2017-05-26

Dual-tail approach was employed to design novel Carbonic Anhydrase (CA) IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site, which also contains a zinc ion as part of the catalytic center. The classic sulfanilamide moiety was used as the zinc binding group. An amino glucosamine fragment was chosen as the hydrophilic part and a cinnamamide fragment as the hydrophobic part in order to draw favorable interactions with the corresponding halves of the active site. In comparison with sulfanilamide which is largely devoid of the hydrophilic and hydrophobic interactions with the two halves of the active site, the compounds so designed and synthesized in this study showed 1000-fold improvement in binding affinity. Most of the compounds inhibited the CA effectively with IC 50 values in the range of 7-152 nM. Compound 14e (IC 50 : 7 nM) was more effective than the reference drug acetazolamide (IC 50 : 30 nM). The results proved that the dual-tail approach to simultaneously matching the hydrophobic and hydrophilic halves of the active site by linking hydrophobic and hydrophilic fragments was useful for designing novel CA inhibitors. The effectiveness of those compounds was elucidated by both the experimental data and molecular docking simulations. This work laid a solid foundation for further development of novel CA IX inhibitors for cancer treatment. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Anti-inflammatory and anticholinesterase activity of six flavonoids isolated from Polygonum and Dorstenia species.

PubMed

Dzoyem, Jean Paul; Nkuete, Antoine H L; Ngameni, Barthelemy; Eloff, Jacobus N

2017-10-01

This study was aimed at investigating the anti-inflammatory and anticholinesterase activity of six naturally occurring flavonoids: (-) pinostrobin (1), 2',4'-dihydroxy-3',6'-dimethoxychalcone (2), 6-8-diprenyleriodictyol (3), isobavachalcone (4), 4-hydroxylonchocarpin (5) and 6-prenylapigenin (6). These compounds were isolated from Dorstenia and Polygonum species used traditionally to treat pain. The anti-inflammatory activity was determined by using the Griess assay and the 15-lipoxygenase inhibitory activity was determined with the ferrous oxidation-xylenol orange assay. Acetylcholinesterase inhibition was determined by the Ellman's method. At the lowest concentration tested (3.12 µg/ml), compounds 2, 3 and 4 had significant NO inhibitory activity with 90.71, 84.65 and 79.57 % inhibition respectively compared to the positive control quercetin (67.93 %). At this concentration there was no significant cytotoxicity against macrophages with 91.67, 72.86 and 70.86 % cell viability respectively, compared to 73.1 % for quercetin. Compound 4 had the most potent lipoxygenase inhibitory activity (IC 50 of 25.92 µg/ml). With the exception of (-) pinostrobin (1), all the flavonoids had selective anticholinesterase activity with IC 50 values ranging between 5.93 and 8.76 µg/ml compared to the IC 50 4.94 µg/ml of eserine the positive control. These results indicate that the studied flavonoids especially isobavachalcone are potential anti-inflammatory natural products that may have the potential to be developed as therapeutic agents against inflammatory conditions and even Alzheimer's disease.

Evaluation of bisindole as potent β-glucuronidase inhibitors: synthesis and in silico based studies.

PubMed

Khan, Khalid Mohammed; Rahim, Fazal; Wadood, Abdul; Taha, Muhammad; Khan, Momin; Naureen, Shagufta; Ambreen, Nida; Hussain, Shafqat; Perveen, Shahnaz; Choudhary, Mohammad Iqbal

2014-04-01

Bisindole analogs 1-17 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. Out of seventeen compounds, the analog 1 (IC50=1.62±0.04 μM), 6 (IC50=1.86±0.05 μM), 10 (IC50=2.80±0.29 μM), 9 (IC50=3.10±0.28 μM), 14 (IC50=4.30±0.08 μM), 2 (IC50=18.40±0.09 μM), 19 (IC50=19.90±1.05 μM), 4 (IC50=20.90±0.62 μM), 7 (IC50=21.50±0.77 μM), and 3 (IC50=22.30±0.02 μM) showed superior β-glucuronidase inhibitory activity than the standard (d-saccharic acid 1,4-lactone, IC50=48.40±1.25 μM). In addition, molecular docking studies were performed to investigate the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of potent β-glucouronidase inhibitors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells.

PubMed

Loa, Jacky; Chow, Pierce; Zhang, Kai

2009-05-01

To study anticancer activities of 68 plant polyphenols with different backbone structures and various substitutions and to analyze the structure-activity relationships. Antiproliferative activity of 68 plant polyphenols on human liver cancer cells were screened by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide method. Structure-activity relationships were analyzed by comparison of their activities with selected structures. Cell cycle progression was assayed by flow cytometry analysis and apoptosis was analyzed by DNA fragment assay. Based on their backbone structures, 68 polyphenols were sub-classed to flavonoids (chalcones, flavanones, flavones and isoflavones), chromones and coumarins. The order of their potency to suppress the human liver cancer cells is chalcones > flavones > chromones > isoflavones > flavanones > coumarins. Chalcones comprise the most potent group with IC(50) values ranging from 21.69 to 197 microM. Top nine most potent chalcones in the group have hydroxylation at 2'-carbon position in B-ring. Flavones ranked second in their potencies. Quercetin, 4-hydroxyflavone and luteolin are three hydroxyflavones with highest potencies in this group. Their IC(50) values are 30.81, 39.29 and 71.17 microM, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC(50) ranges of 61 to >400, 131 to >400, 138 to >400 and 360.85 to >400 microM, respectively. In mechanistic studies, the most potent chalcone, 2,2'-dihydroxychalcone could induce G2/M arrest and then apoptosis of the cancer cells. An analysis of structure-activity relationship showed that following structures are required for their inhibitory potencies on human liver cancer cells: (1) of the six sub-classes of the polyphenols tested, the unique backbone structure of chalcones with a open C-ring; (2) within the chalcone group, hydroxyl substitution at 2'-carbon of B-ring; (3) hydroxyl substitution at 3'-carbon in B-ring of flavones. However, some other structures were found to decrease their potencies: e.g. substitutions by sugar moieties in flavones. These data are valuable for design and modification of new polyphenols, which could be potential antiproliferative agents of cancer cells.

Discovery of novel EGFR tyrosine kinase inhibitors by structure-based virtual screening.

PubMed

Li, Siyuan; Sun, Xianqiang; Zhao, Hongli; Tang, Yun; Lan, Minbo

2012-06-15

By using of structure-based virtual screening, 13 novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were discovered from 197,116 compounds in the SPECS database here. Among them, 8 compounds significantly inhibited EGFR kinase activity with IC(50) values lower than 10 μM. 3-{[1-(3-Chloro-4-fluorophenyl)-3,5-dioxo-4-pyrazolidinylidene]methyl}phenyl 2-thiophenecarboxylate (13), particularly, was the most potent inhibitor possessing the IC(50) value of 3.5 μM. The docking studies also provide some useful information that the docking models of the 13 compounds are beneficial to find a new path for designing novel EGFR inhibitors. Copyright © 2012 Elsevier Ltd. All rights reserved.

8-9' linked neolignans with cytotoxicity from Alpinia conchigera.

PubMed

Xu, Jun-Ju; Zeng, Guang-Zhi; Yang, Sheng-Chao; Shen, Yong; Tan, Ning-Hua

2013-12-01

Five new 8-9' linked neolignans conchigeranals A-E (1-5), together with three known compounds galanganal (6), galanganols A (7) and B (8), were isolated from the whole plant of Alpinia conchigera. Their structures were established by spectroscopic analysis, including 2D-NMR spectroscopic techniques. Cytotoxicities of compounds 1-8 were tested against two cancer cell lines A549 and Hela. Results showed that 4, 5, 7 and 8 exhibited cytotoxicity against A549 with the IC50 values of 12.36, 9.72, 10.26, 13.05 μg/ml, respectively, and 1-8 against Hela with the IC50 values from 1.53 to 5.29 μg/ml. © 2013.

Compounds from the aerial parts of Piper bavinum and their anti-cholinesterase activity.

PubMed

Dung, Hoang Viet; Cuong, To Dao; Chinh, Nguyen Minh; Quyen, Do; Kim, Jeong Ah; Byeon, Jeong Su; Woo, Mi Hee; Choi, Jae Sui; Min, Byung Sun

2015-01-01

A new alkenylphenol, bavinol A (1), together with six known compounds (2-7) were isolated from the aerial parts of Piper bavinum (Piperaceae). The chemical structures of these compounds were determined by spectroscopic analyses including 2D NMR spectroscopy. The anti-Alzheimer effects of compounds 1-7 were evaluated from acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity assays. Bavinol A (1), ampelopsin (3), and violanthin (4) exhibited AChE inhibitory activities with IC50 values of 29.80, 59.47 and 79.80 μM. Compound 1 also showed the most potent BChE inhibitory activity with an IC50 value of 19.25 μM.

Antioxidant and free radical scavenging activity of Spondias pinnata

PubMed Central

Hazra, Bibhabasu; Biswas, Santanu; Mandal, Nripendranath

2008-01-01

Background Many diseases are associated with oxidative stress caused by free radicals. Current research is directed towards finding naturally-occurring antioxidants of plant origin. The aim of the present study was to evaluate the in vitro antioxidant activities of Spondias pinnata stem bark extract. Methods A 70% methanol extract of Spondias pinnata stem bark was studied in vitro for total antioxidant activity, for scavenging of hydroxyl radicals, superoxide anions, nitric oxide, hydrogen peroxide, peroxynitrite, singlet oxygen and hypochlorous acid, and for iron chelating capacity, reducing power, and phenolic and flavonoid contents. Results The extract showed total antioxidant activity with a trolox equivalent antioxidant concentration (TEAC) value of 0.78 ± 0.02. The IC50 values for scavenging of free radicals were 112.18 ± 3.27 μg/ml, 13.46 ± 0.66 μg/ml and 24.48 ± 2.31 μg/ml for hydroxyl, superoxide and nitric oxide, respectively. The IC50 for hydrogen peroxide scavenging was 44.74 ± 25.61 mg/ml. For the peroxynitrite, singlet oxygen and hypochlorous acid scavenging activities the IC50 values were 716.32 ± 32.25 μg/ml, 58.07 ± 5.36 μg/ml and 127.99 ± 6.26 μg/ml, respectively. The extract was found to be a potent iron chelator with IC50 = 66.54 ± 0.84 μg/ml. The reducing power was increased with increasing amounts of extract. The plant extract (100 mg) yielded 91.47 ± 0.004 mg/ml gallic acid-equivalent phenolic content and 350.5 ± 0.004 mg/ml quercetin-equivalent flavonoid content. Conclusion The present study provides evidence that a 70% methanol extract of Spondias pinnata stem bark is a potential source of natural antioxidants. PMID:19068130

Synthesis and evaluation of new benzodioxole-based dithiocarbamate derivatives as potential anticancer agents and hCA-I and hCA-II inhibitors.

PubMed

Altıntop, Mehlika Dilek; Sever, Belgin; Akalın Çiftçi, Gülşen; Kucukoglu, Kaan; Özdemir, Ahmet; Soleimani, Seyedeh Sara; Nadaroglu, Hayrunnisa; Kaplancıklı, Zafer Asım

2017-01-05

In the current work, new benzodioxole-based dithiocarbamate derivatives were synthesized via the reaction of N-(1,3-benzodioxol-5-ylmethyl)-2-chloroacetamide with appropriate sodium salts of N,N-disubstituted dithiocarbamic acids. These derivatives were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and C6 rat glioma cell lines. N-(1,3-Benzodioxol-5-ylmethyl)-2-[4-(4-nitrophenyl)-1-piperazinylthiocarbamoylthio]acetamide (10) can be identified as the most promising anticancer agent against C6 cell line due to its notable inhibitory effect on C6 cells with an IC 50 value of 23.33 ± 7.63 μg/mL when compared with cisplatin (IC 50  = 19.00 ± 5.29 μg/mL). On the other hand, compound 10 did not show any significant cytotoxic activity against A549 cell line. The compounds were also tested for their in vitro inhibitory effects on hCA-I and hCA-II. Generally, the tested compounds were more effective on CAs than acetazolamide, the reference agent. Among these compounds, N-(1,3-benzodioxol-5-ylmethyl)-2-[(morpholinyl)thiocarbamoylthio]acetamide (3) and N-(1,3-benzodioxol-5-ylmethyl)-2-[(thiomorpholinyl)thiocarbamoylthio]acetamide (4) were found to be the most effective compounds on hCA-I with IC 50 values of 0.346 nM and 0.288 nM, and hCA-II with IC 50 values of 0.287 nM and 0.338 nM, respectively. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Cytotoxic, Antimitotic, and Antiproliferation Studies on Rasam: A South Indian Traditional Functional Food.

PubMed

Devarajan, Agilandeswari; Mohan Maruga Raja, M K

2017-10-01

Rasam is a traditional South Indian food, prepared using tamarind juice as a base, with a variety of spices. Rasam , with all its ingredients medicinally claimed for various ailments, is a functional food. Systematic consumption of traditional functional food provides an excellent preventive measure to ward off many diseases. To study rasam for cytotoxic, antimitotic, and antiproliferation potential beyond its culinary and nutritional effect. Brine shrimp lethality assay, onion root tip inhibition assay, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in Calu-6, HeLa, MCF-7 cell lines for four stage-wise samples in the preparation of rasam (RS1, RS2, RS3, and RS4) were studied. RS4, the end product of rasam showed high lethality with an LC 50 value of 38.7 μL/mL. It showed maximum antimitotic activity in a dose-dependent manner compared to other samples with an IC 50 value of 189.86 μL/mL. RS4 also showed an IC 50 value of 350.22 and 410.15 μL/mL in MCF-7 and Calu-6 cell lines, respectively. From this study, we suggest that rasam is a classic example of traditional functional food and it can treat breast and lung cancer on chronic use. Rasam , a South Indian traditional functional food, showed high lethality (LC 50 = 38.7 mL/mL) against brine shrimps Rasam also showed potential antimitotic activity (IC 50 = 189.86 mL/mL) by inhibiting the onion root tips Rasam showed an IC 50 value of 350.22 and 410.15 mL/mL against MCF-7 and Calu-6 cell lines respectively Rasam , when consumed on daily dietary basis, can treat breast and lung cancer. Abbreviations used: SS 316: Stainless Steel 316 grade; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DMEM: Dulbecco's modified Eagle medium; FBS: Fetal bovine serum media; TPVG: Trypsin phosphate versene glucose; EDTA: Ethylene diamine tetra acetic acid; PBS: Phosphate buffered saline; DMSO: Dimethyl sulfoxide.

Application of the Kombucha 'tea fungus' for the enhancement of antioxidant and starch hydrolase inhibitory properties of ten herbal teas.

PubMed

Watawana, Mindani I; Jayawardena, Nilakshi; Choo, Candy; Waisundara, Viduranga Y

2016-03-01

Ten herbal teas (Acacia arabica, Aegle marmelos flower, A. marmelos root bark, Aerva lanata, Asteracantha longifolia, Cassia auriculata, Hemidesmus indicus, Hordeum vulgare, Phyllanthus emblica, Tinospora cordifolia) were fermented with the Kombucha 'tea fungus'. The pH values of the fermented beverages ranged from 4.0 to 6.0 by day 7, while the titratable acidity ranged from 2.5 to 5.0g/mL (P<0.05). Gallic acid had statistically significantly increased (P<0.05) in almost all the samples by day 7. The Oxygen radical absorbance capacity assay indicated 5 of the Kombucha beverages to have statistically significant increases (P<0.05) by day 7. The α-amylase inhibitory activities ranged from 52.5 to 67.2μg/mL in terms of IC50 values following fermentation, while the α-glucosidase inhibitory activities ranged from 95.2 to 196.1μg/mL. In conclusion, an enhancement of the antioxidant and starch hydrolase inhibitory potential of the herbal teas was observed by adding the tea fungus. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nonprenylated Xanthones from Gentiana lutea, Frasera caroliniensis, and Centaurium erythraea as Novel Inhibitors of Vascular Smooth Muscle Cell Proliferation.

PubMed

Waltenberger, Birgit; Liu, Rongxia; Atanasov, Atanas G; Schwaiger, Stefan; Heiss, Elke H; Dirsch, Verena M; Stuppner, Hermann

2015-11-13

Aberrant proliferation of vascular smooth muscle cells (VSMC) plays a major role in restenosis, the pathological renarrowing of the blood vessel lumen after surgical treatment of stenosis. Since available anti-proliferative pharmaceuticals produce unfavorable side effects, there is high demand for the identification of novel VSMC proliferation inhibitors. A natural product screening approach using a resazurin conversion assay enabled the identification of gentisin (1) from Gentiana lutea as a novel inhibitor of VSMC proliferation with an IC50 value of 7.84 µM. Aiming to identify further anti-proliferative compounds, 13 additional nonprenylated xanthones, isolated from different plant species, were also tested. While some compounds showed no or moderate activity at 30 µM, 1-hydroxy-2,3,4,5-tetramethoxyxanthone (4), swerchirin (6), and methylswertianin (7) showed IC50 values between 10.2 and 12.5 µM. The anti-proliferative effect of 1, 4, 6, and 7 was confirmed by the quantification of DNA synthesis (BrdU incorporation) in VSMC. Cell death quantification (determined by LDH release in the culture medium) revealed that the compounds are not cytotoxic in the investigated concentration range. In conclusion, nonprenylated xanthones are identified as novel, non-toxic VSMC proliferation inhibitors, which might contribute to the development of new therapeutic applications to combat restenosis.

Cytotoxic Effects of Sarcophyton sp. Soft Corals—Is There a Correlation to Their NMR Fingerprints?

PubMed Central

Farag, Mohamed A.; Fekry, Mostafa I.; Al-Hammady, Montasser A.; Khalil, Mohamed N.; El-Seedi, Hesham R.; Meyer, Achim; Westphal, Hildegard; Wessjohann, Ludger A.

2017-01-01

Sarcophyton sp. soft corals are rich in cembranoid diterpenes, which represent the main chemical defense of corals against their natural predators in addition to their myriad biological effects in humans. Quantitative NMR (qNMR) was applied for assessing the diterpene variation in 16 soft coral specimens in the context of their genotype, origin, and growing habitat. qNMR revealed high diterpene levels in Sarcophyton sp. compared to Sinularia and Lobophyton, with (ent)sarcophines as major components (17–100 µg/mg) of the coral tissues. Multivariate data analysis was employed to classify samples based on the quantified level of diterpenes, and compared to the untargeted NMR approach. Results revealed that qNMR provided a stronger classification model of Sarcophyton sp. than untargeted NMR fingerprinting. Additionally, cytotoxicity of soft coral crude extracts was assessed against androgen-dependent prostate cancer cell lines (PC3) and androgen-independent colon cancer cell lines (HT-29), with IC50 values ranging from 10–60 µg/mL. No obvious correlation between the extracts’ IC50 values and their diterpene levels was found using either Spearman or Pearson correlations. This suggests that this type of bioactivity may not be easily predicted by NMR metabolomics in soft corals, or is not strongly correlated to measured diterpene levels. PMID:28677625

The Effect of Vinpocetine on Human Cytochrome P450 Isoenzymes by Using a Cocktail Method.

PubMed

Kong, Lingti; Song, Chunli; Ye, Linhu; Guo, Daohua; Yu, Meiling; Xing, Rong

2016-01-01

Vinpocetine is a derivative of the alkaloid vincamine, which had been prescribed for chronic cerebral vascular ischemia and acute ischemic stroke or used as a dietary supplement for its several different mechanisms of biological activities. However, information on the cytochrome P450 (CYP) enzyme-mediated drug metabolism has not been previously studied. The present study was performed to investigate the effects of vinpocetine on CYPs activity, and cocktail method was used, respectively. To evaluate the effects of vinpocetine on the activity of human CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, human liver microsomes were utilized to incubate with the mixed CYPs probe substrates and the target components. The results indicate that vinpocetine exhibited weak inhibitory effect on the CYP2C9, where the IC50 value is 68.96 μM, whereas the IC50 values for CYP3A4, CYP2C19, CYP2D6, and CYP2E1 were all over range of 100 μM, which showed that vinpocetine had no apparent inhibitory effects on these CYPs. In conclusion, the results indicated that drugs metabolized by CYP2C9 coadministrated with vinpocetine may require attention or dose adjustment.

The Effect of Vinpocetine on Human Cytochrome P450 Isoenzymes by Using a Cocktail Method

PubMed Central

Kong, Lingti; Song, Chunli; Ye, Linhu; Guo, Daohua; Yu, Meiling; Xing, Rong

2016-01-01

Vinpocetine is a derivative of the alkaloid vincamine, which had been prescribed for chronic cerebral vascular ischemia and acute ischemic stroke or used as a dietary supplement for its several different mechanisms of biological activities. However, information on the cytochrome P450 (CYP) enzyme-mediated drug metabolism has not been previously studied. The present study was performed to investigate the effects of vinpocetine on CYPs activity, and cocktail method was used, respectively. To evaluate the effects of vinpocetine on the activity of human CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, human liver microsomes were utilized to incubate with the mixed CYPs probe substrates and the target components. The results indicate that vinpocetine exhibited weak inhibitory effect on the CYP2C9, where the IC50 value is 68.96 μM, whereas the IC50 values for CYP3A4, CYP2C19, CYP2D6, and CYP2E1 were all over range of 100 μM, which showed that vinpocetine had no apparent inhibitory effects on these CYPs. In conclusion, the results indicated that drugs metabolized by CYP2C9 coadministrated with vinpocetine may require attention or dose adjustment. PMID:27006677

Cellular uptake and anticancer activity of carboxylated gallium corroles.

PubMed

Pribisko, Melanie; Palmer, Joshua; Grubbs, Robert H; Gray, Harry B; Termini, John; Lim, Punnajit

2016-04-19

We report derivatives of gallium(III) tris(pentafluorophenyl)corrole, 1 [Ga(tpfc)], with either sulfonic (2) or carboxylic acids (3, 4) as macrocyclic ring substituents: the aminocaproate derivative, 3 [Ga(ACtpfc)], demonstrated high cytotoxic activity against all NCI60 cell lines derived from nine tumor types and confirmed very high toxicity against melanoma cells, specifically the LOX IMVI and SK-MEL-28 cell lines. The toxicities of 1, 2, 3, and 4 [Ga(3-ctpfc)] toward prostate (DU-145), melanoma (SK-MEL-28), breast (MDA-MB-231), and ovarian (OVCAR-3) cancer cells revealed a dependence on the ring substituent: IC50values ranged from 4.8 to >200 µM; and they correlated with the rates of uptake, extent of intracellular accumulation, and lipophilicity. Carboxylated corroles 3 and 4, which exhibited about 10-fold lower IC50values (<20 µM) relative to previous analogs against all four cancer cell lines, displayed high efficacy (Emax= 0). Confocal fluorescence imaging revealed facile uptake of functionalized gallium corroles by all human cancer cells that followed the order: 4 > 3 > 2 > 1 (intracellular accumulation of gallium corroles was fastest in melanoma cells). We conclude that carboxylated gallium corroles are promising chemotherapeutics with the advantage that they also can be used for tumor imaging.

Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase.

PubMed

Arias, D G; Herrera, F E; Garay, A S; Rodrigues, D; Forastieri, P S; Luna, L E; Bürgi, M D L M; Prieto, C; Iglesias, A A; Cravero, R M; Guerrero, S A

2017-01-05

The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC 50 value in the range of Nfx, but compound 13 exhibited an improved effect with an IC 50 of 1.0 ± 0.1 μM and a selective index of 70 in its toxicity against HeLa cells. We analyzed the activity of compounds 8, 12 and 13 to interfere in the central redox metabolic pathway in trypanosomatids, which is dependent of reduced trypanothione as the major pivotal thiol. The three compounds behaved as better inhibitors of trypanothione reductase than Nfx (Ki values of 118 μM, 61 μM and 68 μM for 8, 12 and 13, respectively, compared with 245 μM for Nfx), all following an uncompetitive enzyme inhibition pattern. Docking analysis predicted a binding of inhibitors to the enzyme-substrate complex with binding energy calculated in-silico that supports such molecular interaction. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Cellular uptake and anticancer activity of carboxylated gallium corroles

PubMed Central

Pribisko, Melanie; Palmer, Joshua; Grubbs, Robert H.; Gray, Harry B.; Termini, John; Lim, Punnajit

2016-01-01

We report derivatives of gallium(III) tris(pentafluorophenyl)corrole, 1 [Ga(tpfc)], with either sulfonic (2) or carboxylic acids (3, 4) as macrocyclic ring substituents: the aminocaproate derivative, 3 [Ga(ACtpfc)], demonstrated high cytotoxic activity against all NCI60 cell lines derived from nine tumor types and confirmed very high toxicity against melanoma cells, specifically the LOX IMVI and SK-MEL-28 cell lines. The toxicities of 1, 2, 3, and 4 [Ga(3-ctpfc)] toward prostate (DU-145), melanoma (SK-MEL-28), breast (MDA-MB-231), and ovarian (OVCAR-3) cancer cells revealed a dependence on the ring substituent: IC50 values ranged from 4.8 to >200 µM; and they correlated with the rates of uptake, extent of intracellular accumulation, and lipophilicity. Carboxylated corroles 3 and 4, which exhibited about 10-fold lower IC50 values (<20 µM) relative to previous analogs against all four cancer cell lines, displayed high efficacy (Emax = 0). Confocal fluorescence imaging revealed facile uptake of functionalized gallium corroles by all human cancer cells that followed the order: 4 >> 3 > 2 >> 1 (intracellular accumulation of gallium corroles was fastest in melanoma cells). We conclude that carboxylated gallium corroles are promising chemotherapeutics with the advantage that they also can be used for tumor imaging. PMID:27044076

Cytotoxic Effects of Sarcophyton sp. Soft Corals-Is There a Correlation to Their NMR Fingerprints?

PubMed

Farag, Mohamed A; Fekry, Mostafa I; Al-Hammady, Montasser A; Khalil, Mohamed N; El-Seedi, Hesham R; Meyer, Achim; Porzel, Andrea; Westphal, Hildegard; Wessjohann, Ludger A

2017-07-04

Sarcophyton sp. soft corals are rich in cembranoid diterpenes, which represent the main chemical defense of corals against their natural predators in addition to their myriad biological effects in humans. Quantitative NMR (qNMR) was applied for assessing the diterpene variation in 16 soft coral specimens in the context of their genotype, origin, and growing habitat. qNMR revealed high diterpene levels in Sarcophyton sp. compared to Sinularia and Lobophyton , with (ent)sarcophines as major components (17-100 µg/mg) of the coral tissues. Multivariate data analysis was employed to classify samples based on the quantified level of diterpenes, and compared to the untargeted NMR approach. Results revealed that qNMR provided a stronger classification model of Sarcophyton sp. than untargeted NMR fingerprinting. Additionally, cytotoxicity of soft coral crude extracts was assessed against androgen-dependent prostate cancer cell lines (PC3) and androgen-independent colon cancer cell lines (HT-29), with IC 50 values ranging from 10-60 µg/mL. No obvious correlation between the extracts' IC 50 values and their diterpene levels was found using either Spearman or Pearson correlations. This suggests that this type of bioactivity may not be easily predicted by NMR metabolomics in soft corals, or is not strongly correlated to measured diterpene levels.

Antibacterial and Antibiofilm Activities of Makaluvamine Analogs

PubMed Central

Nijampatnam, Bhavitavya; Nadkarni, Dwayaja H.; Wu, Hui; Velu, Sadanandan E.

2014-01-01

Streptococcus mutans is a key etiological agent in the formation of dental caries. The major virulence factor is its ability to form biofilms. Inhibition of S. mutans biofilms offers therapeutic prospects for the treatment and the prevention of dental caries. In this study, 14 analogs of makaluvamine, a marine alkaloid, were evaluated for their antibacterial activity against S. mutans and for their ability to inhibit S. mutans biofilm formation. All analogs contained the tricyclic pyrroloiminoquinone core of makaluvamines. The structural variations of the analogs are on the amino substituents at the 7-position of the ring and the inclusion of a tosyl group on the pyrrole ring N of the makaluvamine core. The makaluvamine analogs displayed biofilm inhibition with IC50 values ranging from 0.4 μM to 88 μM. Further, the observed bactericidal activity of the majority of the analogs was found to be consistent with the anti-biofilm activity, leading to the conclusion that the anti-biofilm activity of these analogs stems from their ability to kill S. mutans. However, three of the most potent N-tosyl analogs showed biofilm IC50 values at least an order of magnitude lower than that of bactericidal activity, indicating that the biofilm activity of these analogs is more selective and perhaps independent of bactericidal activity. PMID:25767719

Trypanocidal and Leishmanicidal Activities of Sesquiterpene Lactones from Ambrosia tenuifolia Sprengel (Asteraceae) ▿

PubMed Central

Sülsen, Valeria P.; Frank, Fernanda M.; Cazorla, Silvia I.; Anesini, Claudia A.; Malchiodi, Emilio L.; Freixa, Blanca; Vila, Roser; Muschietti, Liliana V.; Martino, Virginia S.

2008-01-01

Bioassay-guided fractionation of the organic extract of Ambrosia tenuifolia Sprengel (Asteraceae) led to the isolation of two bioactive sesquiterpene lactones with significant trypanocidal and leishmanicidal activities. By spectroscopic methods (1H- and 13C-nuclear magnetic resonance, distortionless enhancement by polarization transfer, correlated spectroscopy, heteronuclear multiple-quantum coherence, electron impact-mass spectrometry, and infrared spectroscopy), these compounds were identified as psilostachyin and peruvin. Both compounds showed a marked in vitro trypanocidal activity against Trypanosoma cruzi epimastigotes with 50% inhibitory concentration (IC50) values of less than 2 μg/ml. Psilostachyin exerted a significant in vitro activity against the trypomastigote forms of T. cruzi (IC50, 0.76 μg/ml) and was selected for in vivo testing. Psilostachyin-treated mice had a survival of 100% and lower parasitemia values than control mice. Both compounds were also tested on Leishmania sp. promastigotes: psilostachyin (IC50, 0.12 μg/ml) and peruvin (IC50, 0.39 μg/ml) exerted significant leishmanicidal activities. This is the first time that the trypanocidal and leishmanicidal activities of these compounds have been reported. The selectivity index (SI) was employed to evaluate the cytotoxic effect of lactones on T lymphocytes. Although the SIs of both compounds were high for T. cruzi epimastigotes, psilostachyin was more selective against trypomastigotes (SI, 33.8) while peruvin showed no specificity for this parasite. Both compounds presented high selectivity for Leishmania spp. The results shown herein suggest that psilostachyin and peruvin could be considered potential candidates for the development of new antiprotozoal agents against Chagas' disease and leishmaniasis. PMID:18443111

The pharmacological profile of CGP 28238, a novel highly potent anti-inflammatory compound.

PubMed

Wiesenberg-Boettcher, I; Schweizer, A; Green, J R; Mueller, K; Maerki, F; Pfeilschifter, J

1989-01-01

CGP 28238 (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone ) exhibits very potent anti-inflammatory activity in rat adjuvant arthritis (ED40 = 0.05 mg/kg, p.o.) and pronounced analgesic and antipyretic activity in acute models in mice and rats (ED50 2-5 mg/kg, p.o.), but has clear advantages over reference NSAIDs with respect to gastro-intestinal tolerability. Threshold doses for gastro-intestinal ulcerogenicity in rats after single and repeated (10x) doses were found to be 30 mg/kg, p.o., and prostaglandin (PGE2) production in rat gastric and ileal mucosa was only marginally inhibited (ED50 greater than 30 mg/kg, p.o.). On the other hand, PGE2 production in rat inflammatory exudate and thromboxane synthesis in rat blood were inhibited with ED50 values of less than or equal to 2 mg/kg, p.o. Although CGP28238 does not inhibit cyclooxygenase in bovine seminal vesicle microsomal preparations (IC50 greater than 10(-3) mol/l), potent inhibition of prostaglandin synthesis was shown in various in vitro systems using human and animal cells with IC50 values of less than 10(-6) mol/l. IL-1-stimulated bone resorption and PGE2 production in murine calvarial cultures were inhibited with IC50 values of 3 x 10(-7) and 2 x 10(-8) mol/l, respectively. 5-Lipoxygenase (murine macrophages), phospholipase A2 (human PMN) and phospholipase C (human platelets) were not inhibited. CGP 28238 may represent a novel highly potent anti-inflammatory compound with improved gastro-intestinal safety.

A Green Synthesis of Chalcones As an Antioxidant and Anticancer

NASA Astrophysics Data System (ADS)

Susanti VH, Elfi; Agustina Eko Setyowati, Widiastuti

2018-01-01

Three chalcones (4’-amino-4-methoxy chalcone, 4’-amino-3,4-dimethoxy chalcone and 4’-amino-3,4,5-trimethoxy chalcone) has been synthesized by a green chemistry approach using grinding technique. Antioxidant activity of the chalcones were assessed using 1,1-biphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Cytotoxicity of chalcones sythesized was evaluated using a tetrazolium (MTT) colorimetric assay against cervical cancer cell line, HeLa. The antioxidant activity test showed that 4’-amino-4-methoxy chalcone had a stronger activity than the 4’-amino-3,4-dimethoxy chalcone and 4’-amino-3,4,5-trimethoxy chalcone, respectively with IC50 58.85, 64.79 and 210.3 μg/mL. These results indicate that there is a relationship between the structure of chalcone with antioxidant activity, the more methoxy groups in the ring B of the chalcone, antioxidant activity is getting smaller. The chalcone synthesized showed cytotoxicity against HeLa cell line with IC50 value of 31.75, 36.65, 49.04 μg/mL, respectively. It was observed that the highest cytotoxic activity was found at 4’-amino-4-methoxy chalcone (IC50 31.75 μg/mL). Lower activity was showed by 4’-amino-3,4,5-trimethoxy chalcone with IC50 value of 49,04 μg/mL. There is a relationship cytotoxicity with chalcone structure, the more the number of methoxy groups in ring B chalcone, will decrease the activity of cytotoxicity.

Synthesis, Biological Evaluation and Molecular Docking Study of Hydrazone-Containing Pyridinium Salts as Cholinesterase Inhibitors.

PubMed

Parlar, Sulunay; Bayraktar, Gulsah; Tarikogullari, Ayse Hande; Alptüzün, Vildan; Erciyas, Ercin

2016-01-01

A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The cholinesterase (ChE) inhibitory activity studies were carried out by using the Ellman's colorimetric method. All compounds displayed considerable AChE and BuChE inhibitory activity and some of the compounds manifested remarkable anti-AChE activity compared to the reference compound, galantamine. Among the title compounds, the series including benzofuran aromatic ring exhibited the best inhibitory activity both on AChE and BuChE enzymes. Compound 3b, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-(3-phenylpropyl)pyridinium bromide, was the most active compound with IC50 value of 0.23 (0.24) µM against enantiomeric excess (ee)AChE (human (h)AChE) while compound 3a, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-phenethylpyridinium bromide, was the most active compound with IC50 value of 0.95 µM against BuChE. Moreover, 3a and b exhibited higher activity than the reference compound galantamine (eeAChE (hAChE) IC50 0.43 (0.52) µM; BuChE IC50 14.92 µM). Molecular docking studies were carried out on 3b having highest inhibitory activity against AChE.

Bioaccessibility and inhibitory effects on digestive enzymes of carnosic acid in sage and rosemary.

PubMed

Ercan, Pınar; El, Sedef Nehir

2018-04-28

In this study, the aim was to determine the bioaccessibilities of carnosic acid in sage and rosemary and in vitro inhibitory effects of these samples on lipid and starch digestive enzymes by evaluating the lipase, α-amylase and α-glucosidase enzyme inhibition activities. The content of carnosic acid in rosemary (18.72 ± 0.33 mg/g) was found to be higher than that content of that in sage (3.76 ± 0.13 mg/g) (p < 0.05). The carnosic acid bioaccessibilities were found as 45.10 ± 1.88% and 38.32 ± 0.21% in sage and rosemary, respectively. The tested sage and rosemary showed inhibitory activity against α-glucosidase (Concentration of inhibitor required to produce a 50% inhibition of the initial rate of reaction - IC 50 88.49 ± 2.35, 76.80 ± 1.68 μg/mL, respectively), α-amylase (IC 50 107.65 ± 12.64, 95.65 ± 2.73 μg/mL, respectively) and lipase (IC 50 6.20 ± 0.63, 4.31 ± 0.62 μg/mL, respectively). Furthermore, to the best of our knowledge, this is the first work that carnosic acid standard equivalent inhibition capacities (CAEIC 50 ) for these food samples were determined and these values were in agreement with the IC 50 values. These results show that sage and rosemary are potent inhibitors of lipase, α-amylase and α-glucosidase digestive enzymes. Copyright © 2018 Elsevier B.V. All rights reserved.

Biological activities and chemical composition of lichens from Serbia

PubMed Central

Kosanic, Marijana; Rankovic, Branislav; Stanojkovic, Tatjana; Vasiljevic, Perica; Manojlovic, Nedeljko

2014-01-01

The aim of this study is to investigate chemical composition of acetone extracts of the lichens Parmelia arseneana and Acarospora fuscata and in vitro antioxidant, antimicrobial, and anticancer activities of these extracts and gyrophoric acid isolated from A. fuscata. The HPLC-UV method was used for the identification of secondary metabolites. Stictic acid, norstictic acid, gyrophoric acid, usnic acid, atranorin and chloroatranorin were identified in the A. fuscata. In P. arseneana, we detected stictic acid, norstictic acid, usnic acid and atranorin, while gyrophoric acid was not identified. Antioxidant activity was evaluated by measuring the scavenging capacity of tested samples on DPPH and superoxide anion radicals, reducing the power of samples and determination of total phenolic compounds in extracts. As a result of the study, gyrophoric acid was found to have the largest DPPH radical scavenging activity with an IC50 value of 105.75 µg/ml. Moreover, the tested samples had an effective superoxide anion radical scavenging and reducing power. The total content of phenol in extracts was determined as pyrocatechol equivalent. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method. The most active was also gyrophoric acid, with minimum inhibitory concentration values ranging from 0.019 to 1.25 mg/ml. Anticancer activity was tested against LS174 (human colon carcinoma cell line), A549 (human lung carcinoma cell line), Fem-x (malignant melanoma cell line), and a chronic myelogeneous leukaemia K562 cell line using the MTT method. Extract of P. arseneana expressed the strongest anticancer activity against all cell lines with IC50 values ranging from 11.61 to 47.06 µg/ml. PMID:26417336

Development of an enzyme-linked immunosorbent assay for the detection of dicamba.

PubMed

Clegg, B S; Stephenson, G R; Hall, J C

2001-05-01

A competitive indirect enzyme-linked immunosorbent assay (CI-ELISA) was developed to quantitate the herbicide dicamba (3,6-dichloro-2-methoxybenzoic acid) in water. The CI-ELISA has a detection limit of 2.3 microg L(-1) and a linear working range of 10--10000 microg L(-1) with an IC(50) value of 195 microg L(-1). The dicamba polyclonal antisera did not cross-react with a number of other herbicides tested but did cross-react with a dicamba metabolite, 5-hydroxydicamba, and structurally related chlorobenzoic acids. The assay was used to estimate quantitatively dicamba concentrations in water samples. Water samples were analyzed directly, and no sample preparation was required. To improve detection limits, a C(18) (reversed phase) column concentration step was devised prior to analysis, and the detection limits were increased by at least by 10-fold. After the sample preconcentration, the detection limit, IC(50), and linear working range were 0.23, 19.5, and 5-200 microg L(-1), respectively. The CI-ELISA estimations in water correlated well with those from gas chromatography-mass spectrometry (GC-MS) analysis (r(2) = 0.9991). This assay contributes to reducing laboratory costs associated with the conventional GC-MS residue analysis techniques for the quantitation of dicamba in water.

Two new lignans from Saururus chinensis and their DGAT inhibitory activity.

PubMed

Li, Na; Tuo, Zhen-Dong; Qi, Shi-Zhou; Xing, Shan-Shan; Lee, Hyun-Sun; Chen, Jian-Guang; Cui, Long

2015-03-01

Two new lignans were isolated from Saururus chinensis, along with eight known compounds. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against DGAT1 and DGAT2. Among them, compounds 2, 3, 5 and 7 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 44.3±1.5 to 87.5±1.3μM. Copyright © 2014 Elsevier B.V. All rights reserved.

Lanostane triterpenoids from Tricholoma pardinum with NO production inhibitory and cytotoxic activities.

PubMed

Zhang, Shuai-Bing; Li, Zheng-Hui; Stadler, Marc; Chen, He-Ping; Huang, Ying; Gan, Xiao-Qing; Feng, Tao; Liu, Ji-Kai

2018-05-11

Eight undescribed lanostane triterpenoids, pardinols A‒H, along with one previously reported lanostane triterpenoid, namely saponaceol B, were isolated from the fruiting bodies of Tricholoma pardinum. Their structures and stereoconfigurations were established via combination of extensive spectroscopic analyses, alkaline methanolysis method and TDDFT/ECD calculations. Pardinols B and E-H exhibited certain inhibition activities of nitric oxide (NO) production with IC 50 value ranging from 5.3 to 14.7 μM, as well as cytotoxicities against human cancer cell-lines. Copyright © 2018 Elsevier Ltd. All rights reserved.

Potent Cytotoxic Peptides from the Australian Marine Sponge Pipestela candelabra

PubMed Central

Tran, Trong D.; Pham, Ngoc B.; Fechner, Gregory A.; Hooper, John N. A.; Quinn, Ronald J.

2014-01-01

Two consecutive prefractionated fractions of the Australian marine sponge extract, Pipestela candelabra, were identified to be selectively active on the human prostate cancer cells (PC3) compared to the human neonatal foreskin fibroblast non-cancer cells (NFF). Twelve secondary metabolites were isolated in which four compounds are new small peptides. Their structures were characterized by spectroscopic and chemical analysis. These compounds inhibited selectively the growth of prostate cancer cells with IC50 values in the picomolar to sub-micromolar range. Structure-activity relationship of these compounds is discussed. PMID:24901701

Triterpenoid Saponins from the Seeds of Aesculus chinensis and Their Cytotoxicities.

PubMed

Cheng, Jin-Tang; Chen, Shi-Tao; Guo, Cong; Jiao, Meng-Jiao; Cui, Wen-Jin; Wang, Shu-Hui; Deng, Zhe; Chen, Chang; Chen, Sha; Zhang, Jun; Liu, An

2018-02-01

Six new triterpenoid saponins, aesculusosides A-F (1-6), together with 19 known ones, were isolated from the seeds of Aesculus chinensis. The new structures were elucidated through extensive spectroscopic analyses and by comparison with previously reported data. Some of the isolates were evaluated for their cytotoxic activities against MCF-7 cell line by an MTT assay, and compounds 15, 16, 19, and 23-25 exhibited inhibitory activities against MCF-7 with IC 50 values ranging from 7.1 to 31.3 μM.

Iminosugars as a new class of cholinesterase inhibitors.

PubMed

Decroocq, Camille; Stauffert, Fabien; Pamlard, Olivier; Oulaïdi, Farah; Gallienne, Estelle; Martin, Olivier R; Guillou, Catherine; Compain, Philippe

2015-02-15

To further extend the scope of iminosugar biological activity, a systematic structure-activity relationship investigation has been performed by synthesizing and evaluating as cholinesterase inhibitors a library of twenty-three iminoalditols with different substitutions and stereochemistry patterns. These compounds have been evaluated in vitro for the inhibition of cholinesterases (different sources of acetylcholinesterase and butyrylcholinesterase). Some compounds have IC50 values in the micromolar range and display significant inhibition selectivity for butyrylcholinesterase over acetylcholinesterase. These are the first examples of iminosugar-based inhibitors of cholinesterases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biological evaluation of some uracil derivatives as potent glutathione reductase inhibitors

NASA Astrophysics Data System (ADS)

Güney, Murat; Ekinci, Deniz; Ćavdar, Huseyin; Şentürk, Murat; Zilbeyaz, Kani

2016-04-01

Discovery of glutathione reductase (GR) inhibitors has become very popular recently due to antimalarial and anticancer activities. In this study, GR inhibitory capacities of some uracil derivatives (UDCs) (1-4) were reported. Some commercially available molecules (5-6) were also tested for comparison reasons. The novel UDCs were obtained in high yields using simple chemical procedures and exhibited much potent inhibitory activities against GR at low nanomolar concentrations with IC50 values ranging from 2.68 to 166.6 nM as compared with well-known agents.

Cytotoxic deoxybenzoins and diphenylethylenes from Arundina graminifolia.

PubMed

Hu, Qiu-Fen; Zhou, Bin; Ye, Yan-Qing; Jiang, Zhi-Yong; Huang, Xiang-Zhong; Li, Yin-Ke; Du, Gang; Yang, Guang-Yu; Gao, Xue-Mei

2013-10-25

Eight new C-4-alkylated deoxybenzoins (1-8), three new diphenylethylenes (9-11), and five known diphenylethylenes were isolated from Arundina graminifolia. The structures of 1-11 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 9-11 are the first naturally occurring diphenylethylenes possessing a hydroxyethyl unit. Compounds 1-11 were evaluated for cytotoxicity against five human tumor cell lines. Compounds 4, 5, and 9-11 showed significant cytotoxicity against five cancer cell lines, with IC50 values ranging from 1.8 to 8.7 μM.

Antioxidant farnesylated hydroquinones from Ganoderma capense.

PubMed

Peng, Xingrong; Li, Lei; Wang, Xia; Zhu, Guolei; Li, Zhongrong; Qiu, Minghua

2016-06-01

Phytochemical investigation of the fruiting bodies of Ganoderma capense led to isolation of eight aromatic meroterpenoids (1-8). Ganocapensins A and B (1, 2) possessed a thirteen-membered and a fourteen-membered ether rings, respectively. The structures of new isolates including absolute configuration were elucidated on the basis of extensive spectroscopic technologies and Mosher's method. All isolated compounds showed significant antioxidant effects with IC50 values ranging from 6.00±0.11 to 8.20±0.30μg/ml in the DPPH radical scavenging assay. Copyright © 2016 Elsevier B.V. All rights reserved.

Screening North American plant extracts in vitro against Trypanosoma brucei for discovery of new antitrypanosomal drug leads.

PubMed

Jain, Surendra; Jacob, Melissa; Walker, Larry; Tekwani, Babu

2016-05-18

Human African Trypanosomiasis (HAT) is a protozoan parasitic disease caused by Trypanosoma brucei. The disease is endemic in regions of sub-Saharan Africa, covering 36 countries and more than 60 million people at the risk. Only few drugs are available for the treatment of HAT. Current drugs suffer from severe toxicities and require intramuscular or intravenous administrations. The situation is further aggravated due to the emergence of drug resistance. There is an urgent need of new drugs that are effective orally against both stages of HAT. Natural products offer an unmatched source for bioactive molecules with new chemotypes. The extracts prepared from 522 plants collected from various parts of the North America were screened in vitro against blood stage trypamastigote forms of T. brucei. Active extracts were further screened at concentrations ranging from 10 to 0.4 μg/mL. Active extracts were also investigated for toxicity in Differentiated THP1 cells at 10 μg/mL concentration. The results were computed for dose-response analysis and determination of IC50/IC90 values. A significant number (150) of extracts showed >90 % inhibition of growth of trypomastigote blood forms of T. brucei in primary screening at 20 μg/mL concentration. The active extracts were further investigated for dose-response inhibition of T. brucei growth. The antitrypansomal activity of 125 plant extracts was confirmed with IC50 < 10 μg/mL. None of these active extracts showed toxicity against differentiated THP1 cells. Eight plants extracts namely, Alnus rubra, Hoita macrostachya, Sabal minor, Syzygium aqueum, Hamamelis virginiana, Coccoloba pubescens, Rhus integrifolia and Nuphar luteum were identified as highly potent antitrypanosomal extracts with IC50 values <1 μg/mL. Limited phytochemical and pharmacological reports are available for the lead plant extracts with potent antitrypanosomal activity. Follow up evaluation of these plant extracts is likely to yield new antitrypanosomal drug-leads or alternate medicines for treatment of HAT.

Tanzawaic acid derivatives from a marine isolate of Penicillium sp. (SF-6013) with anti-inflammatory and PTP1B inhibitory activities.

PubMed

Quang, Tran Hong; Ngan, Nguyen Thi Thanh; Ko, Wonmin; Kim, Dong-Cheol; Yoon, Chi-Su; Sohn, Jae Hak; Yim, Joung Han; Kim, Youn-Chul; Oh, Hyuncheol

2014-12-15

Chemical investigation of a marine-derived fungus Penicillium sp. SF-6013 resulted in the discovery of a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (1), together with four known analogues, tanzawaic acids A (2) and D (3), a salt form of tanzawaic acid E (4), and tanzawaic acid B (5). Their structures were mainly determined by analysis of NMR and MS data, along with chemical methods. Preliminary screening for anti-inflammatory effects in lipopolysaccharide (LPS)-activated microglial BV-2 cells showed that compounds 1, 2, and 5 inhibited the production of nitric oxide (NO) with IC50 values of 37.8, 7.1, and 42.5 μM, respectively. Compound 2 also inhibited NO production in LPS-stimulated RAW264.7 murine macrophages with an IC50 value of 27.0 μM. Moreover, these inhibitory effects correlated with the suppressive effect of compound 2 on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 and BV2 cells. In addition, compounds 2 and 5 significantly inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with the same IC50 value (8.2 μM). Copyright © 2014 Elsevier Ltd. All rights reserved.

Understanding drugs in breast cancer through drug sensitivity screening.

PubMed

Uhr, Katharina; Prager-van der Smissen, Wendy J C; Heine, Anouk A J; Ozturk, Bahar; Smid, Marcel; Göhlmann, Hinrich W H; Jager, Agnes; Foekens, John A; Martens, John W M

2015-01-01

With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

Antioxidant potential of n-butanol fraction from extract of Jasminum mesnyi Hance leaves.

PubMed

Borar, Sakshi; Punia, Priyanka; Kalia, A N

2011-01-01

Methanolic extract of Jasminum mesnyi Hance leaves having antidiabetic activity was subjected to fractionation to obtain antioxidant and antihyperglycemic rich fraction. Different concentrations of ethyl acetate and n-butanol fractions were subjected to antioxidant assay by DPPH method, nitric oxide scavenging activity and reducing power assay. The fractions showed dose dependent free radical scavenging property in all the models. IC50 values for ethyl acetate and n-butanol fractions were 153.45 +/- 6.65 and 6.22 +/- 0.25 microg/ml, respectively, as compared to L-ascorbic acid and rutin (as standards; IC50 values 6.54 +/- 0.24 and 5.43 +/- 0.21 microg/ml, respectively) in DPPH model. In nitric oxide scavenging activity, IC50 values were 141.54 +/- 9.95 microg/ml, 35.12 +/- 1.58 microg/ml, 21.06 +/- 0.95 microg/ml and 29.93 +/- 0.32 microg/ml for ethyl acetate, n-butanol fractions, L-ascorbic acid and rutin, respectively. n-Butanol fraction showed a good reducing potential and better free radical scavenging activity as compared to ethyl acetate fraction. Potent antioxidant n-butanol fraction showed better oral glucose tolerance test (antihyperglycemic) at par with metformin (standard drug), n-Butanol fraction contained secoiridoid glycosides which might be responsible for both antioxidant and antihyperglycemic activity.

Flavonoids from Machilus japonica Stems and Their Inhibitory Effects on LDL Oxidation

PubMed Central

Joo, Se-Jin; Park, Hee-Jung; Park, Ji-Hae; Cho, Jin-Gyeong; Kang, Ji-Hyun; Jeong, Tae-Sook; Kang, Hee Cheol; Lee, Dae-Young; Kim, Hack-Soo; Byun, Sang-Yo; Baek, Nam-In

2014-01-01

Stems of Machilus japonica were extracted with 80% aqueous methanol (MeOH) and the concentrated extract was successively extracted with ethyl acetate (EtOAc), normal butanol (n-BuOH), and water. Six flavonoids were isolated from the EtOAc fraction: (+)-taxifolin, afzelin, (−)-epicatechin, 5,3'-di-O-methyl-(−)-epicatechin, 5,7,3'-tri-O-methyl-(−)-epicatechin, and 5,7-di-O-methyl-3',4'-methylenedioxyflavan-3-ol. The chemical structures were identified using spectroscopic data including NMR, mass spectrometry and infrared spectroscopy. This is the first report of isolation of these six compounds from M. japonica. The compounds were evaluated for their diphenyl picryl hydrazinyl scavenging activity and inhibitory effects on low-density lipoprotein oxidation. Compounds 1 and 3–6 exhibited DPPH antioxidant activity equivalent with that of ascorbic acid, with half maximal inhibitory concentration (IC50) values of 0.16, 0.21, 0.17, 0.15 and 0.07 mM, respectively. The activity of compound 1 was similar to the positive control butylated hydroxytoluene, which had an IC50 value of 1.9 µM, while compounds 3 and 5 showed little activity. Compounds 1, 3, and 5 exhibited LDL antioxidant activity with IC50 values of 2.8, 7.1, and 4.6 µM, respectively. PMID:25229822

Combination of Oxaliplatin and Vit.E-TPGS in Lipid Nanosystem for Enhanced Therapeutic Efficacy in Colon Cancers.

PubMed

Wang, Yanlei; Zhang, Xiang; Zhang, Wenqiang; Dong, Hao; Zhang, Wenjie; Mao, Jiajia; Dai, Yong

2018-01-08

The main aim of present study was to prepare the oxaliplatin (OXL)-loaded D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS)-based lipid nanoparticles to enhance the anticancer effect in colon cancer cells. The nanoparticles were nanosized and spherical shaped and exhibited controlled release kinetics. Flow cytometer and confocal laser scanning microscopy (CLSM) showed a remarkable uptake of nanoparticles in cancer cells in a time-dependent manner. The presence of TPGS remarkably increased the anticancer effect of OXL in HT-29 colon cancer cells. The IC50 value of free OXL was 4.25 μg/ml whereas IC50 value of OXL-loaded TPGS-based lipid nanoparticles (OXL/TLNP) was 1.12 μg/ml. The 3-fold lower IC50 value of OXL/TLNP indicates the superior anticancer effect of nanoparticle-based OXL. Consistently, OXL/TLNP induced a remarkable apoptosis of cancer cells. Approximately, ~52% of cells were in early apoptosis phase and ~13% of cells were in late apoptosis phase indicating the potent anticancer effect of the formulations. The findings from this study provide novel insights into the use of TPGS and lipid nanoparticle together for the better antitumor effect in colon cancers. Future studies will involve the detailed in vitro and in vivo studies on clinically relevant animals.

Evaluation of the antibacterial and antifungal potential of Peltophorum africanum: toxicological effect on human Chang liver cell line.

PubMed

Okeleye, Benjamin I; Mkwetshana, Noxolo T; Ndip, Roland N

2013-01-01

We assessed the in vitro antimicrobial activity of Peltophorum africanum by means of the agar well and macrodilution methods. The toxicity on a normal human liver cell (Chang liver cell) was determined using the CellTiter-Blue cell viability assay, and the compounds contained in the fractions were identified using GC-MS. Zone diameter of inhibition of the extract ranged from 12.5 ± 0.7  to  32 ± 2.8 mm for bacteria and from  7.5 ± 0.7  to  26.4 ± 3.4 mm for yeast. Marked activity of the extract was observed against Plesiomonas shigelloides ATCC 51903, with MIC and MLC values of 0.15625 and 0.3125 mg/mL, respectively. The extract was both bactericidal (MIC(index) ≤ 2) and bacteriostatic/fungistatic (MIC(index) > 2) in activity. Lethal dose at 50 (LD50) showed 82.64 ± 1.40 degree of toxicity at 24 hrs, and 95 percentile of cell death dose activity ranged from log 3.12 ± 0.01  to  4.59 ± 0.03. The activity of the eight fractions tested ranged from 1.0 ± 0.5  to  3.7 ± 1.6 mg/mL (IC50) and from  2.1 ± 0.8  to  6.25 ± 0 mg/mL (IC90). The extract was toxic to human Chang liver cell lines.

Antiviral activity of four types of bioflavonoid against dengue virus type-2

PubMed Central

2011-01-01

Background Dengue is a major mosquito-borne disease currently with no effective antiviral or vaccine available. Effort to find antivirals for it has focused on bioflavonoids, a plant-derived polyphenolic compounds with many potential health benefits. In the present study, antiviral activity of four types of bioflavonoid against dengue virus type -2 (DENV-2) in Vero cell was evaluated. Anti-dengue activity of these compounds was determined at different stages of DENV-2 infection and replication cycle. DENV replication was measured by Foci Forming Unit Reduction Assay (FFURA) and quantitative RT-PCR. Selectivity Index value (SI) was determined as the ratio of cytotoxic concentration 50 (CC50) to inhibitory concentration 50 (IC50) for each compound. Results The half maximal inhibitory concentration (IC50) of quercetin against dengue virus was 35.7 μg mL-1 when it was used after virus adsorption to the cells. The IC50 decreased to 28.9 μg mL-1 when the cells were treated continuously for 5 h before virus infection and up to 4 days post-infection. The SI values for quercetin were 7.07 and 8.74 μg mL-1, respectively, the highest compared to all bioflavonoids studied. Naringin only exhibited anti-adsorption effects against DENV-2 with IC50 = 168.2 μg mL-1 and its related SI was 1.3. Daidzein showed a weak anti-dengue activity with IC50 = 142.6 μg mL-1 when the DENV-2 infected cells were treated after virus adsorption. The SI value for this compound was 1.03. Hesperetin did not exhibit any antiviral activity against DENV-2. The findings obtained from Foci Forming Unit Reduction Assay (FFURA) were corroborated by findings of the qRT-PCR assays. Quercetin and daidzein (50 μg mL-1) reduced DENV-2 RNA levels by 67% and 25%, respectively. There was no significant inhibition of DENV-2 RNA levels with naringin and hesperetin. Conclusion Results from the study suggest that only quercetin demonstrated significant anti-DENV-2 inhibitory activities. Other bioflavonoids, including daidzein, naringin and hesperetin showed minimal to no significant inhibition of DENV-2 virus replication. These findings, together with those previously reported suggest that select group of bioflavonoids including quercetin and fisetin, exhibited significant inhibitory activities against dengue virus. This group of flavonoids, flavonol, could be investigated further to discover the common mechanisms of inhibition of dengue virus replication. PMID:22201648

Antiviral activity of four types of bioflavonoid against dengue virus type-2.

PubMed

Zandi, Keivan; Teoh, Boon-Teong; Sam, Sing-Sin; Wong, Pooi-Fong; Mustafa, Mohd Rais; Abubakar, Sazaly

2011-12-28

Dengue is a major mosquito-borne disease currently with no effective antiviral or vaccine available. Effort to find antivirals for it has focused on bioflavonoids, a plant-derived polyphenolic compounds with many potential health benefits. In the present study, antiviral activity of four types of bioflavonoid against dengue virus type -2 (DENV-2) in Vero cell was evaluated. Anti-dengue activity of these compounds was determined at different stages of DENV-2 infection and replication cycle. DENV replication was measured by Foci Forming Unit Reduction Assay (FFURA) and quantitative RT-PCR. Selectivity Index value (SI) was determined as the ratio of cytotoxic concentration 50 (CC50) to inhibitory concentration 50 (IC50) for each compound. The half maximal inhibitory concentration (IC50) of quercetin against dengue virus was 35.7 μg mL-1 when it was used after virus adsorption to the cells. The IC50 decreased to 28.9 μg mL-1 when the cells were treated continuously for 5 h before virus infection and up to 4 days post-infection. The SI values for quercetin were 7.07 and 8.74 μg mL-1, respectively, the highest compared to all bioflavonoids studied. Naringin only exhibited anti-adsorption effects against DENV-2 with IC50 = 168.2 μg mL-1 and its related SI was 1.3. Daidzein showed a weak anti-dengue activity with IC50 = 142.6 μg mL-1 when the DENV-2 infected cells were treated after virus adsorption. The SI value for this compound was 1.03. Hesperetin did not exhibit any antiviral activity against DENV-2. The findings obtained from Foci Forming Unit Reduction Assay (FFURA) were corroborated by findings of the qRT-PCR assays. Quercetin and daidzein (50 μg mL-1) reduced DENV-2 RNA levels by 67% and 25%, respectively. There was no significant inhibition of DENV-2 RNA levels with naringin and hesperetin. Results from the study suggest that only quercetin demonstrated significant anti-DENV-2 inhibitory activities. Other bioflavonoids, including daidzein, naringin and hesperetin showed minimal to no significant inhibition of DENV-2 virus replication. These findings, together with those previously reported suggest that select group of bioflavonoids including quercetin and fisetin, exhibited significant inhibitory activities against dengue virus. This group of flavonoids, flavonol, could be investigated further to discover the common mechanisms of inhibition of dengue virus replication.

Design, synthesis, and biological evaluation of 2-substituted-2,3,4,9-tetrahydrospiro-β-carboline-3-carboxylic acid derivatives as first-in-class mast cell stabilizers.

PubMed

Singh, Jatinder; Shah, Ramanpreet; Singh, Dhandeep; Jaggi, Amteshwar S; Singh, Nirmal

2018-05-01

Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic rhinitis, and conjunctivitis as well as anaphylactic shock; hence, there is an unmet need for developing new mast cells stabilizers. The reported mast cell stabilizers have a heterocyclic moiety and an acidic group. Furthermore, the role of tryptophan in suppression of mast cell activation is established. Hence, we prepared constrained analogs of tryptophan, which are derivatives of 2,3,4,9-tetrahydrospiro-β-carboline-3-carboxylic acid, and evaluated them for ex vivo inhibition of compound 48/80-induced mast degranulation activity. By comparing IC 50 (μM) values with that of the standard drug sodium cromoglycate (IC 50  = 0.489 ± 0.003 μM), compounds with bulky groups like heptyl (compound 9; IC 50  = 0.389 ± 0.015 μM) and octyl (compound 10; IC 50  = 0.354 ± 0.023 μM) were found to be of similar potency as sodium cromoglycate. Furthermore, the polar group-containing compounds like the chloropropyl (compound 16; IC 50  = 0.382 ± 0.083 μM) and benzoyl derivative (compound 14; IC 50  = 00.469 ± 0.032 μM) were also found to be of similar potency as sodium cromoglycate. This is a seminal study of spiro-β-carboline mast cell stabilization having a wider scope in mast cell research; yet, the mechanism of action remains elusive. © 2018 Deutsche Pharmazeutische Gesellschaft.

Constituents of the anti–asthma herbal formula ASHMI™ synergistically inhibit IL–4 and IL–5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro

PubMed Central

Jayaprakasam, Bolleddula; Yang, Nan; Wen, Ming-Chun; Wang, Rong; Goldfarb, Joseph; Sampson, Hugh; Li, Xiu-Min

2015-01-01

OBJECTIVE Anti-asthma herbal medicine intervention (ASHMI™), a combination of three traditional Chinese medicinal herbs developed in our laboratory, has demonstrated efficacy in both mouse models of allergic asthma, and a double-blind placebo-controlled clinical trial in patients with asthma. This study was designed to determine if the anti-inflammatory effects of individual herbal constituents of ASHMI™ exhibited synergy. METHODS Effects of ASHMI and its components aqueous extracts of Lingzhi (Ganoderma lucidum), Kushen (Sophora flavescens) and Gancao (Glycyrrhiza uralensis), on Th2 cytokine secretion by murine memory Th2 cells (D10.G4.1) and eotaxin-1 secretion by human lung fibroblast (HLF-1) cells were determined by measuring levels in culture supernatants by enzyme-linked immunosorbent assay. Potential synergistic effects were determined by computing interaction indices from concentration-effect curve parameters. RESULTS Individual Lingzhi, Kushen and Gancao extracts and ASHMI (the combination of individual extracts) inhibited production of interleukin (IL)-4 and IL-5 by murine memory Th2 cells and eotaxin-1 production by HLF-1 cells. The mean 25%-inhibitory-concentration (IC25) values (mg/mL) for ASHMI, Lingzhi, Kushen and Gancao for IL-4 production were 30.9, 79.4, 123, and 64.6, respectively; for IL-5 production were 30.2, 263, 123.2 and 100, respectively; for eotaxin-1 were 13.2, 16.2, 30.2, and 25.1, respectively. The IC50 values (mg/mL) for ASHMI, Lingzhi, Kushen and Gancao for IL-4 production were 158.5, 239.9, 446.7, and 281.8, respectively; for eotaxin-1 were 38.1, 33.1, 100, and 158.5, respectively. The interaction indices of ASHMI constituents at IC25 were 0.35 for IL-4, 0.21 for IL-5 and 0.59 for eotaxin-1. The interaction indices at IC50 values were 0.50 for IL-4 and 0.62 for eotaxin-1 inhibition. Inhibition of IL-5 did not reach IC50 values. All interaction indices were below 1 which indicated synergy. CONCLUSION By comparing the interaction index values, we find that constituents in ASHMI™ synergistically inhibited eotaxin-1 production as well as Th2 cytokine production. PMID:23743163

Drug repurposing: In-vitro anti-glycation properties of 18 common drugs

PubMed Central

Rasheed, Saima; Sánchez, Sara S.; Yousuf, Sammer; Honoré, Stella M.; Choudhary, M. Iqbal

2018-01-01

Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover “new targets” for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 μM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 μM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 μM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 μM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 μM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 μM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents. PMID:29300762

In vitro piperaquine susceptibility is not associated with the Plasmodium falciparum chloroquine resistance transporter gene

PubMed Central

2013-01-01

Background Dihydroartemisinin-piperaquine is a new ACT that is administered as single daily dose for three days and has been demonstrated to be tolerated and highly effective for the treatment of uncomplicated Plasmodium falciparum malaria. Piperaquine was used alone to replace chloroquine as the first-line treatment for uncomplicated malaria in China in response to increasing chloroquine resistance in the 1970s. However, the rapid emergence of piperaquine-resistant strains that resulted in the cessation of its use in China in the 1980s, suggests that there is cross-resistance between piperaquine and chloroquine. Very few data are available on cross-resistance between piperaquine and chloroquine, and the data that do exist are often contradictory. Methods In total, 280 P. falciparum isolates, collected between April 2008 and June 2012 from patients hospitalized in France with imported malaria from a malaria-endemic country, were assessed ex vivo for piperaquine and chloroquine susceptibilities by using the standard 42-hour 3H-hypoxanthine uptake inhibition method. The chloroquine resistance-associated mutation K76T in pfcrt was also investigated for the 280 isolates. Results The IC50 for piperaquine ranged from 9.8 nM to 217.3 nM (mean = 81.3 nM. The IC50 for chloroquine ranged from 5.0 nM to 1,918 nM (mean = 83.6 nM. A significant but low correlation was observed between the Log IC50 values for piperaquine and chloroquine (r = 0.145, p < 0.001). However, the coefficient of determination of 0.021 indicates that only 2.1% of the variation in the response to piperaquine is explained by the variation in the response to chloroquine. The mean value for piperaquine was 74.0 nM in the Pfcrt K76 wild-type group (no = 125) and 87.7 nM in the 76 T mutant group (no = 155). This difference was not significant (p = 0.875, Mann Whitney U test). Conclusions The present work demonstrates that there was no cross-resistance between piperaquine and chloroquine among 280 P. falciparum isolates and that piperaquine susceptibility is not associated with pfcrt, the gene involved in chloroquine resistance. These results confirm the efficacy of piperaquine in association with dihydroartemisinin and support its use in areas in which parasites are resistant to chloroquine. PMID:24274185

In vitro and in vivo anti-plasmodial activity of essential oils, including hinokitiol.

PubMed

Fujisaki, Ryuichi; Kamei, Kiyoko; Yamamura, Mariko; Nishiya, Hajime; Inouye, Shigeharu; Takahashi, Miki; Abe, Shigeru

2012-03-01

Abstract. The anti-plasmodial activity of 47 essential oils and 10 of their constituents were screened for in vitro activity against Plasmodium falciparum. Five of these essential oils (sandalwood, caraway, monarda, nutmeg, and Thujopsis dolabrata var. hondai) and 2 constituents (thymoquinone and hinokitiol) were found to be active against P. falciparum in vitro, with 50% inhibitory concentration (IC50) values equal to or less than 1.0 microg/ml. Furthermore, in vivo analysis using a rodent model confirmed the anti-plasmodial potential of subcutaneously administered sandalwood oil, and percutaneously administered hinokitiol and caraway oil against rodent P. berghei. Notably, these oils showed no efficacy when administered orally, intraperitoneally or intravenously. Caraway oil and hinokitiol dissolved in carrier oil, applied to the skin of hairless mice caused high levels in the blood, with concentrations exceeding their IC50 values.

Design, synthesis, and molecular hybrids of caudatin and cinnamic acids as novel anti-hepatitis B virus agents.

PubMed

Wang, Li-Jun; Geng, Chang-An; Ma, Yun-Bao; Luo, Jie; Huang, Xiao-Yan; Chen, Hao; Zhou, Ning-Jia; Zhang, Xue-Mei; Chen, Ji-Jun

2012-08-01

Forty-six conjugated derivatives of caudatin with substituted cinnamic acids were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Most of the derivatives exhibited potent anti-HBV activity, especially inhibiting the HBV DNA replication with the IC(50) values from 2.44 to 22.89 μΜ. Compound 18 showed significant activity against the secretion of HBsAg, HBeAg, and HBV DNA replication with IC(50) values of 5.52, 5.52, 2.44 μΜ, respectively, and had good safety (LD(50) > 1250 mg/kg) according to the acute toxicity study. Preliminary mechanism investigation suggested that compound 18 exerted antivirus effects via interfering HBV X promoter and enhancer I to influence HBV transcriptions. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

New hydrazonoindolin-2-ones: Synthesis, exploration of the possible anti-proliferative mechanism of action and encapsulation into PLGA microspheres.

PubMed

Attia, Mohamed I; Eldehna, Wagdy M; Afifi, Samar A; Keeton, Adam B; Piazza, Gary A; Abdel-Aziz, Hatem A

2017-01-01

The synthesis and molecular characterization of new isatin-based hydrazonoindolin-2-ones 4a-o and 7a-e are reported. The in vitro anti-proliferative potential of the synthesized compounds 4a-o and 7a-e was examined against HT-29 (colon), ZR-75 (breast) and A549 (lung) human cancer cell lines. Compounds 7b, 7d and 7e were the most active congeners against the tested human cancer cell lines with average IC50 values of 4.77, 3.39 and 2.37 μM, respectively, as compared with the reference isatin-based drug, sunitinib, which exhibited an average IC50 value of 8.11 μM. Compound 7e was selected for further pharmacological evaluation in order to gain insight into its possible mechanism of action. It increased caspase 3/7 activity by 2.4- and 1.85-fold between 4 and 8 h of treatment, respectively, at 10 μM and it caused a decrease in the percentage of cells in the G1 phase of the cell cycle with a corresponding increase in the S-phase. In addition, compound 7e increased phosphorylated tyrosine (p-Tyr) levels nearly two-fold with an apparent IC50 value of 3.8 μM. The 7e-loaded PLGA microspheres were prepared using a modified emulsion-solvent diffusion method. The average encapsulation efficiency of the 7e-loaded PLGA microspheres was 85% ± 1.3. While, the in vitro release profile of the 7e-loaded microspheres was characterized by slow and continuous release of compound 7e during 21 days and the release curve was fitted to zero order kinetics. Incorporation of 7e into PLGA microspheres improved its in vitro anti-proliferative activity toward the human cancer cell line A549 after 120 h incubation period with an IC50 value less than 0.8 μM.

Low level tumor necrosis factor-alpha protects cardiomyocytes against high level tumor necrosis factor-alpha: brief insight into a beneficial paradox.

PubMed

Cacciapaglia, Fabio; Salvatorelli, Emanuela; Minotti, Giorgio; Afeltra, Antonella; Menna, Pierantonio

2014-12-01

Whether tumor necrosis factor-alpha (TNFα) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNFα agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNFα agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNFα. To shed light on these mixed findings, we characterized the effects of TNFα in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNFα, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNFα and then re-challenged with increasing concentrations of TNFα and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNFα increasing approximately 16-fold. TNFα preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNFα receptors [(soluble TNFα receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNFα at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by "low TNFα" helped cardiomyocyte to withstand toxicity from "high TNFα" or other agents. These results also suggested that beneficial or detrimental effects of anti-TNFα agents might well depend on whether these agents spared or intercepted discrete amounts of TNFα that preconditioned cardiomyocytes and made them more resistant to high concentrations of TNFα.

Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design.

PubMed

Yu, Wenying; Xiao, Hui; Lin, Jiayuh; Li, Chenglong

2013-06-13

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.

Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum.

PubMed

Pradines, B; Fusai, T; Daries, W; Laloge, V; Rogier, C; Millet, P; Panconi, E; Kombila, M; Parzy, D

2001-08-01

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca²⁺ overload.

PubMed

Wang, Yue; Wang, Fang; Yu, Jun-Ping; Jiang, Feng-Chao; Guan, Xin-Lei; Wang, Can-Ming; Li, Lei; Cao, Hui; Li, Ming-Xing; Chen, Jian-Guo

2012-11-01

In this study, a series of multipotent phenylthiazole-tacrine hybrids (7a-7e, 8, and 9a-9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole-tacrine hybrids were potent cholinesterase inhibitors with pIC(50) (-logIC(50)) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole-tacrine hybrids (9a-9m) could efficiently prevent Aβ(1-42) self-aggregation. The structure-activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4'-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca(2+) overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer's disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Anti-inflammatory Ingenane Diterpenoids from the Roots of Euphorbia kansui.

PubMed

Zhang, Jun-Sheng; Weng, Han-Zhuang; Huang, Jia-Luo; Tang, Gui-Hua; Yin, Sheng

2018-06-25

Bioassay-guided fractionation of the ethanolic extract of the roots of Euphorbia kansui led to the isolation of two new ingenane diterpenoids, euphorkans A (1: ) and B (2: ), together with 16 known analogues (3:  - 18: ). Their structures were determined by combined spectral and chemical methods. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells. Compounds 1:  - 6: and 10:  - 13: exhibited pronounced inhibitory activity with IC 50 values in the range of 2.78 - 10.6 µM, and were more potent than the positive control, quercetin (IC 50  = 15.8 µM). Compounds 1: and 5: were selected for further assays toward the key inflammation mediators TNF- α and IL-6, and showed a significant inhibition in a dose-dependent manner. The preliminary mechanistic study revealed that 1: and 5: inhibited NF- κ B activity, which may exert a role in their anti-inflammatory activity. Georg Thieme Verlag KG Stuttgart · New York.

The Evolution of Rotation and Activity in Young Open Clusters: the Zero-Age Main Sequence.

NASA Astrophysics Data System (ADS)

Patten, Brian Michael

1995-01-01

I have undertaken a program of ground- and space -based observations to measure photometric rotation periods and X-ray luminosities for late-type stars in the young open clusters IC 2391 and IC 2602. With cluster ages of ~30 Myr, IC 2391 and IC 2602 are ideal sites in which to observe conditions at the ZAMS since the solar-type stars in these clusters have not been on the main sequence long enough to undergo significant magnetic braking. The ROSAT survey of IC 2391 revealed 80 X-ray sources, 44 of which were found to be associated with stars which are now classified as new cluster members. Among the solar-type stars in both IC 2391 and IC 2602, I find a factor of ~25 spread in the distribution of rotation periods, which range from 0.21 to 4.86 day. I also find a factor of ~10-20 spread in the range of LX about a median LX value of ~10^{30 } erg s^{-1} for both clusters. These results show conclusively that stars arrive on the ZAMS with a wide range of rotation rates and coronal activity levels. When compared to data from older clusters, such as the Pleiades and the Hyades, there is an overall decline observed in both the rotation rates and median X-ray luminosity of cluster members with increasing age, however, while the spread in the range of rotation rates decreases to a small value, the spread in the range of LX values as a fraction of the median is observed to increase with age. This behavior is best explained through a dependence of LX on P rot which is weak in the young clusters and strong in the older clusters. The Rossby diagram shows there is a tight correlation between L X/Lbol and the Rossby number, Prot divided by the convective turnover time. Young, rapidly rotating, main sequence stars lie along a plateau of magnetic saturation, where LX has a weak dependence on rotation period, while older, more slowly rotating stars lie in a region on the Rossby diagram where LX has a strong dependence on rotation period.

In vitro anti-glycation and anti-oxidant properties of synthesized Schiff bases.

PubMed

Jhaumeer-Laulloo, Sabina; Bhowon, Minu Gupta; Mungur, Shabneez; Mahomoodally, Mohamad Fawzi; Subratty, Anwar Hussein

2012-05-01

A series of mono, bis and mixed Schiff bases (1-7) were synthesised and evaluated for potential anti-glycation and anti-oxidant activities using the bovine serum albumin-glucose assay and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay respectively. All compounds showed significant (p<0.05) antiglycating activities with IC50 values (4.02x10(-24)±0.1-2.88x10(-1)±1.35 mM) which were lower than the standard positive control aminoguanidine (IC50: 1.51x10(-3)±2.11 mM). Moreover, compounds 1-7 were found to possess significant (p<0.05) DPPH radical scavenging properties with SC50 values (1.31x10(-19)±0.05 to 2.25x10(-1)±1.24 mM) lower than the standard ascorbic acid (SC50: 5.50x10(-3)±2.11 mM). Compound 6 was found to be the most potent anti-glycating molecule (IC50 value: 4.02x10(-24)±0.1 mM) while compound 5 was the most potent anti-oxidant molecule (SC50: 1.31x10(-19)±0.05 mM); both being significantly lower (p<0.05) than the respective positive controls used. The present data showed that the number of phenolic OH together with structural changes influence both the anti-glycation and anti-oxidant observed herein. This study provides for the first time a series of potential template molecules for possible pharmaceutical applications that warrant further investigation as potential anti-glycation and anti-oxidant agents which could be of importance in metabolic diseases including diabetes mellitus.

Synthesis of novel amides based on acridone scaffold with interesting antineoplastic activity.

PubMed

Mahajan, Anand A; Rane, Rajesh A; Amritkar, Anish A; Naphade, Shital S; Miniyar, Pankaj B; Bangalore, Pavan Kumar; Karpoormath, Rajshekhar

2015-01-01

In search of novel cytotoxic agents based on acridone scaffold, twenty five derivatives of acridone-2- carboxamide were synthesized and evaluated against a panel of eleven cancer cell lines by using MTT assay. Amides, A5 and A8 (IC50 = 0.3 µM) exhibited good cytotoxicity against MCF7. Compound A22 (IC50 = 4.3 µM) was found to be selectively cytotoxic against cancer cell line MCF7 and KB403. Particularly, promising cytotoxic activities were shown by amides A6 (IC50 = 0.7 µM), A16 (IC50 = 6.3 µM), A8 (IC50 = 0.9 µM ), A21 (IC50 = 1.3 µM), A5 (IC50 = 2.9 µM), A8 (IC50 = 2.8 µM), A14 (IC50 = 0.8 µM), A9 (IC50 = 0.8 µM) and A8 (IC50 = 0.4 µM) against cell lines; PA1, WRL68, CaCO2, TK-10, K-562, PC-3, HOP-92, ECV-304 and UACC-257, respectively. The favorable cytotoxic profile and non-toxicity towards normal human cells displayed by the derivative revealed their potential for further anticancer drug developments.

In vitro metabolism of brucine by human liver microsomes and its interactions with CYP substrates.

PubMed

Li, Xin; Wang, Kai; Wei, Wei; Liu, Yong-yu; Gong, Lu

2013-08-25

Brucine, one of the main active ingredients in semen Strychni, has been included in many oral prescriptions of traditional Chinese medicine. In this study, we investigated the in vitro metabolism of brucine by human liver microsomes (HLMs) and the metabolic interactions of brucine with the substrates of cytochrome P450 (CYP450). Brucine was incubated with HLMs or CYP3A4 and then analysed by Liquid chromatography/mass spectrometry. The Km and Vmax values for HLMs were 30.53±3.14μM and 0.08±0.0029nmol/mg protein/min, respectively, while the corresponding values for CYP3A4 were 20.12±3.05μM and 6.40±0.21nmol/nmol P450/min. CYP3A4 may be the major enzyme responsible for brucine metabolism in HLMs, other human isoforms of CYP showed minimal or no effect on brucine metabolism. The inhibitory action of brucine was observed in CYP3A4 for the 1'-hydroxylation of midazolam, with inhibitory concentration 50 (IC50) of 8.4-fold higher than specific inhibitors in HLMs. Furthermore, brucine significantly inhibited the CYP3A4-catalyzed midazolam 1'-hydroxylation (Ki=2.14μM) at a concentration lower than 10μM, but no obvious inhibitory effects were observed on other CYP substrates (IC50>50μM). These results suggest that brucine has the potential to interact with a wide range of xenobiotics and endogenous chemicals especially CYP3A4 substrates. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

In vitro antimalarial activity of different extracts of Eremostachys macrophylla Montbr. & Auch.

PubMed

Asnaashari, Solmaz; Heshmati Afshar, Fariba; Ebrahimi, Atefeh; Bamdad Moghadam, Sedigheh; Delazar, Abbas

2015-01-01

The risk of drug resistance and the use of medicinal plants in malaria prevention and treatment have led to the search for new antimalarial compounds with natural origin. In the current study, six extracts with different polarity from aerial parts and rhizomes of Eremostachys macrophylla Montbr. & Auch., were screened for their antimalarial properties by cell-free β-hematin formation assay. Dichloromethane (DCM) extracts of both parts of plant showed significant antimalarial activities with IC50 values of 0.797 ± 0.016 mg/mL in aerial parts and 0.324 ± 0.039 mg/mL in rhizomes compared to positive control (Chloroquine, IC50 = 0.014 ± 0.003 mg/mL, IC90 = 0.163 ± 0.004 mg/mL). Bioactivity-guided fractionation of the most potent part (DCM extract of rhizomes) by vacuum liquid chromatography (VLC) afforded seven fractions. Sixty percent ethyl acetate/n-hexane fraction showed considerable antimalarial activity with IC50 value of 0.047 ± 0.0003 mg/mL. From 6 extracts with different polarity of E. macrophylla,s aerial parts and rhizomes, the DCM extract of both parts were the most active extract in this assay. The preliminary phytochemical study on the VLC fractions of the most potent part persuades us to focus on purifying the active components of these extracts and to conduct further investigation towards in vivo evaluation.

In vivo quality assurance of volumetric modulated arc therapy for ano-rectal cancer with thermoluminescent dosimetry and image-guidance.

PubMed

Dipasquale, Giovanna; Nouet, Philippe; Rouzaud, Michel; Dubouloz, Angèle; Miralbell, Raymond; Zilli, Thomas

2014-06-01

To assess in vivo dose distribution using cone-beam computed tomography scans (CBCTs) and thermoluminescent dosimeters (TLDs) in patients with anal or rectal cancer treated with volumetric modulated arc therapy (VMAT). Intracavitary (IC) in vivo dosimetry (IVD) was performed in 11 patients using adapted endorectal probes containing TLDs, with extra measurements at the perianal skin (PS) for anal margin tumors. Measured doses were compared to calculated ones obtained from image fusion of CBCT with CT treatments plans. A total of 55 IC and 6 PS measurements were analyzed. IC TLD median planned and measured doses were 1.81 Gy (range, 0.25-2.02 Gy) and 1.82 Gy (range, 0.19-2.12 Gy), respectively. In comparison to the planned doses all IC TLD dose measurements differed by a median dose of 0.02 Gy (range, -0.11/+0.19 Gy, p=0.102) (median difference of 1.1%, range -6.1%/+10.6%). Overall, 95% of IC measurements were within ±7.7% of the expected percentage doses and only 1 value was above +10%. For PS measurements, only one was not within ±7.7% of expected values (i.e., -8.9%). Image guidance using CBCT for IVD with TLDs is helpful to validate the delivered doses in patients treated with VMAT for ano-rectal tumors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[Cytotoxicity of chemicals used in household products: 1997- 2004].

PubMed

Ikarashi, Yoshiaki; Kaniwa, Masa-aki; Tsuchiya, Toshie

2005-01-01

The cytotoxicities of chemicals used in household products were evaluated using a neutral red (NR) uptake assay. The chemicals tested during 1997-2004 were rubber additives (accelerators, antioxidants and retarders), solvents, plasticizers and biocides, such as antimicrobials, fungicides, preservatives used in paints, paper, wood and plastic products. The cytotoxicity potential of each chemical was classified by determining the concentrations inducing 50% reduction of NR uptake into Chinese hamster fibroblast V79 cells compared to control (IC50). In vivo eye irritancy of each chemical was estimated by the IC50 value. Most biocides tested showed strong cytotoxicity and had a high probability of inducing strong eye irritation.

Development and validation of an indirect competitive enzyme-linked immunosorbent assay for the screening of tylosin and tilmicosin in muscle, liver, milk, honey and eggs.

PubMed

Peng, Dapeng; Ye, Shengqiang; Wang, Yulian; Chen, Dongmei; Tao, Yanfei; Huang, Lingli; Liu, Zhenli; Dai, Menghong; Wang, Xiaoqing; Yuan, Zonghui

2012-01-11

Incorrect use of tylosin and tilmicosin could result in allergy and select resistance. To monitor the illegal use of these antibiotics in animals, a monoclonal-based indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) has been established. Several haptens were synthesized and conjugated to carrier protein. Female Balb/c mice were inoculated with the four different conjugates to produce monoclonal antibodies according to the schemes of immunization. Aftercell fusion and culture several times, nine hybridoma cell lines were isolated. Only one, 3C4 that has isotype IgG2a, was selected for detailed study. The cross-reactivity of the monoclonal antibody 3C4 to tylosin and tilmicosin was 100% and 51% respectively. The standard curves based on the tylosin and tilmicosin matrix calibration ranged from 2.5 to 40 μg L(-1), with an IC(50) value of 6.1 μg L(-1) and 12.1 μg L(-1), respectively. The limits of detection of the ic-ELISA ranged from 5.1 μg kg(-1) to 13.8 μg kg(-1) in edible animal tissues. The recoveries were 74.1% to 120.7% with less than 18.6% of the coefficient of variation when tylosin and tilmicosin were spiked in various biological matrices with the concentrations of 25.0-200.0 μg kg(-1). Good correlations between the results of the ic-ELISA and high performance liquid chromatography were observed in the incurred tissues. These results suggest that the ic-ELISA is a sensitive, accurate and low-cost method that would be a useful tool for the screening of the residues of tylosin and tilmicosin in muscle, liver, milk, honey and eggs.

Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group.

PubMed Central

Japour, A J; Mayers, D L; Johnson, V A; Kuritzkes, D R; Beckett, L A; Arduino, J M; Lane, J; Black, R J; Reichelderfer, P S; D'Aquila, R T

1993-01-01

A standardized antiviral drug susceptibility assay for clinical human immunodeficiency virus type 1 (HIV-1) isolates has been developed for use in clinical trials. The protocol is a two-step procedure that first involves cocultivation of patient infected peripheral blood mononuclear cells (PBMC) with seronegative phytohemagglutinin-stimulated donor PBMC to obtain an HIV-1 stock. The virus stock is titrated for viral infectivity (50% tissue culture infective dose) by use of serial fourfold virus dilutions in donor PBMC. A standardized inoculum of 1,000 50% tissue culture infective doses per 10(6) cells is used in the second step of the procedure to acutely infect seronegative donor PBMC in a 7-day microtiter plate assay with triplicate wells containing zidovudine (ZDV) concentrations ranging from 0 to 5.0 microM. The ZDV 50% inhibitory concentrations (IC50) for reference ZDV-susceptible and ZDV-resistant HIV-1 isolates ranged from 0.002 to 0.113 microM and from 0.15 to > 5.0 microM, respectively. Use of this consensus protocol reduced interlaboratory variability for ZDV IC50 determinations with reference HIV-1 isolates. Among eight laboratories, the coefficient of variation ranged from 0.85 to 1.25 with different PBMC protocols and was reduced to 0.39 to 0.98 with the standardized assay. Among the clinical HIV-1 isolates assayed by the standardized drug susceptibility assay, the median ZDV IC50 increased gradually with more ZDV therapy. This protocol provides an efficient and reproducible means to assess the in vitro susceptibility to antiretroviral agents of virtually all clinical HIV-1 isolates. PMID:8517697

Pharmacological profile of zacopride and new quaternarized fluorobenzamide analogues on mammalian α7 nicotinic acetylcholine receptor.

PubMed

Bourdin, Céline M; Lebreton, Jacques; Mathé-Allainmat, Monique; Thany, Steeve H

2015-08-15

From quaternarization of quinuclidine enantiomers of 2-fluoro benzamide LMA10203 in dichloromethane, the corresponding N-chloromethyl derivatives LMA10227 and LMA10228 were obtained. Here, we compared the agonist action of known zacopride and its 2-fluoro benzamide analogues, LMA10203, LMA10227 and LMA10228 against mammalian homomeric α7 nicotinic acetylcholine receptor expressed in Xenopus oocytes. We found that LMA10203 was a partial agonist of α7 receptor with a pEC50 value of 4.25 ± 0.06 μM whereas LMA10227 and LMA10228 were poorly active on α7 homomeric nicotinic receptor. LMA10227 and LMA10228 were identified as antagonists of acetylcholine-induced currents with IC50 values of 28.4 μM and 39.3 μM whereas LMA10203 and zacopride possessed IC50 values of 8.07 μM and 7.04 μM, respectively. Moreover, despite their IC50 values, LMA10227 was the most potent inhibitor of nicotine-induced current amplitudes (65.7 ± 2.1% inhibition). LMA10203 and LMA10228 had the same inhibitory effects (26.5 ± 7.5% and 33.2 ± 4.1%, respectively), whereas zacopride had no significant inhibitory effect (4.37 ± 4%) on nicotine-induced responses. Our results revealed different pharmacological properties between the four compounds on acetylcholine and nicotine currents. The mode of action of benzamide compounds may need to be reinterpreted with respect to the potential role of α7 receptor. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemoenzymatic Synthesis and α-Glucosidase Inhibitory Activity of Dimeric Neolignans Inspired by Magnolol.

PubMed

Pulvirenti, Luana; Muccilli, Vera; Cardullo, Nunzio; Spatafora, Carmela; Tringali, Corrado

2017-05-26

A chemoenzymatic synthesis of a small library of dimeric neolignans inspired by magnolol (1) is reported. The 2-iodoxybenzoic acid (IBX)-mediated regioselective ortho-hydroxylation of magnolol is described, affording the bisphenols 6 and 7. Further magnolol analogues (12, 13, 15-17, 19-23) were obtained from eugenol (3), tyrosol (4), and homovanillic alcohol (5), through horseradish peroxidase (HRP)-mediated oxidative coupling and regioselective ortho-hydroxylation or ortho-demethylation in the presence of IBX, followed by reductive treatment with Na 2 S 2 O 4 . A chemoselective protection/deprotection of the alcoholic group of 4 and 5 was carried out by lipase-mediated acetylation/deacetylation. The dimeric neolignans, together with 1 and honokiol (2), were evaluated as inhibitors of yeast α-glucosidase, in view of their possible utilization and optimization as antidiabetic drugs. The synthetic analogues of magnolol showed a strong inhibitory activity with IC 50 values in the range 0.15-4.1 μM, much lower than those of honokiol and the reference compounds quercetin and acarbose. In particular, a very potent inhibitory activity, with an IC 50 of 0.15 μM, was observed for 1,1'-dityrosol-8,8'-diacetate (15), and comparable inhibitory activities were also shown by bisphenols 6 (0.49 μM), 13 (0.50 μM), and 22 (0.86 μM). A kinetic study showed that 15 acts as a competitive inhibitor, with a K i value of 0.86 μM.

The effect of coniine on presynaptic nicotinic receptors.

PubMed

Erkent, Ulkem; Iskit, Alper B; Onur, Rustu; Ilhan, Mustafa

2016-01-01

Toxicity of coniine, an alkaloid of Conium maculatum (poison hemlock), is manifested by characteristic nicotinic clinical signs including excitement, depression, hypermetria, seizures, opisthotonos via postsynaptic nicotinic receptors. There is limited knowledge about the role of presynaptic nicotinic receptors on the pharmacological and toxicological effects of coniine in the literature. The present study was undertaken to evaluate the possible role of presynaptic nicotinic receptors on the pharmacological and toxicological effects of coniine. For this purpose, the rat anococcygeus muscle and guinea-pig atria were used in vitro. Nicotine (100 μM) elicited a biphasic response composed of a relaxation followed by contraction through the activation of nitrergic and noradrenergic nerve terminals in the phenylephrine-contracted rat anococcygeus muscle. Coniine inhibited both the nitrergic and noradrenergic response in the muscle (-logIC(50) = 3.79 ± 0.11 and -logIC(50) = 4.57 ± 0.12 M, respectively). The effect of coniine on nicotinic receptor-mediated noradrenergic transmission was also evaluated in the guinea-pig atrium (-logIC(50) = 4.47 ± 0.12 M) and did not differ from the -logIC(50) value obtained in the rat anococcygeus muscle. This study demonstrated that coniine exerts inhibitory effects on nicotinic receptor-mediated nitrergic and noradrenergic transmitter response.

Structures and bioactivities of seven flavonoids from Osmanthus fragrans 'Jinqiu' essential oil extraction residues.

PubMed

Zhou, Jiang-Lian; Fang, Xian-Ying; Wang, Jing-Qiu; Zhao, Lin-Guo; Li, Yi; Tang, Feng; Yue, Yong-De

2018-03-01

Osmanthus fragrans are well-known for their fragrance, but it is wasteful if to discard O. fragrans flower after extracting their essential oils. In this paper, we found that O. fragrans flower residues were rich in flavonoids. Six flavonoids and one phenylethanoid glycoside were isolated from the ethanol extract of O. fragrans flower residues, identified as quercetin (1), rutin (2), verbascoside (3), genistin (4), kaempferol (5), isorhamnetin (6) and naringin (7). In bioactivity study, kaempferol (IC 50  = 1.43 μg/mL) showed the best anti-inflammatory activity. Isorhamnetin, quercetin, kaempferol, verbascoside and rutin (the values of IC 50 were 18.30, 11.05, 16.88, 20.21 and 22.76 μg/mL, respectively) showed excellent DPPH free radical scavenging activity. Verbascoside performed relatively well at inhibiting the growth of both CT26 colonic carcinoma cells (IC 50  = 46.87 μg/mL) and HepG2 hepatocarcinoma cells (IC 50  = 30.58 μg/mL). In addition, quercetin and kaempferol showed strong anti-proliferation activity against HepG2 cells.

Doxorubicin-anti-carcinoembryonic antigen immunoconjugate activity in vitro.

PubMed

Richardson, V J; Ford, C H; Tsaltas, G; Gallant, M E

1989-04-01

An in vitro model consisting of a series of 11 human cancer cell lines with varying density of expression of membrane carcinoembryonic antigen (CEA) has been used to evaluate conjugates of doxorubicin (Adriamycin) covalently linked by a carbodiimide method to goat polyclonal antibodies and mouse monoclonal antibodies to CEA. Conjugates were produced which retained both antigen binding and drug cytotoxicity. IC50 values were determined for free drug, free drug mixed with unconjugated antibodies and for the immunoconjugates. Cell lines that were very sensitive to free drug (IC50 less than 100 ng/ml) were also found to be highly sensitive to conjugated drug and similarly cell lines resistant to drug (IC50 greater than 1,000 ng/ml) were also resistant to conjugated drug. Although there was no correlation between CEA expression and conjugates efficacy, competitive inhibition studies using autologous antibody to block conjugate binding to cells indicated immunoconjugates specificity for the CEA target.

New chemical constituents from the Piper betle Linn. (Piperaceae).

PubMed

Atiya, Akhtar; Sinha, Barij Nayan; Ranjan Lal, Uma

2018-05-01

The phytochemical investigation of chloroform extract from Piper betle var. haldia, Piperaceae, leaves has resulted in the isolation of two new chemical constituents which were identified as 1-n-dodecanyloxy resorcinol (H1) and desmethylenesqualenyl deoxy-cepharadione-A (H4), on the basis of spectroscopic data 1D NMR ( 1 H and 13 C) and 2D NMR ( 1 H- 1 H COSY and HMBC) as well as ESI-MS, FT-IR and HR-ESI-MS analyses. Compounds H1 and H4 showed excellent antioxidant DPPH free radical scavenging activity with IC 50 values of 7.14 μg/mL and 8.08 μg/mL compared to ascorbic acid as a standard antioxidant drug with IC 50 value of 2.52 μg/mL, respectively. Evaluation of cytotoxic activity against human hepatoma cell line (PLC-PRF-5) showed moderate effect with the GI 50 values of 35.12 μg/mL for H1, 31.01 μg/mL for H4, compared to Doxorubicin ® as a standard cytotoxic drug with GI 50 value of 18.80 μg/mL.

Asphodosides A-E, anti-MRSA metabolites from Asphodelus microcarpus.

PubMed

Ghoneim, Mohammed M; Elokely, Khaled M; El-Hela, Atef A; Mohammad, Abd-Elsalam I; Jacob, Melissa; Radwan, Mohamed M; Doerksen, Robert J; Cutler, Stephen J; Ross, Samir A

2014-09-01

Bioassay guided fractionation of the ethanolic extract of Asphodelus microcarpus Salzm. et Viv. (Xanthorrhoeaceae or Asphodelaceae) resulted in isolation of five compounds identified as asphodosides A-E (1-5). Compounds 2-4 showed activity against methicillin resistant Staphylococcus aureus (MRSA) with IC50 values of 1.62, 7.0 and 9.0μg/mL, respectively. They also exhibited activity against Staphylococcus aureus (non-MRSA) with IC50 values of 1.0, 3.4 and 2.2μg/mL, respectively. The structure elucidation of isolated metabolites was carried out using spectroscopic data (1D and 2D NMR), optical rotation and both experimental and calculated electronic circular dichroism (ECD). Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular Docking Study on Galantamine Derivatives as Cholinesterase Inhibitors.

PubMed

Atanasova, Mariyana; Yordanov, Nikola; Dimitrov, Ivan; Berkov, Strahil; Doytchinova, Irini

2015-06-01

A training set of 22 synthetic galantamine derivatives binding to acetylcholinesterase was docked by GOLD and the protocol was optimized in terms of scoring function, rigidity/flexibility of the binding site, presence/absence of a water molecule inside and radius of the binding site. A moderate correlation was found between the affinities of compounds expressed as pIC50 values and their docking scores. The optimized docking protocol was validated by an external test set of 11 natural galantamine derivatives and the correlation coefficient between the docking scores and the pIC50 values was 0.800. The derived relationship was used to analyze the interactions between galantamine derivatives and AChE. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of new potent inhibitor of aldose reductase from Ocimum basilicum.

PubMed

Bhatti, Huma Aslam; Tehseen, Yildiz; Maryam, Kiran; Uroos, Maliha; Siddiqui, Bina S; Hameed, Abdul; Iqbal, Jamshed

2017-12-01

Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3-hydroxypropyl)-3-methyl-8-β-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6'-hydroxyhex-3'-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC 50 value of 2.095±0.77µM compare to standard sorbinil (IC 50 =3.14±0.02µM). Moreover, the compound (1) also showed multifolds higher activity (IC 50 =0.783±0.07µM) against AKR1A1 as compared to standard valproic acid (IC 50 =57.4±0.89µM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC 50 =4.324±1.25µM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases. Copyright © 2017 Elsevier Inc. All rights reserved.

Discovery of compounds blocking the proliferation of Toxoplasma gondii and Plasmodium falciparum in a chemical space based on piperidinyl-benzimidazolone analogs.

PubMed

Saïdani, Nadia; Botté, Cyrille Y; Deligny, Michael; Bonneau, Anne-Laure; Reader, Janette; Lasselin, Ronald; Merer, Goulven; Niepceron, Alisson; Brossier, Fabien; Cintrat, Jean-Christophe; Rousseau, Bernard; Birkholtz, Lyn-Marie; Cesbron-Delauw, Marie-France; Dubremetz, Jean-François; Mercier, Corinne; Vial, Henri; Lopez, Roman; Maréchal, Eric

2014-05-01

A piperidinyl-benzimidazolone scaffold has been found in the structure of different inhibitors of membrane glycerolipid metabolism, acting on enzymes manipulating diacylglycerol and phosphatidic acid. Screening a focus library of piperidinyl-benzimidazolone analogs might therefore identify compounds acting against infectious parasites. We first evaluated the in vitro effects of (S)-2-(dibenzylamino)-3-phenylpropyl 4-(1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)piperidine-1-carboxylate (compound 1) on Toxoplasma gondii and Plasmodium falciparum. In T. gondii, motility and apical complex integrity appeared to be unaffected, whereas cell division was inhibited at compound 1 concentrations in the micromolar range. In P. falciparum, the proliferation of erythrocytic stages was inhibited, without any delayed death phenotype. We then explored a library of 250 analogs in two steps. We selected 114 compounds with a 50% inhibitory concentration (IC50) cutoff of 2 μM for at least one species and determined in vitro selectivity indexes (SI) based on toxicity against K-562 human cells. We identified compounds with high gains in the IC50 (in the 100 nM range) and SI (up to 1,000 to 2,000) values. Isobole analyses of two of the most active compounds against P. falciparum indicated that their interactions with artemisinin were additive. Here, we propose the use of structure-activity relationship (SAR) models, which will be useful for designing probes to identify the target compound(s) and optimizations for monotherapy or combined-therapy strategies.

Cost Analysis of Fluconazole Prophylaxis for Prevention of Neonatal Invasive Candidiasis.

PubMed

Swanson, Jonathan R; Vergales, Jeff; Kaufman, David A; Sinkin, Robert A

2016-05-01

Fluconazole prophylaxis (FP) in premature infants is well studied and has been shown to decrease invasive candidiasis (ICs). IC in neonates has significant financial costs; determining the cost-benefit of FP may provide additional justification for targeting high-risk neonates. We aimed to determine the IC rate in premature infants at which FP is cost-beneficial. A decision tree cost-analysis model using cost of FP related to costs associated with IC was used. We searched PubMed for all papers that used intravenous FP and reported rates of IC in very low birth weight neonates. Average IC rates in those who received FP (2.0%; range, 0-6.1%) and in those who did not receive FP (9.2%; range, 0-20.5%) were used. Incremental hospital costs because of IC and for FP were retrieved from the literature. Sensitivity analysis was performed to determine the incremental cost of FP across the range of published IC rates. The average cost per patient attributed to IC in patients receiving FP was $785 versus $2617 in those not receiving FP. Sensitivity analysis demonstrates the rate of IC would need to be <2.8% for FP to lose its cost-benefit. In Monte Carlo simulation, targeting infants <1000 g would lead to $50,304,333 in cost savings per year in the United States. FP provides a cost-advantage across most IC rates seen in the youngest premature infants. Using a rate of 2.8% for their individual high-risk neonatal intensive care unit patients, providers can determine if FP is cost-beneficial in determining for whom to provide IC prophylaxis.

Bitter tastant responses in the amoeba Dictyostelium correlate with rat and human taste assays.

PubMed

Cocorocchio, Marco; Ives, Robert; Clapham, David; Andrews, Paul L R; Williams, Robin S B

2016-01-01

Treatment compliance is reduced when pharmaceutical compounds have a bitter taste and this is particularly marked for paediatric medications. Identification of bitter taste liability during drug discovery utilises the rat in vivo brief access taste aversion (BATA) test which apart from animal use is time consuming with limited throughput. We investigated the suitability of using a simple, non-animal model, the amoeba Dictyostelium discoideum to investigate taste-related responses and particularly identification of compounds with a bitter taste liability. The effect of taste-related compounds on Dictyostelium behaviour following acute exposure (15 minutes) was monitored. Dictyostelium did not respond to salty, sour, umami or sweet tasting compounds, however, cells rapidly responded to bitter tastants. Using time-lapse photography and computer-generated quantification to monitor changes in cell membrane movement, we developed an assay to assess the response of Dictyostelium to a wide range of structurally diverse known bitter compounds and blinded compounds. Dictyostelium showed varying responses to the bitter tastants, with IC50 values providing a rank order of potency. Comparison of Dictyostelium IC50 values to those observed in response to a similar range of compounds in the rat in vivo brief access taste aversion test showed a significant (p = 0.0172) positive correlation between the two models, and additionally a similar response to that provided by a human sensory panel assessment test. These experiments demonstrate that Dictyostelium may provide a suitable model for early prediction of bitterness for novel tastants and drugs. Interestingly, a response to bitter tastants appears conserved from single-celled amoebae to humans.

Efficient Synthesis and Discovery of Schiff Bases as Potent Cholinesterase Inhibitors.

PubMed

Razik, Basma M Abd; Osman, Hasnah; Ezzat, Mohammed O; Basiri, Alireza; Salhin, Abdussalam; Kia, Yalda; Murugaiyah, Vikneswaran

2016-01-01

The search for new cholinesterase inhibitors is still a promising approach for management of Alzheimer`s disease. Schiff bases are considered as important class of organic compounds, which have wide range of applications including as enzyme inhibitors. In the present study, a new green ionic liquid mediated strategy was developed for convenient synthesis of two series of Schiff bases 3(a-j) and 5(a-j) as potential cholinesterase inhibitors using aromatic aldehydes and primary amines in [bmim]Br. The synthesized compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential by modified Ellman's method. The molecular interactions between the most active compound and the enzyme were analyzed by molecular docking. Among them, 3j displayed higher inhibitory activities than reference drug, galanthamine, with IC50 values of 2.05 and 5.77 µM, for AChE and BChE, respectively. Interestingly, all the compounds except 3b displayed higher BChE inhibitions than galanthamine with IC50 values ranging from 5.77 to 18.52 µM. Molecular docking of compound 3j inside the TcAChE and hBChE completely coincided with the inhibitory activities observed. The compound forms strong hydrogen bonding at the peripheral anionic site of AChE whereas on BChE, it had hydrophobic and mild polar interactions. An efficient and eco-friendly synthetic methodology has been developed to synthesize Schiff bases in a very short reaction time and excellent yields in ionic solvent, whereby the compounds from series 3 showed promising cholinesterase inhibitory activity.

Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

PubMed Central

Nies, Anne T.; Hofmann, Ute; Resch, Claudia; Schaeffeler, Elke; Rius, Maria; Schwab, Matthias

2011-01-01

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy. PMID:21779389

Cannabidiol-2',6'-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor.

PubMed

Takeda, Shuso; Usami, Noriyuki; Yamamoto, Ikuo; Watanabe, Kazuhito

2009-08-01

The inhibitory effect of nordihydroguaiaretic acid (NDGA) (a nonselective lipoxygenase (LOX) inhibitor)-mediated 15-LOX inhibition has been reported to be affected by modification of its catechol ring, such as methylation of the hydroxyl group. Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity. Based on the phenomenon observed in NDGA, we investigated whether or not methylation of CBD affects its inhibitory potential against 15-LOX, because CBD contains a resorcinol ring, which is an isomer of catechol. Although CBD inhibited 15-LOX activity with an IC(50) value (50% inhibition concentration) of 2.56 microM, its monomethylated and dimethylated derivatives, CBD-2'-monomethyl ether and CBD-2',6'-dimethyl ether (CBDD), inhibited 15-LOX activity more strongly than CBD. The number of methyl groups in the resorcinol moiety of CBD (as a prototype) appears to be a key determinant for potency and selectivity in inhibition of 15-LOX. The IC(50) value of 15-LOX inhibition by CBDD is 0.28 microM, and the inhibition selectivity for 15-LOX (i.e., the 5-LOX/15-LOX ratio of IC(50) values) is more than 700. Among LOX isoforms, 15-LOX is known to be able to oxygenate cholesterol esters in the low-density lipoprotein (LDL) particle (i.e., the formation of oxidized LDL). Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.

One Pot Selective Arylation of 2-Bromo-5-Chloro Thiophene; Molecular Structure Investigation via Density Functional Theory (DFT), X-ray Analysis, and Their Biological Activities.

PubMed

Rasool, Nasir; Kanwal, Aqsa; Rasheed, Tehmina; Ain, Quratulain; Mahmood, Tariq; Ayub, Khurshid; Zubair, Muhammad; Khan, Khalid Mohammed; Arshad, Muhammad Nadeem; M Asiri, Abdullah; Zia-Ul-Haq, Muhammad; Jaafar, Hawa Z E

2016-06-28

Synthesis of 2,5-bisarylthiophenes was accomplished by sequential Suzuki cross coupling reaction of 2-bromo-5-chloro thiophenes. Density functional theory (DFT) studies were carried out at the B3LYP/6-31G(d, p) level of theory to compare the geometric parameters of 2,5-bisarylthiophenes with those from X-ray diffraction results. The synthesized compounds are screened for in vitro bacteria scavenging abilities. At the concentration of 50 and 100 μg/mL, compounds 2b, 2c, 2d, 3c, and 3f with IC50-values of 51.4, 52.10, 58.0, 56.2, and 56.5 μg/mL respectively, were found most potent against E. coli. Among all the synthesized compounds 2a, 2d, 3c, and 3e with the least values of IC50 77, 76.26, 79.13 μg/mL respectively showed significant antioxidant activities. Almost all of the compounds showed good antibacterial activity against Escherichia coli, whereas 2-chloro-5-(4-methoxyphenyl) thiophene (2b) was found most active among all synthesized compound with an IC50 value of 51.4 μg/mL. All of the synthesized compounds were screened for nitric oxide scavenging activity as well. Frontier molecular orbitals (FMOs) and molecular electrostatic potentials of the target compounds were also studied theoretically to account for their relative reactivity.

Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice

PubMed Central

Johnson, Emily J.; Won, Christina S.; Köck, Kathleen; Paine, Mary F.

2017-01-01

Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells and the probe substrate estrone 3-sulfate, IC50s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6′,7′-dihydroxybergamottin), and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice juice. Nobiletin was the most potent (IC50, 3.7 μM); 6′,7′-dihydroxybergamottin, naringin, naringenin, and tangeretin were moderately potent (IC50, 20–50 μM); and bergamottin and hesperidin were the least potent (IC50, >300 μM) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine ratios of unbound concentration to IC50 for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions. PMID:28032362

Novel potent pyridoxine-based inhibitors of AChE and BChE, structural analogs of pyridostigmine, with improved in vivo safety profile.

PubMed

Strelnik, Alexey D; Petukhov, Alexey S; Zueva, Irina V; Zobov, Vladimir V; Petrov, Konstantin A; Nikolsky, Evgeny E; Balakin, Konstantin V; Bachurin, Sergey O; Shtyrlin, Yurii G

2016-08-15

We report a novel class of carbamate-type ChE inhibitors, structural analogs of pyridostigmine. A small library of congeneric pyridoxine-based compounds was designed, synthesized and evaluated for AChE and BChE enzymes inhibition in vitro. The most active compounds have potent enzyme inhibiting activity with IC50 values in the range of 0.46-2.1μM (for AChE) and 0.59-8.1μM (for BChE), with moderate selectivity for AChE comparable with that of pyridostigmine and neostigmine. Acute toxicity studies using mice models demonstrated excellent safety profile of the obtained compounds with LD50 in the range of 22-326mg/kg, while pyridostigmine and neostigmine are much more toxic (LD50 3.3 and 0.51mg/kg, respectively). The obtained results pave the way to design of novel potent and safe cholinesterase inhibitors for symptomatic treatment of neuromuscular disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mechanism of ascaridole activation in Leishmania.

PubMed

Geroldinger, Gerald; Tonner, Matthias; Hettegger, Hubert; Bacher, Markus; Monzote, Lianet; Walter, Martin; Staniek, Katrin; Rosenau, Thomas; Gille, Lars

2017-05-15

Endoperoxides (EP) are an emerging class of drugs which have potential in antiparasitic therapy, but also in other fields. For malaria therapy the EP artemisinin (Art) and its derivatives are successfully used. We have shown in the past that the EP ascaridole (Asc) is useful for the treatment of cutaneous leishmaniasis in a mouse model. Biomimetic experiments suggested that these drugs need activation in the respective target pathogens to exert their function. In spite of this idea, direct activation of EP to radicals inside cells has never been demonstrated. Therefore, this study was initiated to explore the activation of Asc in biomimetic systems and inside Leishmania in comparison to Art. Using electron paramagnetic resonance spectroscopy (EPR) in combination with spin-trapping we identified the secondary alkyl radical intermediates arising from reduction by Fe 2+ in cell-free systems. Combined GC/NMR analysis confirmed the loss of isopropyl residues from Asc during this process as intermediates. This activation of Asc was stimulated by low molecular Fe 2+ complexes or alternatively by hemin in conjunction with thiol reductants, such as cysteine (Cys). In Leishmania tarentolae promastigotes (LtP) as model for pathogenic forms of Leishmania carbon-centered radicals were identified in the presence of Asc by EPR spin-trapping. Both Asc and Art inhibited the viability in LtP with IC 50 values in the low micromolar range while IC 50 values for J774 macrophages were considerably higher. A similar structure without EP bridge (1,4-cineole) resulted in no detectable radicals and possessed much less cytotoxicity in LtP and no selectivity for LtP compared to J774 cells. The Asc-derived radical formation in LtP was inhibited by the iron chelator deferoxamine (DFO), and stimulated by Cys (a suitable reductant for hemin). The IC 50 values for LtP viability in the presence of Asc or Art were increased significantly by the spin trap DMPO, while Cys and DFO increased only IC 50 values for Art. In a heme association assay Asc demonstrated a lower binding affinity to heme than Art. ICP-OES measurements revealed that in LtP the total iron concentrations were twice as high as values in J774 macrophages. Since low molecular iron was important in Asc activation we studied the influence of Asc on the labile iron pool (LIP) in LtP. Low temperature EPR experiments demonstrated that Asc shifts the redox balance of iron in the LIP to its oxidized state. These data demonstrate that univalent cleavage of Asc/Art in LtP is an essential part of their pharmacological mechanism. The structure of the EP determines whether activation by low molecular iron or heme is favored and the availability of these intracellular activators modulates their cytotoxicity. These findings may be helpful for synthesis of new Asc derivatives and understanding the action of EP in other cell types. Copyright © 2017 Elsevier Inc. All rights reserved.

Histone Deacetylase Inhibitors through Click Chemistry

PubMed Central

Shen, Jie; Woodward, Robert; Kedenburg, James Patrick; Liu, Xianwei; Chen, Min; Fang, Lanyan; Sun, Duxin; Wang, Peng George

2012-01-01

Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5g (NSC746457) was discovered that inhibited HDAC1 at an IC50 value of 104 ± 30 nM and proved quite potent in the cancer cell line screen with GI50 values ranging from 3.92 μM to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach. PMID:19007204

Design, synthesis, kinetic mechanism and molecular docking studies of novel 1-pentanoyl-3-arylthioureas as inhibitors of mushroom tyrosinase and free radical scavengers.

PubMed

Larik, Fayaz Ali; Saeed, Aamer; Channar, Pervaiz Ali; Muqadar, Urooj; Abbas, Qamar; Hassan, Mubashir; Seo, Sung-Yum; Bolte, Michael

2017-12-01

A series of novel 1-pentanoyl-3-arylthioureas was designed as new mushroom tyrosinase inhibitors and free radical scavengers. The title compounds were obtained in excellent yield and characterized by FTIR, 1 H NMR, 13 C NMR and X-ray crystallography in case of compound (4a). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 1-Pentanoyl-3-(4-methoxyphenyl) thiourea (4f) showed tyrosinase inhibitory activity (IC 50 1.568 ± 0.01 mM) comparable to Kojic acid (IC 50 16.051 ± 1.27 mM). Interestingly compound 4f exhibited higher antioxidant potential compared to other derivatives. The docking studies of synthesized 1-Pentanoyl-3-arylthioureas analogues were also carried out against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC 50 values. The predicted binding affinities are in good agreement with the IC 50 values as compound (4f) showed highest binding affinity (-7.50 kcal/mol) compared to others derivatives. The kinetic mechanism analyzed by Line-weavere Burk plots exhibited that compound (4f) inhibit the enzyme inhibits the tyrosinase non-competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (4f) is 1.10 μM. It was also found from kinetic analysis that derivative 4f irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound (4f) may serve as lead structure for the design of more potent tyrosinase inhibitors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box

PubMed Central

Spalenka, Jérémy; Escotte-Binet, Sandie; Bakiri, Ali; Hubert, Jane; Renault, Jean-Hugues; Velard, Frédéric; Duchateau, Simon; Aubert, Dominique; Huguenin, Antoine

2017-01-01

ABSTRACT Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. The drugs currently used against toxoplasmosis are few in number and show several limitations, such as drug intolerance, poor bioavailability, or drug resistance mechanism developed by the parasite. Thus, it is important to find new compounds able to inhibit parasite invasion or proliferation. In this study, the 400 compounds of the open-access Pathogen Box, provided by the Medicines for Malaria Venture (MMV) foundation, were screened for their anti-Toxoplasma gondii activity. A preliminary in vitro screening performed over 72 h by an enzyme-linked immunosorbent assay (ELISA) revealed 15 interesting compounds that were effective against T. gondii at 1 μM. Their cytotoxicity was estimated on Vero cells, and their 50% inhibitory concentrations (IC50) were further calculated. As a result, eight anti-Toxoplasma gondii compounds with an IC50 of less than 2 μM and a selectivity index (SI) value of greater than 4 were identified. The most active was MMV675968, showing an IC50 of 0.02 μM and a selectivity index value equal to 275. Two other compounds, MMV689480 and MMV687807, also showed a good activity against T. gondii, with IC50s of 0.10 μM (SI of 86.6) and 0.15 μM (SI of 11.3), respectively. Structure-activity relationships for the eight selected compounds also were discussed on the basis of fingerprinting similarity measurements using the Tanimoto method. The anti-Toxoplasma gondii compounds highlighted here represent potential candidates for the development of new drugs that could be used against toxoplasmosis. PMID:29133550

Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box.

PubMed

Spalenka, Jérémy; Escotte-Binet, Sandie; Bakiri, Ali; Hubert, Jane; Renault, Jean-Hugues; Velard, Frédéric; Duchateau, Simon; Aubert, Dominique; Huguenin, Antoine; Villena, Isabelle

2018-02-01

Toxoplasma gondii is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. The drugs currently used against toxoplasmosis are few in number and show several limitations, such as drug intolerance, poor bioavailability, or drug resistance mechanism developed by the parasite. Thus, it is important to find new compounds able to inhibit parasite invasion or proliferation. In this study, the 400 compounds of the open-access Pathogen Box, provided by the Medicines for Malaria Venture (MMV) foundation, were screened for their anti- Toxoplasma gondii activity. A preliminary in vitro screening performed over 72 h by an enzyme-linked immunosorbent assay (ELISA) revealed 15 interesting compounds that were effective against T. gondii at 1 μM. Their cytotoxicity was estimated on Vero cells, and their 50% inhibitory concentrations (IC 50 ) were further calculated. As a result, eight anti- Toxoplasma gondii compounds with an IC 50 of less than 2 μM and a selectivity index (SI) value of greater than 4 were identified. The most active was MMV675968, showing an IC 50 of 0.02 μM and a selectivity index value equal to 275. Two other compounds, MMV689480 and MMV687807, also showed a good activity against T. gondii , with IC 50 s of 0.10 μM (SI of 86.6) and 0.15 μM (SI of 11.3), respectively. Structure-activity relationships for the eight selected compounds also were discussed on the basis of fingerprinting similarity measurements using the Tanimoto method. The anti- Toxoplasma gondii compounds highlighted here represent potential candidates for the development of new drugs that could be used against toxoplasmosis. Copyright © 2018 Spalenka et al.

Incidence and clinical characteristics of interstitial cystitis in the community.

PubMed

Patel, Ronak; Calhoun, Elizabeth A; Meenan, Richard T; O'Keeffe Rosetti, Maureen C; Kimes, Terry; Clemens, J Quentin

2008-08-01

We utilized physician-coded diagnoses and chart reviews to estimate the incidence of interstitial cystitis (IC) in women. A computer search of the Kaiser Permanente database was performed to identify newly coded diagnoses of IC (ICD-9 code 595.1) between May 2002 and May 2005. Chart reviews were performed and patient demographics, diagnosing physicians, and symptom characteristics were recorded. The IC incidence rate was 15 per 100,000 women per year. The mean age of the patients was 51 years (range 31-81 years). The most common presenting symptoms were frequency (70%), dysuria (52%), urgency (50%), suprapubic pain (50%), nocturia (35%), and dyspareunia (13%). Cases diagnosed by primary care physicians had a shorter median symptom duration (9 months) compared with those diagnosed by urologists (1 year) and gynecologists (3 years). IC is an uncommon diagnosis in the community setting, with an incidence rate of 15 per 100,000 women per year.

“Dynamic Range” of Inferred Phenotypic HIV Drug Resistance Values in Clinical Practice

PubMed Central

Swenson, Luke C.; Pollock, Graham; Wynhoven, Brian; Mo, Theresa; Dong, Winnie; Hogg, Robert S.; Montaner, Julio S. G.; Harrigan, P. Richard

2011-01-01

Background ‘Virtual’ or inferred phenotypes (vPhenotypes) are commonly used to assess resistance to antiretroviral agents in patients failing therapy. In this study, we provide a clinical context for understanding vPhenotype values. Methods All HIV-infected persons enrolled in the British Columbia Drug Treatment Program with a baseline plasma viral load (pVL) and follow-up genotypic resistance and pVL results were included up to October 29, 2008 (N = 5,277). Change from baseline pVL was determined as a function of Virco vPhenotype, and the “dynamic range” (defined here by the 10th and 90th percentiles for fold-change in IC50 amongst all patients) was estimated from the distribution of vPhenotye fold-changes across the cohort. Results The distribution of vPhenotypes from a large cohort of HIV patients who have failed therapy are presented for all available antiretroviral agents. A maximum change in IC50 of at least 13-fold was observed for all drugs. The dideoxy drugs, tenofovir and most PIs exhibited small “dynamic ranges” with values of <4-fold change observed in >99% of samples. In contrast, zidovudine, lamivudine, emtricitabine and the non-nucleoside reverse transcriptase inihibitors (excluding etravirine) had large dynamic ranges. Conclusion We describe the populational distribution of vPhenotypes such that vPhenotype results can be interpreted relative to other patients in a drug-specific manner. PMID:21390218

cis-fumagillin, a new methionine aminopeptidase (type 2) inhibitor produced by Penicillium sp. F2757.

PubMed

Kwon, J Y; Jeong, H W; Kim, H K; Kang, K H; Chang, Y H; Bae, K S; Choi, J D; Lee, U C; Son, K H; Kwon, B M

2000-08-01

Selective inhibition against the yeast MetAP2 (methionine aminopeptidase type 2) was detected in the fermentation broth of a fungus F2757 that was later identified as Penicillium janczewskii. A new compound cis-fumagillin methyl ester (1) was isolated from the diazomethane treated fermentation extracts together with the known compound fumagillin methyl ester (2). The cis-fumagillin methyl ester, a stereoisomer of fumagillin methyl ester at the C2'-C3' position of the aliphatic side chain, selectively inhibited growth of the map1 mutant yeast strain (MetAP1 deletion strain) at a concentration as low as 1 ng. However, the wild type yeast w303 and the mutant map2 (MetAP2 deleted) strains were resistant up to 10 microg of the compound. In enzyme experiments, compound 1 inhibited the MetAP2 with an IC50 value of 6.3 nM, but it did not inhibit the MetAP1 (IC50 >200 microM). Compound 2 also inhibited the MetAP2 with an IC50 value of 9.2 nM and 105 microM against MetAP1.

Cytotoxic activity of erypogein d from erythrina poeppigiana (leguminosae) against cervical cancer (HeLa), breast cancer (MCF-7) and ovarian cancer (SKOV-3) cells

NASA Astrophysics Data System (ADS)

Herlina, T.; Gaffar, S.; Widowati, W.

2018-05-01

Cancer is the uncontrolled growth of abnormal cells and continues to divide rapidly in the body. Current anticancer treatment usually causes many side effects. Natural products are then explored to be new alternatives for cancer treatment. Flavonoids have been known to possess medicinal properties, including anticancer. This study was performed to observe the cytotoxic activity of isoflavanone compound, erypogein D from Erythrina poeppigiana, toward cervical cancer (HeLa), breast cancer (MCF-7) and ovarian cancer (SKOV-3) cells. The cytotoxic activity of erypogein D was tested using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxyme-thoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. The percentage of cell mortality was calculated and the IC50 was analyzed using probit analysis. The result showed that cytotoxic activity of the erypogein D against HeLa, SKOV-3, and MCF-7 cells had an IC50 value 225, 70.74, and 30.12 μM, respectively. Based on IC50 value can be concluded that erypogein D is the most cytotoxic to breast cancer MCF-7 cell. However the cytotoxic activity of erypogein D toward MCF7 is moderate.

Isolation of cholinesterase and β-secretase 1 inhibiting compounds from Lycopodiella cernua.

PubMed

Nguyen, Van Thu; To, Dao Cuong; Tran, Manh Hung; Oh, Sang Ho; Kim, Jeong Ah; Ali, Md Yousof; Woo, Mi-Hee; Choi, Jae Sue; Min, Byung Sun

2015-07-01

Three new serratene-type triterpenoids (1-3) and a new hydroxy unsaturated fatty acid (13) together with nine known compounds (4-12) were isolated from Lycopodiella cernua. The chemical structures were established using NMR, MS, and Mosher's method. Compound 13 showed the most potent inhibitory activity against acetylcholinesterase (AChE) with an IC50 value of 0.22μM. For butyrylcholinesterase (BChE) inhibitory activity, 5 showed the most potent activity with an IC50 value of 0.42μM. Compound 2 showed the most potent activity with an IC50 of 0.23μM for BACE-1 inhibitory activity. The kinetic activities were investigated to determine the type of enzyme inhibition involved. The types of AChE inhibition shown by compounds 4, 5, and 13 were mixed; BChE inhibition by 5 was competitive, while 2 and 6 showed mixed-types. In addition, molecular docking studies were performed to investigate the interaction of these compounds with the pocket sites of AChE. The docking results revealed that the tested inhibitors 3, 4, and 13 were stably present in several pocket domains of the AChE residue. Copyright © 2015 Elsevier Ltd. All rights reserved.

Determination of total phenolic content and antioxidant activitity of methanol extract of Maranta arundinacea L fresh leaf and tuber

NASA Astrophysics Data System (ADS)

Kusbandari, A.; Susanti, H.

2017-11-01

Maranta arundinacea L is one of herbaceous plants in Indonesia which have flavonoid content. Flavonoids has antioxidants activity by inhibition of free radical oxidation reactions. The study aims were to determination total phenolic content and antioxidant activity of methanol extract of fresh leaf and tuber of M. arundinacea L by UV-Vis spectrophotometer. The methanol extracts were obtained with maceration and remaseration method of fresh leaves and tubers. The total phenolic content was assayed with visible spectrophotometric using Folin Ciocalteau reagent. The antioxidant activity was assayed with 1,1-diphenyl-2-picrilhidrazil (DPPH) compared to gallic acid. The results showed that methanol extract of tuber and fresh leaf of M. arundinacea L contained phenolic compound with total phenolic content (TPC) in fresh tuber of 3.881±0.064 (% GAE) and fresh leaf is 6.518±0.163 (% b/b GAE). IC50 value from fresh tuber is 1.780±0.0005 μg/mL and IC50 fresh leaf values of 0.274±0.0004 μg/mL while the standard gallic acid is IC50 of 0.640±0.0002 μg/mL.

Bioactive metabolites from an endophytic Cryptosporiopsis sp. inhabiting Clidemia hirta.

PubMed

Zilla, Mahesh K; Qadri, Masroor; Pathania, Anup S; Strobel, Gary A; Nalli, Yedukondalu; Kumar, Sunil; Guru, Santosh K; Bhushan, Shashi; Singh, Sanjay K; Vishwakarma, Ram A; Riyaz-Ul-Hassan, Syed; Ali, Asif

2013-11-01

An endophytic Cryptosporiopsis sp. was isolated from Clidemia hirta and analyzed for its secondary metabolites that lead to the isolation of three bioactive molecules. The compounds were purified from the culture broth of the fungus and their structures were determined by spectroscopic methods as (R)-5-hydroxy-2-methylchroman-4-one (1), 1-(2,6-dihydroxyphenyl)pentan-1-one (2) and (Z)-1-(2-(2-butyryl-3-hydroxyphenoxy)-6-hydroxyphenyl)-3-hydroxybut-2-en-1-one (3). Compound 1 exhibited significant cytotoxic activity against the human leukemia cell line, HL-60 with an IC50 of 4 μg/ml. This compound induced G2 arrest of the HL-60 cell cycle significantly. In addition, out of these compounds, 2 and 3 were active against several bacterial pathogens. Compound 2 was active against Bacillus cereus, Escherichia coli and Staphylococcus aureus with IC50 values varying from 18 to 30 μg/ml, and compound 3 displayed activity against Pseudomonas fluorescens with an IC50 value of 6 μg/ml. Compounds 2 and 3 are novel whereas compound 1 was reported earlier but the stereochemistry of its C-2 methyl is established for the first time. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparative evaluation of antiproliferative effects of Brazilian green propolis, its main source Baccharis dracunculifolia, and their major constituents artepillin C and baccharin.

PubMed

de Oliveira, Pollyanna Francielli; de Souza Lima, Ildercílio Mota; Munari, Carla Carolina; Bastos, Jairo Kenupp; da Silva Filho, Ademar Alves; Tavares, Denise Crispim

2014-04-01

This study evaluated the antiproliferative activity of the Brazilian green propolis and Baccharis dracunculifolia extracts and their major compounds artepillin C and baccharin in different tumor cell lines. The lowest IC50 values observed for Brazilian green propolis and B. dracunculifolia extracts were 41.0 ± 4.5 µg/mL for U343 and 44.9 ± 7.1 µg/mL for HepG2, respectively. Regarding artepillin C and baccharin, the lowest IC50 values were 20.1 ± 2.9 for U343 and 13.0 ± 1.5 µg/mL for B16F10, respectively. For the association of artepillin C plus baccharin, the lowest IC50 result was 35.2 ± 0.5 µg/mL for B16F10. Artepillin C and baccharin were more cytotoxic than both Brazilian green propolis and B. dracunculifolia extracts. No additive or synergistic effect was observed for the association of artepillin C plus baccharin. Georg Thieme Verlag KG Stuttgart · New York.

Phytochemical constituents, nutritional values, phenolics, flavonols, flavonoids, antioxidant and cytotoxicity studies on Phaleria macrocarpa (Scheff.) Boerl fruits

PubMed Central

2014-01-01

Background The edible fruits of Phaleria macrocarpa (Scheff.) Boerl are widely used in traditional medicine in Indonesia. It is used to treat a variety of medical conditions such as - cancer, diabetes mellitus, allergies, liver and heart diseases, kidney failure, blood diseases, high blood pressure, stroke, various skin diseases, itching, aches, and flu. Therefore, it is of great interest to determine the biochemical and cytotoxic properties of the fruit extracts. Methods The methanol, hexane, chloroform, ethyl acetate, and water extracts of P. macrocarpa fruits were examined for phytochemicals, physicochemicals, flavonols, flavonoids and phenol content. Its nutritional value (A.O.A.C method), antioxidant properties (DPPH assay) and cytotoxicity (MTT cell proliferation assay) were also determined. Results A preliminary phyotochemical screening of the different crude extracts from the fruits of P. macrocarpa showed the presence secondary metabolites such as of flavonoids, phenols, saponin glycosides and tannins. The ethyl acetate and methanol extracts displayed high antioxidant acitivity (IC50 value of 8.15±0.02 ug/mL) in the DPPH assay comparable to that of the standard gallic acid (IC50 value of 10.8±0.02 ug/mL). Evaluation of cytotoxic activity showed that the crude methanol extract possessed excellent anti-proliferative activity against SKOV-3 (IC50 7.75±2.56 μg/mL) after 72 hours of treatment whilst the hexane and ethyl acetate extracts displayed good cytotoxic effect against both SKOV-3 and MDA-MB231 cell lines. The chloroform extract however, showed selective inhibitory activity in the breast cancer cell line MDA-MB231 (IC50 7.80±1.57 μg/mL) after 48 hours of treatment. There was no cytotoxic effect observed in the Ca Ski cell line and the two normal cell lines (MRC-5 and WRL-68). Conclusion The methanol extract and the ethyl acetate fraction of P. macrocarpa fruits exhibited good nutritional values, good antioxidant and cytotoxic activities, and merits further investigation to identify the specific compound(s) responsible for these activities. PMID:24885709

New Metabolites and Bioactive Chlorinated Benzophenone Derivatives Produced by a Marine-Derived Fungus Pestalotiopsis heterocornis

PubMed Central

Lei, Hui; Lin, Xiuping; Han, Li; Ma, Jian; Ma, Qingjuan; Zhong, Jialiang; Liu, Yonghong; Sun, Tiemin; Wang, Jinhui; Huang, Xueshi

2017-01-01

Four new compounds, including two isocoumarins, pestaloisocoumarins A and B (1, 2), one sesquiterpenoid degradation, isopolisin B (4), and one furan derivative, pestalotiol A (5), together with one known isocoumarin, gamahorin (3), and three chlorinated benzophenone derivatives, pestalachloride B (6), pestalachloride E (7) and a mixture of pestalalactone atropisomers (8a/8b), were isolated from a culture of the fungus Pestalotiopsis heterocornis associated with sponge Phakellia fusca. These new chemical structures were established using NMR and MS spectroscopic data, as well as single-crystal X-ray crystallographic analysis and CD Cotton effects. All of the isolated compounds were evaluated for their antimicrobial and cytotoxic activities. Isocoumarins 1–3, showed antibacterial activities against Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis with MIC values ranging from 25 to 100 μg/mL and weak antifungal activities. Chlorinated benzophenone derivatives 6–8 exhibited antibacterial activities against S. aureus and B. subtilis with MIC values ranging from 3.0 to 50 μg/mL and cytotoxicities against four human cancer cell lines with IC50 values of 6.8–87.8 μM. PMID:28335391

Biogenesis of silver nanoparticles using endophytic fungus Pestalotiopsis microspora and evaluation of their antioxidant and anticancer activities.

PubMed

Netala, Vasudeva Reddy; Bethu, Murali Satyanarayana; Pushpalatha, Bobbu; Baki, Vijaya Bhaskar; Aishwarya, Sani; Rao, J Venkateswara; Tartte, Vijaya

An endophytic fungal strain isolated from the leaves of Gymnema sylvestre was identified as Pestalotiopsis microspora VJ1/VS1 based on nucleotide sequencing of internal transcribed spacer region (ITS 1-5.8S-ITS 2) of 18S rRNA gene (NCBI accession number KX213894). In this study, an efficient and ecofriendly approach has been reported for the synthesis of silver nanoparticles (AgNPs) using aqueous culture filtrate of P. microspora . Ultraviolet-visible analysis confirmed the synthesis of AgNPs by showing characteristic absorption peak at 435 nm. Fourier transform infrared spectroscopy analysis revealed the presence of phenolic compounds and proteins in the fungal filtrate, which are plausibly involved in the biosynthesis and capping of AgNPs. Transmission electron microscopy (TEM) showed that the AgNPs were spherical in shape of 2-10 nm in size. Selected area electron diffraction and X-ray diffraction studies determined the crystalline nature of AgNPs with face-centered cubic (FCC) lattice phase. Dynamic light scattering analysis showed that the biosynthesized AgNPs possess high negative zeta potential value of -35.7 mV. Biosynthesized AgNPs were proved to be potential antioxidants by showing effective radical scavenging activity against 2,2'-diphenyl-1-picrylhydrazyl and H 2 O 2 radicals with IC 50 values of 76.95±2.96 and 94.95±2.18 µg/mL, respectively. The biosynthesized AgNPs exhibited significant cytotoxic effects against B16F10 (mouse melanoma, IC 50 =26.43±3.41 µg/mL), SKOV3 (human ovarian carcinoma, IC 50 =16.24±2.48 µg/mL), A549 (human lung adenocarcinoma, IC 50 =39.83±3.74 µg/mL), and PC3 (human prostate carcinoma, IC 50 =27.71±2.89 µg/mL) cells. The biosynthesized AgNPs were found to be biocompatible toward normal cells (Chinese hamster ovary cell line, IC 50 =438.53±4.2 µg/mL). Cytological observations on most susceptible SKOV3 cells revealed concentration-dependent apoptotic changes that include cell membrane blebbing, cell shrinkage, pyknotic nuclei, karyorrhexis followed by destructive fragmentation of nuclei. The results together in this study strongly provided a base for the development of potential and versatile biomedical applications of biosynthesized AgNPs in the near future.

Biogenesis of silver nanoparticles using endophytic fungus Pestalotiopsis microspora and evaluation of their antioxidant and anticancer activities

PubMed Central

Netala, Vasudeva Reddy; Bethu, Murali Satyanarayana; Pushpalatha, Bobbu; Baki, Vijaya Bhaskar; Aishwarya, Sani; Rao, J Venkateswara; Tartte, Vijaya

2016-01-01

An endophytic fungal strain isolated from the leaves of Gymnema sylvestre was identified as Pestalotiopsis microspora VJ1/VS1 based on nucleotide sequencing of internal transcribed spacer region (ITS 1-5.8S-ITS 2) of 18S rRNA gene (NCBI accession number KX213894). In this study, an efficient and ecofriendly approach has been reported for the synthesis of silver nanoparticles (AgNPs) using aqueous culture filtrate of P. microspora. Ultraviolet-visible analysis confirmed the synthesis of AgNPs by showing characteristic absorption peak at 435 nm. Fourier transform infrared spectroscopy analysis revealed the presence of phenolic compounds and proteins in the fungal filtrate, which are plausibly involved in the biosynthesis and capping of AgNPs. Transmission electron microscopy (TEM) showed that the AgNPs were spherical in shape of 2–10 nm in size. Selected area electron diffraction and X-ray diffraction studies determined the crystalline nature of AgNPs with face-centered cubic (FCC) lattice phase. Dynamic light scattering analysis showed that the biosynthesized AgNPs possess high negative zeta potential value of −35.7 mV. Biosynthesized AgNPs were proved to be potential antioxidants by showing effective radical scavenging activity against 2,2′-diphenyl-1-picrylhydrazyl and H2O2 radicals with IC50 values of 76.95±2.96 and 94.95±2.18 µg/mL, respectively. The biosynthesized AgNPs exhibited significant cytotoxic effects against B16F10 (mouse melanoma, IC50 =26.43±3.41 µg/mL), SKOV3 (human ovarian carcinoma, IC50 =16.24±2.48 µg/mL), A549 (human lung adenocarcinoma, IC50 =39.83±3.74 µg/mL), and PC3 (human prostate carcinoma, IC50 =27.71±2.89 µg/mL) cells. The biosynthesized AgNPs were found to be biocompatible toward normal cells (Chinese hamster ovary cell line, IC50 =438.53±4.2 µg/mL). Cytological observations on most susceptible SKOV3 cells revealed concentration-dependent apoptotic changes that include cell membrane blebbing, cell shrinkage, pyknotic nuclei, karyorrhexis followed by destructive fragmentation of nuclei. The results together in this study strongly provided a base for the development of potential and versatile biomedical applications of biosynthesized AgNPs in the near future. PMID:27826190

Helichrysum gymnocephalum essential oil: chemical composition and cytotoxic, antimalarial and antioxidant activities, attribution of the activity origin by correlations.

PubMed

Afoulous, Samia; Ferhout, Hicham; Raoelison, Emmanuel Guy; Valentin, Alexis; Moukarzel, Béatrice; Couderc, François; Bouajila, Jalloul

2011-09-29

Helichrysum gymnocephalum essential oil (EO) was prepared by hydrodistillation of its leaves and characterized by GC-MS and quantified by GC-FID. Twenty three compounds were identified. 1,8-Cineole (47.4%), bicyclosesquiphellandrene (5.6%), γ-curcumene (5.6%), α-amorphene (5.1%) and bicyclogermacrene (5%) were the main components. Our results confirmed the important chemical variability of H. gymnocephalum. The essential oil was tested in vitro for cytotoxic (on human breast cancer cells MCF-7), antimalarial (Plasmodium falciparum: FcB1-Columbia strain, chloroquine-resistant) and antioxidant (ABTS and DPPH assays) activities. H. gymnocephalum EO was found to be active against MCF-7 cells, with an IC(50) of 16 ± 2 mg/L. The essential oil was active against P. falciparum (IC(50) = 25 ± 1 mg/L). However, the essential oil exhibited a poor antioxidant activity in the DPPH (IC(50) value > 1,000 mg/L) and ABTS (IC(50) value = 1,487.67 ± 47.70 mg/L) assays. We have reviewed the existing results on the anticancer activity of essential oils on MCF-7 cell line and on their antiplasmodial activity against the P. falciparum. The aim was to establish correlations between the identified compounds and their biological activities (antiplasmodial and anticancer). β-Selinene (R² = 0.76), α-terpinolene (R² = 0.88) and aromadendrene (R² = 0.90) presented a higher relationship with the anti-cancer activity. However, only calamenene (R² = 0.70) showed a significant correlation for the antiplasmodial activity.

Potential of aryl-urea-benzofuranylthiazoles hybrids as multitasking agents in Alzheimer's disease.

PubMed

Kurt, Belma Zengin; Gazioglu, Isil; Basile, Livia; Sonmez, Fatih; Ginex, Tiziana; Kucukislamoglu, Mustafa; Guccione, Salvatore

2015-09-18

New benzofuranylthiazole derivatives containing the aryl-urea moiety were synthesized and evaluated in vitro as dual acetylcholinesterase (AChE)-butyrylcholinesterase (BuChE) inhibitors. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were assayed. The result showed that all the synthesized compounds exhibited inhibitory activity on both AChE and BuChE with 1-(4-(5-bromobenzofuran-2-yl)thiazol-2-yl)-3-(2-fluorophenyl)urea (e25, IC50 value of 3.85 μM) and 1-(4-iodophenyl)-3-(4-(5-nitrobenzofuran-2-yl)thiazol-2-yl)urea (e38, IC50 value of 2.03 μM) as the strongest inhibitors against AChE and BuChE, respectively. Compound e38 was 8.5-fold more potent than galanthamine. The selectivity index of e25 and e38 was 2.40 and 0.37 against AChE and BuChE, respectively. Compound e2, e4 and e11 (IC50 = 0.2, 0.5 and 1.13 μM, respectively) showed a better ABTS cation radical scavenging ability than the standard quercetin (IC50 = 1.18 μM). Best poses of compounds e38 on BuChE and e25 on AChE indicate that the thiazole ring and the amidic moiety are important sites of interaction with both ChEs. In addition, the benzofuran ring and phenyl ring are anchored to the side chains of both enzymes by π-π(pi-pi) interactions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

The effects of acute pesticide exposure on neuroblastoma cells chronically exposed to diazinon.

PubMed

Axelrad, J C; Howard, C V; McLean, W G

2003-03-14

Speculation about potential neurotoxicity due to chronic exposure to low doses of organophosphate (OP) pesticides is not yet supported by experimental evidence. The objective of this work was to use a cell culture model of chronic OP exposure to determine if such exposure can alter the sensitivity of nerve cells to subsequent acute exposure to OPs or other compounds. NB2a neuroblastoma cells were grown in the presence of 25 microM diazinon for 8 weeks. The OP was then withdrawn and the cells were induced to differentiate in the presence of various other pesticides or herbicides, including OPs and OP-containing formulations. The resulting outgrowth of neurite-like structures was measured by light microscopy and quantitative image analysis and the IC(50) for each OP or formulation was calculated. The IC(50) values in diazinon-pre-exposed cells were compared with the equivalent values in cells not pre-exposed to diazinon. The IC(50) for inhibition of neurite outgrowth by acute application of diazinon, pyrethrum, glyphosate or a commercial formulation of glyphosate was decreased by between 20 and 90% after pre-treatment with diazinon. In contrast, the IC(50) for pirimiphos methyl was unaffected and those for phosmet or chlorpyrifos were increased by between 1.5- and 3-fold. Treatment of cells with chlorpyrifos or with a second glyphosate-containing formulation led to the formation of abnormal neurite-like structures in diazinon-pre-exposed cells. The data support the view that chronic exposure to an OP may reduce the threshold for toxicity of some, but by no means all, environmental agents.

Discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants: Bio-inspired based design, synthesis, biological evaluation, cytotoxic and Insilico molecular docking studies

NASA Astrophysics Data System (ADS)

Sharma, Vashundhra; Jaiswal, Pradeep K.; Saran, Mukesh; Yadav, Dharmendra Kumar; Saloni; Mathur, Manas; Swami, Ajit K.; Misra, Sanjeev; Kim, Mi-hyun; Chaudhary, Sandeep

2018-03-01

The discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants is disclosed. All the analogues 20a-20ab have been synthesized via “on water” ultrasound-assisted in excellent yields (upto 98%). All the compounds have been evaluated for their in vitro antioxidant activities using DPPH free radical scavenging assay as well as FRAP assay. The result showed promising antioxidant activities having IC50 values in the range of 4.74 ± 0.08 to 92.20 ± 1.54 μg/mL taking ascorbic acid (IC50 = 4.57 μg/mL) as standard reference. In this study, compounds 20b and 20t, the most active compound of the series, showed IC50 values of 6.89 ± 0.07μg/mL and 4.74 ± 0.08 μg/mL, respectively in comparison with ascorbic acid. In addition, the detailed SAR study shows that electron-withdrawing group increases antioxidant activity and vice versa. Furthermore, in the FRAP assay, eight compounds (20c, 20j, 20m, 20n, 20r, 20u, 20z and 20aa) were found more potent than standard reference BHT (C0.5FRAP = 546.0 ± 13.6 μM). The preliminary cytotoxic study reveals the non-toxic nature of active compounds 20b and 20t in non-cancerous 3T3 fibroblast cell lines in MTT assay up to 250 μg/mL concentration. The results were validated via carrying out insilico molecular docking studies of promising compounds 20a, 20b and 20t in comparison with standard reference. To the best of our knowledge, this is the first detailed study of C-3 tethered 2-oxo-benzo[1,4]oxazines as potential antioxidant agents.

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

PubMed Central

Chan, Jeannine; Oshiro, Tyler; Thomas, Sarah; Higa, Allyson; Black, Stephen; Todorovic, Aleksandar; Elbarbry, Fawzy

2016-01-01

Human exposure to trans-cinnamic aldehyde [t-CA; cinnamaldehyde; cinnamal; (E)-3-phenylprop-2-enal] is common through diet and through the use of cinnamon powder for diabetes and to provide flavor and scent in commercial products. We evaluated the likelihood of t-CA to influence metabolism by inhibition of P450 enzymes. IC50 values from recombinant enzymes indicated that an interaction is most probable for CYP2A6 (IC50 = 6.1 µM). t-CA was 10.5-fold more selective for human CYP2A6 than for CYP2E1; IC50 values for P450s 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 were 15.8-fold higher or more. t-CA is a type I ligand for CYP2A6 (KS = 14.9 µM). Inhibition of CYP2A6 by t-CA was metabolism-dependent; inhibition required NADPH and increased with time. Glutathione lessened the extent of inhibition modestly and statistically significantly. The carbon monoxide binding spectrum was dramatically diminished after exposure to NADPH and t-CA, suggesting degradation of the heme or CYP2A6 apoprotein. Using a static model and mechanism-based inhibition parameters (KI = 18.0 µM; kinact = 0.056 minute−1), changes in the area under the concentration-time curve (AUC) for nicotine and letrozole were predicted in the presence of t-CA (0.1 and 1 µM). The AUC fold-change ranged from 1.1 to 3.6. In summary, t-CA is a potential source of pharmacokinetic variability for CYP2A6 substrates due to metabolism-dependent inhibition, especially in scenarios when exposure to t-CA is elevated due to high dietary exposure, or when cinnamon is used as a treatment of specific disease states (e.g., diabetes). PMID:26851241

Investigating the effect of emetic compounds on chemotaxis in Dictyostelium identifies a non-sentient model for bitter and hot tastant research.

PubMed

Robery, Steven; Mukanowa, Janina; Percie du Sert, Nathalie; Andrews, Paul L R; Williams, Robin S B

2011-01-01

Novel chemical entities (NCEs) may be investigated for emetic liability in a range of unpleasant experiments involving retching, vomiting or conditioned taste aversion/food avoidance in sentient animals. We have used a range of compounds with known emetic /aversive properties to examine the possibility of using the social amoeba, Dictyostelium discoideum, for research into identifying and understanding emetic liability, and hence reduce adverse animal experimentation in this area. Twenty eight emetic or taste aversive compounds were employed to investigate the acute (10 min) effect of compounds on Dictyostelium cell behaviour (shape, speed and direction of movement) in a shallow chemotaxic gradient (Dunn chamber). Compound concentrations were chosen based on those previously reported to be emetic or aversive in in vivo studies and results were recorded and quantified by automated image analysis. Dictyostelium cell motility was rapidly and strongly inhibited by four structurally distinct tastants (three bitter tasting compounds--denatonium benzoate, quinine hydrochloride, phenylthiourea, and the pungent constituent of chilli peppers--capsaicin). In addition, stomach irritants (copper chloride and copper sulphate), and a phosphodiesterase IV inhibitor also rapidly blocked movement. A concentration-dependant relationship was established for five of these compounds, showing potency of inhibition as capsaicin (IC(50) = 11.9 ± 4.0 µM) > quinine hydrochloride (IC(50) = 44.3 ± 6.8 µM) > denatonium benzoate (IC(50) = 129 ± 4 µM) > phenylthiourea (IC(50) = 366 ± 5 µM) > copper sulphate (IC(50) = 1433 ± 3 µM). In contrast, 21 compounds within the cytotoxic and receptor agonist/antagonist classes did not affect cell behaviour. Further analysis of bitter and pungent compounds showed that the effect on cell behaviour was reversible and not cytotoxic, suggesting an uncharacterised molecular mechanism of action for these compounds. These results therefore demonstrate that Dictyostelium has potential as a non-sentient model in the analysis of the molecular effects of tastants, although it has limited utility in identification of emetic agents in general.