Synthesis of 4-hydroxy-1-methylindole and benzo[b]thiophen-4-ol based unnatural flavonoids as new class of antimicrobial agents.

PubMed

Yadav, Prem P; Gupta, Prasoon; Chaturvedi, A K; Shukla, P K; Maurya, Rakesh

2005-03-01

Synthesis of nitrogen and sulfur heterocyclic mimics of furanoflavonoids have been achieved for the first time. Synthesized flavonoid alkaloids and thiophenyl flavonoids have been screened for antifungal and antibacterial activities. All the test compounds barring 25 exhibited antifungal activity. The compound 19 was the best and showed comparable MICs to the known compound karanjin. Compounds 5, 12, 14 and 22 also showed comparable MIC to karanjin.

Head-space, small-chamber and in-vehicle tests for volatile organic compounds (VOCs) emitted from air fresheners for the Korean market.

PubMed

Jo, Wan-Kuen; Lee, Jong-Hyo; Kim, Mo-Keun

2008-02-01

The present study investigated the emission characteristics of gel-type air fresheners (AFs), using head-space, small-chamber, and in-vehicle tests. Five toxic or hazardous analytes were found in the headspace phase of AFs (toluene, benzene, ethyl benzene, and m,p-xylene) at a frequency of more than 50%. Limonene and linalool, which are known to be unsaturated ozone-reactive VOCs, were detected at a frequency of 58 and 35%, respectively. The empirical model fitted well with the time-series concentrations in the chamber, thereby suggesting that the empirical model was suitable for testing emissions. Limonene exhibited the highest emission rate, followed by m,p-xylene, toluene, ethyl benzene, and benzene. For most target VOCs, higher air change per hour (ACH) levels exhibited increased emission rates. In contrast, higher ACH levels resulted in lower chamber concentrations. The mean concentration of limonene was significantly higher in passenger cars with an AF than without. For other target compounds, there were no significant differences between the two conditions tested. Consequently, it was suggested that unlike limonene, the emission strength for aromatic compounds identified in the chamber tests was not strong enough to elevate in-vehicle levels.

Facile synthesis and antibacterial, antitubercular, and anticancer activities of novel 1,4-dihydropyridines.

PubMed

Sirisha, Kalam; Achaiah, Garlapati; Reddy, Vanga Malla

2010-06-01

A series of twenty new 4-substituted-2,6-dimethyl-3,5-bis-N-(heteroaryl)-carbamoyl-1,4-dihydropyridines have been prepared from a three-component one-pot condensation reaction of N-heteroaryl acetoacetamide, an aromatic/heteroaromatic aldehyde, and ammonium acetate under four different experimental conditions. Except for the conventional method, all the experimental conditions were simple, eco-friendly, economical, and the reactions were rapid and high-yielding. The methods employed have been compared in terms of yields, cost, and simplicity. The synthesized compounds were characterized by different spectroscopic techniques and evaluated for their in-vitro anticancer, antibacterial, and antitubercular activities. Amongst the compounds tested, compound 25 exhibited the highest anticancer activity while compounds 14 and 18 exhibited significant antibacterial and antitubercular activities.

Synthesis and structure-activity relationship of novel cinnamamide derivatives as antidepressant agents.

PubMed

Han, Min; Ma, Xiaohui; Jin, Yuanpeng; Zhou, Wangyi; Cao, Jing; Wang, Yahu; Zhou, Shuiping; Wang, Guocheng; Zhu, Yonghong

2014-11-15

Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure-activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b-c and 6a-b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold. Copyright © 2014 Elsevier Ltd. All rights reserved.

Design and synthesis of some new 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-ureas as potent anticonvulsant and antidepressant agents.

PubMed

Mishra, Chandra Bhushan; Kumari, Shikha; Tiwari, Manisha

2016-05-01

A series of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives (29-42) were designed, synthesized and evaluated for their anticonvulsant activity by using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurotoxicity was checked by rotarod assay. Most of the test compounds were found effective in both seizure tests. Compound 30 (1-{4-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3-phenyl-urea) exhibited marked anticonvulsant activity in MES as well as scPTZ tests. The phase II anticonvulsant quantification study of compound 30 indicates the ED50 value of 28.5 mg/kg against MES induced seizures. In addition, this compound also showed considerable protection against pilocarpine induced status epilepticus in rats. Seizures induced by 3-mercaptopropionic acid model and thiosemicarbazide were significantly attenuated by compound 30, which suggested its broad spectrum of anticonvulsant activity. Interestingly, compound 30 displayed better antidepressant activity than standard drug fluoxetine. Moreover, compound 30 appeared as a non-toxic chemical entity in sub-acute toxicity studies.

Synthesis and biological evaluation of pyrazolylthiazole carboxylic acids as potent anti-inflammatory-antimicrobial agents.

PubMed

Khloya, Poonam; Kumar, Satish; Kaushik, Pawan; Surain, Parveen; Kaushik, Dhirender; Sharma, Pawan K

2015-03-15

Current Letter presents design, synthesis and biological evaluation of a novel series of pyrazolylthiazole carboxylates 1a-1p and corresponding acid derivatives 2a-2p. All 32 novel compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema method as well as for in vitro antimicrobial activity. All the tested compounds exhibited excellent AI activity profile. Three compounds 1p (R=Cl, R(1)=Cl), 2c (R=H, R(1)=F) and 2n (R=Cl, R(1)=OCH3) were identified as potent anti-inflammatory agents exhibiting edema inhibition of 93.06-89.59% which is comparable to the reference drug indomethacin (91.32%) after 3h of carrageenan injection while most of the other compounds displayed inhibition ⩾80%. In addition, pyrazolylthiazole carboxylic acids (2a-2p) also showed good antimicrobial profile. Compound 2h (R=OCH3, R(1)=Cl) showed excellent antimicrobial activity (MIC 6.25μg/mL) against both Gram positive bacteria comparable with the reference drug ciprofloxacin (MIC 6.25μg/mL). Copyright © 2015 Elsevier Ltd. All rights reserved.

Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas.

PubMed

Mahat, Bimit; Chae, Jung-Woo; Baek, In-Hwan; Song, Gyu-Yong; Song, Jin-Sook; Cho, Seong-Kwon; Kwon, Kwang-Il

2012-01-01

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The present study provided a physicochemical and toxicological characterization of compounds in A. gigas NAKAI (decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin). Diketone decursin (173.16 μg/mL) and epoxide decursin (122.12 μg/mL) exhibited >100 μg/mL kinetic solubility after applying nephelometry, suggesting a highly soluble compound. The Student’s t-test revealed significant differences in the pKa ranges of the compounds by automatic titration from capillary electrophoresis (p<0.05). Diketone decursin, epoxide decursin and oxim decursin might be formulated into an oral dosage form (log P: 0-3) by an automatic titration analysis. A parallel artificial membrane permeability assay demonstrated permeability coefficients of <10 x 10⁻⁶ cm/s for all of the compounds, suggesting poor permeability. Ether decursin exhibited a toxic effect after being applied to mouse (NIH 3T3, EC₅₀: 57.9 μM) and human (HT-29, EC₅₀: 36.1 μM; Hep-G2, EC₅₀: 4.92 μM) cells. Additionally, epoxide and oxim decursin were toxic through acute oral toxicity (four and three deaths of Institute of Cancer Research (ICR) mice) and mutation toxicity testing by applying Salmonella typhimurium cells with and without S9. Although diketone decursin exhibited less permeability, it is potentially valuable pharmacological compound that should be investigated.

Algicidal activity of thiazolidinedione derivatives against harmful algal blooming species.

PubMed

Kim, Yeon-Mi; Wu, Ying; Duong, Thi Uyen; Jung, Seul-Gi; Kim, Si Wouk; Cho, Hoon; Jin, Eonseon

2012-06-01

Thiazolidinedione (TD) derivatives exhibit algicidal activity against harmful algal blooming species such as Chattonella marina, Heterosigma akashiwo, and Cochlodinium polykrikoides, as reported previously. In this study, the efficacies and selectivities of TD derivatives were tested by analyzing the structure-activity relationships of various TD derivatives. To investigate structure-activity relationships for growth inhibition of harmful algae, we added a methylene group between the cyclohexyl ring and oxygen of 5-(3-chloro-4-hydroxybenzylidene)-TD, which decreased the inhibitory potency of compound 17. Interestingly, another addition of a methylene group significantly increased the inhibitory potency against C. polykrikoides. The addition of 1 μM compound 17 resulted in the cell rupture of harmful algae after less than 10 h incubation at 20 °C. Compound 17 was applied to both harmful and non-harmful algae and showed a drastic reduction in the efficiency of photosystem II, resulting in reduced photosynthetic oxygen evolution. Compound 17 at a 5 μM concentration destroyed all of the harmful algae, while algicidal activity against non-harmful algae did not exceed 30% of the control within the concentration range tested. In contrast, a herbicide, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, tested at a 5 μM concentration, exhibited 40-70% algicidal activity relative to that of the control against both harmful and non-harmful algae. Compound 17 is a promising lead compound for the development of algicides to control harmful algal blooming species.

Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

PubMed Central

Salomé, Christophe; Salomé-Grosjean, Elise; Stables, James P.; Kohn, Harold

2010-01-01

Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3″-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases. PMID:20394379

Merging the structural motifs of functionalized amino acids and alpha-aminoamides: compounds with significant anticonvulsant activities.

PubMed

Salomé, Christophe; Salomé-Grosjean, Elise; Stables, James P; Kohn, Harold

2010-05-13

Functional amino acids (FAAs) and alpha-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4'-((3''-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED(50) values of 13, 14, approximately 10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.

THE SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME 4-HYDROXYCOUMARIN DERIVATIVES

PubMed Central

Završnik, Davorka; Muratović, Samija; Špirtović, Selma; Softić, Dženita; Medić-Šarić, Marica

2008-01-01

Due to exceptional reactivity of 4-hydroxycoumarin, the synthesis of new coumarin derivatives of dimer and tetramer type has been carried out. The synthesis was carried out from 4-hydroxycoumarin and various aromatic aldehydes. In this way, compounds of the dimer 3,3’-(benzilidene)bis (4-hydroxycoumarin) type, as well as of the tetramer 3,3,’3’,’3’’’-(1,4-dim- ethylenphenyl)tetra (4-hydroxycoumarin) type were prepared. The newly synthesized derivatives contain different functional groups, and as such they could exhibit microbiological activity. Therefore, we tested the microbiological activity of these derivatives on various species of bacteria and fungi. The tested compounds have shown different activity in terms of growth inhibition of microorganisms. Newly synthesized derivatives exhibit antibacterial activities, manifested as growth inhibition on Grampositive bacteria types (Bacillus, Staphylococcus), while the activity against Candida was much weaker. The same compound did not show any antimicrobial activity against two Gram-negative bacteria types (Escherichia coli, Pseudomonas aeruginosa). The compound 1 showed the best microbiological activity. The obtained results confirmed its good antibacterial and antimycotic activities against different microorganisms. PMID:18816263

Three-component, one-pot synthesis of anthranilamide Schiff bases bearing 4-aminoquinoline moiety as Mycobacterium tuberculosis gyrase inhibitors.

PubMed

Salve, Preeti S; Alegaon, Shankar G; Sriram, Dharmarajan

2017-04-15

An efficient three-component, one-pot protocol is described for the synthesis of biologically interesting 2-(benzylideneamino)-N-(7-chloroquinolin-4-yl)benzohydrazide derivatives from isatoic anhydride, 7-chloro-4-hydrazinylquinoline and aromatic and/or hetero aromatic aldehydes under catalyst free condensation by using water as reaction media. All synthesized compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (MTB) and cytotoxicity activity against normal VERO cell lines. The synthesized compounds exhibited minimum inhibitory concentration (MIC) ranging from 0.78 to 25μM. Among the tested compounds 4c, 4o, 4r, and 4u exhibited promising inhibitory activity (MIC=3.12μM). Compounds 4h and 4i stand out, showing MIC values of 0.78 and 1.56μM respectively. Both compounds were further screened for their Mycobacterium tuberculosis DNA gyrase inhibitory assay which suggested that these compounds have a great potential for further optimization and development as antitubercular agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

Microwave Assisted Synthesis of 1-[5-(Substituted Aryl)-1H-Pyrazol-3-yl]-3,5-Diphenyl-1H-1,2,4-Triazole as Antinociceptive and Antimicrobial Agents

PubMed Central

Khanage, Shantaram Gajanan; Mohite, Popat Baban; Pandhare, Ramdas Bhanudas; Raju, S. Appala

2014-01-01

Purpose: An efficient technique has been developed for microwave assisted synthesis of 1-[5-(substituted aryl)-1H-pyrazol-3-yl]-3,5-diphenyl-1H-1,2,4-triazole as antinociceptive and antimicrobial agents. Methods: The desired compounds (S1-S10) were synthesized by the microwave irradiation via cyclization of formerly synthesized chalcones of 3,5-diphenyl-1H-1,2,4-triazole and hydrazine hydrate in mild acidic condition. All newly synthesized compounds were subjected to study their antinociceptive and antimicrobial activity. The analgesic potential of compounds was tested by acetic acid induced writhing response and hot plate method. The MIC values for antimicrobial activity were premeditated by liquid broth method. Results: The compounds S1, S2, S4, S6 and S10 were found to be excellent peripherally acting analgesic agents when tested on mice by acetic acid induced writhing method and compounds S3, S6 and S1 at dose level of 100 mg/kg were exhibited superior centrally acting antinociceptive activity when tested by Eddy’s hot plate method. In antimicrobial activity compound S10 found to be broad spectrum antibacterial agent at MIC value of 15.62 µg/ml and compound S6 was exhibited antifungal potential at 15.62 µg/mL on both fungal strains. Conclusion: Some novel pyrazoles clubbed with 1,2,4-triazole derivatives were synthesized and evaluated as possible antimicrobial, centrally and peripherally acting analgesics. PMID:24511473

Fluorine bearing sydnones with styryl ketone group: synthesis and their possible analgesic and anti-inflammatory activities.

PubMed

Deshpande, Shreenivas Ramachandrarao; Pai, Karkala Vasantakumar

2012-04-01

In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone group 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2a-i, was synthesized as better analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated at 100 mg\\kg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice. Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine substitution.

Antimicrobial and hypoglycemic activities of novel N-Mannich bases derived from 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thiones.

PubMed

Al-Abdullah, Ebtehal S; Al-Tuwaijri, Hanaa M; Hassan, Hanan M; Haiba, Mogedda E; Habib, Elsayed E; El-Emam, Ali A

2014-12-11

The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).

Cytotoxic withanolides from Physalis angulata L.

PubMed

He, Qing-Ping; Ma, Lei; Luo, Jie-Ying; He, Fu-Yuan; Lou, Li-Guang; Hu, Li-Hong

2007-03-01

Four new withanolides, physagulins L-O (1-4), were isolated from the MeOH extract of the aerial parts of Physalis angulata L. (Solanaceae), together with seven known withanolides, compounds 5-11. Their structures were determined by spectroscopic techniques, including 1H-, 13C-NMR (DEPT), and 2D-NMR (HMBC, HMQC, 1H,1H-COSY, NOESY) experiments, as well as by HR-MS. All eleven compounds were tested for their antiproliferative activities towards human colorectal-carcinoma (HCT-116) and human non-small-cell lung-cancer (NCI-H460) cells. Compound 5 exhibited the highest anticancer activity against the HCT-116 cell line, with an IC50 value of 1.64+/-0.06 microM. Compound 9 exhibited the highest cytotoxicity towards the NCI-H460 cell line, with an IC50 value of 0.43+/-0.02 microM.

Synthesis of 1-Substituted Carbazolyl-1,2,3,4-tetrahydro- and Carbazolyl-3,4-dihydro-β-carboline Analogs as Potential Antitumor Agents

PubMed Central

Shen, Ya-Ching; Chang, Yao-To; Lin, Chun-Ling; Liaw, Chia-Ching; Kuo, Yao Haur; Tu, Lan-Chun; Yeh, Sheau Farn; Chern, Ji-Wang

2011-01-01

A series of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and carbazolyl-3,4-dihydro-β-carboline analogs have been synthesized and evaluated for antitumor activity against human tumor cells including KB, DLD, NCI-H661, Hepa, and HepG2/A2 cell lines. Among these, compounds 2, 6, 7, and 9 exhibited the most potent and selective activity against the tested tumor cells. As for inhibition of topoisomerase II, compounds 1–14 and 18 showed better activity than etoposide. Among them, compounds 3, 4, 7, 9, and 10 exhibited potent activity. The structure and activity relationship (SAR) study revealed correlation between carbon numbers of the side chain and biological activities. The molecular complex with DNA for compound 2 was proposed. PMID:21566798

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.

Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes.

PubMed

Zhang, Xiangming; Liu, Huijuan; Sun, Bo; Sun, Yan; Zhong, Weilong; Liu, Yanrong; Chen, Shuang; Ling, Honglei; Zhou, Lei; Jing, Xiangyan; Qin, Yuan; Xiao, Ting; Sun, Tao; Zhou, Honggang; Yang, Cheng

2016-11-17

Peroxisome proliferator-activated receptor γ (PPARγ) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPARγ agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPARγ. Eight novel podophyllotoxin-like derivatives were synthesized and assayed for toxicity and functional activity toward PPARγ to reduce the possible systemic toxic effects of podophyllotoxin and to maintain partial agonist activity toward PPARγ. Cell-based transactivation assays showed that compounds (E)-3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-4-(4(trifluoromethyl)styryl)dihydrofuran-2(3H)-one (3a) and (E)-4-(3-acetylstyryl)-3-(hydroxyl (3,4,5-trimethoxyphenyl)methyl)dihydrofuran-2(3H)-one (3f) exhibited partial agonist activity. An experiment using human hepatocarcinoma cells (HepG2) that were induced to become an insulin-resistant model showed that compounds 3a and 3f improved insulin sensitivity and glucose consumption. In addition, compounds 3a and 3f significantly improved hyperglycemia and insulin resistance in high-fat diet-fed streptozotocin (HFD-STZ)-induced type 2 diabetic rats at a dose of 15 mg/kg/day administered orally for 45 days, without significant weight gain. Cell toxicity testing also showed that compounds 3a and 3f exhibited weaker toxicity than pioglitazone. These findings suggested that compounds 3a and 3f improved insulin resistance in vivo and in vitro and that the compounds exhibited potential for the treatment of type 2 diabetes mellitus.

Schiff Bases of Benzothiazol-2-ylamine and Thiazolo[5,4-b] pyridin-2-ylamine as Anticonvulsants: Synthesis, Characterization and Toxicity Profiling.

PubMed

Shukla, Rashmi; Singh, Ajeet P; Sonar, Pankaj K; Mishra, Mudita; Saraf, Shailendra K

2016-01-01

Schiff bases have a broad spectrum of biological activities like antiinflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic and so forth. Thus, after a thorough perusal of literature, it was decided to conjugate benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine with aromatic and heteroaromatic aldehydes to get a series of Schiff bases. Synthesis, characterization, in-silico toxicity profiling and anticonvulsant activity of the Schiff bases of Benzothiazol-2-ylamine and Thiazolo [5, 4-b] pyridin-2-ylamine. Aniline/4-aminopyridine was converted to the corresponding thiourea derivatives, which were cyclized to obtain benzothiazol-2-ylamine/thiazolo [5, 4-b] pyridin-2-ylamine. Finally, these were condensed with various aromatic and heteroaromatic aldehydes to obtain Schiff bases of benzothiazol-2-ylamine and thiazolo [5, 4-b] pyridin-2-ylamine. The synthesized compounds were characterized and screened for their anticonvulsant activity using maximal electroshock (MES) test and isoniazid (INH) induced convulsions test. In-silico toxicity profiling of all the synthesized compounds was done through "Lazar" and "Osiris" properties explorer. Majority of the compounds were more potent against MES induced convulsions than INH induced convulsions. Schiff bases of benzothiazol-2-ylamine were more effective than thiazolo [5, 4-b] pyridin-2-ylamine against MES induced convulsions. The compound benzothiazol-2-yl-(1H-indol-2-ylmethylene)-amine (VI) was the most potent member of the series against both types of convulsions. Compound VI exhibited the most significant activity profile in both the models. The compounds did not exhibit any carcinogenicity or acute toxicity in the in-silico studies. Thus, it may be concluded that the Schiff bases of benzothiazol-2-ylamine exhibit the potential to be promising and non-toxic anticonvulsant agents.

Practical Synthesis, Antidepressant, and Anticonvulsant Activity of 3-Phenyliminoindolin-2-one Derivatives.

PubMed

Ma, Jian-Yin; Quan, Ying-Chun; Jin, Hong-Guo; Zhen, Xing-Hua; Zhang, Xue-Wu; Guan, Li-Ping

2016-03-01

Herein, a series of 3-phenyliminoindolin-2-one derivatives were designed, synthesized, and screened for their antidepressant and anticonvulsant activities. The IR spectra of the compounds afforded NH stretching (3340-3346 cm(-1)) bands and C=O stretching (1731-1746 cm(-1)). In the (1)H-NMR spectra of the compounds, N-H protons of indoline ring were observed at 10.65-10.89 ppm generally as broad bands, and (13)C-NMR spectra of the compounds C=O were seen at 161.72-169.27 ppm. Interestingly, compounds 3o, 3p and 3r significantly shortened immobility time in the The forced swimming test (FST) and The tail suspension test (TST) at 50 mg/kg dose levels. In addition, compound 3r exhibited higher levels of efficacy than the reference standard fluoxetine but had no effect on locomotor activity in the open-field test. Compound 3r significantly increased serotonin and norepinephrine and the metabolite 5-hydroxyindoleacetic acid in mouse brain, suggesting that the effects of compound 3r may be mediated through these neurotransmitters. In the seizure screen, 15 compounds showed some degree against PTZ-induced seizure at a dose of 100 mg/kg, and the tested compounds did not show any neurotoxicity at a dose of 300 mg/kg in the rotarod test. © 2015 John Wiley & Sons A/S.

Photolytic fate and genotoxicity of benzophenone-derived compounds and their photodegradation mixtures in the aqueous environment.

PubMed

Kotnik, Kristina; Kosjek, Tina; Žegura, Bojana; Filipič, Metka; Heath, Ester

2016-03-01

This study investigates the environmental fate of eight benzophenone derivatives (the pharmaceutical ketoprofen, its phototransformation products 3-ethylbenzophenone and 3-acetylbenzophenone, and five benzophenone-type UV filters) by evaluating their photolytic behaviour. In addition, the genotoxicity of these compounds and the produced photodegradation mixtures was studied. Laboratory-scale irradiation experiments using a medium pressure UV lamp revealed that photodegradation of benzophenones follows pseudo-first-order kinetics. Ketoprofen was the most photolabile (t1/2 = 0.8 min), while UV filters were more resistant to UV light with t1/2 between 17 and 99 h. The compounds were also exposed to irradiation by natural sunlight and showed similar photostability as predicted under laboratory conditions. Solar photodegradation experiments were performed in distilled water, lake and seawater, and revealed that photosensitizers present in natural waters significantly affect the photolytic behaviour of the investigated compounds. In this case, the presence of lake water resulted in accelerated photodecomposition, while seawater showed different effects on photodegradation, depending on a compound. Further, it was shown that the transformation products of ketoprofen 3-ethylbenzophenone and 3-acetylbenzophenone were formed under environmental conditions when ketoprofen was exposed to natural sunlight. Genotoxicity testing of parent benzophenone compounds using the SOS/umuC assay revealed that UV filters exhibited weak genotoxic activity in the presence of a metabolic activation system, however the concentrations tested were much higher than found in the environment (≥125 μg mL(-1)). After irradiation of benzophenones, the produced photodegradation mixtures showed that, with the exception of benzophenone that exhibited weak genotoxic activity, all the other compounds tested did not elicit any activity when exposed to UV light. Copyright © 2015 Elsevier Ltd. All rights reserved.

Contact toxicities of anuran skin alkaloids against the fire ant ( Solenopsis invicta)

NASA Astrophysics Data System (ADS)

Weldon, Paul J.; Cardoza, Yasmin J.; Vander Meer, Robert K.; Hoffmann, W. Clint; Daly, John W.; Spande, Thomas F.

2013-02-01

Nearly 500 alkaloids, representing over 20 structural classes, have been identified from the skin of neotropical poison frogs (Dendrobatidae). These cutaneous compounds, which are derived from arthropod prey of the frogs, generally are believed to deter predators. We tested the red imported fire ant ( Solenopsis invicta) for toxicosis following contact with 20 alkaloids (12 structural classes) identified from dendrobatids or other anurans. Individual ants forced to contact the dried residues of 13 compounds exhibited convulsions and/or reduced ambulation. We estimated the cutaneous concentrations of several compounds based on their reported recoveries from skin extracts of free-ranging frogs and our measurements of the skin surface areas of museum specimens. Pumiliotoxin 251D exhibited contact toxicity below its estimated cutaneous concentration in the Ecuadorian frog, Epipedobates anthonyi, an observation consistent with the hypothesized role of this compound in anuran chemical defense. Our results and those of a previous study of mosquitoes indicate that some anuran skin compounds function defensively as contact toxins against arthropods, permeating their exoskeleton.

Synthesis and pharmacological evaluation of polyfunctional benzimidazole-NSAID chimeric molecules combining anti-inflammatory, immunomodulatory and antioxidant activities.

PubMed

Bansal, Yogita; Silakari, Om

2014-11-01

Polyfunctional compounds comprise a novel class of therapeutic agents for treatment of multifactorial diseases. The present study reports a series of benzimidazole-non-steroidal anti-inflammatory drugs (NSAIDs) conjugates (1-10) as novel polyfunctional compounds synthesized in the presence of orthophosphoric acid. The compounds were evaluated for anti-inflammatory (carageenan-induced paw edema model), immunomodulatory (direct haemagglutination test and carbon clearance index models), antioxidant (in vitro and in vivo) and for ulcerogenic effects. Each of the compound has retained the anti-inflammatory activity of the corresponding parent NSAID while exhibiting significantly reduced gastric ulcers. Additionally, the compounds are found to possess potent immunostimulatory and antioxidant activities. The compound 8 was maximally potent (antibody titre value 358.4 ± 140.21, carbon clearance index 0.053 ± 0.002 and antioxidant EC50 value 0.03 ± 0.006). These compounds, exhibiting such multiple pharmacological activities, can be taken as lead for the development of potent drugs for the treatment of chronic multifactorial diseases involving inflammation, immune system modulation and oxidative stress such as cancers. The Lipinski's parameters suggested the compounds to be bear drug like properties.

Toxicity, uptake, and mutagenicity of particulate and soluble nickel compounds.

PubMed Central

Fletcher, G G; Rossetto, F E; Turnbull, J D; Nieboer, E

1994-01-01

Toxicity testing in AS52 cells (24-hr exposures) gave LC50 values of 2 to 130 micrograms Ni/ml for particulate nickel compounds and 45 to 60 micrograms Ni/ml for water-soluble salts (NiCl2, NiSO4, Ni(CH3COO)2). The Ni(OH)2, NiCO3, and sulfides (Ni3S2, Ni7S6, "amorphous NiS") exhibited similar toxicities (LC50's of 2 to 8 micrograms Ni/ml), while three nickel oxides were more variable and less toxic (LC50's of 18 to 130 micrograms Ni/ml). Most compounds displayed nuclear to cytoplasmic nickel ratios of approximately 1:1.5 to 1:5 (except approximately 1:20 for nickel salts). At the LC50's, a 75-fold range in exposure levels occurred compared to a 10-fold range in cytoplasmic and nuclear nickel concentrations, [Ni]. Cellular nickel distribution indicated three groupings: inert compounds (green NiO, lithium nickel oxide, relatively low nuclear and cytosolic [Ni]); water-soluble salts (very low nuclear [Ni]; high cytosolic [Ni]), and slightly soluble compounds (relatively high cytosolic and nuclear [Ni]). Nickel compounds are considered to be only weak or equivocal mutagens. In this study, a low but significant increase in mutation rate at the gpt locus was shown. Although the results would not be sufficient to deem nickel compounds mutagenic by traditional criteria, characterization by PCR analysis indicated that the spontaneous and nickel-induced mutants exhibited different and compound-specific mutational spectra (thus confirming nickel compound involvement). The results reported illustrate some of the methodologic problems involved in testing "weak" mutagens and indicate that alternative approaches may be necessary in classifying the mutagenicity of nickel and other compounds. PMID:7843140

Chemotherapy of Malaria

DTIC Science & Technology

1975-05-31

Vietnam was resistant to drugs such as chloroquine and quinine, gene-ally r,,conized snce World War II as satisfactory antimalarial agents. Tr,e...Trypanosoma rhodesiense infections in mice. (3) structural analogues of compounds found active in our test system and representing several novel chemical...with chloroquine , dapsone, cycloguanil, or pyrimethamine. Out of the 17 good compounds 7 exhibited quinine equivalent values of greater than 25. These 7

Insight into the structural requirements of proton pump inhibitors based on CoMFA and CoMSIA studies.

PubMed

Nayana, M Ravi Shashi; Sekhar, Y Nataraja; Nandyala, Haritha; Muttineni, Ravikumar; Bairy, Santosh Kumar; Singh, Kriti; Mahmood, S K

2008-10-01

In the present study, a series of 179 quinoline and quinazoline heterocyclic analogues exhibiting inhibitory activity against Gastric (H+/K+)-ATPase were investigated using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods. Both the models exhibited good correlation between the calculated 3D-QSAR fields and the observed biological activity for the respective training set compounds. The most optimal CoMFA and CoMSIA models yielded significant leave-one-out cross-validation coefficient, q(2) of 0.777, 0.744 and conventional cross-validation coefficient, r(2) of 0.927, 0.914 respectively. The predictive ability of generated models was tested on a set of 52 compounds having broad range of activity. CoMFA and CoMSIA yielded predicted activities for test set compounds with r(pred)(2) of 0.893 and 0.917 respectively. These validation tests not only revealed the robustness of the models but also demonstrated that for our models r(pred)(2) based on the mean activity of test set compounds can accurately estimate external predictivity. The factors affecting activity were analyzed carefully according to standard coefficient contour maps of steric, electrostatic, hydrophobic, acceptor and donor fields derived from the CoMFA and CoMSIA. These contour plots identified several key features which explain the wide range of activities. The results obtained from models offer important structural insight into designing novel peptic-ulcer inhibitors prior to their synthesis.

Synthesis, spectroscopic characterization, DFT study and antimicrobial activity of novel alkylaminopyrazole derivatives

NASA Astrophysics Data System (ADS)

Zalaru, Christina; Dumitrascu, Florea; Draghici, Constantin; Tarcomnicu, Isabela; Tatia, Rodica; Moldovan, Lucia; Chifiriuc, Mariana-Carmen; Lazar, Veronica; Marinescu, Maria; Nitulescu, Mihai George; Ferbinteanu, Marilena

2018-03-01

A new series of substituted N,N-bis-[(1H-pyrazol-1-yl)methyl]-aminohexadecane Mannich bases were synthesized, characterized by IR, 1H NMR 13C NMR, UV-Vis, MS and elemental analysis, and tested for their biological activity. All the synthesized compounds were tested for in vitro antimicrobial activity against a panel of selected bacterial and fungal strains using erythromycin and clotrimazole as standards. Most of the synthesized compounds demonstrated very good activity at minimum inhibitory concentrations (MICs). Compound 3b with an halogen atom into the pharmacophore structure exhibited the most significant activity against Bacillus subtilis (MIC = 0.007 μgmLL-1) versus erythromycin as standard. In vitro cytotoxicity of the new compounds was studied using MTT assay. The analysis of the test cells showed that the newly synthesized alkylaminopyrazoles derivatives were biocompatible until a concentration of 5 μgmL-1; two compounds presented a high degree of biocompatibility on the studied concentration range.

Synthesis and evaluation of new 3-phenylcoumarin derivatives as potential antidepressant agents.

PubMed

Sashidhara, Koneni V; Rao, K Bhaskara; Singh, Seema; Modukuri, Ram K; Aruna Teja, G; Chandasana, Hardik; Shukla, Shubha; Bhatta, Rabi S

2014-10-15

A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test (FST), a model to screen antidepressant activity in rodents. Among the series, compounds 5c and 6a potentially decreased the immobility time by 73.4% and 79.7% at a low dose of 0.5 mg/kg as compared to standard drug fluoxetine (FXT) which reduced the immobility time by 74% at a dose of 20 mg/kg, ip. Additionally, these active compounds also exhibited significant efficacy in tail suspension test (TST) (another model to screen antidepressant compounds). Interestingly, rotarod and locomotor activity tests confirmed that these two compounds do not have any motor impairment effect and neurotoxicity in mice. Our studies demonstrate that the new 3-phenylcoumarin derivatives may serve as a promising antidepressant lead and hence pave the way for further investigation around this chemical space. Copyright © 2014 Elsevier Ltd. All rights reserved.

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice

PubMed Central

Shajib, Md. Shafiullah; Rashid, Ridwan B.; Ming, Long C.; Islam, Shanta; Sarker, Md. Moklesur R.; Nahar, Lutfun; Sarker, Satyajit D.; Datta, Bidyut K.; Rashid, Mohammad A.

2018-01-01

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3′,5,6,7,8-hexamethoxy-4′,5′-methylenedioxyflavone (1), 3,3′,4′,5′,5,6,7,8-octamethoxyflavone (exoticin) (2), 6,7,4′,5′-dimethylenedioxy-3,5,3′-trimethoxyflavone (3), and 3,3′,4′,5,5′,8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified from N. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1, 3, and 4 (12.5–25 mg/kg b.w.) exhibited dose-dependent and significant (p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+ channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1, 3, and 4 (12.5 mg/kg b.w.) demonstrated significant (p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAA receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5–25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1–4) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents. PMID:29515437

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice.

PubMed

Shajib, Md Shafiullah; Rashid, Ridwan B; Ming, Long C; Islam, Shanta; Sarker, Md Moklesur R; Nahar, Lutfun; Sarker, Satyajit D; Datta, Bidyut K; Rashid, Mohammad A

2018-01-01

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia , an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3',5,6,7,8-hexamethoxy-4',5'-methylenedioxyflavone ( 1 ), 3,3',4',5',5,6,7,8-octamethoxyflavone (exoticin) ( 2 ), 6,7,4',5'-dimethylenedioxy-3,5,3'-trimethoxyflavone ( 3 ), and 3,3',4',5,5',8-hexamethoxy-6,7-methylenedioxyflavone ( 4 ), isolated and identified from N. plumbaginifolia . Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1 , 3 , and 4 (12.5-25 mg/kg b.w.) exhibited dose-dependent and significant ( p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K + channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1 , 3 , and 4 (12.5 mg/kg b.w.) demonstrated significant ( p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABA A receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5-25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones ( 1-4 ) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents.

Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for activity toward monoamine transporters.

PubMed

Kharkar, Prashant S; Batman, Angela M; Zhen, Juan; Beardsley, Patrick M; Reith, Maarten E A; Dutta, Aloke K

2009-07-01

A novel series of optically active molecules based on a 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.Herein we describe the synthesis and biological evaluation of a series of asymmetric 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol-based dihydroxy compounds in which the hydroxy groups are located on both the piperidine ring and the N-phenylethyl side chain. In vitro uptake inhibition data of these molecules indicate high affinity for the dopamine transporter (DAT) in addition to moderate to high affinity for the norepinephrine transporter (NET). Interestingly, compounds 9 b and 9 d exhibit affinities for all three monoamine transporters, with highest potency at DAT and NET, and moderate potency at the serotonin transporter (SERT) (K(i): 2.29, 78.4, and 155 nM for 9 b and 1.55, 14.1, and 259 nM for 9 d, respectively). Selected compounds 9 a, 9 d, and 9 d' were tested for their locomotor activity effects in mice and for their ability to occasion the cocaine-discriminative stimulus in rats. These test compounds generally exhibit a much longer duration of action than cocaine for elevating locomotor activity, and completely generalize the cocaine-discriminative stimulus in a dose-dependent manner.

Aquatic Pseudomonads Inhibit Oomycete Plant Pathogens of Glycine max

PubMed Central

Wagner, Andrew; Norris, Stephen; Chatterjee, Payel; Morris, Paul F.; Wildschutte, Hans

2018-01-01

Seedling root rot of soybeans caused by the host-specific pathogen Phytophthora sojae, and a large number of Pythium species, is an economically important disease across the Midwest United States that negatively impacts soybean yields. Research on biocontrol strategies for crop pathogens has focused on compounds produced by microbes from soil, however, recent studies suggest that aquatic bacteria express distinct compounds that efficiently inhibit a wide range of pathogens. Based on these observations, we hypothesized that freshwater strains of pseudomonads might be producing novel antagonistic compounds that inhibit the growth of oomycetes. To test this prediction, we utilized a collection of 330 Pseudomonas strains isolated from soil and freshwater habitats, and determined their activity against a panel of five oomycetes: Phytophthora sojae, Pythium heterothalicum, Pythium irregulare, Pythium sylvaticum, and Pythium ultimum, all of which are pathogenic on soybeans. Among the bacterial strains, 118 exhibited antagonistic activity against at least one oomycete species, and 16 strains were inhibitory to all pathogens. Antagonistic activity toward oomycetes was significantly more common for aquatic isolates than for soil isolates. One water-derived strain, 06C 126, was predicted to express a siderophore and exhibited diverse antagonistic profiles when tested on nutrient rich and iron depleted media suggesting that more than one compound was produced that effectively inhibited oomycetes. These results support the concept that aquatic strains are an efficient source of compounds that inhibit pathogens. We outline a strategy to identify other strains that express unique compounds that may be useful biocontrol agents. PMID:29896163

2,3-Dideoxyglucosides of selected terpene phenols and alcohols as potent antifungal compounds.

PubMed

James Bound, D; Murthy, Pushpa S; Srinivas, P

2016-11-01

The antifungal activities of novel 2,3-unsaturated and 2,3-dideoxy 1-O-glucosides of carvacrol, thymol, and perillyl alcohol were tested against Aspergillus flavus, Aspergillus ochraceus, Fusarium oxysporum, Saccharomyces cerevisiae and Candida albicans. In the agar well diffusion tests, zones of inhibition for the derivatives of carvacrol, thymol and perillyl alcohol were higher (15-30mm) in the case of filamentous fungi than those for the parent compounds. Their MIC and MFC values indicated that the 2,3-unsaturated and 2,3-dideoxy 1-O-glucosides of carvacrol and thymol exhibited more fungicidal activity than the other compounds. Further, the 2,3-dideoxyglucosides of carvacrol and thymol, exhibited antitoxigenic effects against A. ochraceus and A. flavus and inhibited the production of ochratoxin and aflatoxin-B2. Propidium iodide influx assay demonstrated the lysis of C. albicans cells by carvacrol and its 2,3-unsaturated 1-O-glucoside and the loss of the membrane integrity. These new 2,3-dideoxyglucosides can be useful as antifungal agents and condiments in foods. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure-activity relationships among substituted N-benzoyl derivatives of phenylalanine and its analogs in a microbial antitumor prescreen I: Derivatives of o-fluoro-DL-phenylalanine.

PubMed

Otani, T T; Briley, M R

1982-02-01

Twelve derivatives of 0-fluoro-dl-phenylalanine containing fluorine, chlorine, methoxy, and nitro radicals in various positions of the aromatic ring of the benzoyl group were prepared and tested in a Lactobacillus casei system. It was found that most substitutions in the benzoyl phenyl ring resulted in a compound exhibiting greater growth-inhibiting activity than the nonsubstituted benzoyl-o-fluorophenylalanine. The greatest activity was observed in the ortho-substituted fluoro compound and the meta- and para-substituted chloro and nitro compounds. With the methoxy group, the position of substitution appeared unimportant, since all three methoxy isomers exhibited essentially equal inhibition. Nitro substitution in the ortho position had a protective effect in that the product was less active than the unsubstituted benzoyl-o-fluoro-dl-phenylalanine.

Biodegradation of individual and multiple chlorinated aliphatic hydrocarbons by methane-oxidizing cultures.

PubMed Central

Chang, H L; Alvarez-Cohen, L

1996-01-01

The microbial degradation of chlorinated and nonchlorinated methanes, ethanes, and ethanes by a mixed methane-oxidizing culture grown under chemostat and batch conditions is evaluated and compared with that by two pure methanotrophic strains: CAC1 (isolated from the mixed culture) and Methylosinus trichosporium OB3b. With the exception of 1,1-dichloroethylene, the transformation capacity (Tc) for each chlorinated aliphatic hydrocarbon was generally found to be in inverse proportion to its chlorine content within each aliphatic group (i.e., methanes, ethanes, and ethenes), whereas similar trends were not observed for degradation rate constants. Tc trends were similar for all methane-oxidizing cultures tested. None of the cultures were able to degrade the fully chlorinated aliphatics such as perchloroethylene and carbon tetrachloride. Of the four cultures tested, the chemostat-grown mixed culture exhibited the highest Tc for trichloroethylene, cis-1,2-dichloroethylene, tetrachloroethane, 1,1,1-trichloroethane, and 1,2-dichloroethane, whereas the pure batch-grown OB3b culture exhibited the highest Tc for all other compounds tested. The product toxicity of chlorinated aliphatic hydrocarbons in a mixture containing multiple compounds was cumulative and predictable when using parameters measured from the degradation of individual compounds. The Tc for each chlorinated aliphatic hydrocarbon in a mixture (Tcmix) and the total Tc for the mixture (sigma Tcmix) are functions of the individual Tc, the initial substrate concentration (S0), and the first-order rate constant (k/Ks) of each compound in the mixture, indicating the importance of identifying the properties and compositions of all potentially degradable compounds in a contaminant mixture. PMID:8795228

Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease.

PubMed

Yang, Hua-Li; Cai, Pei; Liu, Qiao-Hong; Yang, Xue-Lian; Li, Fan; Wang, Jin; Wu, Jia-Jia; Wang, Xiao-Bing; Kong, Ling-Yi

2017-09-29

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC 50 , 0.027 ± 0.004 μM for MAO-B; 3.275 ± 0.040 μM for MAO-A) and Aβ 1-42 aggregation (54.0 ± 1.1%, 25 μM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF-7, A-549, HCT-116, and BGC-823 cell lines.

PubMed

Zhou, Wu-Xi; Cao, Jia-Qing; Wang, Xu-De; Guo, Jun-Hui; Zhao, Yu-Qing

2017-02-15

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

New Butyrolactone Type Lignans from Arctii Fructus and Their Anti-inflammatory Activities.

PubMed

Yang, Ya-Nan; Huang, Xiao-Ying; Feng, Zi-Ming; Jiang, Jian-Shuang; Zhang, Pei-Cheng

2015-09-16

Arctiidilactone (1), a novel rare butyrolactone lignan with a 6-carboxyl-2-pyrone moiety, and 11 new butyrolactone lignans (2-12) were isolated from the fruits of Arctium lappa L., together with 5 known compounds (13-17). Their structures were elucidated by interpretation of their spectroscopic data (1D and 2D NMR, UV, IR, ORD, and HRESIMS) and comparison to literature data. The absolute configurations of compounds 1-12 were determined by a combination of rotating-frame nuclear Overhauser effect spectroscopy (ROESY), circular dichroism (CD) spectroscopy, and Rh2(OCOCF3)4-induced CD spectroscopy. All of the compounds were tested for their anti-inflammatory properties in terms of suppressing the production of NO in lipopolysaccharide-induced BV2 cells. Compounds 1, 6, 8, and 10 exhibited stronger anti-inflammatory effects than the positive control curcumin, particularly 1, which exhibited 75.51, 70.72, and 61.17% inhibition at 10, 1, and 0.1 μM, respectively.

Synthesis and antimicrobial evaluation of L-phenylalanine-derived C5-substituted rhodanine and chalcone derivatives containing thiobarbituric acid or 2-thioxo-4-thiazolidinone.

PubMed

Jin, Xin; Zheng, Chang-Ji; Song, Ming-Xia; Wu, Yan; Sun, Liang-Peng; Li, Yin-Jing; Yu, Li-Jun; Piao, Hu-Ri

2012-10-01

Four novel series of compounds, including the l-phenylalanine-derived C5-substituted rhodanine (6a-q, 7a-j) and chalcone derivatives containing thiobarbituric acid or 2-thioxo-4-thiazolidinone (9a-e, 11a-e) have been designed, synthesized, characterized, and evaluated for their antibacterial activity. Some of these compounds showed significant antibacterial activity against Gram-positive bacterias, especially against the strains of multidrug-resistant clinical isolates, among which compounds 6c-e, 6g, 6i, 6j and 6q exhibiting high levels of antimicrobial activity against Staphylococcus aureus RN4220 with minimum inhibitory concentration (MIC) values of 2 μg/mL. Compound 6q showed the most potent activity of all of the compounds against all of the test multidrug-resistant clinical isolates tested. Unfortunately, however, none of the compounds were active against Gram-negative bacteria at 64 μg/mL. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

In vitro evaluation of cytotoxicity and leishmanicidal activity of phthalimido-thiazole derivatives.

PubMed

Aliança, Amanda Silva Dos Santos; Oliveira, Arsênio Rodrigues; Feitosa, Ana Paula Sampaio; Ribeiro, Karla Raíza Cardoso; de Castro, Maria Carolina Accioly Brelaz; Leite, Ana Cristina Lima; Alves, Luiz Carlos; Brayner, Fábio André

2017-07-15

It is estimated that the worldwide prevalence of leishmaniasis is around 12 million individuals in 80 countries, with 400,000new cases per year. In the search for new leishmanicidal agents, the hybrid phthalimido-thiazoles have been identified as an important scaffold for drug design and discovery. The present study thus reports the in vitro activity of a series of phthalimido-thiazole derivatives. Cytotoxicity against a strain of L. infantum, Vero cells, J774 macrophages and peritoneal macrophages was evaluated, as well as nitric oxide (NO) production. Activity against amastigote and promastigote forms of L. infantum and microscopic changes in the parasite and intracellular targets of the parasite were achieved. The results show that the compounds arising from hybridization of phthalimide and 1,3-thiazole exhibit promising leishmanicidal activity. Compounds 2j and 2m were the most potent of the series tested and the parasites treated with these compounds exhibited ultrastructural changes, such as cell body shrinkage, loss of cellular membrane integrity, vacuolization of cytoplasm, membrane profiles surrounding organelles and swelling of mitochondria. The data showed that these compounds reduced the survival of intracellular amastigotes and presented low toxicity for mammalian cells. The compounds produced increased NO production compared to untreated cells in non-infected macrophages. Treated promastigote forms showed an increase in the number of cells stained with propidium iodide. The compounds brought about significant changes in mitochondrial membrane potential. According to the present study, phthalimido-thiazole compounds exhibit leishmanicidal activity and could be used to develop novel antileishmaniasis drugs and explore potential molecular targets. Copyright © 2017 Elsevier B.V. All rights reserved.

Synthesis and investigation of dihydroxychalcones as calpain and cathepsin inhibitors.

PubMed

Baek, Kyung Hye; Karki, Radha; Lee, Eung-Seok; Na, Younghwa; Kwon, Youngjoo

2013-12-01

In order to identify potential calpain and cathepsin inhibitors we prepared 12 dihydroxychalcone analogues and tested their ability to inhibit μ-calpain, m-calpain, cathepsins B and L. In the calpain inhibition test, compound 10 exhibited the most active inhibitory activity against m-calpain with an IC50 value of 25.25±0.901μM. With respect to inhibition of cathepsins B and L, compound 13 exhibited the most potent inhibitory activity on cathepsin L and moderate inhibitory activity on cathepsin B with IC50 values of 2.80±0.100 and 11.47±0.087μM, respectively. Our results suggest the possibility of developing dual calpain and cathepsin inhibitors by properly modulating structures and/or combining the essential aspects of the functional group effective for specific calpain and cathepsin inhibition. Copyright © 2013 Elsevier Inc. All rights reserved.

Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for monoamine transporters

PubMed Central

Kharkar, Prashant S.; Batman, Angela M.; Zhen, Juan; Beardsley, Patrick M.; Reith, Maarten E. A.

2012-01-01

In this report we describe synthesis and biological evaluation of a series of asymmetric 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol based dihydroxy compounds where the hydroxy groups are located both on the piperidine ring and also on the N-phenylethyl side chain exo-cyclically. In vitro uptake inhibition data indicates high affinity of these molecules for the dopamine transporter (DAT) in addition to their moderate to high affinity for the norepinephrine transporter (NET). Interestingly, compounds 9b and 9d exhibited affinities for all three monoamine transporters with highest potency at DAT and NET and moderate potency at the serotonin transporter (SERT) (Ki 2.29, 78.4 and 155 nM for 9b and 1.55, 14.1 and 259 nM for 9d, respectively). Selected compounds, 9a, 9d and 9d’ were tested for their locomotor activity effects in mice, and for their ability to occasion the cocaine discriminative stimulus in rats. These test compounds generally exhibited a much longer duration of action than cocaine for elevating locomotor activity, and dose-dependently completely generalized the cocaine discriminative stimulus. PMID:19449323

Water-soluble derivatives of 25-OCH3-PPD and their anti-proliferative activities.

PubMed

Zhou, Wu-Xi; Sun, Yuan-Yuan; Yuan, Wei-Hui; Zhao, Yu-Qing

2017-05-01

(20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH 3 -PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH 3 -PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH 3 -PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH 3 -PPD and its derivatives was tested and the results showed that the solubility of 25-OCH 3 -PPD sulfamic acid and diacid derivatives were better than that of 25-OCH 3 -PPD in water, which may provide valuable data for the research and development of new anti-tumor agents. Copyright © 2017 Elsevier Inc. All rights reserved.

Antioxidant and biological properties of bioactive phenolic compounds from Quercus suber L.

PubMed

Fernandes, Ana; Fernandes, Iva; Cruz, Luís; Mateus, Nuno; Cabral, Miguel; de Freitas, Victor

2009-12-09

Phenolic compounds, namely, hydrolyzable tannins and low molecular weight phenolic compounds, were isolated and purified from Portuguese cork from Quercus suber L. Some of these compounds were studied to evaluate their antioxidant activity, including free-radical scavenging capacity (DPPH method) and reducing capacity (FRAP method). All compounds tested showed significant antioxidant activity, namely, antiradical and reducing properties. The antiradical capacity seemed to increase with the presence of galloyl groups. Regarding the reducing capacity, this structure-activity relationship was not so clear. These compounds were also studied to evaluate the growth inhibitory effect on the estrogen responsive human breast cancer cell line (ER+) MCF-7 and two other colon cancer cell lines (Caco-2 and HT-29). Generally, all the compounds tested exhibited, after a continuous exposure during a 48 h period, a dose-dependent growth inhibitory effect. Relative inhibitory activity was primarily related to the number of phenolic hydroxyl groups (galloyl and HHDP moieties) found in the active structures, with more groups generally conferring increased effects, except for HHDP-di-galloyl-glucose. Mongolicain B showed a greater potential to inhibit the growth of the three cell lines tested, identical to the effect observed with castalagin. Since these compounds are structurally related with each other, this activity might be based within the C-glycosidic ellagitannin moiety.

Discovery of Rigidified α,β-Unsaturated Imines as New Resistance-breaking Insecticides for Malaria Vector Control.

PubMed

Arlt, Alexander; Böhnke, Niels; Horstmann, Sebastian; Vermeer, Arnoldus W P; Werner, Stefan; Velten, Robert

2016-10-01

During our continuous search for new resistance-breaking insecticides applicable to malaria vector control, a new class of α,β-unsaturated imines was identified by applying the principle of conformational rigidification as a powerful tool for compound optimisation. Herein we describe the successful synthesis of these compounds and their biological test results. Our lead compound 16 from this insecticidal class outperforms market standards, notably for the control of mosquito strains that exhibit either metabolic or target-site resistance to these established insecticides. In our model system for insecticide-treated mosquito nets the compound reveals long-lasting efficacy for up to several months.

Phenolic Molding Compounds

NASA Astrophysics Data System (ADS)

Koizumi, Koji; Charles, Ted; de Keyser, Hendrik

Phenolic Molding Compounds continue to exhibit well balanced properties such as heat resistance, chemical resistance, dimensional stability, and creep resistance. They are widely applied in electrical, appliance, small engine, commutator, and automotive applications. As the focus of the automotive industry is weight reduction for greater fuel efficiency, phenolic molding compounds become appealing alternatives to metals. Current market volumes and trends, formulation components and its impact on properties, and a review of common manufacturing methods are presented. Molding processes as well as unique advanced techniques such as high temperature molding, live sprue, and injection/compression technique provide additional benefits in improving the performance characterisitics of phenolic molding compounds. Of special interest are descriptions of some of the latest innovations in automotive components, such as the phenolic intake manifold and valve block for dual clutch transmissions. The chapter also characterizes the most recent developments in new materials, including long glass phenolic molding compounds and carbon fiber reinforced phenolic molding compounds exhibiting a 10-20-fold increase in Charpy impact strength when compared to short fiber filled materials. The role of fatigue testing and fatigue fracture behavior presents some insight into long-term reliability and durability of glass-filled phenolic molding compounds. A section on new technology outlines the important factors to consider in modeling phenolic parts by finite element analysis and flow simulation.

Phenolic compounds from the leaf extract of artichoke (Cynara scolymus L.) and their antimicrobial activities.

PubMed

Zhu, Xianfeng; Zhang, Hongxun; Lo, Raymond

2004-12-01

A preliminary antimicrobial disk assay of chloroform, ethyl acetate, and n-butanol extracts of artichoke (Cynara scolymus L.) leaf extracts showed that the n-butanol fraction exhibited the most significant antimicrobial activities against seven bacteria species, four yeasts, and four molds. Eight phenolic compounds were isolated from the n-butanol soluble fraction of artichoke leaf extracts. On the basis of high-performance liquid chromatography/electrospray ionization mass spectrometry, tandem mass spectrometry, and nuclear magnetic resonance techniques, the structures of the isolated compounds were determined as the four caffeoylquinic acid derivatives, chlorogenic acid (1), cynarin (2), 3,5-di-O-caffeoylquinic acid (3), and 4,5-di-O-caffeoylquinic acid (4), and the four flavonoids, luteolin-7-rutinoside (5), cynaroside (6), apigenin-7-rutinoside (7), and apigenin-7-O-beta-D-glucopyranoside (8), respectively. The isolated compounds were examined for their antimicrobial activities on the above microorganisms, indicating that all eight phenolic compounds showed activity against most of the tested organisms. Among them, chlorogenic acid, cynarin, luteolin-7-rutinoside, and cynaroside exhibited a relatively higher activity than other compounds; in addition, they were more effective against fungi than bacteria. The minimum inhibitory concentrations of these compounds were between 50 and 200 microg/mL.

Synthesis of some novel orcinol based coumarin triazole hybrids with capabilities to inhibit RANKL-induced osteoclastogenesis through NF-κB signaling pathway.

PubMed

Rama Krishna, Boddu; Thummuri, Dinesh; Naidu, V G M; Ramakrishna, Sistla; Venkata Mallavadhani, Uppuluri

2018-08-01

A total of twenty-two novel coumarin triazole hybrids (4a-4k and 6a-6k) were synthesized from orcinol in good to excellent yields of 70-94%. The structures of all the synthesized compounds were elucidated by spectroscopic techniques such as 1 H NMR, 13 C NMR, and HRMS. The anti-inflammatory potential of synthesized compounds was investigated against the proinflammatory cytokine, TNF-α on U937 cell line and compounds 4d, 4j, and 6j were found to exhibit promising anti-inflammatory activity. These three compounds were further screened against TNF-α on LPS-stimulated RAW 264.7 cells, which confirm their anti-inflammatory potential. Furthermore, the above said active compounds were tested for their inhibitory effect on RANKL-induced osteoclastogenesis in RAW 264.7 cells by using tartrate resistant acid phosphatase (TRAP) staining assay at 10 µM. Molecular mechanism studies demonstrated that compound 4d exhibited dose dependent inhibition of RANKL-induced osteoclastogenesis by suppression of the NF-kB pathway. Thus, compound 4d is a promising candidate for further optimization to develop as a potent anti-osteoporotic agent. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of Muscle Atrophy on Motor Control: Cage-size Effects

NASA Technical Reports Server (NTRS)

Stuart, D. G.

1985-01-01

Two populations of male Sprague-Dawley rats were raised either in conventional minimum-specification cages or in a larger cage. When the animals were mature (125 to 150 d), the physiological status of the soleus (SOL) and extensor digitorum longus (EDL) muscles of the small- and large-cage animals were compared. Analysis of whole-muscle properties including the performance of the test muscle during a standardized fatigue test in which the nerve to the test muscle was subjected to supramaximal intermittent stimulation shows: (1) the amplitude, area, mean amplitude, and peak-to-peak rate of the compound muscle action potential decreased per the course of the fatigue test; (2) cage size did not affect the profile of changes for any of the action-potential measurements; (3) changes exhibited in the compound muscle action potential by SOL and EDL were substantially different; and (4) except for SOL of the large-cage rats, there was a high correlation between all four measures of the compound muscle action potential and the peak tetanic force during the fatigue test; i.e., either the electrical activity largely etermines the force profile during the fatigue test or else contractile-related activity substantially affects the compound muscle action potential.

Synthesis, characterization and biological studies of Schiff bases derived from heterocyclic moiety.

PubMed

Shanty, Angamaly Antony; Philip, Jessica Elizabeth; Sneha, Eeettinilkunnathil Jose; Prathapachandra Kurup, Maliyeckal R; Balachandran, Sreedharannair; Mohanan, Puzhavoorparambil Velayudhan

2017-02-01

Some new Schiff bases (H 1 -H 7 ) have been synthesized by the condensation of 2-aminophenol, 2-amino-4-nitrophenol, 2-amino-4-methylphenol, 2-amino benzimidazole with thiophene-2-carboxaldehyde and pyrrole-2-carboxaldehyde. The structures of newly synthesized compounds were characterized by elemental analysis, FT-IR, 1 H NMR, UV-VIS, and single crystal X-ray crystallography. The in vitro antibacterial activity of the synthesized compounds has been tested against Salmonella typhi, Bacillus coagulans, Bacillus pumills, Escherichia coli, Bacillus circulans, Pseudomonas, Clostridium and Klebsilla pneumonia by disk diffusion method. The quantitative antimicrobial activity of the test compounds was evaluated using Resazurin based Microtiter Dilution Assay. Ampicillin was used as standard antibiotics. Schiff bases individually exhibited varying degrees of inhibitory effects on the growth of the tested bacterial species. The antioxidant activity of the synthesized compounds was determined by the 1,1-diphenyl-2-picrylhydrazyl(DPPH) method. IC 50 value of synthesized Schiff bases were calculated and compared with standard BHA. Copyright © 2016 Elsevier Inc. All rights reserved.

Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516.

PubMed

Ciocoiu, Calin C; Ravna, Aina W; Sylte, Ingebrigt; Rustan, Arild C; Hansen, Trond Vidar

2011-12-01

(±)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic acid (2a) has been prepared and subjected to biological testing against all three subtypes of the PPARs. This compound exhibited agonist effects with EC(50) values of 560 and 55 nM against PPARα and PPARδ, respectively, in a luciferase assay. Moreover, compound (±)-2a also exhibited potent ability to induce oleic acid oxidation in a human myotube cell assay with EC(50)=3.7 nM. Compound (±)-2a can be classified as a dual PPARα/δ agonist with a 10-fold higher potency against the PPARδ receptor than against the PPARα receptor. Molecular modeling studies revealed that both enantiomers of 2a bind to the PPARδ receptor with similar binding energies. Copyright © 2011 Elsevier Ltd. All rights reserved.

Anti-malarial property of steroidal alkaloid conessine isolated from the bark of Holarrhena antidysenterica.

PubMed

Dua, Virendra K; Verma, Gaurav; Singh, Bikram; Rajan, Aswathy; Bagai, Upma; Agarwal, Dau Dayal; Gupta, N C; Kumar, Sandeep; Rastogi, Ayushi

2013-06-10

In the face of chronic and emerging resistance of parasites to currently available drugs and constant need for new anti-malarials, natural plant products have been the bastion of anti-malarials for thousands of years. Moreover natural plant products and their derivatives have traditionally been a common source of drugs, and represent more than 30% of the current pharmaceutical market. The present study shows evaluation of anti-malarial effects of compound conessine isolated from plant Holarrhena antidysenterica frequently used against malaria in the Garhwal region of north-west Himalaya. In vitro anti-plasmodial activity of compound was assessed using schizont maturation and parasite lactate dehydrogenase (pLDH) assay. Cytotoxic activities of the examined compound were determined on L-6 cells of rat skeletal muscle myoblast. The four-day test for anti-malarial activity against a chloroquine-sensitive Plasmodium berghei NK65 strain in BALB/c mice was used for monitoring in vivo activity of compound. In liver and kidney function test, the activity of alkaline phosphatase (ALP) was examined by p-NPP method, bilirubin by Jendrassik and Grof method. The urea percentage was determined by modified Berthelot method and creatinine by alkaline picrate method in serum of mice using ENZOPAK/CHEMPAK reagent kits. Compound conessine showed in vitro anti-plasmodial activity with its IC₅₀ value 1.9 μg/ml and 1.3 μg/ml using schizont maturation and pLDH assay respectively. The compound showed cytotoxity IC₅₀= 14 μg/ml against L6 cells of rat skeletal muscle myoblast. The isolated compound from plant H. antidysenterica significantly reduced parasitaemia (at 10 mg/kg exhibited 88.95% parasite inhibition) in P. berghei-infected mice. Due to slightly toxic nature (cytotoxicity = 14), biochemical analysis (liver and kidney function test) of the serum from mice after administration of conessine were also observed. The present investigation demonstrates that the compound conessine exhibited substantial anti-malarial property. The isolated compound could be chemically modified to obtain a more potent chemical entity with improved characteristics against malaria.

Antimutagenic activity of polymethoxyflavonoids from Citrus aurantium.

PubMed

Miyazawa, M; Okuno, Y; Fukuyama, M; Nakamura, S; Kosaka, H

1999-12-01

The methanol extract from Citrus aurantium showed a suppressive effect on umu gene expression of SOS response in Salmonella typhimurium TA1535/pSK1002 against the mutagen 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (furylfuramide). The methanol extract from C. aurantium was successively re-extracted with hexane, dichloromethane, butanol, and water. A dichloromethane fraction showed a suppressive effect. The suppressive compounds in the dichloromethane fraction were isolated by SiO(2) column chromatography and identified as tetra-O-methylscutellarein (1), sinensetin (2), and nobiletin (3) by EI-MS and (1)H- and (13)C NMR spectroscopy. These compounds suppressed the furylfuramide-induced SOS response in the umu test. Gene expression was suppressed 67%, 45%, and 25% at a concentration of 0.6 micromol/mL, respectively. The ID(50) value (50% inhibition dose) of compound 1 was 0. 19 micromol/mL. These compounds were assayed with other mutagens, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), which requires liver metabolizing enzymes, activated Trp-P-1, and UV irradiation. These compounds showed of all mutagen-induced SOS response in the umu test. In addition, compounds 1-3 exhibited antimutagenic activity in the S. typhimurium TA100 Ames test.

Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests.

PubMed

Ferreira, Maria do Perpetuo Socorro Borges Carriço; Cardoso, Mariana Filomena do Carmo; da Silva, Fernando de Carvalho; Ferreira, Vitor Francisco; Lima, Emerson Silva; Souza, João Vicente Braga

2014-07-06

This study evaluated the antifungal activities of synthetic naphthoquinones against opportunistic and dermatophytic fungi and their preliminary mechanisms of action. The minimum inhibitory concentrations (MICs) of four synthetic naphthoquinones for 89 microorganisms, including opportunistic yeast agents, dermatophytes and opportunistic filamentous fungi, were determined. The compound that exhibited the best activity was assessed for its action against the cell wall (sorbitol test), for interference associated with ergosterol interaction, for osmotic balance (K+ efflux) and for membrane leakage of substances that absorb at the wavelength of 260 nm. All tested naphthoquinones exhibited antifungal activity, and compound IVS320 (3a,10b-dihydro-1H-cyclopenta [b] naphtho [2,3-d] furan-5,10-dione)-dione) demonstrated the lowest MICs across the tested species. The MIC of IVS320 was particularly low for dermatophytes (values ranging from 5-28 μg/mL) and Cryptococcus spp. (3-5 μg/mL). In preliminary mechanism-of-action tests, IVS320 did not alter the fungal cell wall but did cause problems in terms of cell membrane permeability (efflux of K+ and leakage of substances that absorb at 260 nm). This last effect was unrelated to ergosterol interactions with the membrane.

Cytotoxic constituents of Achillea clavennae from Montenegro.

PubMed

Trifunović, Snezana; Vajs, Vlatka; Juranić, Zorica; Zizak, Zeljko; Tesević, Vele; Macura, Slobodan; Milosavljević, Slobodan

2006-05-01

Examination of the aerial parts of Achillea clavennae afforded eight guaianolides (1-8), three bisabolenes (9-11), four flavonols (12-15), sesamin (lignan) and isofraxidin (coumarin). The structures of the new compounds (2, 4, 5, 7 and 10) were determined by spectroscopic methods. The antiproliferative action of 2, 8, 9 and 12 were tested to HeLa, K562 and Fem-X human cancer cell lines. Guaianolides 2 (9alpha-acetoxyartecanin) and 8 (apressin) showed significant cytotoxic effects to all tested lines and inducumenone (9) exhibited a moderate activity. The most active was flavonol centaureidin (12), already known as cytotoxic compound.

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.

A Dinitroaniline-Resistant Mutant of Eleusine indica Exhibits Cross-Resistance and Supersensitivity to Antimicrotubule Herbicides and Drugs 1

PubMed Central

Vaughn, Kevin C.; Marks, M. David; Weeks, Donald P.

1987-01-01

A dinitroaniline-resistant (R) biotype of Eleusine indica (L.) Gaertner. (goosegrass) is demonstrated to be cross-resistant to a structurally non-related herbicide, amiprophosmethyl, and supersensitive to two other classes of compounds which disrupt mitosis. These characteristics of the R biotype were discovered in a comparative test of the effects of 24 different antimitotic compounds on the R biotype and susceptible (S) wild-type Eleusine. The compounds tested could be classified into three groups based upon their effects on mitosis in root tips of the susceptible (S) biotype. Class I compounds induced effects like the well known mitotic disrupter colchicine: absence of cortical and spindle microtubules, mitosis arrested at prometaphase, and the formation of polymorphic nuclei after arrested mitosis. The R biotype was resistant to treatment with some class I inhibitors (all dinitroaniline herbicides and amiprophosmethyl) but not all (e.g. colchicine, podophyllotoxin, vinblastine, and pronamide). Roots of the R biotype, when treated with either dinitroaniline herbicides or amiprophosmethyl, exhibited no or only small increases in the mitotic index nor were the spindle and cortical microtubules affected. Compounds of class II (carbamate herbicides and griseofulvin) cause misorientation of microtubules which results in multinucleated cells. Compounds of class III (caffeine and structually related alkaloids) cause imcomplete cell walls to form at telophase. Each of these last two classes of compounds affected the R biotype more than the S biotype (supersensitivity). The cross-resistance and high levels of resistance of the R biotype of Eleusine to the dinitroaniline herbicides and the structurally distinct herbicide, amiprophosmethyl, indicate that a mechanism of resistance based upon metabolic modification, translocation, or compartmentation of the herbicides is probably not operative. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 Fig. 6 PMID:16665371

A Dinitroaniline-Resistant Mutant of Eleusine indica Exhibits Cross-Resistance and Supersensitivity to Antimicrotubule Herbicides and Drugs.

PubMed

Vaughn, K C; Marks, M D; Weeks, D P

1987-04-01

A dinitroaniline-resistant (R) biotype of Eleusine indica (L.) Gaertner. (goosegrass) is demonstrated to be cross-resistant to a structurally non-related herbicide, amiprophosmethyl, and supersensitive to two other classes of compounds which disrupt mitosis. These characteristics of the R biotype were discovered in a comparative test of the effects of 24 different antimitotic compounds on the R biotype and susceptible (S) wild-type Eleusine. The compounds tested could be classified into three groups based upon their effects on mitosis in root tips of the susceptible (S) biotype. Class I compounds induced effects like the well known mitotic disrupter colchicine: absence of cortical and spindle microtubules, mitosis arrested at prometaphase, and the formation of polymorphic nuclei after arrested mitosis. The R biotype was resistant to treatment with some class I inhibitors (all dinitroaniline herbicides and amiprophosmethyl) but not all (e.g. colchicine, podophyllotoxin, vinblastine, and pronamide). Roots of the R biotype, when treated with either dinitroaniline herbicides or amiprophosmethyl, exhibited no or only small increases in the mitotic index nor were the spindle and cortical microtubules affected. Compounds of class II (carbamate herbicides and griseofulvin) cause misorientation of microtubules which results in multinucleated cells. Compounds of class III (caffeine and structually related alkaloids) cause imcomplete cell walls to form at telophase. Each of these last two classes of compounds affected the R biotype more than the S biotype (supersensitivity). The cross-resistance and high levels of resistance of the R biotype of Eleusine to the dinitroaniline herbicides and the structurally distinct herbicide, amiprophosmethyl, indicate that a mechanism of resistance based upon metabolic modification, translocation, or compartmentation of the herbicides is probably not operative.

Cytotoxic cassaine diterpenoid-diterpenoid amide dimers and diterpenoid amides from the leaves of Erythrophleum fordii.

PubMed

Du, Dan; Qu, Jing; Wang, Jia-Ming; Yu, Shi-Shan; Chen, Xiao-Guang; Xu, Song; Ma, Shuang-Gang; Li, Yong; Ding, Guang-Zhi; Fang, Lei

2010-10-01

Detailed phytochemical investigation from the leaves of Erythrophleum fordii resulted in the isolation of 13 compounds, including three cassaine diterpenoid-diterpenoid amide dimers (1, 3 and 5), and seven cassaine diterpenoid amides (6 and 8-13), together with three previously reported ones, erythrophlesins D (2), C (4) and 3beta-hydroxynorerythrosuamide (7). Compounds 1, 3 and 5 are further additions to the small group of cassaine diterpenoid dimers represented by erythrophlesins A-D. Their structures were determined by analysis of extensive one- and two-dimensional NMR experiments and ESIMS methods. Cytotoxic activities of the isolated compounds were tested against HCT-8, Bel-7402, BGC-823, A549 and A2780 human cancer cell lines in the MTT test. Results showed that compounds 1 and 3-5 exhibited significantly selective cytotoxic activities (IC(50)<10 microM) against these cells, respectively. Copyright © 2010 Elsevier Ltd. All rights reserved.

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.

Antimicrobial and Cytotoxic Activity of Extracts of Ferula heuffelii Griseb. ex Heuff. and Its Metabolites.

PubMed

Pavlović, Ivan; Petrović, Silvana; Milenković, Marina; Stanojković, Tatjana; Nikolić, Dejan; Krunić, Aleksej; Niketić, Marjan

2015-10-01

The antimicrobial and cytotoxic activities of isolates (CHCl3 and MeOH extracts and selected metabolites) obtained from the underground parts of the Balkan endemic plant Ferula heuffelii Griseb. ex Heuff. were assessed. The CHCl3 and MeOH extracts exhibited moderate antimicrobial activity, being more pronounced against Gram-positive than Gram-negative bacteria, especially against Staphylococcus aureus (MIC=12.5 μg/ml for both extracts) and Micrococcus luteus (MIC=50 and 12.5 μg/ml, resp.). Among the tested metabolites, (6E)-1-(2,4-dihydroxyphenyl)-3,7,11-trimethyl-3-vinyldodeca-6,10-dien-1-one (2) and (2S*,3R*)-2-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-2,3-dihydro-7-hydroxy-2,3-dimethylfuro[3,2-c]coumarin (4) demonstrated the best antimicrobial activity. Compounds 2 and 4 both strongly inhibited the growth of M. luteus (MIC=11.2 and 5.2 μM, resp.) and Staphylococcus epidermidis (MIC=22.5 and 10.5 μM, resp.) and compound 2 additionally also the growth of Bacillus subtilis (MIC=11.2 μM). The cytotoxic activity of the isolates was tested against three human cancer cell lines, viz., cervical adenocarcinoma (HeLa), chronic myelogenous leukemia (K562), and breast cancer (MCF-7) cells. The CHCl3 extract exhibited strong cytotoxic activity against all cell lines (IC50 <11.0 μg/ml). All compounds strongly inhibited the growth of the K562 and HeLa cell lines. Compound 4 exhibited also a strong activity against the MCF-7 cell line, comparable to that of cisplatin (IC50 =22.32±1.32 vs. 18.67±0.75μM). Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity.

PubMed

Mojzych, Mariusz; Tarasiuk, Paweł; Kotwica-Mojzych, Katarzyna; Rafiq, Muhammad; Seo, Sung-Yum; Nicewicz, Michał; Fornal, Emilia

2017-12-01

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC 50 0.037, 0.044 and 0.042 μM, respectively, while IC 50 of thiourea is 20.9 μM.

Wightianines A-E, dihydro-β-agarofuran sesquiterpenes from Parnassia wightiana, and their antifungal and insecticidal activities.

PubMed

Wang, Dong-Mei; Zhang, Cheng-Chen; Zhang, Qiang; Shafiq, Nusrat; Pescitelli, Gennaro; Li, Deng-Wu; Gao, Jin-Ming

2014-07-16

Five new sesquiterpene polyol esters with a dihydro-β-agarofuran skeleton, designated as wightianines A-E (1-5), besides two known compounds, were isolated from the methanolic extract of the whole plant of the traditional herbal medicine Parnassia wightiana Wall. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses, including two-dimensional nuclear magnetic resonance techniques (correlation spectroscopy, heteronuclear multiple-quantum coherence, nuclear Overhauser effect spectrometry, and heteronuclear multiple-bond correlation) and electronic circular dichroism studies. The antifungal and insecticidal activities of five compounds were evaluated against several plant pathogenic fungi and armyworm larvae (Mythimna separata Walker). Among the test metabolites, compounds 2 and 7 both exhibited potent antifungal activity against the phytopathogenic fungus Cytospora sp. with minimum inhibitory concentration values of 0.78 μg/mL, which are equal to the two positive controls, hymexazol and carbendazim. However, no insecticidal activity of the test compounds was observed in the present study. Compounds 2 and 7 could be promising leads for developing new fungicides against agriculturally important fungus Cytospora sp.

The antiplasmodial agents of the stem bark of Entandrophragma angolense (Meliaceae).

PubMed

Bickii, Jean; Tchouya, Guy Raymond Feuya; Tchouankeu, Jean Claude; Tsamo, Etienne

2006-11-13

In the search of active principles from the stem bark of Entandrophragma angolense, we submitted the compounds isolated from the dichloromethane-methanol (1:1) extract of the stem bark to antimalarial test against chloroquine resistant strain W2 of Plasmodium falciparum malaria parasite. Only 7alpha-obacunyl acetate and a cycloartane derivative exhibited a good activity, with IC(50)s of 2 and 5.4 microg/ml respectively. Other compounds were moderately active.

Identification of B. anthracis N(5)-carboxyaminoimidazole ribonucleotide mutase (PurE) active site binding compounds via fragment library screening.

PubMed

Lei, Hao; Jones, Christopher; Zhu, Tian; Patel, Kavankumar; Wolf, Nina M; Fung, Leslie W-M; Lee, Hyun; Johnson, Michael E

2016-02-15

The de novo purine biosynthesis pathway is an attractive target for antibacterial drug design, and PurE from this pathway has been identified to be crucial for Bacillus anthracis survival in serum. In this study we adopted a fragment-based hit discovery approach, using three screening methods-saturation transfer difference nucleus magnetic resonance (STD-NMR), water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR, and surface plasmon resonance (SPR), against B. anthracis PurE (BaPurE) to identify active site binding fragments by initially testing 352 compounds in a Zenobia fragment library. Competition STD NMR with the BaPurE product effectively eliminated non-active site binding hits from the primary hits, selecting active site binders only. Binding affinities (dissociation constant, KD) of these compounds varied between 234 and 301μM. Based on test results from the Zenobia compounds, we subsequently developed and applied a streamlined fragment screening strategy to screen a much larger library consisting of 3000 computationally pre-selected fragments. Thirteen final fragment hits were confirmed to exhibit binding affinities varying from 14μM to 700μM, which were categorized into five different basic scaffolds. All thirteen fragment hits have ligand efficiencies higher than 0.30. We demonstrated that at least two fragments from two different scaffolds exhibit inhibitory activity against the BaPurE enzyme. Published by Elsevier Ltd.

Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors.

PubMed

Tashima, Toshihiko; Murata, Hiroaki; Kodama, Hidehiko

2014-07-15

Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man.

PubMed

Dragovic, Sanja; Vermeulen, Nico P E; Gerets, Helga H; Hewitt, Philip G; Ingelman-Sundberg, Magnus; Park, B Kevin; Juhila, Satu; Snoeys, Jan; Weaver, Richard J

2016-12-01

The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The 'MIP-DILI' project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.

Antibacterial and cytotoxic activities of naphthoquinone pigments from Onosma visianii Clem.

PubMed

Vukic, Milena D; Vukovic, Nenad L; Djelic, Gorica T; Popovic, Suzana Lj; Zaric, Milan M; Baskic, Dejan D; Krstic, Gordana B; Tesevic, Vele V; Kacaniova, Miroslava M

2017-01-01

In this study, the antibacterial and cytotoxic activities of isolated compounds from the roots of Onosma visianii were investigated. By using different chromatographic techniques and appropriate spectroscopic methods, the seven naphthoquinones were described: deoxyshikonin ( 1 ), isobutyrylshikonin ( 2 ), α-methylbutyrylshikonin ( 3 ), acetylshikonin ( 4 ), β-hydroxyisovalerylshikonin ( 5 ), 5,8- O -dimethyl isobutyrylshikonin ( 6 ) and 5,8- O -dimethyl deoxyshikonin ( 7 ). Among the tested compounds, 3 and 4 exhibited the highest antibacterial activities toward all tested bacterial species (MIC 50 and MIC 90 for gram positive bacteria: 6.40 μg/mL-12.79 μg/mL and 6.82 μg/mL-13.60 μg/mL, respectively; for gram negative bacteria: 4.27 μg/mL-8.53 μg/mL and 4.77 μg/mL-9.54 μg/mL, respectively). Also, naphthoquinones 3 and 4 exhibited strong cytotoxic activity against MDA-MB-231 cells (IC 50 values 86.0 μg/mL and 80.2 μg/mL, respectively), while compounds 1 , 3 , 4 and 5 significantly decreased viability of HCT116 cells (IC 50 values of 97.8 μg/mL, 15.2 μg/mL, 24.6 μg/mL and 30.9 μg/mL, respectively). Our results indicated that all tested naphthoquinone pigments are potential candidates for clinical uses as antibacterial and cytotoxic agents.

Antibacterial and cytotoxic activities of naphthoquinone pigments from Onosma visianii Clem

PubMed Central

Vukic, Milena D.; Vukovic, Nenad L.; Djelic, Gorica T.; Popovic, Suzana Lj.; Zaric, Milan M.; Baskic, Dejan D.; Krstic, Gordana B.; Tesevic, Vele V.; Kacaniova, Miroslava M.

2017-01-01

In this study, the antibacterial and cytotoxic activities of isolated compounds from the roots of Onosma visianii were investigated. By using different chromatographic techniques and appropriate spectroscopic methods, the seven naphthoquinones were described: deoxyshikonin (1), isobutyrylshikonin (2), α-methylbutyrylshikonin (3), acetylshikonin (4), β-hydroxyisovalerylshikonin (5), 5,8-O-dimethyl isobutyrylshikonin (6) and 5,8-O-dimethyl deoxyshikonin (7). Among the tested compounds, 3 and 4 exhibited the highest antibacterial activities toward all tested bacterial species (MIC50 and MIC90 for gram positive bacteria: 6.40 μg/mL-12.79 μg/mL and 6.82 μg/mL-13.60 μg/mL, respectively; for gram negative bacteria: 4.27 μg/mL-8.53 μg/mL and 4.77 μg/mL-9.54 μg/mL, respectively). Also, naphthoquinones 3 and 4 exhibited strong cytotoxic activity against MDA-MB-231 cells (IC50 values 86.0 μg/mL and 80.2 μg/mL, respectively), while compounds 1, 3, 4 and 5 significantly decreased viability of HCT116 cells (IC50 values of 97.8 μg/mL, 15.2 μg/mL, 24.6 μg/mL and 30.9 μg/mL, respectively). Our results indicated that all tested naphthoquinone pigments are potential candidates for clinical uses as antibacterial and cytotoxic agents. PMID:28435429

Optimization of the Caco-2 permeability assay to screen drug compounds for intestinal absorption and efflux.

PubMed

Press, Barry

2011-01-01

In vitro permeability assays are a valuable tool for scientists during lead compound optimization. As a majority of discovery projects are focused on the development of orally bioavailable drugs, correlation of in vitro permeability data to in vivo absorption results is critical for understanding the structural-physicochemical relationship (SPR) of drugs exhibiting low levels of absorption. For more than a decade, the Caco-2 screening assay has remained a popular, in vitro system to test compounds for both intestinal permeability and efflux liability. Despite advances in artificial membrane technology and in silico modeling systems, drug compounds still benefit from testing in cell-based epithelial monolayer assays for lead optimization. This chapter provides technical information for performing and optimizing the Caco-2 assay. In addition, techniques are discussed for dealing with some of the most pressing issues surrounding in vitro permeability assays (i.e., low aqueous solubility of test compounds and low postassay recovery). Insights are offered to help researchers avoid common pitfalls in the interpretation of in vitro permeability data, which can often lead to the perception of misleading results for correlation to in vivo data.

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis

PubMed Central

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50–555 nmol/ear. PMID:24734106

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis.

PubMed

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50-555 nmol/ear.

Biological Evaluation of Azomethine-dihydroquinazolinone Conjugates as Cancer and Cholinesterase Inhibitors.

PubMed

Iqbal, Jamshed; Saeed, Aamer; Shah, Syed J A; al-Rashida, Mariya; Shams-ul Mahmood

2016-01-01

In an attempt to discover novel anti-cancer agents and potent cholinesterase inhibitors, 11 azomethine-dihydroquinazolinone conjugates were evaluated against lung carcinoma cells and cholinesterases. Most of the compounds exhibited significant cytotoxicity at low micromolar concentrations and were less toxic to normal cells. After 24 h incubation period, 2i showed maximum cytotoxicity. The 4-bromine substituted compounds showed higher acetylcholinesterase (AChE) inhibitory activity than other screened compounds. The most active compound 2c, among the series, had an IC50 value 209.8 µM against AChE. The tested compounds showed less inhibition against butyrylcholinesterase. Molecular docking studies were performed in order to investigate the plausible binding modes of synthesized compounds. The compounds can be further optimized to treat cancer and Alzheimer's disease. These derivatives may open new pathways for introducing new therapies for curing cancer and senile dementia.

Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics.

PubMed

Kaczor, Agnieszka A; Silva, Andrea G; Loza, María I; Kolb, Peter; Castro, Marián; Poso, Antti

2016-04-05

Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of the Combined Addition of Y and Ti on the Second Phase and Mechanical Properties of China Low-Activation Martensitic Steel

NASA Astrophysics Data System (ADS)

Zhang, Yangpeng; Zhan, Dongping; Qi, Xiwei; Jiang, Zhouhua; Zhang, Huishu

2018-05-01

In this study, approximately 0.35% Ti and two different Y contents were added to China low-activation martensitic (CLAM) steel during melting in a vacuum induction melting furnace. Scanning electron microscopy, transmission electron microscopy, x-ray diffraction, tensile tests, and Charpy impact tests were used to investigate the effects of the combined addition of Y and Ti on the second phase and mechanical properties. The results indicated that Y and Fe formed the large intermetallic compound Fe-Y; the compound easily aggregated in the grain boundaries and exhibited the strength of CLAM steel. Ti did not combine with Y to form the Y-Ti-O phase; however, it could combine with Ta and W to form MC precipitates, which were generally in the 20-50 nm size range. The CLAM steel with a higher Y content exhibited lower yield and tensile strengths at room temperature, with both steels yielding almost identical strengths at 600 °C.

Effect of the Combined Addition of Y and Ti on the Second Phase and Mechanical Properties of China Low-Activation Martensitic Steel

NASA Astrophysics Data System (ADS)

Zhang, Yangpeng; Zhan, Dongping; Qi, Xiwei; Jiang, Zhouhua; Zhang, Huishu

2018-04-01

In this study, approximately 0.35% Ti and two different Y contents were added to China low-activation martensitic (CLAM) steel during melting in a vacuum induction melting furnace. Scanning electron microscopy, transmission electron microscopy, x-ray diffraction, tensile tests, and Charpy impact tests were used to investigate the effects of the combined addition of Y and Ti on the second phase and mechanical properties. The results indicated that Y and Fe formed the large intermetallic compound Fe-Y; the compound easily aggregated in the grain boundaries and exhibited the strength of CLAM steel. Ti did not combine with Y to form the Y-Ti-O phase; however, it could combine with Ta and W to form MC precipitates, which were generally in the 20-50 nm size range. The CLAM steel with a higher Y content exhibited lower yield and tensile strengths at room temperature, with both steels yielding almost identical strengths at 600 °C.

1-(substituted benzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidones: a series with stimulant and depressant activities.

PubMed

Ellis, K O; Schwan, T J; Wessels, F L; Miles, N J

1980-10-01

A series of 1-(substituted benzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidones was synthesized primarily by catalytic hydrogenation of the corresponding 1-(substituted benzyl)-2(1H)-pyrimidone. The pharmacological evaluation of these compounds in mice revealed a unique profile that included evidence of CNS stimulation and depression within the series and in the same compounds. Some members of this series induced signs of only CNS stimulation, some compounds caused signs of only CNS depression and skeletal muscle relaxation, and some caused signs of both stimulation and depression in the same animal. This apparent dual activity was assessed further in mice with antidepressant tests based on tetrabenazine antagonism and with antianxiety/anticonvulsant tests on the antagonism of a number of convulsants. The 4-chloro-, 4-fluoro-, 4-bromo-, and 3,4-dichlorobenzyl compounds exhibited antidepressant and antianxiety activities in the same dose range. Among these four compounds, the 3,4-dichlorobenzyl compound possessed the lowest antitetrabenazine (17 mg/kg po) and antipentylenetetrazol (23 mg/kg po) ED50 values. The 4-fluoro compound antagonized tetrabenazine-, pentylenetetrazol-, and isoniazid-induced tonic convulsions in the same dose range (congruent to 50 mg/kg po).

Design, chemical synthesis and biological evaluation of 3-spiromorpholinone/3-spirocarbamate androsterone derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 3.

PubMed

Djigoué, Guy Bertrand; Kenmogne, Lucie Carolle; Roy, Jenny; Maltais, René; Poirier, Donald

2015-09-01

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a key enzyme involved in the biosynthesis of testosterone and dihydrotestosterone. These hormones are known to stimulate androgen-dependent prostate cancer. In order to generate effective inhibitors of androgen biosynthesis without androgenic effect, we synthesized a new family of 3-spiromorpholinone and 3-spirocarbamate androsterone derivatives bearing diversified hydrophobic groups. We also tested their inhibitory activity in a microsomal fraction of 17β-HSD3-containing rat testes, and their androgenic effect on androgen-sensitive LAPC-4 cells. From our first structure-activity relationship (SAR) study, we noted that compound 7e inhibited 17β-HSD3 (77% at 0.1 μM) compared to our reference compound RM-532-105 (76% at 0.1 μM), but exhibited a residual androgenic effect. A library of 7e analogue compounds was next synthesized in order to generate compounds with reduced androgenic activity. In this new SAR study, the sulfonamide compound 7e21 and the carboxamide compound 7e22 inhibited 17β-HSD3 (IC50 = 28 and 88 nM, respectively). These two compounds were not androgenic and not cytotoxic even at the highest concentration tested, but their inhibitory activity decreased in intact LNCaP cells overexpressing 17β-HSD3 (LNCaP[17β-HSD3]). Structural modifications of these two lead compounds could however be tested to produce a second generation of 17β-HSD3 inhibitors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of a series of 2-substituted-5-thiopropylpiperazine (piperidine)-1,3,4-oxadiazoles derivatives as atypical antipsychotics.

PubMed

Chen, Yin; Xu, Xiangqing; Liu, Xin; Yu, Minquan; Liu, Bi-Feng; Zhang, Guisen

2012-01-01

It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2) and D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors with low affinity for the serotonin 5-HT(2C) and H(1) receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect. A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3) receptor, and low affinity for serotonin 5-HT(2C) and H(1) receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties. Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.

Semiconducting compounds and devices incorporating same

DOEpatents

Marks, Tobin J; Facchetti, Antonio; Boudreault, Pierre-Luc; Miyauchi, Hiroyuki

2014-06-17

Disclosed are molecular and polymeric compounds having desirable properties as semiconducting materials. Such compounds can exhibit desirable electronic properties and possess processing advantages including solution-processability and/or good stability. Organic transistor and photovoltaic devices incorporating the present compounds as the active layer exhibit good device performance.

Semiconducting compounds and devices incorporating same

DOEpatents

Marks, Tobin J.; Facchetti, Antonio; Boudreault, Pierre-Luc; Miyauchi, Hiroyuki

2016-01-19

Disclosed are molecular and polymeric compounds having desirable properties as semiconducting materials. Such compounds can exhibit desirable electronic properties and possess processing advantages including solution-processability and/or good stability. Organic transistor and photovoltaic devices incorporating the present compounds as the active layer exhibit good device performance.

Five New Guanacastane-Type Diterpenes from Cultures of the Fungus Psathyrella candolleana.

PubMed

Yin, Xia; Feng, Tao; Li, Zheng-Hui; Leng, Ying; Liu, Ji-Kai

2014-06-01

Five new guanacastane-type diterpenes, named guanacastepenes P-T (1-5), were isolated from cultures of the fungus Psathyrella candolleana. Their structures were elucidated on the basis of extensive spectroscopic methods. All of the compounds were tested for their 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitory activity. Compound 3 exhibited inhibitory activity against both human and mouse isozymes of 11β-HSD1 with IC50 values of 6.2 and 13.9 μM, respectively.

Sedative effect of galphimine B, a nor-seco-triterpenoid from Galphimia glauca.

PubMed

Tortoriello, J; Ortega, A

1993-10-01

Galphimia glauca Cav. (Malpighiaceae) is used in Mexican traditional medicine as a sedative in the treatment of mental disorders. Sedative properties of a methanolic extract of the aerial parts of this plant have been established in animal trials and an active compound, named galphimine B, has already been isolated. This compound was submitted to neuropharmacological testing, where it was shown that galphimine B had no significant effect as an anticonvulsant, while it exhibited a strong depressant activity on the nervous system.

Assessing the chemotaxis behavior of Physarum polycephalum to a range of simple volatile organic chemicals.

PubMed

de Lacy Costello, Ben P J; Adamatzky, Andrew I

2013-09-01

The chemotaxis behavior of the plasmodial stage of the true slime mold Physarum Polycephalum was assessed when given a binary choice between two volatile organic chemicals (VOCs) placed in its environment. All possible binary combinations were tested between 19 separate VOCs selected due to their prevalence and biological activity in common plant and insect species. The slime mold exhibited positive chemotaxis toward a number of VOCs with the following order of preference:   Farnesene > β-myrcene > tridecane > limonene > p-cymene > 3-octanone > β-pinene > m-cresol > benzylacetate > cis-3-hexenylacetate. For the remaining compounds, no positive chemotaxis was observed in any of the experiments, and for most compounds there was an inhibitory effect on the growth of the slime mold. By assessing this lack of growth or failure to propagate, it was possible to produce a list of compounds ranked in terms of their inhibitory effect: nonanal > benzaldehyde > methylbenzoate > linalool > methyl-p-benzoquinone > eugenol > benzyl alcohol > geraniol > 2-phenylethanol. This analysis shows a distinct preference of the slime mold for non-oxygenated terpene and terpene-like compounds (farnesene, β-myrcene, limonene, p-cymene and β-pinene). In contrast, terpene-based alcohols such as geraniol and linalool were found to have a strong inhibitory effect on the slime mold. Both the aldehydes utilized in this study had the strongest inhibitory effect on the slime mold of all the 19 VOCs tested. Interestingly, 3-octanone, which has a strong association with a "fungal odor," was the only compound with an oxygenated functionality where Physarum Polycephalum exhibits distinct positive chemotaxis.

Assessing the chemotaxis behavior of Physarum polycephalum to a range of simple volatile organic chemicals

PubMed Central

de Lacy Costello, Ben P.J.; Adamatzky, Andrew I.

2013-01-01

The chemotaxis behavior of the plasmodial stage of the true slime mold Physarum Polycephalum was assessed when given a binary choice between two volatile organic chemicals (VOCs) placed in its environment. All possible binary combinations were tested between 19 separate VOCs selected due to their prevalence and biological activity in common plant and insect species. The slime mold exhibited positive chemotaxis toward a number of VOCs with the following order of preference:   Farnesene > β-myrcene > tridecane > limonene > p-cymene > 3-octanone > β-pinene > m-cresol > benzylacetate > cis-3-hexenylacetate. For the remaining compounds, no positive chemotaxis was observed in any of the experiments, and for most compounds there was an inhibitory effect on the growth of the slime mold. By assessing this lack of growth or failure to propagate, it was possible to produce a list of compounds ranked in terms of their inhibitory effect: nonanal > benzaldehyde > methylbenzoate > linalool > methyl-p-benzoquinone > eugenol > benzyl alcohol > geraniol > 2-phenylethanol. This analysis shows a distinct preference of the slime mold for non-oxygenated terpene and terpene-like compounds (farnesene, β-myrcene, limonene, p-cymene and β-pinene). In contrast, terpene-based alcohols such as geraniol and linalool were found to have a strong inhibitory effect on the slime mold. Both the aldehydes utilized in this study had the strongest inhibitory effect on the slime mold of all the 19 VOCs tested. Interestingly, 3-octanone, which has a strong association with a “fungal odor,” was the only compound with an oxygenated functionality where Physarum Polycephalum exhibits distinct positive chemotaxis. PMID:24265848

Synthesis, crystal structure and larvicidal activity of novel diamide derivatives against Culex pipiens.

PubMed

Wu, Rui; Zhu, Cong; Du, Xiu-Jiang; Xiong, Li-Xia; Yu, Shu-Jing; Liu, Xing-Hai; Li, Zheng-Ming; Zhao, Wei-Guang

2012-09-11

Culex is an important mosquito as vectors for the transmission of serious diseases, such as filariasis, West Nile virus, dengue, yellow fever, chikungunya and other encephalitides. Nearly one billion people in the developing countries are at risk. In order to discover new bioactive molecules and pesticides acting on mosquito, we designed active amide structure and synthesized a series of novel diamide derivatives. A series of novel diamide derivatives were designed and synthesized. Their structures were characterized by 1 H NMR, FTIR and HRMS. The single crystal structure of compound 6n was determined to further elucidate the structure. Biological activities of these compounds were tested. Most of them exhibited higher mosquito larvicidal activity. Especially compound 6r displayed relatively good activity to reach 70% at 2 μg/mL. A practical synthetic route to amide derivatives by the reaction of amide with another acid is presented. This study suggests that the diamide derivatives exhibited good effective against mosquito.

Synthesis and Antihypertensive Screening of New Derivatives of Quinazolines Linked with Isoxazole

PubMed Central

Rahman, Mujeeb Ur; Rathore, Ankita; Siddiqui, Anees A.; Parveen, Gazala; Shahar Yar, M.

2014-01-01

A series of 7-substituted-3-(4-(3-(4-substitutedphenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-substituted quinazolin-4(3H)-one (1–30) have been synthesized by the cyclization of (E)-3-(4-(3-substitutedphenyl)acrylolyl)phenyl)-2-(substitutedphenyl)-7-substituted quinazolin-4-(3H)-one with hydroxylamine hydrochloride. The synthesized compounds were examined for their in vivo antihypertensive activity using albino rats. All the titled compounds exhibited good to moderate antihypertensive activity. Compounds 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5- dihydroisoxazol-5-yl)phenyl)-2-p-tolylquinazolin-4(3H)-one (23) and 7-Chloro-3-(4-(3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)phenyl)-2-(4-methoxyphenyl)quinazolin-4(3H)-one (24) exhibited potent antihypertensive activity through their anticipated α 1-adrenergic receptor blocking property similar to its clinically used analogue, prazosin, without affecting heart rate with prolonged duration of action when tested in adrenaline induced hypertension in anaesthetized rats. PMID:25013797

The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.

PubMed

Helgren, Travis R; Sciotti, Richard J; Lee, Patricia; Duffy, Sandra; Avery, Vicky M; Igbinoba, Osayawemwen; Akoto, Matthew; Hagen, Timothy J

2015-01-15

A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement. Copyright © 2014 Elqsevier Ltd. All rights reserved.

Homoisoflavanones with estrogenic activity from the rhizomes of Polygonatum sibiricum.

PubMed

Chen, Hui; Li, Yu-Jie; Li, Xiao-Fei; Sun, Yan-Jun; Li, Hong-Wei; Su, Fang-Yi; Cao, Yan-Gang; Zhang, Yan-Li; Zheng, Xiao-Ke; Feng, Wei-Sheng

2018-01-01

A new homoisoflavanone, (3R)-5-hydroxy-7-methoxyl-3-(2'-hydroxy-4'- methoxybenzyl)-chroman-4-one (1), together with six known analogs, were isolated from the rhizomes of Polygonatum sibiricum. Their structures were elucidated on the basis of extensive spectroscopic analysis. All compounds were tested for their estrogenic activity using the MCF-7 estrogenresponsive human breast cancer cell lines. At a dose of 0.1 μmol/L, compounds 1-7 exhibited significant proliferative effects on MCF-7 cells compared with E 2 . The molecular docking study results indicated that the activity of compounds 3, 5, 6, and 7 may be the binding with ERR.

Effects of alkanolamide loading on swelling, rheometric and tensile properties of chloroprene rubber compounds

NASA Astrophysics Data System (ADS)

Surya, I.; Ismail, H.

2018-02-01

The effects of Alkanolamide (ALK) addition on swelling, rheometric and tensile properties of unfilled chloroprene rubber (CR) compounds were investigated. The ALK was prepared from Refined Bleached Deodorized Palm Stearin and diethanolamine and -together with magnesium and zinc oxides- incorporated into the CR compounds. The ALK loadings were 0.5, 1.0, 1.5 and 2.0 phr. It was found that ALK enhanced the cure rate and torque difference of the CR compounds. ALK also enhanced the tensile modulus and tensile strength; especially up to a 1.5 phr loading. The swelling test proved that the 1.5 phr of ALK exhibited the highest degree of crosslink density which caused the highest in tensile modulus and tensile strength.

Antioxidant, anti-glycation and anti-inflammatory activities of phenolic constituents from Cordia sinensis.

PubMed

Al-Musayeib, Nawal; Perveen, Shagufta; Fatima, Itrat; Nasir, Muhammad; Hussain, Ajaz

2011-12-08

Nine compounds have been isolated from the ethyl acetate soluble fraction of C. sinensis, namely protocatechuic acid (1), trans-caffeic acid (2), methyl rosmarinate (3), rosmarinic acid (4), kaempferide-3-O-β-D-glucopyranoside (5), kaempferol-3-O-β-D-glucopyranoside (6), quercetin-3-O-β-D-glucopyranoside (7), kaempferide-3-O-α-L-rhamnopyranosyl (1→6)-β-D-glucopyranoside (8) and kaempferol-3-O-α-L-rhamno-pyranosyl (1→6)-β-D-glucopyranoside (9), all reported for the first time from this species. The structures of these compounds were deduced on the basis of spectroscopic studies, including 1D and 2D NMR techniques. Compounds 1-9 were investigated for biological activity and showed significant anti-inflammatory activity in the carrageen induced rat paw edema test. The antioxidant activities of isolated compounds 1-9 were evaluated by the DPPH radical scavenging test, and compounds 1, 2, 4 and 7-9 exhibited marked scavenging activity compared to the standard BHA. These compounds were further studied for their anti-glycation properties and some compounds showed significant anti-glycation inhibitory activity. The purity of compounds 2-5, 8 and 9 was confirmed by HPLC. The implications of these results for the chemotaxonomic studies of the genus Cordia have also been discussed.

Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer activity against breast cancer cell lines.

PubMed

Burra, Srinivas; Voora, Vani; Rao, Ch Prasad; Vijay Kumar, P; Kancha, Rama Krishna; David Krupadanam, G L

2017-09-15

Forskolin C 1 -isoxazole derivatives (3,5-regioisomers) (11a-e, 14, 15a-h and 15, 16a-g) were synthesized regioselectively by adopting 1,3-dipolar cycloadditions. These derivatives were tested using estrogen receptor positive breast cancer cell lines MCF-7 and BT-474. Majority of the compounds exhibited activity against the p53-positive MCF-7 breast cancer cells but not against the p53-negative BT-474 breast cancer cells. Among forskolin derivatives, compounds 11a, 11c, 14a, 14f, 14g, 14h, 15b, 16g and 17b exhibited higher anti-cancer activity against MCF-7 cell line with an IC 50 ≤1µM. The derivative 14f exhibited highest activity in both p53-positive (MCF-7) and p53-negative (BT-474) breast cancer cell lines with an IC 50 of 0.5µM. Copyright © 2017. Published by Elsevier Ltd.

Natural Organochlorines as Precursors of 3-Monochloropropanediol Esters in Vegetable Oils.

PubMed

Tiong, Soon Huat; Saparin, Norliza; Teh, Huey Fang; Ng, Theresa Lee Mei; Md Zain, Mohd Zairey Bin; Neoh, Bee Keat; Md Noor, Ahmadilfitri; Tan, Chin Ping; Lai, Oi Ming; Appleton, David Ross

2018-01-31

During high-temperature refining of vegetable oils, 3-monochloropropanediol (3-MCPD) esters, possible carcinogens, are formed from acylglycerol in the presence of a chlorine source. To investigate organochlorine compounds in vegetable oils as possible precursors for 3-MCPD esters, we tested crude palm, soybean, rapeseed, sunflower, corn, coconut, and olive oils for the presence of organochlorine compounds. Having found them in all vegetable oils tested, we focused subsequent study on oil palm products. Analysis of the chlorine isotope mass pattern exhibited in high-resolution mass spectrometry enabled organochlorine compound identification in crude palm oils as constituents of wax esters, fatty acid, diacylglycerols, and sphingolipids, which are produced endogenously in oil palm mesocarp throughout ripening. Analysis of thermal decomposition and changes during refining suggested that these naturally present organochlorine compounds in palm oils and perhaps in other vegetable oils are precursors of 3-MCPD esters. Enrichment and dose-response showed a linear relationship to 3-MCPD ester formation and indicated that the sphingolipid-based organochlorine compounds are the most active precursors of 3-MCPD esters.

In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes

PubMed Central

Al-Aboudi, Amal; Al-Qawasmeh, Raed A; Shahwan, Alaa; Mahmood, Uzma; Khalid, Asaad; Ul-Haq, Zaheer

2015-01-01

Aim: To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations. Methods: A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase (AChE) and (butyrylcholinesterase) BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software. Results: A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over AChE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data. Conclusion: The new adamantly derivatives selectively inhibit BChE with respect to AChE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer's disease. PMID:25937631

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.

Isoflavones from green vegetable soya beans and their antimicrobial and antioxidant activities.

PubMed

Wang, Taoyun; Liu, Yanli; Li, Xiaoran; Xu, Qiongming; Feng, Yulin; Yang, Shilin

2018-03-01

Green vegetable soya beans, known as Maodou in China, are supplied as vegetable-type fruits of the soybean plant. Previous study indicated that green vegetable soya beans exhibited antioxidative and anti-inflammatory activities. However, the material basis and pharmacological activities of green soybean plant were not unravelled clearly. In this study, we investigated the chemical ingredients and their pharmacological activities. Investigation of the chemical ingredients indicated that two new isoflavones, 2'-hydroxyerythrin A (1), and daidzein-7-O-β-d-{6″-[(E)-but-2-enoyl]}glycoside (2), together with seven known ones - 7,4'-dihydroxy-6-methoxyisoflavone (3), daidzein (4), daidzin (5), genistein (6), formononetin (7), ononin (8), and isoerythrinin A (9) - were obtained. The structures of compounds 1-9 were elucidated on the basis of spectroscopic and chemical analysis. We evaluated the antimicrobial efficacies and free-radical scavenging potential of the isolated compounds (1-9). Compounds 1 and 9 exhibited the most pronounced efficacy against the tested bacterial strains with IC 50 values ranging from 10.6 to 22.6 μg mL -1 . The isolated compounds showed moderate radical scavenging properties with compound 6 being the most active, followed by compounds 3, 1 and 4. This study indicated that the isoflavones from soya beans could be considered as potential antioxidants or antimicrobials in the food, cosmetics and pharmaceutical industries. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Antihypertensive effect of caffeic acid and its analogs through dual renin-angiotensin-aldosterone system inhibition.

PubMed

Bhullar, Khushwant S; Lassalle-Claux, Grégoire; Touaibia, Mohamed; Rupasinghe, H P Vasantha

2014-05-05

Hypertension is a crucial risk factor for cardiovascular diseases and contributes to one third of global mortality. In addition to conventional antihypertensive drugs such as captopril, naturally occurring phytochemicals and their analogs are used for reducing the risk and occurrence of hypertension. Herein, we demonstrate the possible use of caffeic acid and its derivatives in the treatment of hypertension through multi-target modulation of renin-angiotensin-aldosterone system (RAAS). Caffeic acid along with its nineteen novel derivatives, chlorogenic acid, quercetin and captopril were all investigated for the inhibition of renin and angiotensin converting enzyme (ACE) activities and production of aldosterone. Compound 22 with CH2CH(Ph)2 moiety exhibited the strongest renin inhibition (IC50=229µM) among all compounds tested (P≤0.05). Caffeic acid was the weakest renin inhibitor (IC50=5704µM) among all the compounds assayed. Similar to renin inhibition, compound 22 (IC50=9.1µM) also exhibited about 47 times stronger ACE inhibition compared to the parent compound. Analysis of aldosterone revealed that compound 8 with n-Pr moiety was the strongest modulator of aldosterone production among all the derivatives (P≤0.05). Toxicity analysis using human fibroblasts (WI-38 cells) confirmed the non-toxic manifestations of caffeic acid and its derivatives in comparison to clinically used drug captopril. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthesis, Structural Characterization and Antinociceptive Activities of New Arylated Quinolines via Suzuki-Miyaura Cross Coupling Reaction.

PubMed

Ullah, Malik A; Adeel, Muhammad; Tahir, Muhammad N; Rauf, Abdur; Akram, Muhammad; Hadda, Taibi B; Mabkhot, Yahia N; Muhammad, Naveed; Naseer, Fehmida; Mubarak, Mohammad S

2017-01-01

The quinoline ring system is one of the most commonly encountered heterocycles in medicinal chemistry, due to the pharmaceutical and medicinal uses of derivatives containing this ring. These quinoline-based compounds have remarkable biological activity, as they are employed as antimalarial, antibacterial, antifungal, and antitumor agents. The quinoline nucleus can be synthesized by various traditional methods such as the Skraup reaction, Friedlaender synthesis, Combes quinoline synthesis, Larock quinoline synthesis, among others. The aim of the present work is to synthesize a number of new arylated quninolines having significant antinoceciptive effect through the Suzuki-Miyaura cross coupling reaction using 3- bromoquinoline as a starting material. A number of new quinoline derivatives have been synthesized. Structures of the newly synthesized compounds were confirmed by means of IR, NMR, and mass spectrometry, and by elemental analysis. In addition, the molecular structures of two representative derivatives were determined with the aid of X-ray crystallography. Additionally, the antinociceptive activity of the prepared compounds was evaluated in vivo; results revealed that most of the tested compounds exhibited a dosedependent antinociceptive effect. Prepared compounds were found to exhibit significant antinociceptive activities and could be used as potential analgesic agents. Further work, however, may be required to establish the safety and efficacy of these compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Balancing Antioxidant, Hypolipidemic and Anti-inflammatory Activity in a Single Agent: The Example of 2-Hydroxy-2-Substituted Morpholine, 1,4-Benzoxazine and 1,4-Benzothiazine Derivatives as a Rational Therapeutic Approach against Atherosclerosis.

PubMed

Matralis, Alexios N; Bavavea, Eugenia-Ismini; Incerpi, Sandra; Pedersen, Jens Z; Kourounakis, Angeliki P

2017-01-01

In line with our previous studies, novel morpholine and benzoxa(or thia)zine lead compounds have been developed through a rational design that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) intercept and scavenge free radicals, b) inhibit the metal ion (Cu2+)- induced LDL oxidation c) act intracellularly as antioxidants in THP-1 monocytes from a leukemic patient and d) inhibit the pro-inflammatory enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2) in vitro. Furthermore, two representative compounds were tested for their potential to decrease lipidemic parameters (TC, LDL and TG) in hyperlipidemic mice. Most derivatives indicated a remarkable antioxidant activity, while at the same time exhibited a significant in vitro anti-inflammatory activity, inhibiting COX-1 or/and COX-2 activity at 20 μΜ. In addition, after their long-term administration, compounds 6 and 8 afforded considerable activity in a chronic experimental animal model of hyperlipidemia (after high fat diet administration). The multifunctional pharmacological profile exhibited by the compounds of this study renders them interesting lead compounds for the development of novel agents against atherosclerosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Detection of phytoconstituents in column fractions of n-hexane extract of Goldcrest honey exhibiting anti-Helicobacter pylori activity.

PubMed

Manyi-Loh, Christy E; Clarke, Anna M; Ndip, Roland N

2012-04-01

Alternative therapy for Helicobacter pylori eradication from natural products is gaining much attention. This study sought to isolate and characterize the fraction responsible for the antibacterial activity in Goldcrest (GC) n-hexane extract. Thin-layer chromatography (TLC) of the extract was carried out on Silica gel plates to determine the presence of chemical compounds, which were separated and partially purified by column chromatography. The obtained fractions GCCL, GCF2, GCF3 and GCF4 were tested for anti-H. pylori activity using the broth microdilution method. Volatile compounds in the active fractions were identified by gas chromatography-mass spectrometry (GC-MS) analysis. MINITAB was used for statistical analysis at 95% confidence interval. The best antibacterial activity was exhibited by GCF3 (5 mg/mL), which was composed of many compounds with known antimicrobial and antioxidant properties. A total of 16 volatile compounds were identified from fractions GCF2, GCF3 and GCF4 into the following families; alcohol, ketone, aliphatic acid, benzene compound, hydrocarbon, furan and pyran derivatives. The demonstration of antibacterial activity by the column fractions of GC n-hexane extract may provide new lead molecules that could serve as selective agents for H. pylori chemotherapy and control. Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.

Antifungal activity against plant pathogens of metabolites from the endophytic fungus Cladosporium cladosporioides.

PubMed

Wang, Xiaoning; Radwan, Mohamed M; Taráwneh, Amer H; Gao, Jiangtao; Wedge, David E; Rosa, Luiz H; Cutler, Horace G; Cutler, Stephen J

2013-05-15

Bioassay-guided fractionation of Cladosporium cladosporioides (Fresen.) de Vries extracts led to the isolation of four compounds, including cladosporin, 1; isocladosporin, 2; 5'-hydroxyasperentin, 3; and cladosporin-8-methyl ether, 4. An additional compound, 5',6-diacetylcladosporin, 5, was synthesized by acetylation of compound 3. Compounds 1-5 were evaluated for antifungal activity against plant pathogens. Phomopsis viticola was the most sensitive fungus to the tested compounds. At 30 μM, compound 1 exhibited 92.7, 90.1, 95.4, and 79.9% growth inhibition against Colletotrichum acutatum , Colletotrichum fragariae , Colletotrichum gloeosporioides , and P. viticola, respectively. Compound 2 showed 50.4, 60.2, and 83.0% growth inhibition at 30 μM against Co. fragariae, Co. gloeosporioides, and P. viticola, respectively. Compounds 3 and 4 were isolated for the first time from Cl. cladosporioides. Moreover, the identification of essential structural features of the cladosporin nuclei has also been evaluated. These structures provide new templates for the potential treatment and management of plant diseases.

Antifungal Activity Against Plant Pathogens of Metabolites from the Endophytic Fungus Cladosporium cladosporioides

PubMed Central

Wang, Xiaoning; Radwan, Mohamed M.; Taráwneh, Amer H.; Gao, Jiangtao; Wedge, David E.; Rosa, Luiz H.; Cutler, Horace G.; Cutler, Stephen J.

2013-01-01

Bioassay-guided fractionation of Cladosporium cladosporioides (Fresen.) de Vries extracts led to the isolation of four compounds, including cladosporin, 1, isocladosporin, 2, 5′-hydroxyasperentin, 3, and cladosporin-8-methyl ether, 4. An additional compound 5′,6-diacetyl cladosporin, 5, was synthesized by acetylation of compound 3. Compounds 1-5 were evaluated for antifungal activity against plant pathogens. Phomopsis viticola was the most sensitive fungus to the tested compounds. At 30 μM, compound 1 exhibited 92.7%, 90.1%, 95.4% and 79.9% growth inhibition against Colletotrichum acutatum, Co. fragariae, Co. gloeosporioides and Phomopsis viticola, respectively. Compound 2 showed 50.4%, 60.2% and 83.0% growth inhibition at 30 μM against Co. fragariae, Co. gloeosporioides and P. viticola, respectively. Compounds 3 and 4 were isolated for the first time from Cladosporium cladosporioides. Moreover, the identification of essential structural features of the cladosporin nuclei has also been evaluated. These structures provide new templates for the potential treatment and management of plant diseases. PMID:23651409

THE FUNCTIONAL AND STRUCTURAL OBSERVATIONS OF THE NEONATAL REPRODUCTIVE SYSTEM OF ALLIGATORS EXPOSED IN OVO TO ATRAZINE, 2,4-D, OR ESTRADIOL.

EPA Science Inventory

Wild alligators exposed to persistent organochlorine contaminants, municipal waste compounds, and contemporary-use herbicides exhibit reproductive alterations that are thought to be caused by endocrine disruption. This study tests the hypothesis that these alterations, at least i...

Lethal and sublethal effects of marine sediment extracts on fish cells and chromosomes

NASA Astrophysics Data System (ADS)

Landolt, Marsha L.; Kocan, Richard M.

1984-03-01

The cost of conducting conventional chronic bioassays with every potentially toxic compound found in marine ecosystems is prohibitive; therefore short-term toxicity tests which can be used for rapid screening were developed. The tests employ cultured fish cells to measure lethal, sublethal or genotoxic effects of pure compounds and complex mixtures. The sensitivity of these tests has been proven under laboratory conditions; the following study used two of these tests, the anaphase aberration test and a cytotoxicity assay, under field conditions. Sediment was collected from 97 stations within Puget Sound, Washington. Serial washings of the sediment in methanol and dichloromethane yielded an organic extract which was dried, dissolved in DMSO and incubated as a series of dilutions with rainbow trout gonad (RTG-2) cells. The toxic effects of the extract were measured by examining the rate of cell proliferation and the percentage of damaged anaphase figures. Anaphase figures were considered to be abnormal if they exhibited non-disjunctions, chromosome fragments, or chromosome bridges. A second cell line (bluegill fry, BF-2) was also tested for cell proliferation and was included because, unlike the RTG-2 cell line, it contains little or no mixed function oxygenase activity. Of 97 stations tested, 35 showed no genotoxic activity, 42 showed high genotoxic activity (P≤.01) and the remainder were intermediate. Among the toxic sites were several deep water stations adjacent to municipal sewage outfalls and four urban waterways contaminated by industrial and municipal effluents. Extracts from areas that showed genotoxic effects also inhibited cell proliferation and were cytotoxic to RTG-2 cells. Few effects were noted in the MFO deficient BF-2 cells. Short term in vitro tests provide aquatic toxicologists with a versatile and cost effective tool for screening complex environments. Through these tests one can identify compounds or geographic regions that exhibit high cytotoxic or genotoxic potential.

Evaluation of the specificity and effectiveness of selected oral hygiene actives in salivary biofilm microcosms.

PubMed

Ledder, Ruth G; Sreenivasan, Prem K; DeVizio, William; McBain, Andrew J

2010-12-01

The microbiological effects of biocidal products used for the enhancement of oral hygiene relate to the active compound(s) as well as other formulation components. Here, we test the specificities of selected actives in the absence of multiple excipients. Salivary ecosystems were maintained in tissue culture plate-based hydroxyapatite disc models (HDMs) and modified drip-flow biofilm reactors (MDFRs). Test compounds stannous fluoride (SF), SDS, triclosan (TCS), zinc lactate (ZL) and ZL with SF in combination (ZLSF) were delivered to the HDMs once and four times daily for 6 days to MDFRs. Plaques were characterized by differential viable counting and PCR-denaturing gradient gel electrophoresis (DGGE). TCS and SDS were the most effective compounds against HDM plaques, significantly reducing total viable counts (P<0.05), whilst SF, ZL and ZLSF were comparatively ineffective. TCS exhibited specificity for streptococci (P<0.01) and Gram-negative anaerobes (P<0.01) following a single dosing and also on repeated dosing in MDFRs. In contrast to single exposures, multiple dosing with ZLSF also significantly reduced all bacterial groups, whilst SF and ZL caused significant but transient reductions. According to PCR-DGGE analyses, significant (P<0.05) reductions in eubacterial diversity occurred following 6 day dosing with both TCS and ZLSF. Concordance of MDFR eubacterial profiles with salivary inocula ranged between 58 and 97%. TCS and ZL(SF) exhibited similar specificities to those reported for formulations. TCS was the most potent antibacterial, after single and multiple dosage regimens.

Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M.

PubMed

Dallanoce, C; Conti, P; De Amici, M; De Micheli, C; Barocelli, E; Chiavarini, M; Ballabeni, V; Bertoni, S; Impicciatore, M

1999-08-01

Two subseries of nonquaternized (5a-10a) and quaternized derivatives (5b-10b) related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compounds was estimated in three classical in vitro functional assays: M1 rabbit vas deferens, M2 guinea pig left atrium and M3 guinea pig ileum. In addition, the occurrence of central muscarinic effects was evaluated as tremorigenic activity after intraperitoneal administration in mice. In in vitro tests a nonselective muscarinic activity was exhibited by all the derivatives with potencies values that, in some instances, surpassed those of the reference compounds (i.e. 8b). Functional selectivity was evidenced only for the oxotremorine-like derivative 9a, which behaved as a mixed M3-agonist/M1-antagonist (pD2 = 5.85; pA2 = 4.76, respectively). In in vivo tests non-quaternary compounds were able to evoke central muscarinic effects, with a potency order parallel to that observed in vitro.

Influence of Culturing Conditions on Bioprospecting and the Antimicrobial Potential of Endophytic Fungi from Schinus terebinthifolius.

PubMed

Tonial, Fabiana; Maia, Beatriz H L N S; Gomes-Figueiredo, Josiane A; Sobottka, Andrea M; Bertol, Charise D; Nepel, Angelita; Savi, Daiani C; Vicente, Vânia A; Gomes, Renata R; Glienke, Chirlei

2016-02-01

In this study, we analyzed the antimicrobial activity of extracts harvested from 17 endophytic fungi isolated from the medicinal plant Schinus terebinthifolius. Morphological and molecular analyses indicated that these fungal species belonged to the genera Alternaria, Bjerkandera, Colletotrichum, Diaporthe, Penicillium, and Xylaria. Of the endophytes analyzed, 64.7 % produced antimicrobial compounds under at least one of the fermentation conditions tested. Nine isolates produced compounds that inhibited growth of Staphylococcus aureus, four produced compounds that inhibited Candida albicans, and two that inhibited Pseudomonas aeruginosa. The fermentation conditions of the following endophytes were optimized: Alternaria sp. Sect. Alternata-LGMF626, Xylaria sp.-LGMF673, and Bjerkandera sp.-LGMF713. Specifically, the carbon and nitrogen sources, initial pH, temperature, and length of incubation were varied. In general, production of antimicrobial compounds was greatest when galactose was used as a carbon source, and acidification of the growth medium enhanced the production of compounds that inhibited C. albicans. Upon large-scale fermentation, Alternaria sp. Sect. Alternata-LGMF626 produced an extract containing two fractions that were active against methicillin-resistant S. aureus. One of the extracts exhibited high activity (minimum inhibitory concentration of 18.52 µg/mL), and the other exhibited moderate activity (minimum inhibitory concentration of 55.55 µg/mL). The compounds E-2-hexyl-cinnamaldehyde and two compounds of the pyrrolopyrazine alkaloids class were identified in the active fractions by gas chromatography-mass spectrometry.

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds.

PubMed

Rangel-Barajas, Claudia; Malik, Maninder; Mach, Robert H; Luedtke, Robert R

2015-06-01

We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity. Copyright © 2015. Published by Elsevier Ltd.

Synthesis, biological evaluation and molecular modeling of GW 501516 analogues.

PubMed

Ciocoiu, Calin C; Ravna, Aina W; Sylte, Ingebrigt; Hansen, Trond Vidar

2010-11-01

Eleven analogues of GW 501516 (1) were prepared and subjected to biological testing in a semi-high throughput human skeletal muscle cell assay. The assay testing indicated that all analogues elicited oxidation of oleic acid. Among the most potent agonists, 2e (2-{2-ethyl-4-[(4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl)methylthio]phenoxy}-2-methylpropanoic acid), was also subjected to a luciferase-based transfection assay, which showed that this compound is a potent agonist against PPARδ and a moderate agonist against PPARα. Docking of compound 2e into PPARδ revealed that it occupied the agonist binding site and exhibited key hydrogen bonding interactions with His323, His449, and Tyr473.

Rodent-repellent studies. III. Advanced studies in the evaluation of chemical repellents

USGS Publications Warehouse

Bellack, E.; DeWitt, J.B.

1949-01-01

In order to bridge the gap between preliminary screening of chemicals for potential rodent repellency and the application ofthese compounds to paper cartons, more advanced studies in the evaluation ofpromising materials have been carried out. These studies have resulted in: (1) a modification of the food acceptance technique which eliminates doubtful compounds and also provides a closer analogy to the ultimate goal, and (2) a method for rapidly testing chemicals incorporated in paper. When the results of these latter tests are expressed as a function of time, it can be shown that a distinct correlation exists between the deterrency exhibited by treated paper and the repellency of treated food.

Differential agonist and inverse agonist profile of antipsychotics at D2L receptors coupled to GIRK potassium channels.

PubMed

Heusler, Peter; Newman-Tancredi, Adrian; Castro-Fernandez, Annabelle; Cussac, Didier

2007-03-01

The D(2) dopaminergic receptor represents a major target of antipsychotic drugs. Using the coupling of the human D(2long) (hD(2L)) receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus laevis oocytes, we examined the activity of antipsychotic agents of different classes - typical, atypical, and a "new generation" of compounds, exhibiting a preferential D(2) and 5-HT(1A) receptor profile. When the hD(2L) receptor was coexpressed with GIRK channels, a series of reference compounds exhibited full agonist (dopamine, and quinpirole), partial agonist (apomorphine, (-)3-PPP, and (+)-UH232) or inverse agonist (raclopride, and L741626) properties. Sarizotan exhibited only very weak partial agonist action. At higher levels of receptor cRNA injected per oocyte, both partial agonist activity and inverse agonist properties were generally more pronounced. The inverse agonist action of L741626 was reversed by interaction with sarizotan, thus confirming the constitutive activity of wild-type hD(2L) receptors in the oocyte expression system. When antipsychotic agents were tested for their actions at the hD(2L) receptor, typical (haloperidol) as well as atypical (nemonapride, ziprasidone, and clozapine) compounds acted as inverse agonists. In contrast, among D(2)/5-HT(1A) antipsychotics, only SLV313 and F15063 behaved as inverse agonists, whilst the other members of this group (bifeprunox, SSR181507 and the recently marketed antipsychotic, aripiprazole) exhibited partial agonist properties. Thus, the X. laevis oocyte expression system highlights markedly different activity of antipsychotics at the hD(2L) receptor. These differential properties may translate to distinct therapeutic potential of these compounds.

Synthesis and properties of 4-alkoxy-2-[2-hydroxy-3-(4-o,m,p-halogenoaryl-1 -piperazinyl)propyl]-6-methyl-1H-pyrrolo-[3,4-c]pyridine-1,3(2H)-diones with analgesic and sedative activities.

PubMed

Sladowska, Helena; Sabiniarz, Aleksandra; Szkatuła, Dominika; Filipek, Barbara; Sapa, Jacek

2006-01-01

Synthesis of N-substituted derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (17-26) is described. The chlorides, containing OH group, used in the above synthesis can exist in two isomeric forms: chain (12, 14-16) and cyclic (12a, 14a-16a). All final imides studied exhibited analgesic activity in the "writhing syndrome" test which was superior than that of acetylsalicylic acid. In the "hot plate" test only two compounds (19, 20) were active as antinociceptive agents. Furthermore, all compounds tested significantly suppressed the spontaneous locomotor activity of mice.

Identification of flavonoids and flavonoid rhamnosides from Rhododendron mucronulatum for. albiflorum and their inhibitory activities against aldose reductase.

PubMed

Mok, So-Youn; Lee, Sanghyun

2013-01-15

To investigate the therapeutic potential of compounds from natural sources, Rhododendron mucronulatum for. albiflorum flowers (RMAF) and R. mucronulatum flowers (RMF) were tested for inhibition of aldose reductase (AR). The methanol extracts of RMAF and RMF exhibited AR inhibitory activities (IC(50) values 1.07 and 1.29 μg/mL, respectively). The stepwise polarity fractions of RMAF were tested for in vitro inhibition of AR from rat lenses. Of these, the ethyl acetate (EtOAc) fraction exhibited AR inhibitory activity (IC(50) 0.15 μg/mL). A chromatography of the active EtOAc fraction of RMAF led to the isolation of six flavonoids, which were identified by spectroscopic analysis as kaempferol (1), afzelin (2), quercetin (3), quercitrin (4), myricetin (5) and myricitrin (6). Compounds 1-6 exhibited high AR inhibitory activity, with IC(50) values of 0.79, 0.31, 0.48, 0.13, 11.92 and 2.67 μg/mL, respectively. HPLC/UV analysis revealed that the major flavonoids of RMAF and RMF are quercitrin (4) and myricitrin (6). Our results suggest that RMAF containing these six flavonoids could be a useful natural source in the development of a novel AR inhibitory agent against diabetic complications. Copyright © 2012 Elsevier Ltd. All rights reserved.

Fluorescent polymer sensor array for detection and discrimination of explosives in water.

PubMed

Woodka, Marc D; Schnee, Vincent P; Polcha, Michael P

2010-12-01

A fluorescent polymer sensor array (FPSA) was made from commercially available fluorescent polymers coated onto glass beads and was tested to assess the ability of the array to discriminate between different analytes in aqueous solution. The array was challenged with exposures to 17 different analytes, including the explosives trinitrotoluene (TNT), tetryl, and RDX, various explosive-related compounds (ERCs), and nonexplosive electron-withdrawing compounds (EWCs). The array exhibited a natural selectivity toward EWCs, while the non-electron-withdrawing explosive 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) produced no response. Response signatures were visualized by principal component analysis (PCA), and classified by linear discriminant analysis (LDA). RDX produced the same response signature as the sampled blanks and was classified accordingly. The array exhibited excellent discrimination toward all other compounds, with the exception of the isomers of nitrotoluene and aminodinitrotoluene. Of particular note was the ability of the array to discriminate between the three isomers of dinitrobenzene. The natural selectivity of the FPSA toward EWCs, plus the ability of the FPSA to discriminate between different EWCs, could be used to design a sensor with a low false alarm rate and an excellent ability to discriminate between explosives and explosive-related compounds.

Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

NASA Astrophysics Data System (ADS)

Yang, Yang; Ang, Wei; Long, Haiyue; Chang, Ying; Li, Zicheng; Zhou, Liangxue; Yang, Tao; Deng, Yong; Luo, Youfu

2016-10-01

A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.

Synthesis, characterization, X-ray crystal structures of heterocyclic Schiff base compounds and in vitro cholinesterase inhibition and anticancer activity

NASA Astrophysics Data System (ADS)

Arafath, Md. Azharul; Adam, Farook; Al-Suede, Fouad Saleih R.; Razali, Mohd R.; Ahamed, Mohamed B. Khadeer; Abdul Majid, Amin Malik Shah; Hassan, Mohd Zaheen; Osman, Hasnah; Abubakar, Saifullah

2017-12-01

Four heterocyclic embedded Schiff base derivatives (1-4) were synthesized and characterized by melting point, elemental analysis, FTIR, 1H, 13C NMR, UV-Visible spectral data. The structures of compounds 1, 2 and 4 were successfully established through single crystal X-ray diffraction analysis. In vitro cholinesterase inhibition assays showed that the cyclized derivative 1 displayed higher BuChE enzyme inhibitory activity with IC50 value of 1.45 ± 0.09 μM. The anti-proliferative efficacies of the compounds were also evaluated using human colorectal HCT 116 and breast MCF-7 adenocarcinoma cell lines. In addition, a human normal endothelial cell line (Ea.hy926) was also tested to assess the safety and selectivity of the compounds towards normal and cancer cells, respectively. Among the compounds tested, compound 2 displayed potent cytotoxic effect (IC50 = 34 μM) against HCT 116 cells with highest selectivity index of 3.1 with respect to the normal endothelial cells. Whereas, compound 4 exhibited significant anti-proliferative effect (IC50 = 21.1 μM) against MCF-7 cells with highest selectivity index of 3.3 with respect to the normal endothelial cells. The docking result of these compounds against hAChE showed potent activities with different binding modes. These compounds could be a promising pharmacological agent to treat cancer and Alzheimer's disease.

Isolation and Characterization of “Terrein” an Antimicrobial and Antitumor Compound from Endophytic Fungus Aspergillus terreus (JAS-2) Associated from Achyranthus aspera Varanasi, India

PubMed Central

Goutam, Jyoti; Sharma, Gunjan; Tiwari, Vinod K.; Mishra, Amrita; Kharwar, Ravindra N.; Ramaraj, Vijayakumar; Koch, Biplob

2017-01-01

The present study aimed at characterizing biological potentials of endophyte Aspergillus terreus JAS-2 isolated from Achyranthus aspera. Crude extracted from endophytic fungus JAS-2 was purified and chemically characterized by chromatographic and spectroscopic studies respectively. Spectral assignment of NMR (nuclear magnetic resonance) data, 1H proton and 13C carbon analysis along with FTIR data elucidated the structure of compound as 4,5-Dihydroxy-3-(1-propenyl)-2-cyclopenten-1-one. After purification and identification a set of experiment was conducted to explore efficacy of compound. Results revealed that on accessing the antifungal activity of compound, growth diameter of tested phytopathogenic fungi was reduced to 50% at higher concentration taken (10 μgμl−1). Compound exhibited in-vitro bacterial cell inhibition at 20 μgml−1 concentration along with moderate antioxidant behavior. Evaluation of anticancer activity against human lung cancer cell line (A-549) exhibited its IC50 value to be 121.9 ± 4.821 μgml−1. Further cell cycle phase distribution were analyzed on the basis of DNA content and evaluated by FACS (Fluorescence Activated Cell Sorting) and it was revealed that at 150 μgml−1 of compound maximum cells were found in sub G1 phase which represents apoptotic dead cells. Terrein (4, 5-Dihydroxy-3-(1-propenyl)-2-cyclopenten-1-one) a multi-potential was isolated from endophytic fungus JAS-2, from well recognized medicinal herb A. aspera. To best of our knowledge, this is the first report of “Terrein” from endophytic derived fungus. This compound had also exhibited anticancer and antifungal activity against human lung cancer cell line A-549 and Bipolaris sorokiniana respectively which is causal organism of many plants disease. Hence endophytes are serving as alternative sources of drug molecules. PMID:28790982

Evaluation of the Allelopathic Potential of Leaf, Stem, and Root Extracts of Ocotea pulchella Nees et Mart.

PubMed

Candido, Lafayette P; Varela, Rosa M; Torres, Ascensión; Molinillo, José M G; Gualtieri, Sonia C J; Macías, Francisco A

2016-08-01

Despite the increase in recent decades in herbicide research on the potential of native plants, current knowledge is considered to be low. Very few studies have been carried out on the chemical profile or the biological activity of the Brazilian savanna (Cerrado) species. In the study reported here, the allelopathic activity of AcOEt and MeOH extracts of leaves, stems, and roots from Ocotea pulchella Nees was evaluated. The extracts were assayed on etiolated wheat coleoptiles. The AcOEt leaf extract was the most active and this was tested on standard target species (STS). Lycopersicon esculentum and Lactuca sativa were the most sensitive species in this test. A total of eleven compounds have been isolated and characterized. Compounds 1, 2, 4, and 6 have not been identified previously from O. pulchella and ocoteol (9) is reported for the first time in the literature. Eight compounds were tested on wheat coleoptile growth, and spathulenol, benzyl salicylate, and benzyl benzoate showed the highest activities. These compounds showed inhibitory activity on L. esculentum. The values obtained correspond to the activity exhibited by the extract and these compounds may therefore be responsible for the allelopathic activity shown by O. pulchella. © 2016 Wiley-VHCA AG, Zürich.

Antibacterial Evaluation of Synthetic Thiazole Compounds In Vitro and In Vivo in a Methicillin-Resistant Staphylococcus aureus (MRSA) Skin Infection Mouse Model.

PubMed

Mohammad, Haroon; Cushman, Mark; Seleem, Mohamed N

2015-01-01

The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), including strains resistant to current antibiotics, has contributed to an increase in the number of skin infections reported in humans in recent years. New therapeutic options are needed to counter this public health challenge. The aim of the present study was to examine the potential of thiazole compounds synthesized by our research group to be used topically to treat MRSA skin and wound infections. The broth microdilution method confirmed that the lead thiazole compound and four analogues are capable of inhibiting MRSA growth at concentrations as low as 1.3 μg/mL. Additionally, three compounds exhibited a synergistic relationship when combined with the topical antibiotic mupirocin against MRSA in vitro via the checkerboard assay. Thus the thiazole compounds have potential to be used alone or in combination with mupirocin against MRSA. When tested against human keratinocytes, four derivatives of the lead compound demonstrated an improved toxicity profile (were found to be non-toxic up to a concentration of 20 μg/mL). Utilizing a murine skin infection model, we confirmed that the lead compound and three analogues exhibited potent antimicrobial activity in vivo, with similar capability as the antibiotic mupirocin, as they reduced the burden of MRSA present in skin wounds by more than 90%. Taken altogether, the present study provides important evidence that these thiazole compounds warrant further investigation for development as novel topical antimicrobials to treat MRSA skin infections.

Screening of synthetic and natural product databases: Identification of novel androgens and antiandrogens.

PubMed

Bobach, Claudia; Tennstedt, Stephanie; Palberg, Kristin; Denkert, Annika; Brandt, Wolfgang; de Meijere, Armin; Seliger, Barbara; Wessjohann, Ludger A

2015-01-27

The androgen receptor is an important pharmaceutical target for a variety of diseases. This paper presents an in silico/in vitro screening procedure to identify new androgen receptor ligands. The two-step virtual screening procedure uses a three-dimensional pharmacophore model and a docking/scoring routine. About 39,000 filtered compounds were docked with PLANTS and scored by Chemplp. Subsequent to virtual screening, 94 compounds, including 28 steroidal and 66 nonsteroidal compounds, were tested by an androgen receptor fluorescence polarization ligand displacement assay. As a result, 30 compounds were identified that show a relative binding affinity of more than 50% in comparison to 100 nM dihydrotestosterone and were classified as androgen receptor binders. For 11 androgen receptor binders of interest IC50 and Ki values were determined. The compound with the highest affinity exhibits a Ki value of 10.8 nM. Subsequent testing of the 11 compounds in a PC-3 and LNCaP multi readout proliferation assay provides insights into the potential mode of action. Further steroid receptor ligand displacement assays and docking studies on estrogen receptors α and β, glucocorticoid receptor, and progesterone receptor gave information about the specificity of the 11 most active compounds. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Synthesis of Some Novel Thiadiazole Derivative Compounds and Screening Their Antidepressant-Like Activities.

PubMed

Can, Nafiz Öncü; Can, Özgür Devrim; Osmaniye, Derya; Demir Özkay, Ümide

2018-03-21

Novel thiadiazole derivatives were synthesized through the reaction of acetylated 2-aminothiadiazole and piperazine derivatives. The chemical structures of the compounds were clarified by Infrared Spectroscopy (IR), ¹H Nuclear Magnetic Resonance Spectroscopy (¹H-NMR), 13 C Nuclear Magnetic Resonance Spectroscopy ( 13 C-NMR) and Electronspray Ionisation Mass Spectroscopy (ESI-MS) spectroscopic methods. Antidepressant-like activities were evaluated by the tail-suspension (TST) and modified forced swimming (MFST) methods. Besides, possible influence of the test compounds on motor activities of the animals were examined by activity cage tests. In the TST, administration of the compounds 2c , 2d , 2e , 2f , 2g and 2h significantly decreased the immobility time of mice regarding the control values. Further, in the MFST, the same compounds reduced the total number of immobility behaviors while increasing swimming performance. However, no change was observed in the total number of climbing behaviors. These data suggested that compounds 2c , 2d , 2e , 2f , 2g and 2h possess notable antidepressant-like activities. Reference drug fluoxetine (10 mg/kg) was also exhibited its antidepressant activity, as expected. No significant difference was seen between the locomotor activity values of the test groups signifying that observed antidepressant-like activities are specific. Theoretical calculation of absorption, distribution, metabolism, excretion (ADME) properties for the obtained compounds were performed and obtained data supported the antidepressant-like potential of these novel thiadiazole derivatives.

Docking Studies, Synthesis and Biological Evaluation of β-aryl-β-hydroxy Propanoic Acids for Anti-inflammatory Activity.

PubMed

Savic, Jelena; Dilber, Sanda; Milenkovic, Marina; Kotur-Stevuljevic, Jelena; Markovic, Bojan; Vladimirov, Sote; Brboric, Jasmina

2017-01-01

Nonsteriodal anti-inflammatory drugs (NSAIDs) are numerous and widely used for more than 60 years, but there is still a strong need for developing novel selective NSAIDs. The need is justified by the fact that nonselective NSAIDs can produce serious gastric side effects and that some of the selective NSAID are withdrawn due to their cardiotoxic side effects. Eight β-hydroxy-β-arylpropanoic acids, which belong to the arylpropanoic acid class of compounds, structurally similar to some nonsteroidal anti-inflammatory drugs (NSAIDs), were docked into 3D catalytic site of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Seven out of those eight acids were synthesized using already published modification of Reformatsky reaction additionally optimized by increasing temperature. Synthesized compounds were tested in vivo in order to elucidate anti-inflammatory activity, gastric tolerability and impact on liver function of rats. Results of docking studies have indicated that all compounds have potential to selectively inhibit COX-2 isoform, but that the compounds containing polar substituents on phenyl ring are better inhibitors. Results of carrageenan-induced rat paw oedema test have shown that all compounds exhibit dose dependence and good gastric tolerability and none of the tested compounds have shown negative effect on liver function compared to ibuprofen. The compound containing polar nitro group in para position has shown the best docking results, anti-inflammatory activity, low hepatotoxicity and good gastric tolerability. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compound of Cannabis sativa.

PubMed

de Mello Schier, Alexandre R; de Oliveira Ribeiro, Natalia P; Coutinho, Danielle S; Machado, Sergio; Arias-Carrión, Oscar; Crippa, Jose A; Zuardi, Antonio W; Nardi, Antonio E; Silva, Adriana C

2014-01-01

Anxiety and depression are pathologies that affect human beings in many aspects of life, including social life, productivity and health. Cannabidiol (CBD) is a constituent non-psychotomimetic of Cannabis sativa with great psychiatric potential, including uses as an antidepressant-like and anxiolytic-like compound. The aim of this study is to review studies of animal models using CBD as an anxiolytic-like and antidepressant-like compound. Studies involving animal models, performing a variety of experiments on the above-mentioned disorders, such as the forced swimming test (FST), elevated plus maze (EPM) and Vogel conflict test (VCT), suggest that CBD exhibited an anti-anxiety and antidepressant effects in animal models discussed. Experiments with CBD demonstrated non-activation of neuroreceptors CB1 and CB2. Most of the studies demonstrated a good interaction between CBD and the 5-HT1A neuro-receptor.

Synthesis, crystal growth and studies on non-linear optical property of new chalcones

NASA Astrophysics Data System (ADS)

Sarojini, B. K.; Narayana, B.; Ashalatha, B. V.; Indira, J.; Lobo, K. G.

2006-09-01

The synthesis, crystal growth and non-linear optical (NLO) property of new chalcone derivatives are reported. 4-Propyloxy and 4-butoxy benzaldehydes were made to under go Claisen-Schmidt condensation with 4-methoxy, 4-nitro and 4-phenoxy acetophenones to form corresponding chalcones. The newly synthesized compounds were characterized by analytical and spectral data. The Second harmonic generation (SHG) efficiency of these compounds was measured by powder technique using Nd:YAG laser. Among tested compounds three chalcones showed NLO property. The chalcone 1-(4-methoxyphenyl)-3-(4-propyloxy phenyl)-2-propen-1-one exhibited SHG conversion efficiency 2.7 times that of urea. The bulk crystal of 1-(4-methoxyphenyl)-3-(4-butoxyphenyl)-2-propen-1-one (crystal size 65×28×15 mm 3) was grown by slow-evaporation technique from acetone. Microhardness of the crystal was tested by Vicker's microhardness method.

Synthesis and dual PPARalpha/delta agonist effects of 1,4-disubstituted 1,2,3-triazole analogues of GW 501516.

PubMed

Ciocoiu, Calin C; Nikolić, Natasa; Nguyen, Huyen Hoa; Thoresen, G Hege; Aasen, Arne J; Hansen, Trond Vidar

2010-07-01

Ten 1,4-disubstituted 1,2,3-triazoles 2a-2j were prepared and tested for their ability to increase oleic acid oxidation in human myotubes using a high-throughput multiwell assay. Compounds 2e (2-{4-[(1-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) and 2i (2-{4-[(1-(3-chloro-4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) exhibited potent agonist activities. Compounds 2e and 2i also exhibited powerful agonist effects for both PPARalpha and PPARdelta in a luciferase-based assay. Consequently, these triazoles can be categorized as dual PPAR agonists. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Synthesis, DNA binding ability and anticancer activity of 2-heteroaryl substituted benzimidazoles linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates.

PubMed

Kamal, Ahmed; Pogula, Praveen Kumar; Khan, Mohammed Naseer Ahmed; Seshadri, Bobburi Naga; Sreekanth, Kokkonda

2013-08-01

As a continuation of our efforts to develop the benzimidazole-PBD conjugates as potential anticancer agents, a series of heteroaryl substituted benzimidazole linked PBD conjugates has been synthesized and evaluated for their anticancer potential in 60 human cancer cell lines. Most of the compounds exhibited promising anticancer activity and interestingly, compounds 4c and 4d displayed significant activity in most of the cell lines tested. Whereas, compound 4e showed selectivity in renal cancer cells with GI50 values of <10 and 70 nM against RXF 393 and UO-31 cell lines, respectively. Further, these compounds also showed significant DNA-binding affinity by thermal denaturation study using duplex form of calf thymus (CT) DNA.

Synthesis and biological evaluation of febrifugine analogues.

PubMed

Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

2014-12-01

A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity.

Effect of divalent Ba cation substitution with Sr on coupled ‘multiglass’ state in the magnetoelectric multiferroic compound Ba3NbFe3Si2O14

PubMed Central

Rathore, Satyapal Singh; Vitta, Satish

2015-01-01

(Ba/Sr)3NbFe3Si2O14 is a magneto-electric multiferroic with an incommensurate antiferromagnetic spiral magnetic structure which induces electric polarization at 26 K. Structural studies show that both the compounds have similar crystal structure down to 6 K. They exhibit a transition, TN at 26 K and 25 K respectively, as indicated by heat capacity and magnetization, into an antiferromagnetic state. Although Ba and Sr are isovalent, they exhibit very different static and dynamic magnetic behaviors. The Ba-compound exhibits a glassy behavior with critical slowing dynamics with a freezing temperature of ~35 K and a critical exponent of 3.9, a value close to the 3-D Ising model above TN, in addition to the invariant transition into an antiferromagnetic state. The Sr-compound however does not exhibit any dispersive behavior except for the invariant transition at TN. The dielectric constant reflects magnetic behavior of the two compounds: the Ba-compound has two distinct dispersive peaks while the Sr-compound has a single dispersive peak. Thus the compounds exhibit coupled ‘multiglass’ behavior. The difference in magnetic properties between the two compounds is found to be due to modifications to super exchange path angle and length as well as anti-site defects which stabilize either ferromagnetic or antiferromagnetic interactions. PMID:25988657

Antifungal Effect of Novel 2-Bromo-2-Chloro-2-(4-Chlorophenylsulfonyl)-1-Phenylethanone against Candida Strains

PubMed Central

Staniszewska, Monika; Bondaryk, Małgorzata; Wieczorek, Magdalena; Estrada-Mata, Eine; Mora-Montes, Héctor M.; Ochal, Zbigniew

2016-01-01

We investigated the antifungal activity of novel a 2-bromo-2-chloro-2-(4-chlorophenylsulfonyl)-1-phenylethanone (compound 4). The synthesis of compound 4 was commenced from sodium 4-chlorobenzene sulfinate and the final product was obtained by treatment of α-chloro-β-keto-sulfone with sodium hypobromite. The sensitivity of 63 clinical isolates belonging to the most relevant Candida species toward compound 4 using the method M27-A3 was evaluated. We observed among most of the clinical strains of C. albicans MIC ranging from 0.00195 to 0.0078 μg/mL. Compound 4 at 32 μg/mL exhibited fungicidal activity against nine Candida strains tested using the MFC assay. Compound 4 displayed anti-Candida activity (with clear endpoint) against 22% of clinical strains of Candida. Under compound 4, Candida susceptibility and tolerance, namely paradoxical effect (PG), was found for only two clinical isolates (C. glabrata and C. parapsilosis) and reference strain 14053 using both M27-A3 and MFC method. We found that compound 4 does not induce toxicity in vivo against larvae of Galleria mellonella (≥97% survival) and it displays reduced toxicity on mammalian cells in vitro (< CC20 at 64 μg/mL). Furthermore, XTT assay denoted clear metabolic activity of sessile cells in the presence of compound 4. Thus, the effect of compound 4 on formed C. albicans biofilms was minimal. Moreover, strain 90028 exhibited no defects in hyphal growth on Caco-2 monolayer under compound 4 influence at MIC = 16 μg/mL. The MIC values of compound 4 against C. albicans 90028, in medium with sorbitol did not suggest that compound 4 acts by inhibiting fungal cell wall synthesis. Our findings with compound 4 suggest a general strategy for antifungal agent development that might be useful in limiting the emergence of resistance in Candida strains. PMID:27610100

Adrenergic ligands that block oviposition in the cattle tick Rhipicephalus microplus affect ovary contraction

PubMed Central

Cossío-Bayúgar, Raquel; Miranda-Miranda, Estefan; Fernández-Rubalcaba, Manuel; Narváez Padilla, Verónica; Reynaud, Enrique

2015-01-01

The tyraminergic/octopaminergic system is central for the control of arthropod oviposition. Previous works demonstrated that the pharmacological perturbation of this system inhibits oviposition in the cattle tick Rhipicephalus microplus. In this work, we describe a physiologically active whole-mount preparation of the contractile tick ovary that allows the quantitative videometrical analysis of ovary contraction in response to different compounds. Eight adrenergic ligands known to inhibit oviposition, including octopamine and tyramine were tested. These compounds exhibited antagonistic effects; octopamine relaxes the ovary preparation while tyramine induces a very strong contraction. The other adrenergic compounds tested were classified as able to contract or relax ovary muscle tissue. Isoprotenerol has a stronger relaxative effect than octopamine. Tyramine induces the biggest contraction observed of all the compounds tested, followed, in descending amount of contraction, by salbutamol, prazosin, epinastine, clonidine and the acaricide amitraz. The effect of these adrenergic ligands on the ovary preparation, explains why these molecules inhibit tick oviposition and suggest a regulatory mechanism for ovary contraction and relaxation during oviposition. Our results also provide a physiological explanation of the egg-laying inhibition effect of amitraz when used on the cattle tick. PMID:26456007

Adrenergic ligands that block oviposition in the cattle tick Rhipicephalus microplus affect ovary contraction.

PubMed

Cossío-Bayúgar, Raquel; Miranda-Miranda, Estefan; Fernández-Rubalcaba, Manuel; Narváez Padilla, Verónica; Reynaud, Enrique

2015-10-12

The tyraminergic/octopaminergic system is central for the control of arthropod oviposition. Previous works demonstrated that the pharmacological perturbation of this system inhibits oviposition in the cattle tick Rhipicephalus microplus. In this work, we describe a physiologically active whole-mount preparation of the contractile tick ovary that allows the quantitative videometrical analysis of ovary contraction in response to different compounds. Eight adrenergic ligands known to inhibit oviposition, including octopamine and tyramine were tested. These compounds exhibited antagonistic effects; octopamine relaxes the ovary preparation while tyramine induces a very strong contraction. The other adrenergic compounds tested were classified as able to contract or relax ovary muscle tissue. Isoprotenerol has a stronger relaxative effect than octopamine. Tyramine induces the biggest contraction observed of all the compounds tested, followed, in descending amount of contraction, by salbutamol, prazosin, epinastine, clonidine and the acaricide amitraz. The effect of these adrenergic ligands on the ovary preparation, explains why these molecules inhibit tick oviposition and suggest a regulatory mechanism for ovary contraction and relaxation during oviposition. Our results also provide a physiological explanation of the egg-laying inhibition effect of amitraz when used on the cattle tick.

Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.

PubMed

Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

2015-06-01

By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Improved anticancer and antiparasitic activity of new lawsone Mannich bases.

PubMed

Mahal, Katharina; Ahmad, Aamir; Schmitt, Florian; Lockhauserbäumer, Julia; Starz, Kathrin; Pradhan, Rohan; Padhye, Subhash; Sarkar, Fazlul H; Koko, Waleed S; Schobert, Rainer; Ersfeld, Klaus; Biersack, Bernhard

2017-01-27

Substituted lawsone Mannich bases 2a-e, 3a-e and 4a-e were prepared and tested for their biological activities. The new fatty alkyl substituted compounds 2a-c exhibited strong and selective growth inhibitory activities in the low one-digit micromolar and sub-micromolar range against a panel of human cancer cell lines associated with ROS formation. In addition, compounds 2a-c revealed sub-micromolar anti-trypanosomal activities against parasitic Trypanosoma brucei brucei cells via deformation of the microtubule cytoskeleton. The N-hexadecyl compound 2c was also highly active against locally isolated Entamoeba histolytica parasite samples exceeding the activity of metronidazole. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Isolation and identification of antibacterial and cytotoxic compounds from the leaves of Muntingia calabura L.

PubMed

Sufian, Adila S; Ramasamy, Kalavathy; Ahmat, Norizan; Zakaria, Zainul A; Yusof, M Izwan M

2013-03-07

Muntingia calabura (Elaeocarpaceae) is one of the most common roadside trees in Malaysia. Its leaves, barks, flowers and roots have been used as a folk remedy for the treatment of fever, incipient cold, liver disease, as well as an antiseptic agent in Southeast Asia. The aim of this study is to isolate and identify the antibacterial and cytotoxic compounds from the leaves of Muntingia calabura L. Antibacterial and cytotoxic activities were determined by micro-broth dilution and MTT assays, respectively. Seven fractions (F1-F7), three flavones and a chalcone were isolated from the active EtOAc extract using bioassay-guided screening. The structures of four compounds were elucidated by spectroscopic methods and compared with published data. The compounds were further tested for their antibacterial and cytotoxic activities. Three flavones and a chalcone [5,7-dihydroxy-3,8-dimethoxyflavone (1), 2',4'-dihydroxychalcone (2), 5-hydroxy-3,7-dimethoxyflavone (3) and 3,5,7-trihydroxy-8-methoxyflavone (4)] were isolated from the active fraction F5 of EtOAc extract. Compounds 1 and 3 were isolated for the first time from Muntingia calabura L. Antibacterial activity indicates that compound 2 exhibited the most significant activity with MIC value of 50 μg/mL and 100 μg/mL against MSSA and MRSA, respectively. Cytotoxic activity indicates that compounds 2 and 3 exhibited very strong activity against HL60 with IC50 values of 3.43 μg/mL and 3.34 μg/mL, respectively. The antibacterial activity of the leaves of Muntingia calabura L. is ascribable to the active compound 2 while the cytotoxic activity is ascribable to the active compounds 2 and 3. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Screening of pharmacokinetic properties of fifty dihydropyrimidin(thi)one derivatives using a combo of in vitro and in silico assays.

PubMed

Matias, Mariana; Fortuna, Ana; Bicker, Joana; Silvestre, Samuel; Falcão, Amílcar; Alves, Gilberto

2017-11-15

The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, but their pharmacokinetic properties remain almost unknown. Herein, fifty dihydropyrimidin(thi)ones were submitted to in vitro screening tests using parallel artificial membrane permeability assays (PAMPA) to evaluate their apparent permeability (Papp) through intestinal membrane and blood-brain barrier models, and cell-based assays to assess their interference on the efflux transporter P-glycoprotein (P-gp). Moreover, a set of kinetic and toxicological parameters was also estimated employing a new computational tool, the pkCSM. The in vitro results suggested that 82% of the test compounds have good intestinal permeability (Papp>1.1×10 -6 cm/s), and 66% of these are also expected to exhibit good permeability through blood-brain barrier (Papp>2.0×10 -6 cm/s); these findings are consistent with a high transport rate by passive transcellular pathway. In both PAMPA models, thiourea derivatives presented higher Papp values than the respective urea analogues, which were further corroborated by in silico predictions. The in vitro results also suggested a low extent of plasma protein binding for all compounds (Papp<1.0×10 -5 cm/s), and these findings were also supported by in silico data (unbound fraction ranging from 0.13 to 0.59). In addition, although approximately half of the compounds did not modulate P-gp at the tested concentrations (10 and 50μM), nine of them presented a trend to induce P-gp and particularly the chlorinated compounds exhibited a marked P-gp inhibition at 50μM. Furthermore, the in silico predictions suggested that half of the compounds have hepatotoxic potential. Overall, within this group of compounds, the thiourea derivatives containing an unsubstituted or a monosubstituted (NO 2 , CH 3 , OCH 3 ) phenyl ring attached to the position 4 of the dihydropyrimidine ring represented the most promising structures and should be considered in the subsequent studies of the development of new structurally related drug candidates. Copyright © 2017 Elsevier B.V. All rights reserved.

Synthesis and antimalarial activity study of some new Mannich bases of 7-chloro-4-aminoquinoline.

PubMed

Roy, Susanta; Chetia, Dipak; Rudrapal, Mithun; Prakash, Anil

2013-05-01

New derivatives of 7-chloro-4-aminoquinoline Mannich base were prepared by selectively modifying the aliphatic diethyl amino function of isoquine with different aliphatic/aromatic heterocyclic primary amino moieties at Mannich side chain. The synthesized compounds were characterized by their analytical and spectral data, and screened for in-vitro antimalarial activity against a chloroquine-sensitive 3D7 strain of Plasmodium falciparum. All the compounds showed in-vitro antimalarial activity at the tested dose; which, however, was considerably less than that of the standard reference drug, chloroquine. Among synthesized compounds, compounds with cyclohexyl (2f), methyl (2c) substitutions showed better activity than compounds substituted with n-octyl (2a), propyl (2b), 3-aminopropyl (2d) and furan-2- ylmethyl (2e) moieties at aminomethyl side chain. The results clearly demonstrate that the compound substituted with saturated cycloalkyl moiety (cyclohexyl) exhibited to some extent increased activity as compared to the compound containing heterocyclic moiety (furan-2-ylmethyl), and compounds with short chain alkyl substitutions (methyl, propyl) were found to be more active than that of compounds with long chain alkyl substitution (n-octyl).

Design and syntheses of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione and N-(benzothiazol-5-yl)isoindoline-1,3-dione as potent protoporphyrinogen oxidase inhibitors.

PubMed

Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang; Tan, Yin; Wu, Qiong-You; Xi, Zhen; Yang, Guang-Fu

2011-06-08

Discovery of protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors has been one of the hottest research areas in the field of herbicide development for many years. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-diones (1a-p) and N-(benzothiazol-5-yl)isoindoline-1,3-diones (2a-h) were designed and synthesized according to the ring-closing strategy of two ortho-substituents. The bioassay results indicated that some newly synthesized compounds exhibited higher PPO inhibition activity than the control of sulfentrazone. Compound 1a, S-(5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl) O-methyl carbonothioate, was identified as the most potent inhibitor with k(i) value of 0.08 μM, about 9 times higher than that of sulfentrazone (k(i) = 0.72 μM). Further green house assay showed that compound 1b, methyl 2-((5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl)thio)acetate, exhibited herbicidal activity comparable to that of sulfentrazone even at a concentration of 37.5 g ai/ha. In addition, among six tested crops, wheat exhibited high tolerance to compound 1b even at a dosage of 300 g ai/ha. These results indicated that compound 1b might have the potential to be developed as a new herbicide for weed control of wheat field.

Synthesis, Characterization and Biological Activities of Creatinine Amides and Creatinine Schiff Bases.

PubMed

Mumtaz, Amara; Zahoor, Fareeha; Zaib, Sumera; Nawaz, Muhammad Azhar H; Saeed, Aamer; Waseem, Amir; Khan, Afsar; Hussain, Izhar; Iqbal, Jamshed

2017-01-30

In spite of substantial progress in scientific cognizance and medical technology, still infectious diseases are among the leading cause of morbidity and mortality. Creatinine and Schiff bases are well known for their diverse range of biological activities and thought to be emerging and useful therapeutic target for the treatment of several diseases. The present work was aimed to illustrate the influence of substitution of amides and Schiff bases on creatinine and their antimicrobial, antioxidant and anti-urease effectiveness was determined. Creatinine substituted amides (1-2) and creatinine Schiff bases (3-7) were synthesized and characterized by NMR and IR spectral data in combination with elemental analysis. All the compounds (1-7) were investigated on Jack bean urease for their urease inhibitory potential. Investigation of antimicrobial activity of the compounds was made by the agar dilution method. Moreover, 1,1-diphenyl-2- picrylhydrazyl (DPPH) method was used to determine their antioxidant potential. Molecular docking studies were also carried out to elucidate their relationship with the binding pockets of the enzyme. The compounds were found to be potent inhibitors of urease. The synthesized derivatives exhibited significant inhibition against Gram-positive and Gram-negative bacterial strains, as compared to standard, ciprofloxacin. Creatinine based derivatives exhibited potential antifungal activity when tested on infectious and pathogenic fungal strains. Similarly, most of the compounds exhibited good antioxidant activity. These derivatives may serve as a source of potential antioxidants and also help to retard microbial growth in food industry. Similarly, the studies provide a basis for further research to develop more potent urease inhibitory compounds of medicinal /agricultural interest. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex.

PubMed

Sá, Nívea Pereira de; Lima, Caroline Miranda de; Lino, Cleudiomar Inácio; Barbeira, Paulo Jorge Sanches; Baltazar, Ludmila de Matos; Santos, Daniel Assis; Oliveira, Renata Barbosa de; Mylonakis, Eleftherios; Fuchs, Beth Burgwyn; Johann, Susana

2017-08-01

Human cryptococcosis can occur as a primary or opportunistic infection and develops as an acute, subacute, or chronic systemic infection involving different organs of the host. Given the limited therapeutic options and the occasional resistance to fluconazole, there is a need to develop novel drugs for the treatment of cryptococcosis. In this report, we describe promising thiazole compounds 1, 2, 3, and 4 and explore their possible modes of action against Cryptococcus To this end, we show evidence of interference in the Cryptococcus antioxidant system. The tested compounds exhibited MICs ranging from 0.25 to 2 μg/ml against Cryptococcus neoformans strains H99 and KN99α. Interestingly, the knockout strains for Cu oxidase and sarcosine oxidase were resistant to thiazoles. MIC values of thiazole compounds 1, 2, and 4 against these mutants were higher than for the parental strain. After the treatment of C. neoformans ATCC 24067 (or C. deneoformans ) and C. gattii strain L27/01 (or C. deuterogattii ) with thiazoles, we verified an increase in intracellular reactive oxygen species (ROS). Also, we verified the synergistic interactions among thiazoles and menadione, which generates superoxides, with fractional inhibitory concentrations (FICs) equal to 0.1874, 0.3024, 0.25, and 0.25 for the thiazole compounds 1, 2, 3, and 4, respectively. In addition, thiazoles exhibited antagonistic interactions with parasulphonatephenyl porphyrinato ferrate III (FeTPPS). Thus, in this work, we showed that the action of these thiazoles is related to an interference with the antioxidant system. These findings suggest that oxidative stress may be primarily related to the accumulation of superoxide radicals. Copyright © 2017 American Society for Microbiology.

Chemical composition and antibacterial activity of selected essential oils and some of their main compounds.

PubMed

Wanner, Juergen; Schmidt, Erich; Bail, Stefanie; Jirovetz, Leopold; Buchbauer, Gerhard; Gochev, Velizar; Girova, Tanya; Atanasova, Teodora; Stoyanova, Albena

2010-09-01

The chemical composition of essential oils of cabreuva (Myrocarpus fastigiatus Allemao, Fabaceae) from Brazil, cedarwood (Juniperus ashei, Cupressaceae) from Texas, Juniper berries (Juniperus communis L., Cupressaceae) and myrrh (Commiphora myrrha (Nees) Engl., Burseraceae) were analyzed using GC/FID and GC/MS. The antimicrobial activity of these essential oils and some of their main compounds were tested against eleven different strains of Gram-positive and Gram-negative bacteria by using agar diffusion and agar serial dilution methods. Animal and plant pathogens, food poisoning and spoilage bacteria were selected. The volatile oils exhibited considerable inhibitory effects against all tested organisms, except Pseudomonas, using both test methods. Higher activity was observed against Gram-positive strains in comparison with Gram-negative bacteria. Cabreuva oil from Brazil showed similar results, but in comparison with the other oils tested, only when higher concentrations of oil were used.

Aniracetam reverses memory impairment in rats.

PubMed

Martin, J R; Moreau, J L; Jenck, F

1995-02-01

The pyrrolidinone derivative aniracetam given orally immediately after acquisition of an inhibitory avoidance response reproducibly ameliorated scopolamine-induced amnesia in female rats in an extensive series of test sessions conducted over a 1-year period. In a dose-response experiment it was demonstrated that 50 mg kg-1 was the lowest oral dose of aniracetam to significantly ameliorate scopolamine-induced amnesia. Combined results from these numerous test sessions demonstrated that 50 mg kg-1 aniracetam administered to scopolamine-treated rats resulted in 53% of the animals exhibiting correct passive avoidance responding in the retention evaluation versus 9% of the scopolamine-treated rats given vehicle (in comparison, 64% of the rats injected with vehicle rather than scopolamine in this experimental situation exhibited correct responding in the retention test). There was minimal variation in this pattern of results over the successive 1-month blocks constituting the complete experimental period. Thus, the nootropic compound aniracetam replicably exhibited memory enhancing effects in this animal model of reduced cholinergic function.

Antimicrobial azobenzene compounds and their potential use in biomaterials

NASA Astrophysics Data System (ADS)

Sessa, L.; Concilio, S.; Iannelli, P.; De Santis, F.; Porta, A.; Piotto, S.

2016-04-01

We recently synthesized a class of active compounds with azobenzene structure [1] and lowest in silico toxicity values. The antimicrobial activity of these molecules and their thermal stability are very promising and indicate that they may have interesting and therapeutically significant applications. This work aims to develop new materials with antibacterial and antifungal activity inserting different percentages of synthetic antimicrobial azo compounds in commercial polymer matrices. We realized thin films using solvent casting and melt compounding techniques. The obtained materials retained the proprieties of the pure matrices. This means that azo dye dissolved in the matrix does not influence the thermal behavior and the morphology of the material. Tested films exhibited the capability to inhibit biofilms formation of S. aureus and C. albicans. Spectrophotometric investigation of the azo compound released from the polymer matrices confirmed that the realized materials might be interesting for biomedical tools, antibacterial surfaces, and films for active packaging.

Novel urea and bis-urea primaquine derivatives with hydroxyphenyl or halogenphenyl substituents: Synthesis and biological evaluation.

PubMed

Perković, I; Antunović, M; Marijanović, I; Pavić, K; Ester, K; Kralj, M; Vlainić, J; Kosalec, I; Schols, D; Hadjipavlou-Litina, D; Pontiki, E; Zorc, B

2016-11-29

A series of novel compounds 3a-j and 6a-j with primaquine and hydroxyl or halogen substituted benzene moieties bridged by urea or bis-urea functionalities were designed, synthesized and evaluated for biological activity. The title compounds were prepared using benzotriazole as the synthon, through several synthetic steps. 3-[3,5-Bis(trifluoromethyl)phenyl]-1-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}urea (3j) was the most active urea and 1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-3-[3-(trifluoromethyl)phenyl]urea (6h) the most active bis-urea derivative in antiproliferative screening in vitro against eight tested cancer cell lines. Urea derivatives 3a-g with hydroxy group or one halogen atom showed moderate antiproliferative effects against all the tested cell lines, but stronger activity against breast carcinoma MCF-7 cell line, while trifluoromethyl derivatives 3h-j showed antiproliferative effects against all the tested cell lines in low micromolar range. Finally, bis-ureas with hydroxy and fluoro substituents 6a-d showed extreme selectivity and chloro or bromo derivatives 6e-g high selectivity against MCF-7 cells (IC 50 0.1-2.6 μM). p-Fluoro derivative 6d, namely 3-(4-fluorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea, is the most promising compound. Further biological experiments showed that 6d affected cell cycle and induced cell death of MCF-7 cell line. Due to its high activity against MCF-7 cell line (IC 50 0.31 μM), extreme selectivity and full agreement with the Lipinski's and Gelovani's rules for prospective small molecular drugs, 6d may be considered as a lead compound in development of breast carcinoma drugs. Urea 3b and almost all bis-ureas showed high antioxidant activity in DPPH assay, but urea derivatives were more active in lipid peroxidation test. Only few compounds exhibited weak inhibition of soybean lipoxygenase. Compound 3j exhibited the strongest antimicrobial activity in susceptibility assay in vitro (MIC = 1.6-12.5 μg ml -1 ). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Target-specific support vector machine scoring in structure-based virtual screening: computational validation, in vitro testing in kinases, and effects on lung cancer cell proliferation.

PubMed

Li, Liwei; Khanna, May; Jo, Inha; Wang, Fang; Ashpole, Nicole M; Hudmon, Andy; Meroueh, Samy O

2011-04-25

We assess the performance of our previously reported structure-based support vector machine target-specific scoring function across 41 targets, 40 among them from the Directory of Useful Decoys (DUD). The area under the curve of receiver operating characteristic plots (ROC-AUC) revealed that scoring with SVM-SP resulted in consistently better enrichment over all target families, outperforming Glide and other scoring functions, most notably among kinases. In addition, SVM-SP performance showed little variation among protein classes, exhibited excellent performance in a test case using a homology model, and in some cases showed high enrichment even with few structures used to train a model. We put SVM-SP to the test by virtual screening 1125 compounds against two kinases, EGFR and CaMKII. Among the top 25 EGFR compounds, three compounds (1-3) inhibited kinase activity in vitro with IC₅₀ of 58, 2, and 10 μM. In cell cultures, compounds 1-3 inhibited nonsmall cell lung carcinoma (H1299) cancer cell proliferation with similar IC₅₀ values for compound 3. For CaMKII, one compound inhibited kinase activity in a dose-dependent manner among 20 tested with an IC₅₀ of 48 μM. These results are encouraging given that our in-house library consists of compounds that emerged from virtual screening of other targets with pockets that are different from typical ATP binding sites found in kinases. In light of the importance of kinases in chemical biology, these findings could have implications in future efforts to identify chemical probes of kinases within the human kinome.

In vitro screening of organotin compounds and sediment extracts for cytotoxicity to fish cells.

PubMed

Giltrap, Michelle; Macken, Ailbhe; McHugh, Brendan; McGovern, Evin; Foley, Barry; Davoren, Maria

2011-01-01

The present study reports an in vitro screening method for contaminants in sediment samples utilizing an RTG-2 cell line. This technique integrates cytotoxicity testing with analytical chemistry with the aim of achieving a toxicity evaluation of the sediment sample. The toxic effect of individual organotin (OT) compounds and their presence in the sediment sample is the focus of the present study; however, other contaminants are also discussed. The following OT compounds: tributyltin (TBT), dibutyltin (DBT), monobutyltin (MBT), triphenyltin (TPT), diphenyltin (DPT), and a sediment solvent extract are exposed to the RTG-2 fish cell line. Both the alamar blue (AB) and neutral red (NR) assays are used to assess cytotoxicity after 24-h and 96-h exposure. Methodology for preparation of a sediment solvent extract suitable for biological testing and analytical determination is also described. With the RTG-2 cells, the AB and NR assays had comparable sensitivity for each individual OT compound exposure after 24 h, with TPT being the most toxic compound tested. The individual OT compound concentrations required to induce a 50% toxic effect on the cells (369 ng ml⁻¹ TBT, 1,905 ng ml⁻¹ DBT) did not equate to the concentrations of these contaminants present in the sediment extract that induced a 50% effect on the cells (294 ng ml⁻¹ TBT, 109 ng ml⁻¹ DBT). The solvent extract therefore exhibited a greater toxicity, and this suggests that the toxic effects observed were not due to OT compounds alone. The presence of other contaminants in the solvent extract is confirmed with chemical analysis, warranting further toxicity testing of contaminant mixtures and exposure to the cell line to further elucidate a complete toxicity evaluation. © 2010 SETAC.

Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.

PubMed

Quiliano, Miguel; Pabón, Adriana; Moles, Ernest; Bonilla-Ramirez, Leonardo; Fabing, Isabelle; Fong, Kim Y; Nieto-Aco, Diego A; Wright, David W; Pizarro, Juan C; Vettorazzi, Ariane; López de Cerain, Adela; Deharo, Eric; Fernández-Busquets, Xavier; Garavito, Giovanny; Aldana, Ignacio; Galiano, Silvia

2018-05-25

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC 50 s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC 50 s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII.

PubMed

SitaRam; Celik, Gulsah; Khloya, Poonam; Vullo, Daniela; Supuran, Claudiu T; Sharma, Pawan K

2014-03-15

Three series of novel heterocyclic compounds (3a-3g, 4a-4g and 5a-5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a-3g and 4a-4g) showed Ki values in the range of 84-868 nM and 5.6-390 nM, respectively whereas compounds of series 5a-5g were found to be poor inhibitors (Ki values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8-431 nM and 1.3-63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a-5g were comparatively less potent but more selective towards hCA IX and XII. Copyright © 2014 Elsevier Ltd. All rights reserved.

Purification and identification of bioactive angucyclinones from Streptomyces matensis BG5, isolated from the rhizosphere of Rosa indica L.

PubMed

Sajid, Imran; Shaaban, Khaled A; Hasnain, Shahida

2013-01-01

A newly isolated strain Streptomyces sp. BG5 was investigated for the production of bioactive compounds. The strain exhibited broad-spectrum activity against an array of nine test organisms including gram-positive bacteria, gram-negative bacteria, and fungal and microalgal pathogens, along with a moderate cytotoxic response (28.9% mortality) in a microwell cytotoxicity assay against the brine shrimp Artimia salina. The morphological, physiological, and biochemical characterization of the Streptomyces sp. BG5 strongly suggested it to be a member of the genus Streptomyces. The nucleotide sequence of 16S rRNA gene (1433 pb) of the Streptomyces sp. BG5 (Gene bank accession number EU301836) exhibited high similarity (98%) with Streptomyces matensis. The large-scale fermentation of Streptomyces sp. BG5 and subsequent extraction, isolation, and purification of the crude extract afforded three pure compounds. The structures of these compounds were identified as ochromycinone (1a), emycin D (2), and 1-acetyl-β-carbolin (3), based on nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and by comparison with reference data from the literature.

Novel primary amine diazeniumdiolates-Chemical and biological characterization.

PubMed

Puglisi, Melany P; Bradaric, Michael J; Pontikis, John; Cabai, Jonathan; Weyna, Theodore; Tednes, Patrick; Schretzman, Robert; Rickert, Karl; Cao, Zhao; Andrei, Daniela

2018-05-02

Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release nitric oxide (NO . ) and/or their congeneric nitroxyl (HNO). The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO/NO donors and to determine their efficacy as anticancer and antifungal agents in vivo. The seven compounds (3a-3g) were successfully synthesized and characterized, one of which had been previously reported in the literature (3g). Two compounds showed anti-proliferative effects against ovarian (ES2 and SKOV3) and AML monocyte-derived cancer cells (THP-1) when tested with standard MTT assays. Compounds 3a and 3g demonstrated reduced ovarian cancer cell proliferation when treated at doses from 0.033 to 1.0 mg/mL at the 24 hr time point. These compounds also exhibited moderate and selective antifungal activity against Fusarium oxysporum f.sp. lycopersici, one cause of opportunistic infections of immunocompromised patients, inhibiting the growth of the fungi at LD 50 at 10 mg/mL. A third compound (3e) did not exhibit similar activities, possibly due to the alkyl chain. Our results suggest that the primary amine diazeniumdiolates may offer a versatile platform for the development of HNO/NO donors for biomedical applications. © 2018 Wiley Periodicals, Inc.

Antialgal and antilarval activities of bioactive compounds extracted from the marine dinoflagellate Amphidinium carterae

NASA Astrophysics Data System (ADS)

Kong, Xianyu; Han, Xiurong; Gao, Min; Su, Rongguo; Wang, Ke; Li, Xuzhao; Lu, Wei

2016-12-01

With the global ban on the application of organotin-based marine coatings by the International Maritime Organization, the development of environmentally friendly, low-toxic and nontoxic antifouling compounds for marine industries has become an urgent need. Marine microorganisms have been considered as a potential source of natural antifoulants. In this study, the antifouling potential of marine dinoflagellate Amphidinium carterae, the toxic and red-tide microalgae, was investigated. We performed a series of operations to extract the bioactive substances from Amphidinium carterae and tested their antialgal and antilarval activities. The crude extract of Amphidinium carterae showed significant antialgal activity and the EC50 value against Skeletonema costatum was 55.4 μg mL-1. After purification, the isolated bioactive substances (the organic extract C) exhibited much higher antialgal and antilarval activities with EC50 of 12.9 μg mL-1 against Skeletonema costatum and LC50 of 15.1 μg mL-1 against Amphibalanus amphitrite larvae. Subsequently, IR, Q-TOFMS, and GC-MS were utilized for the structural elucidation of the bioactive compounds, and a series of unsaturated and saturated 16- to 22-carbon fatty acids were detected. The data suggested the bioactive compounds isolated from Amphidinium carterae exhibited a significant inhibiting effect against the diatom Skeletonema costatum and Amphibalanus amphitrite larvae, and could be substitutes for persistent, toxic antifouling compounds.

Contact toxicity and repellency of the essential oil from Mentha haplocalyx Briq. against Lasioderma serricorne.

PubMed

Zhang, Wen-Juan; Yang, Kai; You, Chun-Xue; Wang, Cheng-Fang; Geng, Zhu-Feng; Su, Yang; Wang, Ying; Du, Shu-Shan; Deng, Zhi-Wei

2015-05-01

The chemical composition of the essential oil obtained by hydrodistillation from the aerial parts of Mentha haplocalyx was investigated by GC-FID and GC/MS analyses. In sum, 23 components, representing 92.88% of the total oil composition, were identified, and the main compounds were found to be menthol (59.71%), menthyl acetate (7.83%), limonene (6.98%), and menthone (4.44%). By bioassay-guided fractionation (contact toxicity), three compounds were obtained from the essential oil and identified as menthol, menthyl acetate, and limonene. The essential oil and the three isolated compounds exhibited potent contact toxicity against Lasioderma serricorne adults, with LD50 values of 16.5, 7.91, 5.96, and 13.7 μg/adult, respectively. Moreover, the oil and its isolated compounds also exhibited strong repellency against L. serricorne adults. At the lower concentrations tested and at 2 h after exposure, menthol showed even significantly stronger repellency than the positive control DEET. The study revealed that the bioactivity properties of the essential oil can be attributed to the synergistic effects of its diverse major and minor components, which indicates that the M. haplocalyx oil and its isolated compounds have potential for the development as natural insecticides and/or repellents to control insects in stored grains and traditional Chinese medicinal materials. Copyright © 2015 Verlag Helvetica Chimica Acta AG, Zürich.

Repellent activity of estrogenic compounds toward zoospores of the phytopathogenic fungus Aphanomyces cochlioides.

PubMed

Islam, M T; Tahara, S

2001-01-01

Screening chemical compounds, we found that a xenoestrogen, bisphenol A, showed potent repellent activity against the zoospores of Aphanomyces cochlioides. Based on this finding, we tested a number of androgenic and estrogenic compounds (e.g. testosterone, progesterone, estradiols, diethylstilbestrol, estrone, estriol, pregnenolone, dienestrol etc.) on the motility behavior of A. cochlioides zoospores. Interestingly, most of the estrogenic compounds exhibited potent repellent activity (1 microg/ml or less by the "particle method") toward the motile zoospores of A. cochlioides. We derivatized some of the estrogens and discussed the relationship between the structure of active molecules and their repellent activity. Apparently, aromatization of the A ring with a free hydroxyl group at C-3 position of a steroidal structure is necessary for higher repellent activity. Interestingly, methylation of diethylstilbestrol (DES) yielded completely different activity i.e. both mono- and di-methyl ethers of DES showed attractant activity. Moreover, the attracted zoospores were encysted and then germinated in the presence of di-methyl ether of DES. The potential usefulness of this repellent test is discussed for the detection of estrogenic activity of naturally occurring compounds, and the possible role of phytoestrogens in host/parasite interactions. So far, this will be the first report of repellent activity of estrogenic compounds toward trivial fungal zoospores.

Spectroscopic Study on the Interaction of 4-dimethylaminochalcones with Phospholipids

NASA Astrophysics Data System (ADS)

Tomečková, V.; Revická, M.; Sassen, A.; Veliká, B.; Stupák, M.; Perjési, P.

2014-11-01

The ultraviolet-visible and fluorescence spectroscopic properties of 4'-dimethylaminochalcone ( 1a) and its cyclic analogs 2a-4a have been studied in the presence of phospholipid vesicles (i.e., egg yolk lecithin and dipalmitoylpho sphatidylcholine), bovine serum albumin (BSA), and lipoprotein particles (i.e., bovine serum albumin plus egg yolk lecithin). The spectral results showed that compounds 1a-4a formed hydrophobic interactions with the phospholipids, lipoproteins, and BSA at the polar/nonpolar interface. Compounds 3a and 4a exhibited the strongest hydrophobic interactions of all of the compounds tested towards the phospholipids. Compound 2a gave the best fluorescent fluorophore indicating interactions with the lipids, lipoproteins, and proteins. Fluorescent microscopic imaging of breast cancer cells treated with compounds 1a-4a revealed that they could be used to stain all of the cellular components and destroy the nuclear structure. Compounds 1a-4a were found to be concentrated predominantly on the surfaces of the liposomes and lipoproteins.

Environmental bacteria produce abundant and diverse antibiofilm compounds.

PubMed

Farmer, J T; Shimkevitch, A V; Reilly, P S; Mlynek, K D; Jensen, K S; Callahan, M T; Bushaw-Newton, K L; Kaplan, J B

2014-12-01

The aim of this study was to isolate novel antibiofilm compounds produced by environmental bacteria. Cell-free extracts were prepared from lawns of bacteria cultured on agar. A total of 126 bacteria isolated from soil, cave and river habitats were employed. Extracts were tested for their ability to inhibit Staphylococcus aureus biofilm in a 96-well microtitre plate assay. A total of 55/126 extracts (44%) significantly inhibited Staph. aureus biofilm. Seven extracts were selected for further analysis. The antibiofilm activities in all seven extracts exhibited unique patterns of molecular mass, chemical polarity, heat stability and spectrum of activity against Staph. aureus, Staphylococcus epidermidis and Pseudomonas fluorescens, suggesting that these seven antibiofilm activities were mediated by unique chemical compounds with different mechanisms of action. Environmental bacteria produce abundant and diverse antibiofilm compounds. Screening cell-free extracts is a useful method for identifying secreted compounds that regulate biofilm formation. Such compounds may represent a novel source of antibiofilm agents for technological development. © 2014 The Society for Applied Microbiology.

Antibacterial and Hypoglycemic Diterpenoids from Salvia chamaedryoides.

PubMed

Bisio, Angela; De Mieri, Maria; Milella, Luigi; Schito, Anna M; Parricchi, Anita; Russo, Daniela; Alfei, Silvana; Lapillo, Margherita; Tuccinardi, Tiziano; Hamburger, Matthias; De Tommasi, Nunziatina

2017-02-24

A surface extract of the aerial parts of Salvia chamaedryoides afforded 13 diterpenes (1-13), with seven compounds (1, 3, 4, 7-9, 12) described for the first time. The structures of the new compounds were established using 1D and 2D NMR spectroscopic methods, HRESIMS, and ECD data. The potential hypoglycemic effects of the crude extract, fractions, and pure compounds from S. chamaedryoides were investigated by inhibition of α-glucosidase and α-amylase enzymes. The extract and its fractions showed a moderate dose-dependent inhibition; the pure compounds exhibited differential inhibitory activity against these two enzymes. Molecular modeling studies were also performed to suggest the interaction mode of compound 3 in the α-glucosidase enzyme active site. The antimicrobial activity of the purified compounds was investigated against 26 clinical pathogens. No activity was detected for the Gram-negative species tested nor on Candida albicans and C. glabrata, while variable susceptibilities were observed using Gram-positive staphylococcal and enterococcal species.

Rearranged diterpenoids from the biotransformation of ent-trachyloban-18-oic acid by Rhizopus arrhizus.

PubMed

Leverrier, Aurélie; Martin, Marie-Thérèse; Servy, Claudine; Ouazzani, Jamal; Retailleau, Pascal; Awang, Khalijah; Mukhtar, Mat Ropi; Guéritte, Françoise; Litaudon, Marc

2010-06-25

In our search for inhibitors of the antiapoptotic protein Bcl-xL, investigation of Xylopia caudata afforded a new diterpenoid, ent-trachyloban-4beta-ol (2), and five known ent-trachylobane or ent-atisane compounds. Only ent-trachyloban-18-oic acid (1) exhibited weak binding activity to Bcl-xL. These compounds exhibited cytotoxicity against KB and HCT-116 cell lines with IC(50) values between 10 and 30 microM. Bioconversion of compound 1 by Rhizopus arrhizus afforded new hydroxylated metabolites (3-7) of the ent-trachylobane and ent-kaurene type and compound 8, with a rearranged pentacyclic carbon framework that was named rhizopene. Compounds 3-8 were noncytotoxic to the two cancer cell lines, and compounds 3 and 5 exhibited only weak binding affinity for Bcl-xL.

Thiophene/thiazole-benzene replacement on guanidine derivatives targeting α2-Adrenoceptors.

PubMed

Flood, Aoife; Trujillo, Cristina; Sanchez-Sanz, Goar; Kelly, Brendan; Muguruza, Carolina; Callado, Luis F; Rozas, Isabel

2017-09-29

Searching for improved antagonists of α 2 -adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6-311++G(p,d) computational level] confirming that thiophene and thiazole will be good 'ring equivalents' to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α 2 -adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α 2 -adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues. In the case of cycloakyl systems, thiophenes with 6-membered rings showed the largest affinities, while for the thiazoles the 5-membered analogue presented the strongest affinity. From all the compounds tested for noradrenergic activity, only one compound exhibited agonistic activity, while two compounds showed very promising antagonism of α 2 -adrenoceptors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Melatonin and its precursors scavenge nitric oxide

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

Noda, Y.; Mori, A.; Liburdy, R.

Nitric oxide (NO) scavenging activity of melatonin, N-acetyl-5-hydroxytryptamine, serotonin, 5-hydroxytryptophan and L-tryptophan was examined by the Griess reaction using flow injection analysis. 1-Hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene(NOC-7) was used as NO generator. The Griess reagent stoichiometrically reacts with NO2-, which was converted by a cadmium-copper reduction column from the stable end products of NO oxidation. Except for tryptophan, all the compounds examined scavenged NO in a dose-dependent manner. Melatonin, which has a methoxy group in the 5-position and an acetyl side chain, exhibited the most potent scavenging activity among the compounds tested. Serotonin, N-acetyl-5-hydroxytryptamine, and 5-hydroxytryptophan, respectively, showed moderate scavenging activity compared to melatonin.more » Tryptophan, which has neither a methoxy nor a hydroxyl group in the 5-position, exhibited the least NO scavenging activity.« less

DNA binding, anti-inflammatory and analgesic evaluation of metal complexes of N/S/O donor ligands; Synthesis, spectral characterization

NASA Astrophysics Data System (ADS)

Kumar Naik, K. H.; Ashok, B.; Naik, Nagaraja; Mulla, Jameel Ahmed S.; Prakasha, Avinash

2015-04-01

Transition metal complexes containing tri-dentate NSN donor ligands i.e., 5-((1(aminomethyl)cyclohexyl)methyl)-1,3,4-thiadiazol-2-amine (AMTA) (2) and 5-(2-aminophenyl)-1,3,4-thiadiazol-2-amine (ATA) (4i-ii) have been synthesized. The newly synthesized ligands and their respective complexes were characterized by elemental analysis, molar conductance measurement and various spectral studies [infrared (IR), electronic, and NMR (for ligands only)]. Metal complexes are like [M(AMTA)2], [M(ATA)2] type, where M = Mn(II), Co(II) and Cu(II). The proposed geometries of the complexes are octahedral in nature. The synthesized ligands and their complexes were exhibits effective anti-inflammatory, analgesic and DNA binding activities. All the tested compounds exhibited significant analgesic activity, whereas the compound 4i, 4(ia) and 4(iib) is equipotent with Diclofenac sodium.

Synthesis, crystal structure and antimicrobial potential of some fluorinated chalcone-1,2,3-triazole conjugates.

PubMed

Yadav, Pinki; Lal, Kashmiri; Kumar, Lokesh; Kumar, Ashwani; Kumar, Anil; Paul, Avijit K; Kumar, Rajnish

2018-06-02

A simple and green synthesis of some fluorinated chalcone-triazole hybrids from propargylated chalcones and organic azides catalyzed by cellulose supported copper nanoparticles click reaction is reported. All the synthesized compounds were well characterized by various analytical and spectroscopic methods. The X-rays crystallographic study of compounds 6k revealed the self assembling properties. The antimicrobial screening results of all the synthesized compounds revealed that most of the triazole hybrids exhibited significant efficacy against tested bacterial and fungal strains. The activity results showed the synergistic effect of biological activity when two pharmacophoric units, i.e. chalcone and 1,2,3-triazole are conjugated. Further, docking simulation of the most active compounds 6p into Escherichia coli topoisomerase II DNA Gyrase B was also carried out. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Synthesis and biological evaluation of novel flavone/triazole/benzimidazole hybrids and flavone/isoxazole-annulated heterocycles as antiproliferative and antimycobacterial agents.

PubMed

Rao, Yerrabelly Jayaprakash; Sowjanya, Thummala; Thirupathi, Gogula; Murthy, Nandula Yadagiri Sreenivasa; Kotapalli, Sudha Sravanti

2018-06-04

A series of new flavone/isoxazole fused heterocycles 5a-f and flavone/1,2,3-triazole/benzimidazole hybrid heterocycles compounds 7a-t were synthesized via an intramolecular cyclization and Cu(I)-catalyzed click 1,3-dipolar cycloaddition. The products were evaluated for their antiproliferative activity against human breast cancer cell line (MCF-7) using sulforhodamine B assay (SRB) and antimycobacterial activity using turbidometric assay. The majority of the tested compounds exhibited antiproliferative activity and antimycobacterial activity. Compounds 7l, 7q and 7r showed moderate antiproliferative activity with IC50 values 17.9, 14.2, 19.1 [Formula: see text], respectively, and compound 5a showed moderate antimycobacterial activity with 41.7% of inhibition at 30 [Formula: see text] concentration.

Discovery of a novel general anesthetic chemotype using high-throughput screening.

PubMed

McKinstry-Wu, Andrew R; Bu, Weiming; Rai, Ganesha; Lea, Wendy A; Weiser, Brian P; Liang, David F; Simeonov, Anton; Jadhav, Ajit; Maloney, David J; Eckenhoff, Roderic G

2015-02-01

The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-aminoanthracene-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for γ-aminobutyric acid type A receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. From an initial chemical library of more than 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-aminoanthracene binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based on a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. The authors demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype.

A fundamental study on the structural integrity of magnesium alloys joined by friction stir welding

NASA Astrophysics Data System (ADS)

Rao, Harish Mangebettu

The goal of this research is to study the factors that influence the physical and mechanical properties of lap-shear joints produced using friction stir welding. This study focuses on understanding the effect of tool geometry and weld process parameters including the tool rotation rate, tool plunge depth and dwell time on the mechanical performance of similar magnesium alloy and dissimilar magnesium to aluminum alloy weld joints. A variety of experimental activities were conducted including tensile and fatigue testing, fracture surface and failure analysis, microstructure characterization, hardness measurements and chemical composition analysis. An investigation on the effect of weld process conditions in friction stir spot welding of magnesium to magnesium produced in a manner that had a large effective sheet thickness and smaller interfacial hook height exhibited superior weld strength. Furthermore, in fatigue testing of friction stir spot welded of magnesium to magnesium alloy, lap-shear welds produced using a triangular tool pin profile exhibited better fatigue life properties compared to lap-shear welds produced using a cylindrical tool pin profile. In friction stir spot welding of dissimilar magnesium to aluminum, formation of intermetallic compounds in the stir zone of the weld had a dominant effect on the weld strength. Lap-shear dissimilar welds with good material mixture and discontinues intermetallic compounds in the stir zone exhibited superior weld strength compared to lap-shear dissimilar welds with continuous formation of intermetallic compounds in the stir zone. The weld structural geometry like the interfacial hook, hook orientation and bond width also played a major role in influencing the weld strength of the dissimilar lap-shear friction stir spot welds. A wide scatter in fatigue test results was observed in friction stir linear welds of aluminum to magnesium alloys. Different modes of failure were observed under fatigue loading including crack propagation into the top sheet, into the bottom sheet, and interfacial separation. Investigation of the tested welds revealed that the voids in the weld nugget reduced the weld strength, resulting in lower fatigue life. A thin layer of IMCs formed along the faying surface which accelerated the fatigue failure.

Chemical function based pharmacophore generation of endothelin-A selective receptor antagonists.

PubMed

Funk, Oliver F; Kettmann, Viktor; Drimal, Jan; Langer, Thierry

2004-05-20

Both quantitative and qualitative chemical function based pharmacophore models of endothelin-A (ET(A)) selective receptor antagonists were generated by using the two algorithms HypoGen and HipHop, respectively, which are implemented in the Catalyst molecular modeling software. The input for HypoGen is a training set of 18 ET(A) antagonists exhibiting IC(50) values ranging between 0.19 nM and 67 microM. The best output hypothesis consists of five features: two hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI) function. The highest scoring Hip Hop model consists of six features: three hydrophobic (HY), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one negative ionizable (NI). It is the result of an input of three highly active, selective, and structurally diverse ET(A) antagonists. The predictive power of the quantitative model could be approved by using a test set of 30 compounds, whose activity values spread over 6 orders of magnitude. The two pharmacophores were tested according to their ability to extract known endothelin antagonists from the 3D molecular structure database of Derwent's World Drug Index. Thereby the main part of selective ET(A) antagonistic entries was detected by the two hypotheses. Furthermore, the pharmacophores were used to screen the Maybridge database. Six compounds were chosen from the output hit lists for in vitro testing of their ability to displace endothelin-1 from its receptor. Two of these are new potential lead compounds because they are structurally novel and exhibit satisfactory activity in the binding assay.

2[prime] and 3[prime] Carboranyl uridines and their diethyl ether adducts

DOEpatents

Soloway, A.H.; Barth, R.F.; Anisuzzaman, A.K.; Alam, F.; Tjarks, W.

1992-12-15

A process is described for preparing carboranyl uridine nucleoside compounds and their diethyl ether adducts, which exhibit a tenfold increase in boron content over prior art boron containing nucleoside compounds. The carboranyl uridine nucleoside compounds exhibit enhanced lipophilicity and hydrophilic properties adequate to enable solvation in aqueous media for subsequent incorporation of the compounds in methods for boron neutron capture therapy in mammalian tumor cells. No Drawings

2' and 3' Carboranyl uridines and their diethyl ether adducts

DOEpatents

Soloway, Albert H.; Barth, Rolf F.; Anisuzzaman, Abul K.; Alam, Fazlul; Tjarks, Werner

1992-01-01

There is disclosed a process for preparing carboranyl uridine nucleoside compounds and their diethyl ether adducts, which exhibit a tenfold increase in boron content over prior art boron containing nucleoside compounds. Said carboranyl uridine nucleoside compounds exhibit enhanced lipophilicity and hydrophilic properties adequate to enable solvation in aqueous media for subsequent incorporation of said compounds in methods for boron neutron capture therapy in mammalian tumor cells.

Influence of Various Phenolic Compounds on Properties of Gelatin Film Prepared from Horse Mackerel Trachurus japonicus Scales.

PubMed

Le, Thuy; Maki, Hiroki; Okazaki, Emiko; Osako, Kazufumi; Takahashi, Kigen

2018-06-15

Influence of various phenolic compounds on physical properties and antioxidant activity of gelatin film from horse mackerel Trachurus japonicus scales was investigated. Tensile strength (TS) of the film was enhanced whereas elongation at break was declined by adding 1% to 5% phenolic compounds. Rutin was the most effective to improve the TS compared to the other tested phenolic compounds including ferulic acid, caffeic acid, gallic acid, and catechin. Gelatin films with the phenolic compounds showed the excellent UV barrier properties. FTIR spectra exhibited that wavenumber of amide-A band of films decreased with formation of hydrogen bonding between amino groups of gelatin and hydroxyl groups of the phenolic compounds. Gelatin film incorporated with rutin which has the largest number of hydroxyl groups among the tested compounds demonstrated the lowest wavenumber for the amide-A peak. It is indicated that hydroxyl groups contained in the phenolic compounds contribute to formation of hydrogen bonds involved in improvement of the mechanical properties of the films. The incorporation of the phenolic compounds with gelatin films also led to the increasing of total phenolic contents and DPPH radical scavenging activities. Thus, it is concluded that phenolic compounds can promote the quality of gelatin film. Properties of gelatin film derived from horse mackerel scales can be improved by adding of phenolic compounds. Phenolic compounds containing a large number of hydroxyl groups should be selected to enhance physical properties of the gelatin film. A biodegradable film prepared from horse mackerel gelatin incorporated with phenolic compounds, which has good physical properties and antioxidant properties, can solve environmental problems caused by synthetic plastic materials. © 2018 Institute of Food Technologists®.

Green synthesis of nano sized transition metal complexes containing heterocyclic Schiff base: Structural and morphology characterization and bioactivity study

NASA Astrophysics Data System (ADS)

Jawoor, Shailaja S.; Patil, Sangamesh A.; Kumbar, Mahantesh; Ramawadgi, Prashant B.

2018-07-01

In the current involvement of our research work in coordination chemistry, novel transition metal complexes were synthesized from regular reflux method and hydrothermal method using Schiff base prepared via condensation of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate with 8-carbaldehyde-7-hydroxy-4-methylcoumarin. All the synthesized compounds were interpreted using different analytical, physicochemical and spectral methods such as magnetic moment measurement, FT-IR, 1H and 13C NMR, GCMS/ESI-MS, UV/Vis spectroscopy and TGA. The size and morphology of the nano metal complexes were determined using atomic force microscope (AFM), field emission scanning electron spectroscopy (FE-SEM) and X-ray powder diffraction (PXRD). The non-electrolytic nature of the metal complexes was confirmed by molar conductance studies. The obtained FT-IR data supports the binding of metal ion to Schiff base. Elemental analysis study suggests [ML2(H2O)2] stoichiometry, here M = Co(II), Ni(II) and Cu(II), L = deprotonated ligand. Electronic spectral results reveal six-coordinated geometry for the synthesized metal complexes. All the tested compounds show good DNA cleavage (Calf Thymus DNA) and in vitro anticancer activity (PA-I cell line), the activity results for the tested compounds are prominent and compound 9 exhibited a little enhanced activity than the other tested compounds.

Synthesis and anticancer evaluation of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and Mannich bases.

PubMed

Megally Abdo, Nadia Youssef; Kamel, Mona Monir

2015-01-01

A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a-d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a-d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a-d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a-d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a-d with formaldehyde and various secondary amines furnished the Mannich bases 6a-p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.021 µM) than the standard CHS 828 (IC50=0.025 µM). Normal fibroblast cells WI38 were affected to a much lesser extent (IC50>10 µM).

Novel ciprofloxacin hybrids using biology oriented drug synthesis (BIODS) approach: Anticancer activity, effects on cell cycle profile, caspase-3 mediated apoptosis, topoisomerase II inhibition, and antibacterial activity.

PubMed

Kassab, Asmaa E; Gedawy, Ehab M

2018-04-25

As we are interested in synthetizing biologically active leads with dual anticancer and antibacterial activity, we adopted biology oriented drug synthesis (BIODS) strategy to synthesize a series of novel ciprofloxacin (CP) hybrids. The National Cancer Institute (USA) selected seventeen newly synthesized compounds for anticancer evaluation against 59 different human tumor cell lines. Five compounds 3e, 3f, 3h, 3o and 3p were further studied through determination of IC 50 values against the most sensitive cancer cell lines. In vitro results showed that the five compounds exhibited potent anticancer activity against test cell lines in nanomolar to micromolar range, with IC 50 values between 0.72 and 4.92 μM, which was 9 to1.5 folds more potent than doxorubicin. In this study, two promising potent anticancer CP hybrids, 3f and 3o, were identified. The anti-proliferative activity of these compounds appears to correlate well with their ability to inhibit Topo II (IC 50  = 0.58 and 0.86 μM). It is worth mentioning that compound 3f was 6 folds more potent than doxorubicin, 5 folds more potent than amsacrine and 1.5 folds more potent than etoposide. At the same time, compound 3o showed 4 folds more inhibitory activity against Topo II than doxorubicin, 3 folds more potent than amsacrine and almost equipotent activity to etoposide. Activation of damage response pathway of the DNA leads to cell cycle arrest at G2/M phase, accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining, indicating that cell death proceeds through an apoptotic mechanism. Moreover, compounds 3f and 3o showed potent pro-apoptotic effect through induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was confirmed by a significant increase in the level of active caspase-3 compared to control. This observation may indicate that both CP hybrids can chelate with zinc, a powerful inhibitor of procaspase-3 enzymatic activity, so procaspase-3 may process itself to the active form. The synthesized CP derivatives were tested for their in vitro antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa strains. The results proved that all of the test compounds have shown good to excellent antibacterial activity, as compared to its parent molecule ciprofloxacin. Compounds 2, 3b, 3k, 3l, 3m, 3p, 5a, 5b, 5d and 5e exhibited equipotent or comparable activity to ciprofloxacin against the test strains. Compounds 3p and 5a were more potent than ciprofloxacin against Pseudomonas aeruginosa, a common organism causing infections in granulocytopenic cancer patients. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

A bioactive sesquiterpene from Bixa orellana.

PubMed

Raga, Dennis D; Espiritu, Rafael A; Shen, Chien-Chang; Ragasa, Consolacion Y

2011-01-01

A dichloromethane extract of the air-dried leaves of Bixa orellana afforded ishwarane 1, phytol 2, polyprenol 3, and a mixture of stigmasterol 4a and sitosterol 4b by silica gel chromatography. The structure of 1 was elucidated by extensive 1D and 2D NMR spectroscopy. Compound 1 at three doses (25, 50, and 100 mg/kg BW) was tested for prophylactic, gastrointestinal motility, analgesic, hypoglycemic, and antimicrobial potentials. Results of the prophylactic assay demonstrated the anti-toxic property of 1 at 100 mg/kg BW. A 50 mg/kg BW dose of 1 resulted in a more propulsive movement of the gastrointestinal tract (88.38 ± 13.59%) compared to the negative control (78.47 ± 10.61%). Tail flick and acetic acid writhing tests indicated that 100 mg/kg BW 1 had minimal analgesic activity. Compound 1 demonstrated no hypoglycemic potential on the animals tested. Compound 1 exhibited moderate antifungal activity against C. albicans, low activity against T. mentagrophytes, and low antibacterial activity against E. coli, S. aureus, and P. aeruginosa. It was inactive against B. subtilis and A. niger.

Antimicrobial activity and molecular docking studies of a novel anthraquinone from a marine-derived fungus Aspergillus versicolor.

PubMed

Wang, Weiyi; Chen, Ruixuan; Luo, Zhuhua; Wang, Wei; Chen, Jianming

2018-03-01

A novel anthraquinone, 2-(dimethoxymethyl)-1-hydroxyanthracene-9,10-dione (1), together with nine known compounds (2-10), were isolated from the fermentation of Aspergillus versicolor derived from deep sea sediment. Their structures were established through spectroscopic methods. Compound 1 exhibited strong inhibitory activities against MRSA ATCC 43300 and MRSA CGMCC 1.12409 (with MIC values of 3.9 and 7.8 μg/mL respectively) and moderate activities against tested strains of Vibrio (with MIC values ranging from 15.6 to 62.5 μg/mL). Compound 1 was subjected to molecular docking studies for inhibition of topoisomerase IV and AmpC β-lactamase enzymes indicating its usefulness as antimicrobial agent.

Cytotoxic Steroids from the Vietnamese Soft Coral Sinularia conferta.

PubMed

Ngoc, Ninh Thi; Huong, Pham Thi Mai; Thanh, Nguyen Van; Chi, Nguyen Thi Phuong; Dang, Nguyen Hai; Cuong, Nguyen Xuan; Nam, Nguyen Hoai; Thung, Do Cong; Kiem, Phan Van; Minh, Chau Van

2017-03-01

Twelve steroids, including five new compounds 1-5, were isolated and structurally elucidated from a methanol extract of the Vietnamese soft coral Sinularia conferta. Their cytotoxic effects against three human cancer cell lines, lung carcinoma (A-549), cervical adenocarcinoma (HeLa), and pancreatic epithelioid carcinoma (PANC-1), were evaluated using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assays. Among isolated compounds, 10 exhibited potent cytotoxic effects on all three tested cell lines with IC 50 values of 3.64±0.18, 19.34±0.42, and 1.78±0.69 µM, respectively.

β-Sitosterol and flavonoids isolated from Bauhinia malabarica found during screening for Wnt signaling inhibitory activity.

PubMed

Park, Hyun Young; Toume, Kazufumi; Arai, Midori A; Koyano, Takashi; Kowithayakorn, Thaworn; Ishibashi, Masami

2014-01-01

Screening with a cell-based luciferase assay was conducted to identify bioactive natural products which inhibit Wnt signaling activity-guided separation of an MeOH extract of Bauhinia malabarica (Caesalpiniaceae) leaves yielded five compounds, which were identified as β-sitosterol (1), quercetin (2), 6,8-C-dimethyl kaempferol-3-O-rhamnopyranoside (3), hyperin (4), and 6,8-C-dimethyl kaempferol-3-methyl ether (5). The tested compounds 1, 3, and 5 exhibited Wnt signaling inhibitory activity, with IC50 values of 0.77, 0.74, and 16.6 μM, respectively.

Synthesis and biological evaluation of (E)-1-(substituted)-3-phenylprop-2-en-1-ones bearing rhodanines as potent anti-microbial agents.

PubMed

Song, Ming-Xia; Deng, Xian-Qing; Li, Ya-Ru; Zheng, Chang-Ji; Hong, Lan; Piao, Hu-Ri

2014-10-01

Herein, we report the design, syntheses and in vitro anti-microbial activity of two series of rhodanines with chalcone moiety. Anti-microbial tests showed that some of the synthesized compounds exhibited good inhibition (MIC = 1-8 µg/mL) against multi-drug-resistant Gram-positive organisms, including methicillin resistant and quinolone-resistant Staphylococcus aureus, in which the compound 4g was found to be the most potent with minimum inhibitory concentration (MIC) value of 1 µg/mL against two methicillin-resistant S. aureus.

Antifungal activity of eicosanoic acids isolated from the endophytic fungus Mycosphaerella sp. against Cryptococcus neoformans and C. gattii.

PubMed

Pereira, Cristiane Bigatti; Pereira de Sá, Nívea; Borelli, Beatriz Martins; Rosa, Carlos Augusto; Barbeira, Paulo Jorge Sanches; Cota, Betania Barros; Johann, Susana

2016-11-01

The antifungal effects of two eicosanoic acids, 2-amino-3,4-dihydroxy-2-25-(hydroxymethyl)-14-oxo-6,12-eicosenoic acid (compound 1) and myriocin (compound 2), isolated from Mycosphaerella sp. were evaluated against Cryptococcus neoformans and C. gattii. The compounds displayed antifungal activities against several isolates of C. neoformans and C. gattii, with minimal inhibitory concentration (MIC) values ranging from 0.49 to 7.82 μM for compound 1 and 0.48-1.95 μM for compound 2. In the checkerboard microtiter test, both compounds exhibited synergistic activity with amphotericin B against C. gattii. Ultrastructural analysis revealed several signs of damage in C. gattii and C. neoformans cells treated with compounds 1 and 2, including deformities in cell shape, depressions on the surface, and withered cells. The cells of C. gattii treated with compounds 1 and 2 showed less loss of cellular material in comparison to those treated with amphotericin B. The difference in cellular material loss increased in a test compound concentration-dependent manner. Consistent with this observation, compounds 1 and 2 were able to internalize propidium iodide (PI) in C. gattii cells. In addition, compound 2 induced the formation of several pseudohyphae, suggesting that it could reduce virulence in C. gattii cells. The study results show that these natural products led to membrane damage; however, this may not be the main target of action. These compounds have potential antifungal activity and could be useful in further studies for developing more effective combination therapies with amphotericin B and reducing side effects in patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antiprotozoal, antimycobacterial, and anti-inflammatory evaluation of Cnidoscolus chayamansa (Mc Vaugh) extract and the isolated compounds.

PubMed

Pérez-González, Mariana Z; Gutiérrez-Rebolledo, Gabriel A; Yépez-Mulia, Lilián; Rojas-Tomé, Irma S; Luna-Herrera, Julieta; Jiménez-Arellanes, María A

2017-05-01

Cnidoscolus chayamansa is a medicinal and edible plant known as Chaya, is commonly used as an anti-inflammatory, antiprotozoal, antibacterial agent and as a remedy for respiratory illness, gastrointestinal disorders, and vaginal infections related with the inflammation process. In this paper, we describe the plant's phytochemical analysis and biological activities (antimycobacterial, antibacterial, antiprotozoal, and anti-inflammatory properties) of the CHCl 3 :MeOH (1:1) leaves extract and isolated compounds, as well as the acute and sub-acute toxic effects. Chemical identification of isolated compounds was performed by 1 H- and 13 C NMR spectra data. In vitro antibacterial and antimycobacterial activities were determined by disc diffusion and MABA assays, respectively; antiprotozoal test by means of the sub-culture test. Topical and systemic anti-inflammatory effects were tested by TPA and carrageenan assay on BALB/c mice. Moretenol, moretenyl acetate, kaempferol-3,7-dimethyl ether, and 5-hydroxy-7-3',4'-trimethoxyflavanone were the main compounds isolated. The CHCl 3 :MeOH extract showed antiprotozoal (IC 50 ≤65.29μg/mL), antimycobacterial (MIC≤50μg/mL), and anti-inflammatory activities (ED 50 =1.66mg/ear and 467.73mg/kg), but was inactive against the bacterial strains tested. The LD 50 for extract was >2g/kg. In the sub-acute toxicity test, the extract was administered at 1g/kg for 28days and did not cause lethality or any alteration in hematological and biochemical parameters; in addition, liver, kidney, and spleen histological analysis exhibited no structural changes. Moretenol and moretenyl acetate showed MIC=25μg/mL against Mycobacterium tuberculosis H37Rv and against four monoresistant strains of M. tuberculosis H37Rv. Both compounds exhibited moderate activity against Entamoeba histolytica and Giardia lamblia (IC 50 ≤71.70μg/mL). Kaempferol-3,7-dimethyl ether and 5-hydroxy-7-3',4'-trimethoxy-flavanone were more active than the extract against E. histolytica and G. lamblia, showing IC 50 ≤27.43μg/mL. As topical anti-inflammatory agents, moretenol and kaempferol-3,7-dimethyl ether were the most active compounds inhibiting the edema in 30.52 and 26.67%, respectively. Moretenol and moretenyl acetate showed significant antimycobacterial and antiprotozoal activities; in addition, important antiprotozoal effect was detected with kaempferol-3,7-dimethyl ether and 5-hydroxy-7-3',4'-trimethoxyflavanone. The extract and the terpenoids possess good anti-inflammatory activity. The extract did not produce lethality or adverse effects in acute and sub-acute tests. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The effects of plant essential oils on escape response and mortality rate of Aedes aegypti and Anopheles minimus.

PubMed

Sathantriphop, Sunaiyana; Achee, Nicole L; Sanguanpong, Unchalee; Chareonviriyaphap, Theeraphap

2015-12-01

The High Throughput Screening System (HITSS) has been applied in insecticide behavioral response studies with various mosquito species. In general, chemical or natural compounds can produce a range of insect responses: contact irritancy, spatial repellency, knock-down, and toxicity. This study characterized these actions in essential oils derived from citronella, hairy basil, catnip, and vetiver in comparison to DEET and picaridin against Aedes aegypti and Anopheles minimus mosquito populations. Results indicated the two mosquito species exhibited significantly different (P<0.05) contact irritant escape responses between treatment and control for all tested compound concentrations, except with the minimum dose of picaridin (P>0.05) against Ae. aegypti. Spatial repellency responses were elicited in both mosquito species when exposed to all compounds, but the strength of the repellent response was dependent on compound and concentration. Data show that higher test concentrations had greatest toxic effects on both mosquito populations, but vetiver had no toxic effect on Ae. aegypti and picaridin did not elicit toxicity in either Ae. aegypti or An. minimus at any test concentration. Ultimately, this study demonstrates the ability of the HITSS assay to guide selection of effective plant essential oils for repelling, irritating, and killing mosquitoes. © 2015 The Society for Vector Ecology.

Use of a standardized JaCVAM in vivo rat comet assay protocol to assess the genotoxicity of three coded test compounds; ampicillin trihydrate, 1,2-dimethylhydrazine dihydrochloride, and N-nitrosodimethylamine.

PubMed

McNamee, J P; Bellier, P V

2015-07-01

As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), our laboratory examined ampicillin trihydrate (AMP), 1,2-dimethylhydrazine dihydrochloride (DMH), and N-nitrosodimethylamine (NDA) using a standard comet assay validation protocol (v14.2) developed by the JaCVAM validation management team (VMT). Coded samples were received by our laboratory along with basic MSDS information. Solubility analysis and range-finding experiments of the coded test compounds were conducted for dose selection. Animal dosing schedules, the comet assay processing and analysis, and statistical analysis were conducted in accordance with the standard protocol. Based upon our blinded evaluation, AMP was not found to exhibit evidence of genotoxicity in either the rat liver or stomach. However, both NDA and DMH were observed to cause a significant increase in % tail DNA in the rat liver at all dose levels tested. While acute hepatoxicity was observed for these compounds in the high dose group, in the investigators opinion there were a sufficient number of consistently damaged/measurable cells at the medium and low dose groups to judge these compounds as genotoxic. There was no evidence of genotoxicity from either NDA or DMH in the rat stomach. In conclusion, our laboratory observed increased DNA damage from two blinded test compounds in rat liver (later identified as genotoxic carcinogens), while no evidence of genotoxicity was observed for the third blinded test compound (later identified as a non-genotoxic, non-carcinogen). This data supports the use of a standardized protocol of the in vivo comet assay as a cost-effective alternative genotoxicity assay for regulatory testing purposes. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

Synthesis and Biological Evaluation of Ginsenoside Compound K Derivatives as a Novel Class of LXRα Activator.

PubMed

Huang, Yan; Liu, Hongmei; Zhang, Yingxian; Li, Jin; Wang, Chenping; Zhou, Li; Jia, Yi; Li, Xiaohui

2017-07-24

Compound K is one of the active metabolites of Panaxnotoginseng saponins, which could attenuate the formation of atherosclerosis in mice modelsvia activating LXRα. We synthesized and evaluated a series of ginsenoside compound K derivatives modified with short chain fatty acids. All of the structures of this class of ginsenoside compound K derivative exhibited comparable or better biological activity than ginsenoside compound K. Especially structure 1 exhibited the best potency (cholesteryl ester content: 41.51%; expression of ABCA1 mRNA: 319%) and low cytotoxicity.

Synthesis, Characterization and Biological Evaluation of Some Quinoxaline Derivatives: A Promising and Potent New Class of Antitumor and Antimicrobial Agents.

PubMed

Al-Marhabi, Aisha R; Abbas, Hebat-Allah S; Ammar, Yousry A

2015-11-03

In continuation of our endeavor towards the development of potent and effective anticancer and antimicrobial agents; the present work deals with the synthesis of some novel tetrazolo[1,5-a]quinoxalines, N-pyrazoloquinoxalines, the corresponding Schiff bases, 1,2,4-triazinoquinoxalines and 1,2,4-triazoloquinoxalines. These compounds were synthesized via the reaction of the key intermediate hydrazinoquinoxalines with various reagents and evaluated for anticancer and antimicrobial activity. The results indicated that tetrazolo[1,5-a]quinoxaline derivatives showed the best result, with the highest inhibitory effects towards the three tested tumor cell lines, which were higher than that of the reference doxorubicin and these compounds were non-cytotoxic to normal cells (IC50 values > 100 μg/mL). Also, most of synthesized compounds exhibited the highest degrees of inhibition against the tested strains of Gram positive and negative bacteria, so tetrazolo[1,5-a]quinoxaline derivatives show dual activity as anticancer and antimicrobial agents.

Screening of analgesic activity of Tunisian Urtica dioica and analysis of its major bioactive compounds by GCMS.

PubMed

Dhouibi, Raouia; Moalla, Dorsaf; Ksouda, Kamilia; Ben Salem, Maryem; Hammami, Serria; Sahnoun, Zouheir; Zeghal, Khaled Mounir; Affes, Hanen

2017-11-20

The present study was aimed to evaluate the analgesic properties of Urtica dioica (UD) and to profile phytochemicals by gas chromatography-mass spectrometry (GC-MS). The ethanolic extracts were prepared by maceration method and extraction using rotary evaporator. The analgesic activity was analysed by hot plate method, formalin test, acetic acid-induced writhing test and the tail-flick test with different doses of the ethanolic extract. In all tests, the leaf's ethanolic extract exhibited significant analgesic activity (p < .001) at a dose of 400 mg/kg. Even with a low dose, we noticed an analgesic activity with many tests. The GC-MS analysis of the ethanol extract of leaf revealed many compounds; 2-methyltetradecane dodecane, 2,6,11-trimethyl-; 2,6,11-trimethyldodecane, and trimethylhexane which are pharmaceutically the most important. These findings justify that UD can be a valuable natural analgesic source which seemed to provide potential phototherapeutics against various ailments. The analysis of ethanolic extract of UD by GCMS revealed the presence of several compounds including polyphenols, flavonoids, triterpenes which can explain the analgesic effect of UD and its mechanism of action. Hence, UD could be another therapeutic alternative for relieving pain and for minimising the use of drugs that have long-term secondary effects.

Bis-Indolyl Benzenoids, Hydroxypyrrolidine Derivatives and Other Constituents from Cultures of the Marine Sponge-Associated Fungus Aspergillus candidus KUFA0062

PubMed Central

Ramos, Alice A.; Inácio, Ângela; Dethoup, Tida; Lee, Michael; Sekeroglu, Nazim; Rocha, Eduardo

2018-01-01

A previously unreported bis-indolyl benzenoid, candidusin D (2e) and a new hydroxypyrrolidine alkaloid, preussin C (5b) were isolated together with fourteen previously described compounds: palmitic acid, clionasterol, ergosterol 5,8-endoperoxides, chrysophanic acid (1a), emodin (1b), six bis-indolyl benzenoids including asterriquinol D dimethyl ether (2a), petromurin C (2b), kumbicin B (2c), kumbicin A (2d), 2″-oxoasterriquinol D methyl ether (3), kumbicin D (4), the hydroxypyrrolidine alkaloid preussin (5a), (3S, 6S)-3,6-dibenzylpiperazine-2,5-dione (6) and 4-(acetylamino) benzoic acid (7), from the cultures of the marine sponge-associated fungus Aspergillus candidus KUFA 0062. Compounds 1a, 2a–e, 3, 4, 5a–b, and 6 were tested for their antibacterial activity against Gram-positive and Gram-negative reference and multidrug-resistant strains isolated from the environment. Only 5a exhibited an inhibitory effect against S. aureus ATCC 29213 and E. faecalis ATCC29212 as well as both methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) strains. Both 1a and 5a also reduced significant biofilm formation in E. coli ATCC 25922. Moreover, 2b and 5a revealed a synergistic effect with oxacillin against MRSA S. aureus 66/1 while 5a exhibited a strong synergistic effect with the antibiotic colistin against E. coli 1410/1. Compound 1a, 2a–e, 3, 4, 5a–b, and 6 were also tested, together with the crude extract, for cytotoxic effect against eight cancer cell lines: HepG2, HT29, HCT116, A549, A 375, MCF-7, U-251, and T98G. Except for 1a, 2a, 2d, 4, and 6, all the compounds showed cytotoxicity against all the cancer cell lines tested. PMID:29642369

Some Novel Mannich Bases of 5-(3,4-Dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and Their Anti-Inflammatory Activity.

PubMed

Koksal, Meric; Ozkan-Dagliyan, Irem; Ozyazici, Tugce; Kadioglu, Beril; Sipahi, Hande; Bozkurt, Ayhan; Bilge, Suleyman S

2017-09-01

Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of rheumatic arthritis, pain, and many different types of inflammatory disorders, cause serious gastrointestinal (GI) side effects. The free carboxylic acid group existing on their chemical structure is correlated with GI toxicity related with all routine NSAIDs. Replacing this functional group with the 1,3,4-oxadiazole bioisostere is a generally used strategy to obtain an anti-inflammatory agent devoid of GI side effects. In the present work, a novel group of 5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one Mannich bases were synthesized and characterized on the basis of IR, 1 H NMR, and elemental analysis results. The target compounds were first tested for cytotoxicity to determine a non-toxic concentration for anti-inflammatory screening. Anti-inflammatory effects of the compounds were evaluated by in vitro lipopolysaccharide (LPS)-induced NO production and in vivo carrageenan footpad edema with ulcerogenic profile. In LPS-induced RAW 264.7 macrophages, most of the compounds showed inhibitory activity on nitrite production while compounds 5a, 5h, and 5j exhibited the best profiles by suppressing the NO production. To evaluate the in vivo anti-inflammatory potency of the compounds, the inflammatory response was quantified by increment in paw size in the carrageenan footpad edema assay. The anti-inflammatory data scoring showed that compounds 5a-d, 5g, and 5j, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5g was comparable to that of the reference drug indomethacin with 53.9% and 55.5% inhibition in 60 and 120 min, respectively. © 2017 Deutsche Pharmazeutische Gesellschaft.

Discovery of a low-systemic-exposure DGAT-1 inhibitor with a picolinoylpyrrolidine-2-carboxylic acid moiety.

PubMed

Yan, Jianwei; Wang, Gaihong; Dang, Xiangyu; Guo, Binbin; Chen, Wuhong; Wang, Ting; Zeng, Limin; Wang, Heyao; Hu, Youhong

2017-09-01

A series of diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors with a picolinoylpyrrolidine-2-carboxylic acid moiety were designed and synthesized. Of these compounds, compound 22 exhibited excellent DGAT-1-inhibitory activity (hDGAT-1 enzyme assay, 50% inhibitory concentration [IC 50 ]=3.5±0.9nM) and effectively reduced the intracellular triglyceride contents in 3T3-L1, HepG2 and Caco-2 cells. A preliminary study of the plasma and tissue distributions of compound 22 in mice revealed low plasma exposure and high concentrations in different segments of the intestine and liver, which may facilitate targeting DGAT-1. Furthermore, in an acute lipid challenge test, compound 22 showed a dose-dependent inhibitory effect on high-serum triglycerides in C57/KSJ mice induced by olive oil (1, 3, and 10mg/kg, i.g.). Copyright © 2017 Elsevier Ltd. All rights reserved.

Screening for fractions of Oxytropis falcata Bunge with antibacterial activity.

PubMed

Jiang, H; Hu, J R; Zhan, W Q; Liu, X

2009-01-01

Preliminary studies with the four extracts of Oxytropis falcate Bunge exhibited that the chloroform and ethyl acetate extracts showed stronger antibacterial activities against the nine tested Gram-positive and Gram-negative bacteria. The HPLC-scanned and bioassay-guided fractionation led to the isolation and identification of the main flavonoid compounds, i.e. rhamnocitrin, kaempferol, rhamnetin, 2',4'-dihydroxychalcone and 2',4',beta-trihydroxy-dihydrochalcon. Except 2',4',beta-trihydroxy-dihydrochalcon, four other compounds had good antibacterial activities. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of the four compounds ranged between 125 and 515 microg mL(-1). Staphylococcus aureus was the most susceptible to these compounds, with MIC and MBC values from 125 to 130 microg mL(-1). This is the first report of antibacterial activity in O. falcate Bunge. In this study, evidence to evaluate the biological functions of O. falcate Bunge is provided, which promote the rational use of this herb.

Thermoelectric properties of Nb3SbxTe7-x compounds

NASA Technical Reports Server (NTRS)

Snyder, J.; Wang, S.; Caillat, T.

2002-01-01

Niobium antimony telluride, Nb3Sbx,Te7-x, was synthesized and tested for thermoelectric properties in the Thermoelectrics group at the Jet Propulsion Laboratory. The forty atoms per unit cell of Nb3Sb2Te5 and its varied mixture of atoms yield acomplicated structure, suggesting that Nb3Sb2Te5 and related compounds may exhibit low thermal conductivity and hence a higher ZT value. Nb3SbxTe7-x, compounds were synthesized and subsequently analyzed for their Seebeck voltage, heat conduction, and electrical resistivity. Results indicate that Nb3Sb2Te5 is a heavily doped semiconductor whose thermoelectric properties are compromised by compensating n-type and p-type carriers. Attempts to dope in favor of either carrier by varying the Sb:Te ratio yielded samples containing secondary metallic phases that dominated the transport properties of the resulting compounds.

Kushenol A and 8-prenylkaempferol, tyrosinase inhibitors, derived from Sophora flavescens.

PubMed

Kim, Jang Hoon; Cho, In Sook; So, Yang Kang; Kim, Hyeong-Hwan; Kim, Young Ho

2018-12-01

Tyrosinase is known for an enzyme that plays a key role in producing the initial precursor of melanin biosynthesis. Inhibition of the catalytic reaction of this enzyme led to some advantage such as skin-whitening and anti-insect agents. To find a natural compound with inhibitory activity towards tyrosinase, the five flavonoids of kushenol A (1), 8-prenylkaempferol (2), kushenol C (3), formononetin (4) and 8-prenylnaringenin (5) were isolated by column chromatography from a 95% methanol extract of Sophora flavescens. The ability of these flavonoids to block the conversion of L-tyrosine to L-DOPA by tyrosinase was tested in vitro. Compounds 1 and 2 exhibited potent inhibitory activity, with IC50 values less than 10 µM. Furthermore, enzyme kinetics and molecular docking analysis revealed the formation of a binary encounter complex between compounds 1-4 and the enzyme. Also, all of the isolated compounds (1-5) were confirmed to possess antioxidant activity.

Eugenol and its structural analogs inhibit monoamine oxidase A and exhibit antidepressant-like activity.

PubMed

Tao, Guoxin; Irie, Yoshifumi; Li, Dian-Jun; Keung, Wing Ming

2005-08-01

Eugenol (1) is an active principle of Rhizoma acori graminei, a medicinal herb used in Asia for the treatment of symptoms reminiscent of Alzheimer's disease (AD). It has been shown to protect neuronal cells from the cytotoxic effect of amyloid beta peptides (Abetas) in cell cultures and exhibit antidepressant-like activity in mice. Results from this study show that eugenol inhibits monoamine oxidase A (MAOA) preferentially with a K(i)=26 microM. It also inhibits MAOB but at much higher concentrations (K(i)=211 microM). In both cases, inhibition is competitive with respect to the monoamine substrate. Survey of compounds structurally related to eugenol has identified a few that inhibit MAOs more potently. Structure activity relationship reveals structural features important for MAOA and MAOB inhibition. Molecular docking experiments were performed to help explain the SAR outcomes. Four of these compounds, two (1, 24) inhibiting MAOA selectively and the other two (19, 21) inhibiting neither MAOA nor MAOB, were tested for antidepressant-like activity using the forced swim test in mice. Results suggest a potential link between the antidepressant activity of eugenol and its MAOA inhibitory activity.

Medicinal Uses, Phytochemistry, and Pharmacology of Origanum onites (L.): A Review.

PubMed

Tepe, Bektas; Cakir, Ahmet; Sihoglu Tepe, Arzuhan

2016-05-01

Origanum onites L., known as Turkish oregano, has great traditional, medicinal, preservative, and commercial importance. It is used for the treatment of several kinds of ailments, such as gastrointestinal disorders, diabetes, high cholesterol, leukemia, bronchitis, etc. In this review, traditional use, phytochemistry, and pharmacology of O. onites reported between 1988 and 2014 were discussed. This review was prepared based on literature survey on scientific journals and books from libraries and electronic sources, such as Web of Science, PubMed, Scopus, Google Scholar, etc. All databases were searched up to June 2014. Several different classes of terpenoids, triterpene acids, phenolic acids, hydroquinones, flavonoids, hydrocarbons, sterols, pigments, fatty acids, tocopherols, and inorganic compounds were detected mainly in the aerial parts of this plant. Pharmacological studies revealed that extracts obtained from several solvents and individual compounds exhibited antimicrobial, antiviral, antioxidant, insecticidal, anticancer, hepatoprotective, genotoxic, antidiabetic, cholinesterase inhibitory, anti-inflammatory, analgesic activities, etc. O. onites, in general, exhibited remarkable activity potential in almost all test systems. The results of toxicity studies indicated that O. onites did not show any significant toxicity and mutagenicity on Drosophila and Salmonella. Toxicity of the extracts/essential oils and also individual compounds should be evaluated on mammalian cells to ensure their safety. The bioactivity of individual compounds aside from terpenoids should also be assessed in detail. Additionally, mode of action for the bioactive compounds should be evaluated to understand the complex pharmacological effects of these phytochemicals. © 2016 Verlag Helvetica Chimica Acta AG, Zürich.

Human ACAT inhibitory effects of shikonin derivatives from Lithospermum erythrorhizon.

PubMed

An, Sojin; Park, Yong-Dae; Paik, Young-Ki; Jeong, Tae-Sook; Lee, Woo Song

2007-02-15

Three naphthoquinones were isolated by bioassay-guided fractionation from the CHCl(3) extracts of roots of Lithospermum erythrorhizon. They were identified as acetylshikonin (1), isobutyrylshikonin (2), and beta-hydroxyisovalerylshikonin (3) on the basis of their spectroscopic analyses. The compounds 1-3 were tested for their inhibitory activities against human ACAT-1 (hACAT-1) or human ACAT-2 (hACAT-2). Compound 2 preferentially inhibited hACAT-2 (IC(50)=57.5microM) than hACAT-1 (32% at 120microM), whereas compounds 1 and 3 showed weak inhibitory activities in both hACAT-1 and -2. To develop more potent hACAT inhibitor, shikonin derivatives (5-11) were synthesized by semi-synthesis of shikonin (4), which was prepared by hydrolysis of 1-3. Among them, compounds 5 and 7 exhibited the strong inhibitory activities against hACAT-1 and -2. Furthermore, we demonstrated that compound 7 behaved as a potent ACAT inhibitor in not only in vitro assay system but also cell-based assay system.

Formation and ecotoxicity of N-heterocyclic compounds on ammoxidation of mono- and polysaccharides.

PubMed

Klinger, Karl Michael; Liebner, Falk; Fritz, Ines; Potthast, Antje; Rosenau, Thomas

2013-09-25

Ammoxidation of technical lignins under mild conditions is a suitable approach to artificial humic substances. However, carbohydrates as common minor constituents of technical lignins have been demonstrated to be a potential source of N-heterocyclic ecotoxic compounds. Ethyl acetate extracts of ammoxidation mixtures of the monosaccharides glucose and xylose exhibited considerable growth inhibiting activity in the OECD 201 test, with 4-methyl-1H-imidazole, 4-(hydroxymethyl)-1H-imidazole, and 3-hydroxypyridine being the most active compounds. The amount of N-heterocyclic compounds formed at moderate ammoxidation conditions (70 °C, 0.2 MPa O2, 3 h) was significantly lower for the polysaccharides cellulose and xylan (16-30 μg/g of educt) compared to glucose (15.4 mg). Ammoxidation at higher temperature is not recommendable for carbohydrate-rich materials as much higher amounts of N-heterocyclic compounds were formed from both monosaccharides (100 °C: 122.4-160.5 mg/g of educt) and polysaccharides (140 °C: 5.52-16.03 mg/g of educt).

Antioxidant and α-glucosidase inhibitory ingredients identified from Jerusalem artichoke flowers.

PubMed

Wang, Yan-Ming; Zhao, Jian-Qiang; Yang, Jun-Li; Idong, Pema Tsering; Mei, Li-Juan; Tao, Yan-Duo; Shi, Yan-Ping

2017-11-09

Jerusalem artichoke (JA, Helianthus tuberosus L.) has been researched extensively due to its wide range of uses, but there are limited studies on its flowers. In this study, we report the first detailed phytochemical study on JA flowers, which yielded 21 compounds. Compound 4 was identified as a major water-soluble yellow pigment of JA flowers. In addition, the methanol extract of JA flowers and the isolates were evaluated for their antioxidant and α-glucosidase inhibitory activities. Among the tested compounds, compound 13 showed the strongest ABTS + free radical scavenging activity with SC 50 value of 2.30 ± 0.13 μg/mL, and compound 6 showed most potent α-glucosidase inhibitory activity with inhibition rate of 60.0% ± 10.3% at a concentration of 250 μg/mL. Results showed that methanol extract of JA flowers exhibited antioxidant and α-glucosidase inhibitory activities which could be attributed to its phenolic ingredients including chlorogenic acid derivatives, flavonoids and phenols.

Discovery of a Novel General Anesthetic Chemotype Using High-throughput Screening

PubMed Central

McKinstry-Wu, Andrew R.; Bu, Weiming; Rai, Ganesha; Lea, Wendy A.; Weiser, Brian P.; Liang, David F.; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.; Eckenhoff, Roderic G.

2014-01-01

Background The development of novel anesthetics has historically been a process of combined serendipity and empiricism, with most recent new anesthetics developed via modification of existing anesthetic structures. Methods Using a novel high-throughput screen employing the fluorescent anesthetic 1-aminoanthracene (1-AMA) and apoferritin as a surrogate for on-pathway anesthetic protein target(s), we screened a 350,000 compound library for competition with 1-AMA-apoferritin binding. Hit compounds meeting structural criteria had their binding affinities for apoferritin quantified with isothermal titration calorimetry and were tested for γ-aminobutyric acid type A-receptor binding using a flunitrazepam binding assay. Chemotypes with a strong presence in the top 700 and exhibiting activity via isothermal titration calorimetry were selected for medicinal chemistry optimization including testing for anesthetic potency and toxicity in an in vivo Xenopus laevis tadpole assay. Compounds with low toxicity and high potency were tested for anesthetic potency in mice. Results From an initial chemical library of over 350,000 compounds, we identified 2,600 compounds that potently inhibited 1-AMA binding to apoferritin. A subset of compounds chosen by structural criteria (700) was successfully reconfirmed using the initial assay. Based upon a strong presence in both the initial and secondary screens the 6-phenylpyridazin-3(2H)-one chemotype was assessed for anesthetic activity in tadpoles. Medicinal chemistry efforts identified four compounds with high potency and low toxicity in tadpoles, two were found to be effective novel anesthetics in mice. Conclusions We demonstrate the first use of a high-throughput screen to successfully identify a novel anesthetic chemotype and show mammalian anesthetic activity for members of that chemotype. PMID:25603205

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.

Synthesis of different heterocycles-linked chalcone conjugates as cytotoxic agents and tubulin polymerization inhibitors.

PubMed

Shankaraiah, Nagula; Nekkanti, Shalini; Brahma, Uma Rani; Praveen Kumar, Niggula; Deshpande, Namrata; Prasanna, Daasi; Senwar, Kishna Ram; Jaya Lakshmi, Uppu

2017-09-01

A series of new heterocycles-linked chalcone conjugates has been designed and synthesized by varying different alkane spacers. These conjugates were tested for their in vitro cytotoxic potential against a panel of selected human cancer cell lines namely, lung (A549 and NCI-H460), prostate (DU-145 and PC-3), colon (HCT-15 and HCT-116), and brain (U-87 glioblastoma) by MTT assay. Notably, among all the tested compounds, 4a exhibited potent cytotoxicity on NCI-H460 (lung cancer) cells with IC 50 of 1.48±0.19µM. The compound 4a showed significant inhibition of tubulin polymerization and disruption of the formation of microtubules (IC 50 of 9.66±0.06μM). Moreover, phase contrast microscopy and DAPI staining studies indicated that compound 4a can induce apoptosis in NCI-H460 cells. Further, the flow-cytometry analysis revealed that compound 4a arrests NCI-H460 cells in the G2/M phase of the cell cycle. In addition, molecular docking studies of the most active compounds 4a and 4b into the colchicine site of the tubulin, revealed the possible mode of interaction by these new conjugates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis and cytotoxicity of 2,5-dihydroxychalcones and related compounds.

PubMed

Nam, Nguyen-Hai; Hong, Dong-Ho; You, Young-Jae; Kim, Yong; Bang, Seong-Cheol; Kim, Hwan-Mook; Ahn, Byung-Zun

2004-06-01

A series of 2, 5-dihydroxychalcones and related compounds were synthesized, and their cytotoxicities against tumor cell lines and human umbilical venous endothelial cells (HUVEC) evaluated. It was found that chalcones, with electron-withdrawing substituents on an A ring, exhibited significant cytotoxicities. Among the synthesized compounds, 2'-chloro-2, 5-dihydroxychalcone (9) was most potent, with an IC50 value as low as 0.31 microg/mL. This compound also exhibited a significant cytotoxic selectivity toward HUVEC.

Dieckol, a phlorotannin isolated from a brown seaweed, Ecklonia cava, inhibits adipogenesis through AMP-activated protein kinase (AMPK) activation in 3T3-L1 preadipocytes.

PubMed

Ko, Seok-Chun; Lee, Myoungsook; Lee, Ji-Hyeok; Lee, Seung-Hong; Lim, Yunsook; Jeon, You-Jin

2013-11-01

In this study, we assessed the potential inhibitory effect of 5 species of brown seaweeds on adipogenesis the differentiation of 3T3-L1 preadipocytes into mature adipocytes by measuring Oil-Red O staining. The Ecklonia cava extract tested herein evidenced profound adipogenesis inhibitory effect, compared to that exhibited by the other four brown seaweed extracts. Thus, E. cava was selected for isolation of active compounds and finally the three polyphenol compounds of phlorotannins were obtained and their inhibitory effect on adipogenesis was observed. Among the phlorotannins, dieckol exhibited greatest potential adipogenesis inhibition and down-regulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding proteins (C/EBPα), sterol regulatory element-binding protein 1 (SREBP1) and fatty acid binding protein 4 (FABP4) in a dose-dependent manner. The specific mechanism mediating the effects of dieckol was confirmed by AMP-activated protein kinase (AMPK) activation. These results demonstrate inhibitory effect of dieckol compound on adipogenesis through the activation of the AMPK signal pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

Environmental Impact of Ionic Liquids: Automated Evaluation of the Chemical Oxygen Demand of Photochemically Degraded Compounds.

PubMed

Costa, Susana P F; Pereira, Sarah A P; Pinto, Paula C A G; Araujo, André R T S; Passos, Marieta L C; Saraiva, M Lúcia M F S

2017-05-19

A novel automated fluorimetric technique was developed for the assessment of the chemical oxygen demand (COD) of ionic liquids (ILs) and combined with a photodegradation step to promote IL degradation. The method was implemented on a sequential injection analysis (SIA) system and is based on the reduction of cerium(IV) in the presence of irradiated ILs. Compounds incorporating the chloride anion were found to exhibit higher COD values and 1-butyl-3-methylimidazolium chloride ([bmim] + [Cl] - ), 1-butyl-1-methylpyrrolidinium chloride ([bmpyr] + [Cl] - ), and1-hexyl-3-methylimidazolium chloride ([hmim] + [Cl] - ) also exhibited considerable photodegradability, whereas the cholinium cation and methanesulfonate and tetrafluoroborate anions showed resistance to photolysis. The developed methodology proved to be a simple, affordable, and robust method, showing good repeatability under the tested conditions (rsd <3.5 %, n=10). Therefore, it is expected that the developed approach can be used as a screening method for the preliminary evaluation of compounds' potential impact in the aquatic field. Additionally, the photolysis step presents an attractive option to promote degradation of ILs prior to their release into wastewater. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Phenolic profile, antioxidant capacity and anti-inflammatory activity of Anethum graveolens L. essential oil.

PubMed

Kazemi, M

2015-01-01

This study reports the chemical composition, antioxidant and anti-inflammatory properties of Anethum graveolens essential oil and its main compounds. The essential oil was obtained from the aerial parts of the plant by hydrodistillation and analysed by using GC/MS. α-Phellandrene (19.12%), limonene (26.34%), dill ether (15.23%), sabinene (11.34%), α-pinene (2%), n-tetracosane (1.54%), neophytadiene (1.43%), n-docosane (1.04), n-tricosane (1%), n-nonadecane (1%), n-eicosane (0.78%), n-heneicosane (0.67%), β-myrcene (0.23%) and α-tujene (0.21%) were found to be the major constituents of the oil. A. graveolens oil exhibit a higher activity in each antioxidant system with a special attention for β-carotene bleaching test (IC50: 15.3 μg/mL) and reducing power (EC50: 11.24 μg/mL). The TLC-bioautography screening and fractionation resulted in the separation of the main antioxidant compounds, which were identified as limonene (45%) and sabinene (32%). The essential oil and its main compounds exhibited a potent NO-scavenging effect and inhibited the expression of inducible NO synthase.

Anti-plasmodial activity of Dicoma tomentosa (Asteraceae) and identification of urospermal A-15-O-acetate as the main active compound

PubMed Central

2012-01-01

Background Natural products could play an important role in the challenge to discover new anti-malarial drugs. In a previous study, Dicoma tomentosa (Asteraceae) was selected for its promising anti-plasmodial activity after a preliminary screening of several plants traditionally used in Burkina Faso to treat malaria. The aim of the present study was to further investigate the anti-plasmodial properties of this plant and to isolate the active anti-plasmodial compounds. Methods Eight crude extracts obtained from D. tomentosa whole plant were tested in vitro against two Plasmodium falciparum strains (3D7 and W2) using the p-LDH assay (colorimetric method). The Peters’ four-days suppressive test model (Plasmodium berghei-infected mice) was used to evaluate the in vivo anti-plasmodial activity. An in vitro bioguided fractionation was undertaken on a dichloromethane extract, using preparative HPLC and TLC techniques. The identity of the pure compound was assessed using UV, MS and NMR spectroscopic analysis. In vitro cytotoxicity against WI38 human fibroblasts (WST-1 assay) and haemolytic activity were also evaluated for extracts and pure compounds in order to check selectivity. Results The best in vitro anti-plasmodial results were obtained with the dichloromethane, diethylether, ethylacetate and methanol extracts, which exhibited a high activity (IC50 ≤ 5 μg/ml). Hot water and hydroethanolic extracts also showed a good activity (IC50 ≤ 15 μg/ml), which confirmed the traditional use and the promising anti-malarial potential of the plant. The activity was also confirmed in vivo for all tested extracts. However, most of the active extracts also exhibited cytotoxic activity, but no extract was found to display any haemolytic activity. The bioguided fractionation process allowed to isolate and identify a sesquiterpene lactone (urospermal A-15-O-acetate) as the major anti-plasmodial compound of the plant (IC50 < 1 μg/ml against both 3D7 and W2 strains). This was also found to be the main cytotoxic compound (SI = 3.3). While this melampolide has already been described in the plant, this paper is the first report on the biological properties of this compound. Conclusions The present study highlighted the very promising anti-plasmodial activity of D. tomentosa and enabled to identify its main active compound, urospermal A-15-O-acetate. The high anti-plasmodial activity of this compound merits further study about its anti-plasmodial mechanism of action. The active extracts of D. tomentosa, as well as urospermal A 15-O-acetate, displayed only a moderate selectivity, and further studies are needed to assess the safety of the use of the plant by the local population. PMID:22909422

New derivatives of 3,4-dihydroisoquinoline-3-carboxylic acid with free-radical scavenging, D-amino acid oxidase, acetylcholinesterase and butyrylcholinesterase inhibitory activity.

PubMed

Solecka, Jolanta; Guśpiel, Adam; Postek, Magdalena; Ziemska, Joanna; Kawęcki, Robert; Lęczycka, Katarzyna; Osior, Agnieszka; Pietrzak, Bartłomiej; Pypowski, Krzysztof; Wyrzykowska, Agata

2014-09-30

A series of 3,4-dihydroisoquinoline-3-carboxylic acid derivatives were synthesised and tested for their free-radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS·+), superoxide anion radical (O2·-) and nitric oxide radical (·NO) assays. We also studied d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Almost each of newly synthesised compounds exhibited radical scavenging capabilities. Moreover, several compounds showed moderate inhibitory activities against DAAO, AChE and BuChE. Compounds with significant free-radical scavenging activity may be potential candidates for therapeutics used in oxidative-stress-related diseases.

Synthesis and anti-microbial activity of some 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile derivatives.

PubMed

Khidre, Rizk E; Abu-Hashem, Ameen A; El-Shazly, Mohamed

2011-10-01

A new series of 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile such as hydrazide hydrazones 3a-h; ethane-1,2-diaminopyridine 6; phthalimidopyridines 8a,b; hydrazides 10a,b; urea 11a and thiourea 11b were synthesized in a good to excellent yield in step efficient process, using 1-amino-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) as a key intermediate. The antibacterial and antifungal activities of the synthesized compounds were evaluated. The obtained data indicated that the majority of the tested compounds exhibited both antibacterial and antifungal activities, particularly compounds 8a and 8b showed a comparable effect to a well known antibacterial and antifungal agents. Published by Elsevier Masson SAS.

Antibacterial, Anticancer and Neuroprotective Activities of Rare Actinobacteria from Mangrove Forest Soils.

PubMed

Azman, Adzzie-Shazleen; Othman, Iekhsan; Fang, Chee-Mun; Chan, Kok-Gan; Goh, Bey-Hing; Lee, Learn-Han

2017-06-01

Mangrove is a complex ecosystem that contains diverse microbial communities, including rare actinobacteria with great potential to produce bioactive compounds. To date, bioactive compounds extracted from mangrove rare actinobacteria have demonstrated diverse biological activities. The discovery of three novel rare actinobacteria by polyphasic approach, namely Microbacterium mangrovi MUSC 115 T , Sinomonas humi MUSC 117 T and Monashia flava MUSC 78 T from mangrove soils at Tanjung Lumpur, Peninsular Malaysia have led to the screening on antibacterial, anticancer and neuroprotective activities. A total of ten different panels of bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300, ATCC 70069, Pseudomonas aeruginosa NRBC 112582 and others were selected for antibacterial screening. Three different neuroprotective models (hypoxia, oxidative stress, dementia) were done using SHSY5Y neuronal cells while two human cancer cells lines, namely human colon cancer cell lines (HT-29) and human cervical carcinoma cell lines (Ca Ski) were utilized for anticancer activity. The result revealed that all extracts exhibited bacteriostatic effects on the bacteria tested. On the other hand, the neuroprotective studies demonstrated M. mangrovi MUSC 115 T extract exhibited significant neuroprotective properties in oxidative stress and dementia model while the extract of strain M. flava MUSC 78 T was able to protect the SHSY5Y neuronal cells in hypoxia model. Furthermore, the extracts of M. mangrovi MUSC 115 T and M. flava MUSC 78 T exhibited anticancer effect against Ca Ski cell line. The chemical analysis of the extracts through GC-MS revealed that the majority of the compounds present in all extracts are heterocyclic organic compound that could explain for the observed bioactivities. Therefore, the results obtained in this study suggested that rare actinobacteria discovered from mangrove environment could be potential sources of antibacterial, anticancer and neuroprotective agents.

Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model.

PubMed

Piccinelli, Ana Claudia; Santos, Joyce Alencar; Konkiewitz, Elisabete Castelon; Oesterreich, Silvia Aparecida; Formagio, Anelise Samara Nazari; Croda, Julio; Ziff, Edward Benjamim; Kassuya, Cândida Aparecida Leite

2015-07-01

Previous studies have shown that essential oil containing (R)-(+)-limonene and α-phellandrene, extracted from fruits of Schinus terebinthifolius Raddi, exhibit anti-inflammatory activity. This work aimed to verify the antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from S. terebinthifolius fruits in spared nerve injury (SNI) model of neuropathic pain in rats. In the present work, essential oil from fruits of S. terebinthifolius, as well as the pure (R)-(+)-limonene and α-phellandrene compounds, were assayed for their effects on SNI-induced mechanical and cold hyperalgesia, and depressive-like behavior (immobility in forced swim test) in rats. The locomotor activity was evaluated in open-field test. Oral administration for up to 15 days of essential oil of S. terebinthifolius (100 mg/kg), (R)-(+)-limonene (10 mg/kg), α-phellandrene (10 mg/kg), and also subcutaneous 10 mg/kg dose of ketamine (positive control) significantly inhibited SNI-induced mechanical hyperalgesia and increased immobility in the forced swim test. On the 15th day of oral treatment, α-phellandrene, but neither the essential oil from S. terebinthifolius nor (R)-(+)-limonene, prevented the SNI-induced increase in sensitivity to a cold stimulus. The oral treatment with essential oil (100 mg/kg) or with compounds (10 mg/kg) did not interfere on locomotor activity. Together, the results of the present work show that essential oil of S. terebinthifolius and compounds present in this oil, including (R)-(+)-limonene and α-phellandrene, exhibit antihyperalgesic effects against mechanical hyperalgesia, and are antidepressive, while only α-phellandrene inhibited cold hyperalgesia in SNI rats.

New compounds from acid hydrolyzed products of the fruits of Momordica charantia L. and their inhibitory activity against protein tyrosine phosphatas 1B.

PubMed

Zeng, Ke; He, Yan-Ni; Yang, Di; Cao, Jia-Qing; Xia, Xi-Chun; Zhang, Shi-Jun; Bi, Xiu-Li; Zhao, Yu-Qing

2014-06-23

Four new cucurbitane-type triterpene sapogenins, compounds 1-4, together with other eight known compounds were isolated from the acid-hydrolyzed fruits extract of Momordica charantia L. Their chemical structures were established by NMR, mass spectrometry and X-ray crystallography. Compounds 1-7 and 9-12 were evaluated for their inhibitory activities toward protein tyrosine phosphatase 1B (PTP1B), a tyrosine phosphatase that has been implicated as a key target for therapy against type II diabetes. Compounds 1, 2, 4, 7 and 9 were shown inhibitory activities of 77%, 62%, 62% 60% and 68% against PTP1B, respectively. All of these tested compounds were exhibited higher PTP1B inhibition activities than that of the Na3VO4, a known PTP1B inhibitor used as positive control in present study. Structure activity relationship (SAR) analysis indicated that the inhibition activity of PTP1B was associated with the presence and number of -OH groups. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Synthesis and biological evaluation of imidazopyridine-oxindole conjugates as microtubule-targeting agents.

PubMed

Kamal, Ahmed; Reddy, Vangala Santhosh; Karnewar, Santosh; Chourasiya, Sumit S; Shaik, Anver Basha; Kumar, G Bharath; Kishor, Chandan; Reddy, M Kashi; Narasimha Rao, M P; Nagabhushana, Ananthamurthy; Ramakrishna, Kallaganti V S; Addlagatta, Anthony; Kotamraju, Srigiridhar

2013-12-01

A library of imidazopyridine-oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a, 10 e, 10 f, and 10 k, exhibited promising antiproliferative activity with GI50 values ranging from 0.17 to 9.31 μM. Flow cytometric analysis showed that MCF-7 cells treated by these compounds arrested in the G2 /M phase of the cell cycle in a concentration-dependent manner. More particularly, compound 10 f displayed a remarkable inhibitory effect on tubulin polymerisation. All the compounds depolarised mitochondrial membrane potential and caused apoptosis. These results are further supported by the decreased phosphorylation of Akt at Ser473. Studies on embryonic development revealed that the lead compounds 10 f and 10 k caused delay in the development of zebra fish embryos. Docking of compound 10 f with tubulin protein suggested that the imidazo[1,2-a]pyridine moiety occupies the colchicine binding site of tubulin. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel menadione hybrids: Synthesis, anticancer activity, and cell-based studies.

PubMed

Prasad, Chakka Vara; Nayak, Vadithe Lakshma; Ramakrishna, Sistla; Mallavadhani, Uppuluri Venkata

2018-01-01

A series of novel menadione-based triazole hybrids were designed and synthesized by employing copper-catalyzed azide-alkyne cycloaddition (CuAAC). All the synthesized hybrids were characterized by their spectral data ( 1 H NMR, 13 C NMR, IR, and HRMS). The synthesized compounds were evaluated for their anticancer activity against five selected cancer cell lines including lung (A549), prostate (DU-145), cervical (Hela), breast (MCF-7), and mouse melanoma (B-16) using MTT assay. The screening results showed that majority of the synthesized compounds displayed significant anticancer activity. Among the tested compounds, the triazoles 5 and 6 exhibited potent activity against all cell lines. In particular, compound 6 showed higher potency than the standard tamoxifen and parent menadione against MCF-7 cell line. Flow cytometric analysis revealed that compound 6 arrested cell cycle at G0/G1 phase and induced apoptotic cell death which was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and Annexin-V-FITC assay. Thus, compound 6 can be considered as lead molecule for further development as potent anticancer therapeutic agent. © 2017 John Wiley & Sons A/S.

Chimeric Derivatives of Functionalized Amino Acids and α-Aminoamides: Compounds with Anticonvulsant Activity in Seizure Models and Inhibitory Actions on Central, Peripheral, and Cardiac Isoforms of Voltage-gated Sodium Channels

PubMed Central

Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T.; Cummins, Theodore R.

2015-01-01

Six novel 3″-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4′-((3″-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4′-((3″-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI = TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNav1.1, rNav1.3, hNav1.5, or hNav1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation. PMID:25922183

Novel hydrazones - antioxidant potential and stabilization via polysaccharide particles

NASA Astrophysics Data System (ADS)

Hristova-Avakumova, N.; Nikolova-Mladenova, B.; Yoncheva, K.; Hadjimitova, V.

2017-01-01

In this study, we aimed to: i) determine the impact of three new isonicotinoyl hydrazones derivatives in in vitro systems used to investigate free radical processes - radical scavenging approach (ABTS and DPPH) and iron induced peroxidation in lipid containing model systems and ii) evaluate the potential of polysaccharide-based particles to act as protective carriers preserving the antioxidant activity (AOA) of the tested compounds. The tested compounds revealed excellent antioxidant effectiveness in the ABTS system. In the DPPH radical scavenging assay the compounds exhibited very weak or absence of AOA. The data from the iron induced peroxidation methods disclosed better antioxidant properties of the derivatives in the system containing egg yolk homogenate which is more plausible compared to the lecithin containing one. The incorporation of a bromine atom on 5th position in salicylaldehyde moiety is associated with diminishment of the radical scavenging activity in the systems containing stable free radicals but its AOA reduction after encapsulation during the storage was only 9.17%. The obtained data indicate that compounds have proven themselves as promising candidates for further evaluation as antioxidant agents. Their encapsulation in chitosan-alginate particles could be a useful approach for improving the stability of their antioxidant properties.

Mechanisms of nitrogen heterocycle influence on turbine fuel stability

NASA Technical Reports Server (NTRS)

Daniel, S. R.; Worstell, J. H.

1980-01-01

Lewis bases were extracted from a Utah COED syncrude via ligand exchange. Addition of this extract to Jet A at levels as low as 5 ppm N produced deterioration of stability in both JFTOT and accelerated storage tests (7 days at 394 K with 13:1air to fuel ratio). Comparable effects on Jet A stability were obtained by addition of pyridine and quinoline, while pyrrole and indole were less detrimental at the same concentration level. The weight of deposit produced accelerated storage tests was found to be proportional to the concentration of added nitrogen compound. Over the narrow temperature range accessible with the experimental method, Arrhenius plots obtained by assuming specific rate to be proportional to the weight of material deposited in seven days exhibit greater slopes in the presence of those nitrogen compounds producing the greater deposition rates. It is shown that despite variation in appearance the elemental composition and spectral characteristics of the deposits are unaffected by addition of the nitrogen compounds. The linearity of the Arrhenius plots and of a plot of Arrhenius slope versus intercept for all the compounds suggests a constancy of mechanism over the range of temperature and heterocycles studied.

Antimalarial activity of plumbagin in vitro and in animal models.

PubMed

Sumsakul, Wiriyaporn; Plengsuriyakarn, Tullayakorn; Chaijaroenkul, Wanna; Viyanant, Vithoon; Karbwang, Juntra; Na-Bangchang, Kesara

2014-01-12

Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test). Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270-640) and 370 (270-490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time. Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability.

The intra-annular acylamide chelate-coordinated compound: The keto-tautomer of metal (II) milrinone complex

NASA Astrophysics Data System (ADS)

Gong, Yun; Liu, Jinzhi; Tang, Wang; Hu, Changwen

2008-03-01

In the presence of N, N'-dimethyllformamide (DMF), two isostructural metal (II)-milrinone complexes formulated as M(C 12H 8N 3O) 2 (M = Co 1 and Ni 2) have been synthesized and characterized by elemental analysis, IR, TG and single crystal X-ray diffraction. The two compounds crystallize in the tetragonal system, chiral space group P4 32 12. They exhibit similar two dimensional (2D) square grid-like framework, in which milrinone acts as a ditopic ligand with its terminal pyridine and intra-annular acylamide groups covalently bridging different metal centers. The intra-annular acylamide ligand shows a chelate-coordinated mode. Compounds 1 and 2 are stable under 200 °C. Compound 3 formulated as (C 12H 9N 3O) 4·H 2O was obtained in the presence of water, the water molecule in the structure leads to the racemization of compound 3 and it crystallizes in the monoclinic system, non-chiral space group P2 1/ c. Milrinone exhibits a keto-form in the three compounds and compounds 1- 3 exhibit different photoluminescence properties.

Thiosemicarbazone p-Substituted Acetophenone Derivatives Promote the Loss of Mitochondrial Δψ, GSH Depletion, and Death in K562 Cells

PubMed Central

Pessoto, Felipe S.; Yokomizo, Cesar H.; Prieto, Tatiana; Fernandes, Cleverton S.; Silva, Alan P.; Kaiser, Carlos R.; Basso, Ernani A.; Nantes, Iseli L.

2015-01-01

A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics. PMID:26075034

Isolation, identification and characterization of an algicidal bacterium from Lake Taihu and preliminary studies on its algicidal compounds.

PubMed

Tian, Chuan; Liu, Xianglong; Tan, Jing; Lin, Shengqin; Li, Daotang; Yang, Hong

2012-01-01

In an effort to identify a bio-agent capable of controlling cyanobacterial blooms, we isolated a bacterial strain, A27, which exhibited strong algicidal activity against the dominant bloom-forming species of Microcystis aeruginosa in Lake Taihu. Based on 16S rRNA gene sequence analysis, this strain belongs to the genus Exiguobacterium. This is the first report of an algicidal bacterial strain belonging to the genus Exiguobacterium. Strain A27 exhibited algicidal activity against a broad range of cyanobacteria, but elicited little or no algicidal activity against the two green algal strains tested. The algicidal activity of strain A27 was shown to be dependent on the density of the bacteria and to have a threshold density of 1.5x10(6) CFU/mL. Our data also showed that the algicidal activity of strain A27 depended on different growth stages of Microcystis aeruginosa (exponential approximately lag phase > early stationary) rather than that of the bacterium itself. Our results also suggested the algicidal activity of strain A27 occurred via the production of extracellular algicidal compounds. Investigation of the algicidal compounds revealed that there were at least two different algicidal compounds produced by strain A27. These results indicated that strain A27 has great potential for use in the control of outbreaks of cyanobacterial blooms in Lake Taihu.

Combined genetic and bioactivity-based prioritization leads to the isolation of an endophyte-derived antimycobacterial compound.

PubMed

Alvin, A; Kalaitzis, J A; Sasia, B; Neilan, B A

2016-05-01

To initiate a genetic and bioactivity-based screening programme of culturable endophytes to identify micro-organisms capable of producing bioactive polyketides and peptides. Fungal endophytes were isolated from flowers, leaves and roots of Rhoeo spathacea, revealing a community consisting of Colletotrichum sp., Fusarium sp., Guignardia sp., Phomopsis sp., Phoma sp. and Microdochium sp. Genetic screening showed that all isolates had polyketide synthase (PKS) genes and most had nonribosomal peptide synthetase (NRPS) genes. Ethyl acetate extracts of the fungal isolates exhibited antiproliferative activity against at least one of the seven bacterial and mycobacterial test strains. Nuclear Magnetic Resonance -guided fractionation of the crude extract from a Fusarium sp. strain which exhibited strong antiproliferative activity against Mycobacterium tuberculosis resulted in the isolation of the polyketide javanicin. This compound was active against Myco. tuberculosis (MIC = 25 μg ml(-1)) and Mycobacterium phlei (MIC = 50 μg ml(-1)). The medicinal plant R. spathacea hosts a variety of fungal endophytes capable of producing antibacterial and antimycobacterial compounds. There is a positive correlation between the presence of PKS and/or NRPS encoding genes in endophytes and the bioactivity of their respective organic extracts. This is the first report on the fungal endophytic diversity of R. spathacea, and the isolation of an antimycobacterial compound from the plant which has been traditionally used for the treatment of tuberculosis symptoms. © 2016 The Society for Applied Microbiology.

Cytotoxic 2',5'-dihydroxychalcones with unexpected antiangiogenic activity.

PubMed

Nam, Nguyen-Hai; Kim, Yong; You, Young-Jae; Hong, Dong-Ho; Kim, Hwan-Mook; Ahn, Byung-Zun

2003-02-01

A series of 2',5'-dihydroxychalcones were synthesized and evaluated for cytotoxicity against tumor cell lines and human umbilical venous endothelial cells (HUVEC). It was found that chalcones with electron-withdrawing substituents on the B ring exhibited potent cytotoxicity against a variety of tumor cell lines while compounds with electron-releasing groups were less potent in general. Those compounds with B ring replaced by extended or heteroaromatic rings exhibited significant bioactivity. Several compounds were shown to have marked cytotoxic selectivity towards HUVECs. Especially, among the synthesized compounds, 2-chloro-2',5'-dihydroxychalcone (2-3) showed the highest selectivity index up to 66 in comparison to HCT116 cells. This compound also exhibited strong inhibitory effects on the HUVEC tube formation in an in vitro model. When administered into BDF1 mice bearing Lewis lung carcinoma cells at 50 mg kg(-1) day(-1), 2-3 was found to inhibit the growth of tumor mass by 60.5%.

Bioactivity-guided isolation of anticancer agents from Bauhinia kockiana Korth.

PubMed

Chew, Yik Ling; Lim, Yau Yan; Stanslas, Johnson; Ee, Gwendoline Cheng Lian; Goh, Joo Kheng

2014-01-01

Flowers of Bauhinia kockiana were investigated for their anticancer properties. Gallic acid (1), and methyl gallate (2), were isolated via bioassay-directed isolation, and they exhibited anticancer properties towards several cancer cell lines, examined using MTT cell viability assay. Pyrogallol (3) was examined against the same cancer cell lines to deduce the bioactive functional group of the phenolic compounds. The results showed that the phenolic compounds could exhibit moderate to weak cytotoxicity towards certain cell lines (GI50 30 - 86 µM), but were inactive towards DU145 prostate cancer cell (GI50 > 100 µM). It was observed that pyrogallol moiety was one of the essential functional structures of the phenolic compounds in exhibiting anticancer activity. Also, the carboxyl group of compound 1 was also important in anticancer activity. Examination of the PC-3 cells treated with compound 1 using fluorescence microscopy showed that PC-3 cells were killed by apoptosis.

Synthesis of analogues of gingerol and shogaol, the active pungent principles from the rhizomes of Zingiber officinale and evaluation of their anti-platelet aggregation effects.

PubMed

Shih, Hung-Cheng; Chern, Ching-Yuh; Kuo, Ping-Chung; Wu, You-Cheng; Chan, Yu-Yi; Liao, Yu-Ren; Teng, Che-Ming; Wu, Tian-Shung

2014-03-04

The present study was aimed at discovering novel biologically active compounds based on the skeletons of gingerol and shogaol, the pungent principles from the rhizomes of Zingiber officinale. Therefore, eight groups of analogues were synthesized and examined for their inhibitory activities of platelet aggregation induced by arachidonic acid, collagen, platelet activating factor, and thrombin. Among the tested compounds, [6]-paradol (5b) exhibited the most significant anti-platelet aggregation activity. It was the most potent candidate, which could be used in further investigation to explore new drug leads.

Synthesis of Analogues of Gingerol and Shogaol, the Active Pungent Principles from the Rhizomes of Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation Effects

PubMed Central

Shih, Hung-Cheng; Chern, Ching-Yuh; Kuo, Ping-Chung; Wu, You-Cheng; Chan, Yu-Yi; Liao, Yu-Ren; Teng, Che-Ming; Wu, Tian-Shung

2014-01-01

The present study was aimed at discovering novel biologically active compounds based on the skeletons of gingerol and shogaol, the pungent principles from the rhizomes of Zingiber officinale. Therefore, eight groups of analogues were synthesized and examined for their inhibitory activities of platelet aggregation induced by arachidonic acid, collagen, platelet activating factor, and thrombin. Among the tested compounds, [6]-paradol (5b) exhibited the most significant anti-platelet aggregation activity. It was the most potent candidate, which could be used in further investigation to explore new drug leads. PMID:24599082

Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities.

PubMed

Qi, Changxing; Bao, Jian; Wang, Jianping; Zhu, Hucheng; Xue, Yongbo; Wang, Xiaochuan; Li, Hua; Sun, Weiguang; Gao, Weixi; Lai, Yongji; Chen, Jian-Guo; Zhang, Yonghui

2016-10-19

Asperterpenes A ( 1 ) and B ( 2 ), two 3,5-dimethylorsellinic acid-based meroterpenoids that contain a unique β-oriented Me-21 with an unprecedented 1,2,5-trimethyl-4,9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic acid moiety, were obtained from Aspergillus terreus in very limited amounts of 3.6 mg and 1.8 mg, respectively. The absolute structure of 1 was determined using X-ray diffraction. Because of the low yield of 1 , a comprehensive characterization of the BACE1 inhibitory activities of 1 was completed via molecular biological, cell and animal studies guided by in silico target confirmation (ISTC). ISTC assays suggested that compounds 1 and 2 might be BACE1 inhibitors. In cell-based tests, asperterpenes A and B, as natural products, exhibited promising inhibitory activities against BACE1, with IC 50 values of 78 and 59 nM, respectively. LY2811376 (the positive control), one of the most potent clinical BACE1 inhibitors, has shown an IC 50 value of 260 nM. In vivo , compound 1 exhibited activity similar to that of LY2811376 against Alzheimer's disease (AD) in 3xTg AD mice. Taken together, these findings demonstrate that asperterpene A, which contains a novel carbon skeleton, is the first terpenoid to exhibit effective BACE1 inhibitory activity. Moreover, 1 represents a potential lead compound and a versatile scaffold for the development of drugs for the treatment of AD.

Spectrophotometric, voltammetric and cytotoxicity studies of 2-hydroxy-5-methoxyacetophenone thiosemicarbazone and its N(4)-substituted derivatives: A combined experimental-computational study

NASA Astrophysics Data System (ADS)

Akgemci, Emine Guler; Saf, Ahmet Ozgur; Tasdemir, Halil Ugur; Türkkan, Ercan; Bingol, Haluk; Turan, Suna Ozbas; Akkiprik, Mustafa

2015-02-01

In this study, 2-hydroxy-5-methoxyacetophenone thiosemicarbazone (HMAT) and its novel N(4) substituted derivatives were synthesized and characterized by different techniques. The optical band gap of the compounds and the energy of HOMO were experimentally examined by UV-vis spectra and cyclic voltammetry measurements, respectively. Furthermore, the conformational spaces of the compounds were scanned with molecular mechanics method. The geometry optimization, HOMO and LUMO energies, the energy gap of the HOMO-LUMO, dipole moment of the compounds were theoretically calculated by the density functional theory B3LYP/6-311++G(d,p) level. The minimal electronic excitation energy and maximum wavelength calculations of the compounds were also performed by TD-DFT//B3LYP/6-311++G(d,p) level of theory. Theoretically calculated values were compared with the related experimental values. The combined results exhibit that all compounds have good electron-donor properties which affect anti-proliferative activity. The cytotoxic effects of the compounds were also evaluated against HeLa (cervical carcinoma), MCF-7 (breast carcinoma) and PC-3 (prostatic carcinoma) cell lines using the standard MTT assay. All tested compounds showed antiproliferative effect having IC50 values in different range. In comparison with that of HMAT, it was obtained that while ethyl group on 4(N)-substituted position decreased in potent anti-proliferative effect, the phenyl group on the position increased in anti-proliferative effect for the tested cancer cell line. Considering the molecular energy parameters, the cytotoxicity activities of the compounds were discussed.

Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors.

PubMed

Aboutorabzadeh, Sayyed Mohammad; Mosaffa, Fatemeh; Hadizadeh, Farzin; Ghodsi, Razieh

2018-01-01

In the present study, a new series of 6-methoxy-2-arylquinoline analogues was designed and synthesized as P-glycoprotein (P-gp) inhibitors using quinine and flavones as the lead compounds. The cytotoxic activity of the synthesized compounds was evaluated against two human cancer cell lines including EPG85-257RDB, multidrug-resistant gastric carcinoma cells (P-gp-positive gastric carcinoma cell line), and EPG85-257P, drug-sensitive gastric carcinoma cells. Compounds showing low to moderate toxicity in the MTT test were selected to investigate their P-gp inhibition activity. Moreover, trying to explain the results of biological experiments, docking studies of the selected compounds into the homology-modeled human P-gp, were carried out. The physicochemical and ADME properties of the compounds as drug candidate were also predicted. Most of our compounds exhibited negligible or much lower cytotoxic effect in both cancer cells. Among the series, 5a and 5b, alcoholic quinoline derivatives were found to inhibit the efflux of rhodamine 123 at the concentration of 10 μM significantly. Among the tested quinolines, 5a and 5b showed the most potent P-gp inhibitory activity in the series and were 1.3-fold and 2.1-fold stronger than verapamil, respectively. SAR data revealed that hydroxyl methyl in position 4 of quinolines has a key role in P-gp efflux inhibition of our compounds. ADME studies suggested that all of the compounds included in this study may have a good human intestinal absorption.

Evaluation of extracts and essential oil from Callistemon viminalis leaves: antibacterial and antioxidant activities, total phenolic and flavonoid contents.

PubMed

Salem, Mohamed Z M; Ali, Hayssam M; El-Shanhorey, Nader A; Abdel-Megeed, Ahmed

2013-10-01

To investigate antioxidant and antibacterial activities of Callistemon viminalis (C. viminalis) leaves. The essential oil of C. viminalis leaves obtained by hydro-distillation was analyzed by GC/MS. Different extracts were tested for total phenolic and flavonoid contents and in vitro antioxidant (DPPH assay) and antibacterial (agar disc diffusion and 96-well micro-plates methods) actives. Fourteen components were identified in the essential oil, representing 98.94% of the total oil. The major components were 1,8-cineole (64.53%) and α-pinene (9.69%). Leaf essential oil exhibited the highest antioxidant activity of (88.60±1.51)% comparable to gallic acid, a standard compound [(80.00±2.12)%]. Additionally, the biggest zone of inhibitions against the studied bacterial strains was observed by the essential oil when compared to the standard antibiotic (tetracycline). The crude methanol extract and ethyl acetate fraction had a significant antibacterial activity against the tested bacterial strains. It can be suggested that C. viminalis is a great potential source of antibacterial and antioxidant compounds useful for new antimicrobial drugs from the natural basis. The present study revealed that the essential oil as well as the methanol extracts and ethyl acetate fraction of C. viminalis leaves exhibited highly significant antibacterial activity against the tested bacterial strains. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Fumigant toxicity and acetylcholinesterase inhibitory activity of 4 Asteraceae plant essential oils and their constituents against Japanese termite (Reticulitermes speratus Kolbe).

PubMed

Seo, Seon-Mi; Kim, Junheon; Kang, Jaesoon; Koh, Sang-Hyun; Ahn, Young-Joon; Kang, Kyu-Suk; Park, Il-Kwon

2014-07-01

This study investigated the fumigant toxicity of 4 Asteraceae plant essential oils and their constituents against the Japanese termite Reticulitermes speratus Kolbe. Fumigant toxicity varied with plant essential oils or constituents, exposure time, and concentration. Among the tested essential oils, those from Chamaemelum nobile exhibited the strongest fumigant toxicity, followed by those from Santolina chamaecyparissus, Ormenis multicaulis, and Eriocephalus punctulatus at 2 days after treatment. In all, 15, 24, 19, and 9 compounds were identified in the essential oils from C. nobile, E. punctulatus, O. multicaulis, and S. chamaecyparissus, respectively, by using gas chromatography, gas chromatography-mass spectrometry, or open-column chromatography. The identified compounds were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, trans-pinocarveol, caryophyllene oxide, sabinene hydrate, and santolina alcohol showed strong fumigant toxicity against Japanese termites. Acetylcholinesterase (AChE) inhibition activity of the identified compounds from C. nobile, E. punctulatus, O. multicaulis, and S. chamaecyparissus essential oils were tested to determine the mode of their action. The IC50 values of (+)-α-pinene, (-)-limonene, (-)-α-pinene, β-pinene, and β-phellandrene against Japanese termite AChE were 0.03, 0.13, 0.41, 0.42, and 0.67mg/mL, respectively. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control. Copyright © 2014 Elsevier Inc. All rights reserved.

Biodegradation of Oil Slicks on the Marine Environment.

DTIC Science & Technology

1976-11-01

Ransenula, Candida, Rho4o~torula and Penicillium . The substrate range of these organisms wasevaluated on 11 aliphatic , alicyclic and aromatic...and aromatic compounds (TR 1, ],97C). On the basis of the above substrate range tests and growth, characteristic., a Flavobacteri um sp . and a...incubation. ~ -Paraff Ins served as the bestsubstrates for both organisms, but Plavobacteriua sp . exhibited higher rates of mineralization. Branching

Studies at the Ionizable Position of Cephalosporins and Penicillins: Hydroxamates as Substitutes for the Traditional Carboxylate Group

PubMed Central

Majewski, Mark W.; Miller, Patricia A.; Miller, Marvin J.

2016-01-01

Classically, β-lactams need an ionizable group to potentiate antibacterial activity. Sets of cephalosporins and penicillins featuring different substituted hydroxamates in place of the traditional carboxylate group have been synthesized and tested for antibiotic activity. Many of the compounds exhibited anti-bacterial activities with notable MIC values in the range of 6-0.2 μM. PMID:27999444

Traditional Aboriginal Preparation Alters the Chemical Profile of Carica papaya Leaves and Impacts on Cytotoxicity towards Human Squamous Cell Carcinoma.

PubMed

Nguyen, Thao T; Parat, Marie-Odile; Shaw, Paul N; Hewavitharana, Amitha K; Hodson, Mark P

2016-01-01

Carica papaya leaf decoction, an Australian Aboriginal remedy, has been used widely for its healing capabilities against cancer, with numerous anecdotal reports. In this study we investigated its in vitro cytotoxicity on human squamous cell carcinoma cells followed by metabolomic profiling of Carica papaya leaf decoction and leaf juice/brewed leaf juice to determine the effects imparted by the long heating process typical of the Aboriginal remedy preparation. MTT assay results showed that in comparison with the decoction, the leaf juice not only exhibited a stronger cytotoxic effect on SCC25 cancer cells, but also produced a significant cancer-selective effect as shown by tests on non-cancerous human keratinocyte HaCaT cells. Furthermore, evidence from testing brewed leaf juice on these two cell lines suggested that the brewing process markedly reduced the selective effect of Carica papaya leaf on SCC25 cancer cells. To tentatively identify the compounds that contribute to the distinct selective anticancer activity of leaf juice, an untargeted metabolomic approach employing Ultra High Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry followed by multivariate data analysis was applied. Some 90 and 104 peaks in positive and negative mode respectively were selected as discriminatory features from the chemical profile of leaf juice and >1500 putative compound IDs were obtained via database searching. Direct comparison of chromatographic and tandem mass spectral data to available reference compounds confirmed one feature as a match with its proposed authentic standard, namely pheophorbide A. However, despite pheophorbide A exhibiting cytotoxic activity on SCC25 cancer cells, it did not prove to be the compound contributing principally to the selective activity of leaf juice. With promising results suggesting stronger and more selective anticancer effects when compared to the Aboriginal remedy, Carica papaya leaf juice warrants further study to explore its activity on other cancer cell lines, as well as investigation to confirm the identity of compounds contributing to its selective effect, particularly those compounds altered by the long heating process applied during the traditional Aboriginal remedy preparation.

Synthesis of natural-like acylphloroglucinols with anti-proliferative, anti-oxidative and tube-formation inhibitory activity.

PubMed

Sun, Qiu; Schmidt, Sebastian; Tremmel, Martina; Heilmann, Jörg; König, Burkhard

2014-10-06

Two series of natural and natural-like mono- and bicyclic acylphloroglucinols derived from secondary metabolites in the genus Hypericum (Hypericaceae) were synthesised and tested in vitro for anti-proliferative and tube-formation inhibitory activity in human microvascular endothelial cells (HMEC-1). In addition, their anti-oxidative activity was determined via an ORAC-assay. The first series of compounds (4a-e) consisted of geranylated monocyclic acylphloroglucinols with varying aliphatic acyl substitution patterns, which were subsequently cyclised to the corresponding 2-methyl-2-prenylchromane derivatives (5a and 5d). The second series involved compounds containing a 2,2-dimethylchromane skeleton with differing aromatic acyl substitution (6a-d and 7a-e). Compound 7a, (5,7-dihydroxy-2,2-dimethylchroman-6-yl)-(3,4-dihydroxyphenyl)methanone), showed the highest in vitro anti-proliferative activity with an IC50 of 0.88 ± 0.08 μM and a remarkable anti-oxidative activity of 2.8 ± 0.1 TE from the ORAC test. Interestingly, the high anti-proliferative activity of these acylphloroglucinols was not associated with tube-formation inhibition. Compounds (E)-1-(3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4,6-trihydroxyphenyl)-2-methylbutan-1-one (4d) and (5,7-dihydroxy-2,2-dimethylchroman-6-yl)(3,4-dimethoxyphenyl)methanone (6a) exhibited moderate to weak anti-proliferative effects (IC50 11.0 ± 1 μM and 48.0 ± 4.3 μM, respectively) and inhibited the capillary-like tube formation of HMEC-1 in vitro, whereas 7a was inactive. The most active compound in the ORAC assay was 7c, which exhibited an anti-oxidative effect of 6.6 ± 1.0 TE. However, this compound showed only weak activity during the proliferation assay (IC50 53.8 ± 0.3) and did not inhibit tube-formation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Traditional Aboriginal Preparation Alters the Chemical Profile of Carica papaya Leaves and Impacts on Cytotoxicity towards Human Squamous Cell Carcinoma

PubMed Central

Nguyen, Thao T.; Parat, Marie-Odile; Shaw, Paul N.; Hewavitharana, Amitha K.; Hodson, Mark P.

2016-01-01

Carica papaya leaf decoction, an Australian Aboriginal remedy, has been used widely for its healing capabilities against cancer, with numerous anecdotal reports. In this study we investigated its in vitro cytotoxicity on human squamous cell carcinoma cells followed by metabolomic profiling of Carica papaya leaf decoction and leaf juice/brewed leaf juice to determine the effects imparted by the long heating process typical of the Aboriginal remedy preparation. MTT assay results showed that in comparison with the decoction, the leaf juice not only exhibited a stronger cytotoxic effect on SCC25 cancer cells, but also produced a significant cancer-selective effect as shown by tests on non-cancerous human keratinocyte HaCaT cells. Furthermore, evidence from testing brewed leaf juice on these two cell lines suggested that the brewing process markedly reduced the selective effect of Carica papaya leaf on SCC25 cancer cells. To tentatively identify the compounds that contribute to the distinct selective anticancer activity of leaf juice, an untargeted metabolomic approach employing Ultra High Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry followed by multivariate data analysis was applied. Some 90 and 104 peaks in positive and negative mode respectively were selected as discriminatory features from the chemical profile of leaf juice and >1500 putative compound IDs were obtained via database searching. Direct comparison of chromatographic and tandem mass spectral data to available reference compounds confirmed one feature as a match with its proposed authentic standard, namely pheophorbide A. However, despite pheophorbide A exhibiting cytotoxic activity on SCC25 cancer cells, it did not prove to be the compound contributing principally to the selective activity of leaf juice. With promising results suggesting stronger and more selective anticancer effects when compared to the Aboriginal remedy, Carica papaya leaf juice warrants further study to explore its activity on other cancer cell lines, as well as investigation to confirm the identity of compounds contributing to its selective effect, particularly those compounds altered by the long heating process applied during the traditional Aboriginal remedy preparation. PMID:26829042

Precursors to radiopharmaceutical agents for tissue imaging

DOEpatents

Srivastava, Prem C.; Knapp, Jr., Furn F.

1988-01-01

A class of radiolabeled compounds to be used in tissue imaging that exhibits rapid brain uptake, good brain:blood radioactivity ratios, and long retention times. The imaging agents are more specifically radioiodinated aromatic amines attached to dihydropyridine carriers, that exhibit heart as well as brain specificity. In addition to the radiolabeled compounds, classes of compounds are also described that are used as precursors and intermediates in the preparation of the imaging agents.

Investigations on the 4-Quinolone-3-Carboxylic Acid Motif. 5. Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric Approach

PubMed Central

Nocerino, Stefania; Pedani, Valentina; Pasquini, Serena; Tafi, Andrea; De Chiaro, Maria; Bellucci, Luca; Valoti, Massimo; Guida, Francesca; Luongo, Livio; Dragoni, Stefania; Ligresti, Alessia; Rosenberg, Avraham; Bolognini, Daniele; Cascio, Maria Grazia; Pertwee, Roger G.; Moaddel, Ruin; Maione, Sabatino; Di Marzo, Vincenzo

2012-01-01

Three heterocyclic systems were selected as potential surrogates of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, potent and selective CB2 ligands exhibiting scarce water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, the 1,2,3-triazole derivative 11 emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, 11 exhibited inverse agonist activity, whereas, in vivo, in the formalin test in mice, it produced analgesic effects antagonized by a well established inverse agonist. Metabolic studies allowed the identification of the side chain hydroxylated derivative 32 as its only metabolite which, in its racemic form, showed still appreciable CB2 selectivity, but was 150-fold less potent than the parent compound. PMID:22383251

Two structurally distinct inhibitors of glycogen synthase kinase 3 induced centromere positive micronuclei in human lymphoblastoid TK6 cells.

PubMed

Mishima, Masayuki; Tanaka, Kenji; Takeiri, Akira; Harada, Asako; Kubo, Chiyomi; Sone, Sachiko; Nishimura, Yoshikazu; Tachibana, Yukako; Okazaki, Makoto

2008-08-25

Glycogen synthase kinase 3 (GSK3) is an attractive novel pharmacological target. Inhibition of GSK3 is recently regarded as one of the viable approaches to therapy for Alzheimer's disease, cancer, diabetes mellitus, osteoporosis, and bipolar mood disorder. Here, we have investigated the aneugenic potential of two potent and highly specific inhibitors of GSK3 by using an in vitro micronucleus test with human lymphoblastoid TK6 cells. One inhibitor was a newly synthesized maleimide derivative and the other was a previously known aminopyrimidine derivative. Both compounds elicited statistically significant and concentration-dependent increases in micronucleated cells. One hundred micronuclei (MN) of each were analyzed using centromeric DNA staining with fluorescence in situ hybridization. Both the two structurally distinct compounds induced centromere-positive micronuclei (CMN). Calculated from the frequency of MN cells and the percentage of CMN, CMN cell incidence after treatment with the maleimide compound at 1.2 microM, 2.4 microM, and 4.8 microM was 11.6, 27.7, and 56.3 per 1000 cells, respectively; the negative control was 4.5. CMN cell incidence after the treatment with the aminopyrimidine compound at 1.8 microM, 3.6 microM, and 5.4 microM was 6.7, 9.8 and 17.2 per 1000 cells, respectively. Both compounds exhibited concentration-dependent increase in the number of mitotic cells. The frequency of CMN cells correlated well with mitotic cell incidence after treatment with either compound. Furthermore, both inhibitors induced abnormal mitotic cells with asymmetric mitotic spindles and lagging anaphase chromosomes. These results lend further support to the hypothesis that the inhibition of GSK3 activity affects microtubule function and exhibits an aneugenic mode of action.

Cultivation in space flight produces minimal alterations in the susceptibility of Bacillus subtilis cells to 72 different antibiotics and growth-inhibiting compounds.

PubMed

Morrison, Michael D; Fajardo-Cavazos, Patricia; Nicholson, Wayne L

2017-08-18

Past results have suggested that bacterial antibiotic susceptibility is altered during space flight. To test this notion, Bacillus subtilis cells were cultivated in matched hardware, medium, and environmental conditions either in spaceflight microgravity on the International Space Station, termed Flight (FL) samples, or at Earth-normal gravity, termed Ground Control (GC) samples. Susceptibility of FL and GC samples was compared to 72 antibiotics and growth-inhibitory compounds using the Omnilog Phenotype Microarray (PM) system. Only 9 compounds were identified by PM screening as exhibiting significant differences ( P < 0.05, Student's t-test) in FL vs. GC samples: 6-mercaptopurine, cesium chloride, enoxacin, lomefloxacin, manganese (II) chloride, nalidixic acid, penimepicycline, rolitetracycline, and trifluoperazine. Testing of the same compounds by standard broth dilution assay did not reveal statistically significant differences in the IC 50 values between FL and GC samples. The results indicate that the susceptibility of B. subtilis cells to a wide range of antibiotics and growth inhibitors is not dramatically altered by space flight. Importance: This study addresses a major concern of mission planners for human spaceflight, that bacteria accompanying astronauts on long-duration missions might develop a higher level of resistance to antibiotics due to exposure to the spaceflight environment. The results of this study do not support that notion. Copyright © 2017 American Society for Microbiology.

Cultivation in Space Flight Produces Minimal Alterations in the Susceptibility of Bacillus subtilis Cells to 72 Different Antibiotics and Growth-Inhibiting Compounds

PubMed Central

Morrison, Michael D.; Fajardo-Cavazos, Patricia

2017-01-01

ABSTRACT Past results have suggested that bacterial antibiotic susceptibility is altered during space flight. To test this notion, Bacillus subtilis cells were cultivated in matched hardware, medium, and environmental conditions either in space flight microgravity on the International Space Station, termed flight (FL) samples, or at Earth-normal gravity, termed ground control (GC) samples. The susceptibility of FL and GC samples was compared to 72 antibiotics and growth-inhibitory compounds using the Omnilog phenotype microarray (PM) system. Only 9 compounds were identified by PM screening as exhibiting significant differences (P < 0.05, Student's t test) in FL versus GC samples: 6-mercaptopurine, cesium chloride, enoxacin, lomefloxacin, manganese(II) chloride, nalidixic acid, penimepicycline, rolitetracycline, and trifluoperazine. Testing of the same compounds by standard broth dilution assay did not reveal statistically significant differences in the 50% inhibitory concentrations (IC50s) between FL and GC samples. The results indicate that the susceptibility of B. subtilis cells to a wide range of antibiotics and growth inhibitors is not dramatically altered by space flight. IMPORTANCE This study addresses a major concern of mission planners for human space flight, that bacteria accompanying astronauts on long-duration missions might develop a higher level of resistance to antibiotics due to exposure to the space flight environment. The results of this study do not support that notion. PMID:28821547

Copper(II) complexes with 4-(1H-1, 2, 4-trizol-1-ylmethyl) benzoic acid: Syntheses, crystal structures and antifungal activities

NASA Astrophysics Data System (ADS)

Xiong, Pingping; Li, Jie; Bu, Huaiyu; Wei, Qing; Zhang, Ruolin; Chen, Sanping

2014-07-01

Reaction of Cu(II) with an asymmetric semi-rigid organic ligand 4-(1H-1, 2, 4-trizol-1-ylmethyl) benzoic acid (HL), yielded five compounds, [Cu0.5L]n (1), [Cu(HL)2Cl2]n (2), [Cu(HL)2Cl2(H2O)] (3), [Cu(L)2(H2O)]n (4) and [Cu(L)(phen)(HCO2)]n (5), which have been fully characterized by infrared spectroscopy, elemental analysis, and single-crystal X-ray diffraction. As for compounds 1, 2 and 5, Cu(II) is bridged through HL, Cl-, and formic acid, respectively, featuring 1D chain-structure. In compound 3, Cu(II) with hexahedral coordination sphere is assembled through hydrogen-bonding into 3D supramolecular framework. In compound 4, 1D chain units -Cu-O-Cu-O- are ligand-bridged into a 3D network. All compounds were tested on fungi (Fusarium graminearum, Altemaria solani, Macrophoma kawatsukai, Alternaria alternata and Colletotrichum gloeosporioides). Compound 1 exhibits a better antifungal effect compared to other compounds. An effect of structure on the antifungal activity has also been correlated.

Cholinesterase Inhibitory Activity of Some semi-Rigid Spiro Heterocycles: POM Analyses and Crystalline Structure of Pharmacophore Site.

PubMed

Hadda, Taibi Ben; Talhi, Oualid; Silva, Artur S M; Senol, Fatma Sezer; Orhan, Ilkay Erdogan; Rauf, Abdur; Mabkhot, Yahia N; Bachari, Khaldoun; Warad, Ismail; Farghaly, Thoraya A; Althagafi, Ismail I; Mubarak, Mohammad S

2018-01-01

Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drugs for the treatment of AD. our aim in this article was to investigate the inhibitory potential of five known compounds (2-6) with spiro skeleton against AChE and BChE using ELISA microplate assays. In addition to their ChE inhibitory effect, their physico-chemical properties were also calculated. Moreover, the present work aims at investigating the charge/geometrical effect of a hypothetical pharmacophore or bidentate site in a bioactive group, on the inhibition efficiency of spiro compounds 2-6 by using Petra/Osiris/ molinspiration (POM) and X-ray analyses. In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested in vitro for their inhibitory potential against AChE and BChE using ELISA microtiter plate assays at 25 µg/mL. Results revealed that three of the spiro compounds tested exert more than 50% inhibition against one of cholinesterases. Compound 5 displayed 68.73 ± 4.73% of inhibition toward AChE, whereas compound 6 showed 56.17 ± 0.83% of inhibition toward BChE; these two previously synthesized compounds have been the most active hits. Our data obtained from screening of compounds 2-6 against the two cholinesterases indicate that three of these show good potential to selectively inhibit AChE or BChE. Spiro compounds 2, 5, and 6 exhibited the most potent activity of the series against AChE or BChE with inhibition values in the range 55-70%. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design, synthesis, and pharmacological evaluation of a novel series of hormone sensitive lipase inhibitor.

PubMed

Ogiyama, Tomoko; Yamaguchi, Mitsuhiro; Kurikawa, Nobuya; Honzumi, Shoko; Terayama, Koji; Nagaoka, Nobumi; Yamamoto, Yuka; Kimura, Takako; Sugiyama, Daisuke; Inoue, Shin-Ichi

2017-09-01

HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tyrosinase inhibitory components from Aloe vera and their antiviral activity.

PubMed

Kim, Jang Hoon; Yoon, Ju-Yeon; Yang, Seo Young; Choi, Seung-Kook; Kwon, Sun Jung; Cho, In Sook; Jeong, Min Hee; Ho Kim, Young; Choi, Gug Seoun

2017-12-01

A new compound, 9-dihydroxyl-2'-O-(Z)-cinnamoyl-7-methoxy-aloesin (1), and eight known compounds (2-9) were isolated from Aloe vera. Their structures were elucidated using 1D/2D nuclear magnetic resonance and mass spectra. Compound 9 exhibited reversible competitive inhibitory activity against the enzyme tyrosinase, with an IC 50 value of 9.8 ± 0.9 µM. A molecular simulation revealed that compound 9 interacts via hydrogen bonding with residues His244, Thr261, and Val283 of tyrosinase. Additionally, compounds 3 and 7 were shown by half-leaf assays to exhibit inhibitory activity towards Pepper mild mottle virus.

Inhibitory effect of flavonoids from citrus plants on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors.

PubMed

Iwase, Y; Takemura, Y; Ju-ichi, M; Ito, C; Furukawa, H; Kawaii, S; Yano, M; Mou, X Y; Takayasu, J; Tokuda, H; Nishino, H

2000-06-01

To search for possible anti-tumor promoters, thirteen flavones (1-13) obtained from the peel of Citrus plants were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these flavones, 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT) (13) exhibited significant inhibitory effects on the EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, compound 13 exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

Structure-Activity Relationships of Acyclic Selenopurine Nucleosides as Antiviral Agents.

PubMed

Sahu, Pramod K; Umme, Tamima; Yu, Jinha; Kim, Gyudong; Qu, Shuhao; Naik, Siddhi D; Jeong, Lak Shin

2017-07-12

A series of acyclic selenopurine nucleosides 3a - f and 4a - g were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir ( 4a ) exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC 50 = 1.47 µM) and HSV-2 (EC 50 = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4e - g exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative 4d , indicating that they might act as prodrugs of seleno-ganciclovir ( 4d ).

In Vitro Susceptibility of Leishmania infantum to Artemisinin Derivatives and Selected Trioxolanes

PubMed Central

Albuquerque, Andreia; Cabral, Lília I. L.; Lopes, Liliana; Campino, Lenea

2015-01-01

Leishmaniasis is among the world's most neglected diseases. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. A small library of artemisinin-derived trioxanes and synthetic trioxolanes was tested against promastigote and intramacrophage amastigote forms of Leishmania infantum. The trioxolanes LC50 and LC95 presented the best activity and safety profiles, showing potential for further studies in the context of leishmanial therapy. Our results indicate that the compounds tested exhibit peroxide-dependent activity. PMID:26014947

New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

PubMed

Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

2015-06-01

Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antimalarial Activity of Potential Inhibitors of Plasmodium falciparum Lactate Dehydrogenase Enzyme Selected by Docking Studies

PubMed Central

Penna-Coutinho, Julia; Cortopassi, Wilian Augusto; Oliveira, Aline Alves; França, Tanos Celmar Costa; Krettli, Antoniana Ursine

2011-01-01

The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH) has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH) all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH) and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole) were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2). The IC50 values for each drug in both tests were similar, were lowest for posaconazole (<5 µM) and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use. PMID:21779323

Antifungal and phytotoxic activity of essential oil from root of Senecio amplexicaulis Kunth. (Asteraceae) growing wild in high altitude-Himalayan region.

PubMed

Singh, Rajendra; Ahluwalia, Vivek; Singh, Pratap; Kumar, Naresh; Prakash Sati, Om; Sati, Nitin

2016-08-01

This work was aimed to evaluate the essential oil from root of medicinally important plant Senecio amplexicaulis for chemical composition, antifungal and phytotoxic activity. The chemical composition analysed by GC/GC-MS showed the presence of monoterpene hydrocarbons in high percentage with marker compounds as α-phellandrene (48.57%), o-cymene (16.80%) and β-ocimene (7.61%). The essential oil exhibited significant antifungal activity against five phytopathogenic fungi, Sclerotium rolfsii, Macrophomina phaseolina, Rhizoctonia solani, Pythium debaryanum and Fusarium oxysporum. The oil demonstrated remarkable phytotoxic activity in tested concentration and significant reduction in seed germination percentage of Phalaris minor and Triticum aestivum at higher concentrations. The roots essential oil showed high yield for one of its marker compound (α-phellandrene) which makes it important natural source of this compound.

Minor cytotoxic and antibacterial compounds from the rhizomes of Amomum aculeatum.

PubMed

Heilmann, J; Brun, R; Mayr, S; Rali, T; Sticher, O

2001-08-01

A new cytotoxic 1,7-dioxa-dispiro[5.1.5.2]pentadeca-9,12-dien-11-one derivative, aculeatin D, and a new alkenone, 5-hydroxy-hexacos-1-en-3-one, have been isolated as minor compounds from the rhizomes of Amomum aculeatum. Their structures have been determined mainly by NMR spectroscopy and mass spectrometry. Aculeatin D showed high cytotoxicity against the KB and the L-6 cell line with IC(50) of 0.38 microg/ml and 1 microg/ml, respectively. Additionally, it revealed remarkable activity against two Plasmodium falciparum strains, as well as against Trypanosoma brucei rhodesiense and Trypanosoma cruzi. 5-Hydroxy-hexacos-1-en-3-one exhibited neither cytotoxic nor antiprotozoal activity, whereas antibacterial testing against Bacillus cereus, Escherichia coli and Staphylococcus epidermidis showed moderate to strong activity for both compounds.

Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors.

PubMed

Wang, Ling; Wang, Yu; Tian, Yiguang; Shang, Jinling; Sun, Xiaoou; Chen, Hongzhuan; Wang, Hao; Tan, Wen

2017-01-01

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC 50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer's disease (AD) treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents

PubMed Central

Suryadevara, Praveen Kumar; Racherla, Kishore Kumar; Olepu, Srinivas; Norcross, Neil R.; Tatipaka, Hari Babu; Arif, Jennifer A.; Planer, Joseph D.; Lepesheva, Galina; Verlinde, Christophe L. M. J.; Buckner, Frederick S.; Gelb, Michael H.

2014-01-01

New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC50<1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T.cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate. PMID:24120539

Synthesis, Urease Inhibition, Antioxidant, Antibacterial, and Molecular Docking Studies of 1,3,4-Oxadiazole Derivatives

PubMed Central

Hanif, Muhammad; Shoaib, Khurram; Saleem, Muhammad; Hasan Rama, Nasim; Zaib, Sumera; Iqbal, Jamshed

2012-01-01

A series of eighteen 1,3,4-oxadiazole derivatives have been synthesized by treating aromatic acid hydrazides with carbon disulfide in ethanolic potassium hydroxide yielding potassium salts of 1,3,4-oxadiazoles. Upon neutralization with 1 N hydrochloric acid yielded crude crystals of 1,3,4-oxadiazoles, which were purified by recrystallization in boiling methanol. The synthesized 1,3,4-oxadiazoles derivatives were evaluated in vitro for their urease inhibitory activities, most of the investigated compounds were potent inhibitors of Jack bean urease. The molecular docking studies were performed by docking them into the crystal structure of Jack bean urease to observe the mode of interaction of synthesized compounds. The synthesized compounds were also tested for antibacterial and antioxidant activities and some derivatives exhibited very promising results. PMID:22934191

SPF32629A and SPF32629B: enantioselective synthesis, determination of absolute configuration, cytotoxicity and antibacterial evaluation.

PubMed

Vegi, Srinivasa Rao; Boovanahalli, Shanthaveerappa K; Patro, Balaram; Mukkanti, K

2011-05-01

We report herein an efficient enantioselective synthesis of SPF32629A and SPF32629B through one-pot enantioselective reduction and protecting-group-free regioselective O-acylation strategy. The absolute configuration of the enantiomerically pure isomers was established by Mosher ester analysis. The inhibitory potencies of the synthesized compounds were assayed in vitro against a panel of microorganisms and against A549 human lung adenocarcinoma cell line. Compounds 2, 11 and 12 displayed moderate to potent antibacterial activity against all the tested strains and compounds 7, 8, 2, 11 and 12 exhibited significant cytotoxicity in a dose-dependent manner with an IC50 values ranging from 2.92 to 4.14 μg/ml and 8-11 μM. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

CHARACTERIZATION OF GLOVEBOX GLOVES FOR THE SAVANNAH RIVER SITE

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

Korinko, P.

A task was undertaken to characterize glovebox gloves that are currently used in the facilities at Savannah River Site (SRS) as well as some experimental and advanced compound gloves that have been proposed for use. Gloves from four manufacturers were tested for permeation in hydrogen and air, thermal stability, tensile properties, puncture resistance and dynamic mechanical response. The gloves were compared to each other within the type and also to the butyl rubber glove that is widely used at the SRS. The permeation testing demonstrated that the butyl compounds from three of the vendors behaved similarly and exhibited hydrogen permeabilitiesmore » of .52‐.84 x10{sup ‐7} cc H{sub 2}*cm / (cm{sup 2}*atm). The Viton glove performed at the lower edge of this bound, while the more advanced composite gloves exhibited permeabilities greater than a factor of two compared to butyl. Thermogravimetric analysis was used to determine the amount of material lost under slightly aggressive conditions. Glove losses are important since they can affect the life of glovebox stripper systems. During testing at 90, 120, and 150°C, the samples lost most of the mass in the initial 60 minutes of thermal exposure and as expected increasing the temperature increased the mass loss and shortened the time to achieve a steady state loss. The ranking from worst to best was Jung butyl‐Hypalon with 12.9 %, Piercan Hypalon with 11.4 %, and Jung butyl‐Viton with 5.2% mass loss all at approximately 140°C. The smallest mass losses were experienced by the Jung Viton and the Piercan polyurethane. Tensile properties were measured using a standard dog bone style test. The butyl rubber exhibited tensile strengths of 11‐15 MPa and elongations or 660‐843%. Gloves made from other compounds exhibited lower tensile strengths (5 MPa Viton) to much higher tensile strengths (49 MPa Urethane) with a comparable range of elongation. The puncture resistance of the gloves was measured in agreement with an ASTM standard. The Butyl gloves exhibited puncture resistance from 183 - 296 lbs/in for samples of 0.020 - 0.038 thick. Finally, the glass transition temperature and the elastic and viscoelastic properties as a function of temperature up to maximum use temperature were determined for each glove material using Dynamic Mechanical Analysis. The glass transition temperatures of the gloves were ‐60°C for butyl, ‐30°C for polyurethane, ‐ 16°C Hypalon, ‐16°C for Viton, and ‐24°C for polyurethane‐Hypalon. The glass transition was too complex for the butyl‐Hypalon and butyl‐Viton composite gloves to be characterized by a single glass transition temperature. All of the glass transition temperatures exceed the vendor projected use temperatures.« less

Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

PubMed

Han, Xiao-Feng; He, Xing; Wang, Miao; Xu, Di; Hao, Li-Ping; Liang, Ai-Hua; Zhang, Jun; Zhou, Zhi-Ming

2015-10-20

Novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I] Sar(1) Ile(8)-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC₅₀ = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC₅₀ = 7.3 nM), 14R (IC₅₀ = 6.3 nM), and 14S (IC₅₀ = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC₅₀ = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Preparation of an aminopropyl imidazole-modified silica gel as a sorbent for solid-phase extraction of carboxylic acid compounds and polycyclic aromatic hydrocarbons.

PubMed

Wang, Na; Guo, Yong; Wang, Licheng; Liang, Xiaojing; Liu, Shujuan; Jiang, Shengxiang

2014-05-21

In this paper, a kind of aminopropyl imidazole-modified silica sorbent was synthesized and used as a solid-phase extraction (SPE) sorbent for the determination of carboxylic acid compounds and polycyclic aromatic hydrocarbons (PAHs). The resultant aminopropyl imidazole-modified silica sorbent was characterized by Fourier transform infrared spectroscopy (FT-IR) and elemental analysis (EA) to ensure the successful binding of aminopropyl imidazole on the surface of silica gel. Then the aminopropyl imidazole-modified silica sorbent served as a SPE sorbent for the enrichment of carboxylic acid compounds and PAHs. The new sorbent exhibited high extraction efficiency towards the tested compounds and the results show that such a sorbent can offer multiple intermolecular interactions: electrostatic, π-π, and hydrophobic interactions. Several parameters affecting the extraction recovery, such as the pH of sample solution, the pH of eluent, the solubility of eluent, the volume of eluent, and sample loading, were also investigated. Under the optimized conditions, the proposed method was applied to the analysis of four carboxylic acid compounds and four PAHs in environmental water samples. Good linearities were obtained for all the tested compounds with R(2) larger than 0.9903. The limits of detection were found to be in the range of 0.0065-0.5 μg L(-1). The recovery values of spiked river water samples were from 63.2% to 112.3% with relative standard deviations (RSDs) less than 10.1% (n = 4).

Pyridine sulfonamide as a small key organic molecule for the potential treatment of type-II diabetes mellitus and Alzheimer's disease: In vitro studies against yeast α-glucosidase, acetylcholinesterase and butyrylcholinesterase.

PubMed

Riaz, Sadaf; Khan, Islam Ullah; Bajda, Marek; Ashraf, Muhammad; Qurat-Ul-Ain; Shaukat, Ayesha; Rehman, Tanzeel Ur; Mutahir, Sadaf; Hussain, Sajjad; Mustafa, Ghulam; Yar, Muhammad

2015-12-01

This paper presents the efficient high yield synthesis of novel pyridine 2,4,6-tricarbohydrazide derivatives (4a-4i) along with their α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities. The enzymes inhibition results showed the potential of synthesized compounds in controlling both type-II diabetes mellitus and Alzheimer's disease. In vitro biological investigations revealed that most of compounds were more active against yeast α-glucosidase than the reference compound acarbose (IC50 38.25±0.12μM). Among the tested series the compound 4c bearing 4-flouro benzyl group was noted to be the most active (IC50 25.6±0.2μM) against α-glucosidase, and it displayed weak inhibition activities against AChE and BChE. Compound 4a exhibited the most desired results against all three enzymes, as it was significantly active against all the three enzymes; α-glucosidase (IC50 32.2±0.3μM), AChE (IC50 50.2±0.8μM) and BChE (IC50 43.8±0.8μM). Due to the most favorable activity of 4a against the tested enzymes, for molecular modeling studies this compound was selected to investigate its pattern of interaction with α-glucosidase and AChE targets. Copyright © 2015 Elsevier Inc. All rights reserved.

Synthesis and Pharmacological Evaluation of Some New Pyrimidine Derivatives Containing 1,2,4-Triazole

PubMed Central

Khanage, Shantaram Gajanan; Raju, S. Appala; Mohite, Popat Baban; Pandhare, Ramdas Bhanudas

2012-01-01

Purpose: An efficient method has been described for synthesis of 6-(substituted aryl)-4-(3,5-diphenyl-1H-1,2,4-triazol-1-yl)-1, 6-dihydropyrimidine-2-thiol, as a beneficial antimicrobial, anticonvulsant and anticancer agents. Methods: The clalcones of title compounds were synthesized in three steps and subsequently these chalcones were further reacted with thiourea in the presence of KOH in ethanol, which led to the formation of dihydropyrimidine derivatives (4a-j). Compounds 4a-j were screened for their in vitro antimicrobial activity by agar well method and their anticonvulsant activity by the MES model. Anticancer activity of two newly synthesized heterocycles were evaluated at National Cancer Institute (NCI) Maryland, USA against 60 cell lines of different human tumor at a single dose of 10-5 M. Results: Compound 4b, 4c, 4d, 4i and 4j were exhibited significant antimicrobial potential against tested strains at 50μg/ml and 100μg/ml concentrations. Out of the ten compounds studied 4a, 4b, 4c, 4h and 4j showed comparable MES activity to Phenytoin and Carbamazepine after 0.5h. Tested compounds did not showed to be more potent than standard drugs after 4h. Compound 4a and 4d were found active on Non-Small Cell Lung Cancer (HOP-92). Conclusion: Ten noveldihydropyrimidine analogues has been synthesized, characterized and found to bepromising antibacterial, anticonvulsant and antitumor agents. PMID:24312796

Genotoxicity and Cytotoxicity Evaluation of the Neolignan Analogue 2-(4-Nitrophenoxy)-1Phenylethanone and its Protective Effect Against DNA Damage

PubMed Central

Hanusch, Alex Lucas; de Oliveira, Guilherme Roberto; de Sabóia-Morais, Simone Maria Teixeira; Machado, Rafael Cosme; dos Anjos, Murilo Machado; Chen Chen, Lee

2015-01-01

Neolignans are secondary metabolites found in various groups of Angiosperms. They belong to a class of natural compounds with great diversity of chemical structures and pharmacological activities. These compounds are formed by linking two phenylpropanoid units. Several compounds that have ability to prevent genetic damage have been isolated from plants, and can be used to prevent or delay the development of tumor cells. Genetic toxicology evaluation is widely used in risk assessment of new drugs in preclinical screening tests. In this study, we evaluated the genotoxicity and cytotoxicity of the neolignan analogue 2-(4-nitrophenoxy)-1-phenylethanone (4NF) and its protective effect against DNA damage using the mouse bone marrow micronucleus test and the comet assay in mouse peripheral blood. Our results showed that this neolignan analogue had no genotoxic activity and was able to reduce induced damage both in mouse bone marrow and peripheral blood. Although the neolignan analogue 4NF was cytotoxic, it reduced cyclophosphamide-induced cytotoxicity. In conclusion, it showed no genotoxic action, but exhibited cytotoxic, antigenotoxic, and anticytotoxic activities. PMID:26554835

Adsorption and desorption characteristics of methamphetamine, 3,4-methylenedioxymethamphetamine, and pseudoephedrine in soils.

PubMed

Pal, Raktim; Megharaj, Mallavarapu; Kirkbride, K Paul; Naidu, Ravi

2015-06-01

This work presents, for the first time, information on the adsorption-desorption characteristics of illicit drugs and precursors in soils and an estimation of their potential bioavailability. The experiment was conducted using a batch equilibrium technique for the parent drugs methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) and the precursor pseudoephedrine in three South Australian soils varying in physiochemical properties. The individual compounds exhibited different adsorption mechanisms in the test soils, and the results fitted better with the Freundlich isotherm model (r (2) ≥ 0.99). The maximum adsorption capacity was recorded for pseudoephedrine (2,000 μg g(-1)). However, pseudoephedrine recorded lower organic carbon normalized adsorption coefficient values (<250 mL g(-1)), lower magnitudes of Gibb's free energy change, and higher percent desorption (73-92 %) compared to methamphetamine and MDMA. The results thus showed pseudoephedrine to be the most mobile compound in the soils under study, to have the highest availability for degradation of the three compounds, and to have the highest susceptibility to biotic degradation in test soils.

Ionic liquids as lubricants or lubrication additives: an ecotoxicity and biodegradability assessment.

PubMed

Stolte, Stefan; Steudte, Stephanie; Areitioaurtena, Olatz; Pagano, Francesco; Thöming, Jorg; Stepnowski, Piotr; Igartua, Amaya

2012-11-01

This paper reports on the (eco)toxicity and biodegradability of ionic liquids considered for application as lubricants or lubrication additives. Ammonium- and pyrrolidinium-based cations combined with methylsulphate, methylsulphonate and/or (CF(3)SO(2))(2)N(-) anions were investigated in tests to determine their aquatic toxicity using water fleas Daphnia magna, green algae Selenastrum capricornutum and marine bacteria (Vibrio fischeri). Additional test systems with an isolated enzyme (acetylcholinesterase) and isolated leukaemia cells from rats (IPC-81) were used to assess the biological activity of the ionic liquids. These compounds generally exhibit low acute toxicity and biological activity. Their biodegradability was screened according to OECD test procedures 301 B and 301 F. For choline and methoxy-choline ionic liquids ready biodegradability was observed within 5 or 10 d, respectively. Some of the compounds selected have a considerable potential to contribute to the development of more sustainable products and processes. Copyright © 2012 Elsevier Ltd. All rights reserved.

Synthesis of valproic acid amides of a melatonin derivative, a piracetam and amantadine for biological tests.

PubMed

Chatterjie, N; Alexander, G; Wang, H

2001-10-01

Three new amide derivatives of valproic acid have been synthesized and characterized by spectrophotometric studies. The rationale for the preparation of such agents has been based on the observation that chemical combination of the anticonvulsant pharmacophore, valproic acid with amine moieties produces more effective and less toxic amides. The amine components selected in this work also exhibit neuroactivity with the prospect of these agents being biologically active in controlling not just seizures and but also possessing neuroprotective properties. We report here the synthesis and properties of the valproylamides of 5-methoxytryptamine, related to melatonin (1), of N-substituted 2-pyrrolidinone related to piracetam (2), and of adamantylamine related to amantadine (3). In preliminary tests these compounds showed low toxicity and a variety of anticonvulsive properties, including a delay in onset of activity. These compounds and their derivatives are now available to be tested additionally for control of subclinical seizures, enhancement of cognition, behavior modification and alleviation of symptoms and disorders due to neuronal damage.

Herbicidal activity of pure compound isolated from rhizosphere inhabiting Aspergillus flavus.

PubMed

Khattak, Saeed Ullah; Lutfullah, Ghosia; Iqbal, Zafar; Rehman, Irshad Ur; Ahmad, Jamshaid; Khan, Abid Ali

2018-05-01

In the quest for bioactive natural products of fungal origin, Aspergillus flavus was isolated from rhizosphere of Mentha piperita using Potato Dextrose Agar (PDA) and Czapec Yeast Broth (CYB) nutrient media for metabolites production. In total, three different metabolites were purified using HPLC/LCMS and the structures were established using 500 Varian NMR experiments. Further the isolated metabolites in different concentrations (10, 100, 1000 μg/mL) were tested for herbicidal activity using Completely Randomized design (CRD) against the seeds of Silybum marianum and Avena fatua which are major threats to wheat crop in Pakistan. Among the isolated metabolites, one compound was found active against the test weed species whose activity is reported in the present work. The chemical name of the compound is 2-(1, 4-dihydroxybutan-2-yl)-1, 3-dihydroxy-6, 8-dimethoxyanthracene-9, 10(4aH, 9aH)-dione with mass of 388. Results showed that all seeds germinated in control treatment; however, with the metabolite treated, the growth was retarded to different levels in all parts of the weeds. At a dose of 1000 μg/mL of the pure compound, 100% seeds of S. marianum and 60% seeds of A. fatua were inhibited. Interestingly, the pure compound exhibited less inhibition of 10% towards the seeds of common wheat (Triticum aestivum).

Increase in volatilization of organic compounds using air sparging through addition in alcohol in a soil-water system.

PubMed

Chao, Huan-Ping; Hsieh, Lin-Han Chiang; Tran, Hai Nguyen

2018-02-15

This study developed a novel method to promote the remediation efficiency of air sparging. According to the enhanced-volatilization theory presented in this study, selected alcohols added to groundwater can highly enhance the volatilization amounts of organic compounds with high Henry's law constants. In this study, the target organic compounds consisted of n-hexane, n-heptane, benzene, toluene, 1,1,2-trichloroethane, and tetrachloroethene. n-pentanol, n-hexanol, and n-heptanol were used to examine the changes in the volatilization amounts of organic compounds in the given period. Two types of soils with high and low organic matter were applied to evaluate the transport of organic compounds in the soil-water system. The volatilization amounts of the organic compounds increased with increasing alcohol concentrations. The volatilization amounts of the test organic compounds exhibited a decreasing order: n-heptanol>n-hexanol>n-pentanol. When 10mg/L n-heptanol was added to the system, the maximum volatilization enhancement rate was 18-fold higher than that in distilled water. Samples of soil with high organic matter might reduce the volatilization amounts by a factor of 5-10. In the present study, the optimal removal efficiency for aromatic compounds was approximately 98%. Copyright © 2017 Elsevier B.V. All rights reserved.

Potential application of synthesized ferrocenylimines compounds for the elimination of bacteria in water

NASA Astrophysics Data System (ADS)

Ikhile, M. I.; Barnard, T. G.; Ngila, J. C.

2017-08-01

This work reports a study towards a search for environmentally friendly water disinfectant. The most common method for water treatment is based on chlorine which had a wide application over the years as a water disinfectant, but suffer the disadvantage of reacting with natural organic matter to form disinfection by products. In this study, the potential application of novel ferrocenylimines compounds, namely 4-ferrocenylaniline (1), N-(3-bromo-2-hydroxylbenzylidene)-4-ferrocenylimine (2) and N-(3-bromo-5-chlorosalicyl)-4-ferrocenylimine (3) for the elimination of bacteria in water was investigated by evaluating their antibacterial properties against twelve different bacterial strains using microdilution method in sterile 96 well micro titer plates. The in vitro antibacterial activity revealed that the ferrocenylimines compound exhibit higher antibacterial activity than ferrocene, which is one of the starting materials towards the synthesis of this novel ferrocenylimines compounds. The most active ferrocenylimines compound was compound 3 with a minimal inhibitory concentration (MIC) value of 0.30 mg/ml against S. sonnei. In addition, all the ferrocenylimines compounds possessed excellent antibacterial activity against B. cereus with the same MIC value of 0.31 mg/ml. The results obtained so far show great potential in the three tested ferrocenylimines compounds for use in water treatment in killing bacteria in water.

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.

New cytotoxic and anti-inflammatory compounds isolated from Morus alba L.

PubMed

Qin, Jing; Fan, Min; He, Juan; Wu, Xing-De; Peng, Li-Yan; Su, Jia; Cheng, Xiao; Li, Yan; Kong, Ling-Mei; Li, Rong-Tao; Zhao, Qin-Shi

2015-01-01

Six Diels-Alder adducts (1-6) and nine prenylated flavanones (7-15) were isolated from the root bark of Morus alba L. Among them, soroceal B (1) and sanggenol Q (7) were new compounds. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR techniques. Compounds 1-3, 9, 10, 12, 13 and 15 exhibited cytotoxic activity against five human tumour lines and compound 2 inhibited significantly selective cytotoxic activities towards HL-60 and AGS cells with IC50 of 3.4 and 3.6 μM. Compounds 3, 5, 9 and 12 exhibited moderate inhibitory activity against nitric oxide production in LPS-activated RAW264.7.

Polyketide-Terpene Hybrid Metabolites from an Endolichenic Fungus Pestalotiopsis sp.

PubMed

Yuan, Chao; Ding, Gang; Wang, Hai-Ying; Guo, Yu-Hua; Shang, Hai; Ma, Xiao-Jun; Zou, Zhong-Mei

2017-01-01

Five new polyketide-terpene hybrid metabolites ( 1 - 5 ) with highly functionalized groups, together with six known derivatives ( 6 - 11 ), were isolated from the endolichenic fungus Pestalotiopsis sp. Their structures were elucidated by extensive NMR experiments including 1 H, 13 C, HMQC, COSY, and HMBC. The relative configurations of the new compounds were determined by analysis of coupling constants and ROESY correlations. The absolute configurations especially the secondary alcohol at C-15 in 1 and secondary alcohol at C-14 in 5 were established via the CD experiments of the in situ formed [Rh 2 (OCOCF 3 ) 4 ] complex with the acetonide derivatives. These compounds were tested for their inhibition activity against six plant pathogens. Compounds 1 and 5 exhibited pronounced efficiency against Fusarium oxysporum , and compounds 5 and 6 potently inhibited Fusarium gramineum with MIC value of 8  µ g/mL, which revealed the plausible ecological role of endolichenic fungus in providing chemical protection for its host lichen in the fungus-plant relationship. The biosynthetic pathway of compounds 1 - 11 was postulated for the first time, which paved the way for its further biosynthesis research.

Anti-acne activities of pulsaquinone, hydropulsaquinone, and structurally related 1, 4-quinone derivatives.

PubMed

Cho, Soon-Chang; Sultan, Md Zakir; Moon, Surk-Sik

2009-04-01

Quinone type compound, pulsaquinone 1, isolated from the aqueous ethanol extract of the roots of Pulsatilla koreana exhibited antimicrobial activities against an anaerobic non-spore-forming gram-positive bacillus, Propionibacterium acnes, which is related with the pathogenesis of the inflamed lesions in a common skin disease, acne vulgaris. Compound 1 was unstable on standing and thus converted to more stable compound 2, namely hydropulsaquinone by hydrogenation, whose activity was comparable to mother compound 1 (MIC for 1 and 2 against P. acnes: 2.0 and 4.0 microg/mL, respectively). Other structurally-related quinone derivatives (3-13) were also tested for structure-activity relationship against anaerobic and aerobic bacteria, and fungi. The antimicrobial activity was fairly good when the quinone moiety was fused with a nonpolar 6- or 7-membered ring on the right side whether or not conjugated (1,4-naphtoquinone derivatives 3-5), while simple quinone compounds 6-9 showed poor activity. It seems that the methoxy groups at the left side of the quinone function deliver no considerable antimicrobial effect.

Monoterpenes with antibacterial activities from a Cameroonian medicinal plant Canthium Multiflorum (Rubiaceae).

PubMed

Kouam, Simeon Fogue; Ngouonpe, Alain Wembe; Bullach, Anke; Lamshöft, Marc; Kuigoua, Guy Merlin; Spiteller, Michael

2013-12-01

Investigation of the crude extract obtained from the aerial parts of Canthium multiflorum led to the isolation of a new iridoid (1) together with twelve known compounds. The structures of these compounds were elucidated by interpretation of 1D and 2D NMR spectroscopic data, accurate mass measurements and comparison with analytical data of previously known analogues. Most of the isolated compounds have been reported for the first time from C. multiflorium. The antimicrobial activities of the isolated compounds were evaluated on five different bacterial strains using agar diffusion technique. The Gram-positive bacterium Staphylococcus aureus subsp. aureus (DSM 799), and the Gram-negative bacteria Actinobacter calco-aceticus (DSM 30006), Serratia plymuthica (DSM 4540), Pseudomonas stutzeri (DSM 4166) and Escherichia coli (DSM 1116) were employed for this purpose. The new iridoid, named 6-oxo-genipin (1), demonstrated significant inhibitory activity against all microbial strains tested, especially the pathogen Staphylococcus aureus. In addition, the compounds 3, 4 and 9 exhibited antiplasmodial activity against Plasmodium falciparum strain K1 and weak cytotoxicity against L6 cell lines. © 2013 Elsevier B.V. All rights reserved.

Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of antigiardial activity with DNA binding affinity and giardial topoisomerase II inhibition.

PubMed Central

Bell, C A; Dykstra, C C; Naiman, N A; Cory, M; Fairley, T A; Tidwell, R R

1993-01-01

Nine dicationically substituted bis-benzimidazoles were examined for their in vitro activities against Giardia lamblia WB (ATCC 30957). The potential mechanisms of action of these compounds were evaluated by investigating the relationship among in vitro antigiardial activity and the affinity of the molecules for DNA and their ability to inhibit the activity of giardial topoisomerase II. Each compound demonstrated antigiardial activity, as measured by assessing the incorporation of [methyl-3H]thymidine by giardial trophozoites exposed to the test agents. Three compounds exhibited excellent in vitro antigiardial activities, with 50% inhibitory concentrations which compared very favorably with those of two currently used drugs, quinacrine HCl and metronidazole. Putative mechanisms of action for these compounds were suggested by the strong correlation observed among in vitro antigiardial activity and the affinity of the molecules for natural and synthetic DNA and their ability to inhibit the relaxation activity of giardial topoisomerase II. A strong correlation between the DNA binding affinity of these compounds and their inhibition of giardial topoisomerase II activity was also observed. Images PMID:8109934

Penialidins A-C with strong antibacterial activities from Penicillium sp., an endophytic fungus harboring leaves of Garcinia nobilis.

PubMed

Jouda, Jean-Bosco; Kusari, Souvik; Lamshöft, Marc; Mouafo Talontsi, Ferdinand; Douala Meli, Clovis; Wandji, Jean; Spiteller, Michael

2014-10-01

Three new polyketides named penialidins A-C (1-3), along with one known compound, citromycetin (4), were isolated from an endophytic fungus, Penicillium sp., harbored in the leaves of the Cameroonian medicinal plant Garcinia nobilis. Their structures were elucidated by means of spectroscopic and spectrometric methods (NMR and HRMS(n)). The antibacterial efficacies of the new compounds (1-3) were tested against the clinically-important risk group 2 (RG2) bacterial strains of Staphylococcus aureus and Escherichia coli. The ecologically imposing strains of E. coli (RG1), Bacillus subtilis and Acinetobacter sp. BD4 were also included in the assay. Compound 3 exhibited pronounced activity against the clinically-relevant S. aureus as well as against B. subtilis comparable to that of the reference standard (streptomycin). Compound 2 was also highly-active against S. aureus. By comparing the structures of the three new compounds (1-3), it was revealed that altering the substitutions at C-10 and C-2 can significantly increase the antibacterial activity of 1. Copyright © 2014 Elsevier B.V. All rights reserved.

Anti-leptospiral activities of an endemic plant Glyptopetalum calocarpum (Kurz.) Prain used as a medicinal plant by Nicobarese of Andaman and Nicobar Islands.

PubMed

Chander, M Punnam; Kumar, K Vinod; Shriram, A N; Vijayachari, P

2015-01-01

Leaves of an endemic plant Glyptopetalum calocarpum are used by Nicobarese tribes of Andaman and Nicobar Islands, India, to prepare traditional medicine for treating fever. In the present investigation, pharmacologically active compounds were isolated from this plant and their antimicrobial efficacy was evaluated against the leptospiral strains. The anti-leptospiral activity of six plant-derived compounds was determined by both microdilution and macrodilution methods. Two out of six compounds, namely lupenone and stigmasterol, showed anti-leptospiral activity. The minimum inhibitory concentrations of the two compounds tested against pathogenic leptospiral strains belonging to 10 serovars were in the range of 100-200 μg/mL. The range of minimum bactericidal concentrations was 400-800 μg/mL. Compounds lupenone, stigmasterol, lupeol, β-amyrin and β-amyrin acetate had negligible or no haemolytic activity, exhibiting IC50 values of greater than 5 mg/mL. Further in vivo studies are needed to investigate the pharmacological and toxicological properties of G. calocarpum before it can be considered as a new anti-leptospiral agent.

Novel pyrrole derivatives bearing sulfonamide groups: Synthesis in vitro cytotoxicity evaluation, molecular docking and DFT study

NASA Astrophysics Data System (ADS)

Bavadi, Masoumeh; Niknam, Khodabakhsh; Shahraki, Omolbanin

2017-10-01

The synthesis of new derivatives of pyrrole substituted sulfonamide groups is described. The in vitro anticancer activity of these pyrroles was evaluated against MCF7, MOLT-4 and HL-60 cells using MTT assay. The target compounds showed inhibitory activity against tested cell lines. Among the compounds, compound 1a exhibited good cytotoxic activity. The potential of this analog to induce apoptosis was confirmed in a nuclear morphological assay by Hoechst 33258 staining in the PC-12 cells. Finally, molecular docking was performed to determine the probable binding mode of the designed pyrrole derivatives into the active site of FGFR1 protein. DFT calculations were carried out at the B3LYP levels of theory with 6-31+G (d,p) basis set for compound 1a. The point group (C1) of it was obtained based on the optimized structures; the calculation of the FT-IR vibrational frequencies, 1H NMR and 13C NMR chemical shifts of the compound were carried out and compared with those obtained experimentally.

Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

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

Spicer, Timothy P.; Jiang, Jianwen; Taylor, Alexander B.

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$-$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S 1' subsite and in an S 1/S 2* subsite. Type II collagen- andmore » cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$-$drug interactions in humans.« less

Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections.

PubMed

Tan, Liang; Tao, Yunliang; Wang, Ting; Zou, Feng; Zhang, Shuhua; Kou, Qunhuan; Niu, Ao; Chen, Qian; Chu, Wenjing; Chen, Xiaoyan; Wang, Haidong; Yang, Yushe

2017-04-13

Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED 50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.

Formation and Ecotoxicity of N-Heterocyclic Compounds on Ammoxidation of Mono- and Polysaccharides

PubMed Central

2013-01-01

Ammoxidation of technical lignins under mild conditions is a suitable approach to artificial humic substances. However, carbohydrates as common minor constituents of technical lignins have been demonstrated to be a potential source of N-heterocyclic ecotoxic compounds. Ethyl acetate extracts of ammoxidation mixtures of the monosaccharides glucose and xylose exhibited considerable growth inhibiting activity in the OECD 201 test, with 4-methyl-1H-imidazole, 4-(hydroxymethyl)-1H-imidazole, and 3-hydroxypyridine being the most active compounds. The amount of N-heterocyclic compounds formed at moderate ammoxidation conditions (70 °C, 0.2 MPa O2, 3 h) was significantly lower for the polysaccharides cellulose and xylan (16–30 μg/g of educt) compared to glucose (15.4 mg). Ammoxidation at higher temperature is not recommendable for carbohydrate-rich materials as much higher amounts of N-heterocyclic compounds were formed from both monosaccharides (100 °C: 122.4–160.5 mg/g of educt) and polysaccharides (140 °C: 5.52–16.03 mg/g of educt). PMID:23967874

Discovery of Potent and Selective Dipeptidyl Peptidase IV Inhibitors Derived from [beta]-Aminoamides Bearing Subsituted Triazolopiperazines

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

Kim, Dooseop; Kowalchick, Jennifer E.; Brockunier, Linda L.

2008-06-30

A series of {beta}-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC{sub 50} = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds withmore » subnanomolar activity against DPP-4 (42b-49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC{sub 50} = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.« less

Identification of (E,E)-2,4-undecadienal from coriander (Coriandrum sativum L.) as a highly effective deodorant compound against the offensive odor of porcine large intestine.

PubMed

Ikeura, Hiromi; Kohara, Kaori; Li, Xin-Xian; Kobayashi, Fumiyuki; Hayata, Yasuyoshi

2010-10-27

The leaves of coriander ( Coriandrum sativum L.) exhibited a strong deodorizing effect against porcine internal organs (large intestine). The effective deodorizing compounds of coriander were identified by separating the volatile component of coriander, testing the effectiveness of each fraction against the offensive odor of porcine large intestine, and then identifying the compounds by GC-MS. The volatile component of coriander was first separated into six fractions (A-F) by preparative gas chromatography, and the deodorizing activity of each of these fractions against the offensive odor was measured. Fraction D, which showed the strongest deodorizing effect, was then separated into 12 subfractions by preparative GC. The deodorant activity of each subfraction was evaluated, and the deodorant compounds were identified by GC-MS. It was discovered that (E,E)-2,4-undecadienal was the most effective deodorizing compound. The deodorizing activity of (E,E)-2,4-undecadienal on the porcine large intestine increased as with concentration, reaching almost complete deodorizing ability at 10 ppb.

Effects of organic silicon compounds as additives on charge-discharge cycling efficiencies of lithium in nonaqueous electrolytes for rechargeable lithium cells

NASA Astrophysics Data System (ADS)

Yanagisawa, Ryota; Endo, Hisayuki; Unno, Masafumi; Morimoto, Hideyuki; Tobishima, Shin-ichi

2014-11-01

Influence of mixing organic silicon compounds into 1 M (M: mol L-1) LiPF6-ethylene carbonate (EC)/ethylmethyl carbonate (EMC) (mixing volume ratio = 3:7) mixed solvent electrolytes on charge-discharge cycling efficiencies of lithium metal negative electrodes is examined. As organic silicon compounds, polyether-modified siloxanes with polyethylene oxide chains, chlorotrimethylsilane, tetraethoxysilane, cis-tetra [isobutyl (dimethylsiloxy)] cyclotetrasiloxane and cage-type silsesquioxane are investigated. Charge-discharge cycling tests of lithium are galvanostatically carried out using stainless steel working electrodes. Charge-discharge cycling efficiencies of lithium tend to improve by mixing organic silicon compounds. A cage-type silsesquioxane, octaphenyloctasilsesquioxane (Ph8T8) exhibits the highest cycling efficiency of approximately 80% with small mixing amount of 0.02 M Ph8T8. Mechanism of enhancement of lithium cycling efficiencies by mixing organic silicon compounds is considered to be due to the suppression of excess reduction of LiPF6-EC/EMC by lithium and the growth of surface film on lithium.

In vitro functional properties of crude extracts and isolated compounds from banana pseudostem and rhizome.

PubMed

Kandasamy, Saravanan; Ramu, Sasikala; Aradhya, Somaradhya Mallikarjuna

2016-03-15

Pseudostem and rhizome are the significant bio-waste generated (43.48%) from the banana plant post fruit harvest, which are usually left in the plantation or incinerated and wasted. Amounts used in production for consumption are negligible. However, the material has an important part to play in indigenous systems of medicine. Based on the huge volume of bio-waste generated and its traditional medicinal use, it is worth exploiting it as a source of natural bioactive compounds. In the current study, sequential extracts from banana pseudostem (BPS) and rhizome (BR), and isolated compounds including chlorogenic acid, 4-epicyclomusalenone and cycloeucalenol acetate, were tested for their antimicrobial activity, antiplatelet aggregation and cytotoxicity. Isolated compounds and crude extracts exhibited strong antimicrobial activity against a wide range of bacterial and fungal strains, platelet aggregation induced by collagen and cytotoxicity towards human liver cancer (HepG2) cells. Banana plant bio-waste, pseudostem and rhizome may serve as a potential source of multifunctional bioactive compounds and functional ingredient in food and other allied industries. © 2015 Society of Chemical Industry.

Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

DOE PAGES

Spicer, Timothy P.; Jiang, Jianwen; Taylor, Alexander B.; ...

2014-10-20

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$-$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S 1' subsite and in an S 1/S 2* subsite. Type II collagen- andmore » cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$-$drug interactions in humans.« less

Biological evaluation and molecular docking of some chromenyl-derivatives as potential antimicrobial agents.

PubMed

Ionuţ, Ioana; Vodnar, Dan Cristian; Oniga, Ilioara; Oniga, Ovidiu; Tiperciuc, Brînduşa; Tamaian, Radu

2016-01-01

Various thiosemicarbazones (TSCs) and their heterocyclic thiadiazolines (TDZ) possess important biological effects. In addition, chromenyl derivatives exhibit a wide range of pharmacological activities. Based on these findings and as a continuation of our research on nitrogen and sulfur containing compounds, we investigated a series of previously reported chromenyl-TSCs (1a-j) and chromenyl-TDZs (2a-j) for their in vitro antimicrobial activities against two bacterial and four fungal strains. MIC and MBC/MFC (µg/mL) values of these compounds were evaluated and compared to those of Spectinomycin, Moxifloxacin and Fluconazole, used as reference drugs. For a better understanding of the drug-receptor interactions, all the compounds were further subjected to molecular docking against four targets that were chosen based on the specific mechanism of action of the reference drugs used in the antimicrobial screening. All compounds tested showed equal or higher antibacterial/antifungal activities relative to the used reference drugs. In silico studies (molecular docking) revealed that all the investigated compounds showed good binding energies towards four receptor protein targets and supported their antimicrobial properties.

Design, synthesis, insecticidal activity, and structure-activity relationship (SAR): studies of novel triazone derivatives containing a urea bridge group based on transient receptor potential (TRP) channels.

PubMed

Yang, Yan; Liu, Yuxiu; Song, Hongjian; Li, Yongqiang; Wang, Qingmin

2016-11-01

Numerous compounds containing urea bridge and biurea moieties are used in a variety of fields, especially as drugs and pesticides. To search for novel, environmentally benign and ecologically safe pesticides with unique modes of action, four series of novel triazone analogues containing urea, thiourea, biurea, and thiobiurea bridge, respectively, were designed and synthesized, according to various calcium ion channel inhibitors which act on transient receptor potential protein. Their structures were characterized by [Formula: see text] NMR, [Formula: see text] NMR, and HRMS. The insecticidal activities of the new compounds were obtained. The bioassay results indicated that compounds containing a thiourea bridge and a thiobiurea bridge exhibited excellent insecticidal activities against bean aphid. Specifically, compounds [Formula: see text], [Formula: see text], and [Formula: see text] exhibited 85, 90, and 95 % activities, respectively, at 10 mg/kg. Compounds [Formula: see text] (30 %), [Formula: see text] (35 %), [Formula: see text] (30 %), and [Formula: see text] (40 %) exhibited the approximate aphicidal activity of pymetrozine (30 %) at 5 mg/kg. In addition, some target compounds exhibited insecticidal activities against lepidopteran pests. From a molecular design standpoint, the information obtained in this study could help in the further design of new derivatives with improved insecticidal activities.

Design, synthesis and biological evaluation of 5-fluorouracil-derived benzimidazoles as novel type of potential antimicrobial agents.

PubMed

Fang, Xue-Jie; Jeyakkumar, Ponmani; Avula, Srinivasa Rao; Zhou, Qian; Zhou, Cheng-He

2016-06-01

A series of 5-fluorouracil benzimidazoles as novel type of potential antimicrobial agents were designed and synthesized for the first time. Bioactive assay manifested that some of the prepared compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains in comparison with reference drugs norfloxacin, chloromycin and fluconazole. Noticeably, 3-fluorobenzyl benzimidazole derivative 5c gave remarkable antimicrobial activities against Saccharomyces cerevisiae, MRSA and Bacillus proteus with MIC values of 1, 2 and 4μg/mL, respectively. Experimental research revealed that compound 5c could effectively intercalate into calf thymus DNA to form compound 5c-DNA complex which might block DNA replication and thus exert antimicrobial activities. Molecular docking indicated that compound 5c should bind with DNA topoisomerase IA through three hydrogen bonds by the use of fluorine atom and oxygen atoms in 5-fluorouracil with the residue Lys 423. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors.

PubMed

Yan, Guoyi; Hou, Manzhou; Luo, Jiang; Pu, Chunlan; Hou, Xueyan; Lan, Suke; Li, Rui

2018-02-01

Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, and the IC 50 values against human cancer cell lines MV4-11, A375, and HeLa were 4.2, 7.1, and 11.6 μm, respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound-healing migration assay, and Western blotting were carried out to learn the bioactivity of compound 5. © 2017 John Wiley & Sons A/S.

Synthesis, crystal structure, ABTS radical-scavenging activity, antimicrobial and docking studies of some novel quinoline derivatives

NASA Astrophysics Data System (ADS)

Tabassum, Sumaiya; Suresha Kumara, T. H.; Jasinski, Jerry P.; Millikan, Sean P.; Yathirajan, H. S.; Sujan Ganapathy, P. S.; Sowmya, H. B. V.; More, Sunil S.; Nagendrappa, Gopalpur; Kaur, Manpreet; Jose, Gilish

2014-07-01

In this study, a series of nine novel 2-chloroquinolin-3-yl ester derivatives have been synthesized via a two-step protocol from 2-chloroquinoline-3-carbaldehyde. The structures of all these compounds were confirmed by spectral data. The single crystal X-ray structure of two derivatives, (2-chloroquinolin-3-yl)methyl acetate [6a] and (2-chloro-6-methylquinolin-3-yl)methyl acetate [6e] have also been determined. The synthesized compounds were further evaluated for their ABTS radical-scavenging activity and antimicrobial activities. Amongst all the tested compounds, 6a exhibited maximum scavenging activity with ABTS. Concerning antibacterial and antifungal activities, compound (2-chloro-6-methoxyquinolin-3-yl)methyl 2,4-dichlorobenzoate [6i] was found to be the most active in the series against B. subtilis, S. aureus, E. coli, K. pneumonia, C. albicans and A. niger species. The structure-antimicrobial activity relationship of these derivatives were studied using Autodock.

Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via Three-component Cationic Imino Diels-Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors.

PubMed

Rodríguez, Yeray A; Gutiérrez, Margarita; Ramírez, David; Alzate-Morales, Jans; Bernal, Cristian C; Güiza, Fausto M; Romero Bohórquez, Arnold R

2016-10-01

New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC50 = 72 μm) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl-cholinesterase was exhibited by compound 4ae (IC50 = 25.58 μm) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl-cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets. © 2016 The Authors Chemical Biology & Drug Design Published by John Wiley & Sons Ltd.

Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.

PubMed

Dražić, Tonko; Sachdev, Vinay; Leopold, Christina; Patankar, Jay V; Malnar, Martina; Hećimović, Silva; Levak-Frank, Sanja; Habuš, Ivan; Kratky, Dagmar

2015-05-15

The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties.

PubMed

Banerjee, Tuhin Suvro; Paul, Sibasish; Sinha, Surajit; Das, Sumantra

2014-11-01

Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by -CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the μ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and κ-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain. Copyright © 2014 Elsevier Ltd. All rights reserved.

Imidazole incorporated semicarbazone derivatives as a new class of anticonvulsants: design, synthesis and in-vivo screening.

PubMed

Amir, Mohammad; Ali, Israr; Hassan, Mohd Zaheen

2013-06-01

A series of novel imidazole incorporated semicarbazones was synthesized using an appropriate synthetic route and characterized by spectral analysis (IR, 1H NMR, 13C NMR and Mass). The anticonvulsant activity of the synthesized compounds was determined using doses of 30, 100, and 300 mg kg-1 against maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Six compounds exhibited protection in both models and 2-(1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene)-N-p-tolylsemicarbazone emerged as the most active compound of the series without any neurotoxicity and significant CNS depressant effect. Liver enzyme estimations (SGOT, SGPT, Alkaline phosphatase) of the compound also showed no significant change in the enzymes levels. Moreover, it caused 80% elevation of γ-amino butyric acid (GABA) levels in the whole mice brain, thus indicating that it could be a promising candidate in designing of a potent anticonvulsant drug.

Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.

PubMed

Xiong, Yifeng; Ullman, Brett; Choi, Jin-Sun Karoline; Cherrier, Martin; Strah-Pleynet, Sonja; Decaire, Marc; Dosa, Peter I; Feichtinger, Konrad; Teegarden, Bradley R; Frazer, John M; Yoon, Woo H; Shan, Yun; Whelan, Kevin; Hauser, Erin K; Grottick, Andrew J; Semple, Graeme; Al-Shamma, Hussien

2010-08-12

Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.

Environmental process descriptors for TNT, TNT-related compounds and picric acid in marine sediment slurries.

PubMed

Yost, Sally L; Pennington, Judith C; Brannon, James M; Hayes, Charolett A

2007-08-01

Process descriptors were determined for picric acid, TNT, and the TNT-related compounds 2,4DNT, 2,6DNT, 2ADNT, 4ADNT, 2,4DANT, 2,6DANT, TNB and DNB in marine sediment slurries. Three marine sediments of various physical characteristics (particle size ranging from 15 to >90% fines and total organic carbon ranging from <0.10 to 3.60%) were kept in suspension with 20ppt saline water. Concentrations of TNT and its related compounds decreased immediately upon contact with the marine sediment slurries, with aqueous concentrations slowly declining throughout the remaining test period. Sediment-water partition coefficients could not be determined for these compounds since solution phase concentrations were unstable. Kinetic rates and half-lives were influenced by the sediment properties, with the finer grained, higher organic carbon sediment being the most reactive. Aqueous concentrations of picric acid were very stable, demonstrating little partitioning to the sediments. Degradation to picramic acid was minimal, exhibiting concentrations at or just above the detection limit.

Inhibitory Effects of Flavonoids from Spatholobus suberectus on Sortase A and Sortase A-Mediated Aggregation of Streptococcus mutans.

PubMed

Park, Wanki; Ahn, Chan-Hong; Cho, Hyunjoo; Kim, Chang-Kwon; Shin, Jongheon; Oh, Ki-Bong

2017-08-28

Seven flavonoids were isolated from Spatholobus suberectus via repetitive column chromatography and high-performance liquid chromatography. The chemical structures of these compounds were identified by spectroscopic analysis and comparison with values reported in the literature. Among the flavonoids tested, 7-hydroxy-6-methoxyflavanone ( 1 ) and formononetin ( 4 ) exhibited strong inhibitory activity against Streptococcus mutans SrtA, with IC 50 values of 46.1 and 41.8 µM, respectively, but did not affect cell viability. The onset and magnitude of inhibition of saliva-induced aggregation in S. mutans treated with compounds 1 and 4 were comparable to the behavior of a srtA -deletion mutant without treatment.

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.

Novel benzil and isoflavone derivatives from Millettia dielsiana.

PubMed

Gong, Ting; Wang, Dong-Xiao; Chen, Ruo-Yun; Liu, Ping; Yu, De-Quan

2009-02-01

The analysis of vine stem extract from MILLETTIA DIELSIANA Harms yielded a novel benzil ( 1) and five new prenylated isoflavones ( 2 - 6) together with three known isoflavones ( 7 - 10) and one known flavone ( 11), and their structures were elucidated on the basis of chemical and spectral analysis. The absolute configuration of the 3'',4''-diols in 6 was determined by observing the CD induced after addition of dimolybdenum tetraacetate in DMSO solution (Snatzke's method). Some isolates were tested for their anti-inflammatory and antithrombase activities and cytotoxicities. Compound 2, barbigerone, and genistein showed significant anti-inflammatory activity, with inhibitory ratios 59.1 %, 59.5 %, and 58.5 %, respectively, at 10 muM, while compound 4 exhibited moderate cytotoxicity.

Synthesis, characterization, spectroscopic studies and antimicrobial activity of three new Schiff bases derived from Heterocyclic moiety

NASA Astrophysics Data System (ADS)

Mesbah, Mounira; Douadi, Tahar; Sahli, Farida; Issaadi, Saifi; Boukazoula, Soraya; Chafaa, Salah

2018-01-01

Three new Schiff-bases compounds (I-III) were synthesized by a condensation reaction in 1:2 M ratios of 4,4‧-diaminodiphenyl sulfide and pyrrol/thiophene/furan-2-carboxaldehyde in ethanol. The structural determinations of the Schiff-bases were identified with the help of elemental analysis then confirmed by UV-Vis, FT-IR and 1H NMR. The products were obtained in excellent yields. On the other hand, the in vitro antibacterial and antifungal activities of the synthesized compounds were investigated using disc diffusion method. Schiff bases synthesized individually exhibited varying degrees of inhibitory effects on the growth of the tested microbial species.

Biological evaluation of some new N-(2,6-dimethoxypyrimidinyl) thioureido benzenesulfonamide derivatives as potential antimicrobial and anticancer agents.

PubMed

Ghorab, Mostafa M; Alsaid, Mansour S; El-Gaby, Mohamed S A; Safwat, Nesreen A; Elaasser, Mahmoud M; Soliman, Aiten M

2016-11-29

A series of novel heterocyclic thioureas 3a-u containing sulfonamide moiety have been synthesized by the condensation of isothiocyanatobenzenesulfonamide 2 with a variety of heterocyclic amines. The newly synthesized heterocyclic thioureas were investigated for their antimicrobial and anticancer activity. The in vitro antibacterial and antifungal activity were done using well diffusion method. Interestingly, compounds 3j and 3m, showed similar or better activity compared with the reference drug against the tested microorganisms. Although, 3j was less active among its analogues to inhibit the breast carcinoma cells, it exhibit strong broad spectrum antimicrobial activities. However, The results of the cytotoxic activity revealed that compound 3p was the most active against the breast carcinoma cell line (MCF-7) giving promising IC 50 value of 1.72 μg/mL, compared with reference drug (5-flourouracil) with IC 50 value of 4.8 μg/mL. The most potent compounds in cytotoxic activity 3b and 3p were further docked inside the active site of CAIX and were found to exhibit a proper binding with the active site amino acids according to their bond lengths, angles and conformational energy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A Metabolomic Approach to Target Compounds from the Asteraceae Family for Dual COX and LOX Inhibition

PubMed Central

Chagas-Paula, Daniela A.; Zhang, Tong; Da Costa, Fernando B.; Edrada-Ebel, RuAngelie

2015-01-01

The application of metabolomics in phytochemical analysis is an innovative strategy for targeting active compounds from a complex plant extract. Species of the Asteraceae family are well-known to exhibit potent anti-inflammatory (AI) activity. Dual inhibition of the enzymes COX-1 and 5-LOX is essential for the treatment of several inflammatory diseases, but there is not much investigation reported in the literature for natural products. In this study, 57 leaf extracts (EtOH-H2O 7:3, v/v) from different genera and species of the Asteraceae family were tested against COX-1 and 5-LOX while HPLC-ESI-HRMS analysis of the extracts indicated high diversity in their chemical compositions. Using O2PLS-DA (R2 > 0.92; VIP > 1 and positive Y-correlation values), dual inhibition potential of low-abundance metabolites was determined. The O2PLS-DA results exhibited good validation values (cross-validation = Q2 > 0.7 and external validation = P2 > 0.6) with 0% of false positive predictions. The metabolomic approach determined biomarkers for the required biological activity and detected active compounds in the extracts displaying unique mechanisms of action. In addition, the PCA data also gave insights on the chemotaxonomy of the family Asteraceae across its diverse range of genera and tribes. PMID:26184333

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

PubMed

Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed. Copyright © 2016 Elsevier Inc. All rights reserved.

[Identification and evaluation of the neuroleptic activity of phenotropil].

PubMed

Akhapkina, V I; Akhapkin, R V

2013-01-01

The neuroleptic (antipsychotic) activity of phenotropil was studied in an experimental animal model. Phenotropil had a marked neuroleptic activity in models of positive (apomorphine-induced verticalization test) and negative (5-HTP-induced hyperkinesis test) symptoms of psychoses as well as in the m-cholinergic pathway hyperactivation (arecoline-induced tremor test). The compound markedly antagonized haloperidol catalepsy. Used in a single dose or as a course treatment, phenotropil did not provoke aggression nor intensify it. In contrast to typical and atypical antipsychotics, phenotropil had no sedative action and other adverse effects. It exhibited a positive effect on exploratory behavior and motor activity, had anxiolytic and antidepressant action.

meso-Dihydroguaiaretic acid derivatives with antibacterial and antimycobacterial activity.

PubMed

Reyes-Melo, Karen; García, Abraham; Romo-Mancillas, Antonio; Garza-González, Elvira; Rivas-Galindo, Verónica M; Miranda, Luis D; Vargas-Villarreal, Javier; Favela-Hernández, Juan Manuel J; Camacho-Corona, María Del Rayo

2017-10-15

Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium. Additionally, nineteen meso-DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50µg/mL. Seven meso-DGA derivatives bearing amino-ethers (26-31 and 33) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25µg/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N-ethylpiperidine moieties in meso-31) resulted essential to significantly increase the antimycobacterial properties of parent meso-DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Biological activities of phthalocyanines--XVI. Tetrahydroxy- and tetraalkylhydroxy zinc phthalocyanines. Effect of alkyl chain length on in vitro and in vivo photodynamic activities.

PubMed Central

Boyle, R. W.; Leznoff, C. C.; van Lier, J. E.

1993-01-01

Zinc phthalocyanine substituted with four hydroxyl groups attached to the macrocycle, either directly or via spacer chains of three or six carbon atoms, were tested for their photodynamic ability to inactivate Chinese hamster lung fibroblasts (line V-79) in vitro, and to induce regression of EMT-6 tumours grown subcutaneously in Balb/c mice. Their potential to inflict direct cell killing during photodynamic therapy was investigated by examining vascular stasis immediately following photoirradiation using fluorescein as a marker, and also by an in vivo/in vitro EMT-6 cell survival assay. Both of the tetraalkylhydroxy substituted zinc phthalocyanines are effective photodynamic sensitisers in vivo with the tetrapropylhydroxy compound exhibiting about twice the activity of the tetrahexylhydroxy analogue. The differences in activities were accentuated in vitro, the tetrapropylhydroxy compound was two orders of magnitude more potent than the tetrahexylhydroxy analogue in photoinactivating V-79 cells. The tetrahydroxy compound lacking spacer chains failed to exhibit photodynamic activity in either system. Tumour response with the active compounds was preceded by vascular stasis immediate following irradiation which suggests, together with the absence of activity in the in vivo/in vitro assay, that tumour regression involves an indirect response to the photodynamic action rather than direct cell killing. These data demonstrate the importance of the spatial orientation of functional groups around the macrocycle of photosensitisers for their efficacy in the photodynamic therapy of cancer. PMID:8512803

Trivalent metal ions based on inorganic compounds with in vitro inhibitory activity of matrix metalloproteinase 13.

PubMed

Wen, Hanyu; Qin, Yuan; Zhong, Weilong; Li, Cong; Liu, Xiang; Shen, Yehua

2016-10-01

Collagenase-3 (MMP-13) inhibitors have attracted considerable attention in recent years and have been developed as a therapeutic target for a variety of diseases, including cancer. Matrix metalloproteinases (MMPs) can be inhibited by a multitude of compounds, including hydroxamic acids. Studies have shown that materials and compounds containing trivalent metal ions, particularly potassium hexacyanoferrate (III) (K3[Fe(CN)6]), exhibit cdMMP-13 inhibitory potential with a half maximal inhibitory concentration (IC50) of 1.3μM. The target protein was obtained by refolding the recombinant histidine-tagged cdMMP-13 using size exclusion chromatography (SEC). The secondary structures of the refolded cdMMP-13 with or without metal ions were further analyzed via circular dichroism and the results indicate that upon binding with metal ions, an altered structure with increased domain stability was obtained. Furthermore, isothermal titration calorimetry (ITC) experiments demonstrated that K3[Fe(CN)6]is able to bind to MMP-13 and endothelial cell tube formation tests provide further evidence for this interaction to exhibit anti-angiogenesis potential. To the best of our knowledge, no previous report of an inorganic compound featuring a MMP-13 inhibitory activity has ever been reported in the literature. Our results demonstrate that K3[Fe(CN)6] is useful as a new effective and specific inhibitor for cdMMP-13 which may be of great potential for future drug screening applications. Copyright © 2016. Published by Elsevier Inc.

[Formation mechanism and chemical safety of nonintentional chemical substances present in chlorinated drinking water and wastewater].

PubMed

Onodera, Sukeo

2010-09-01

This paper reviews the formation mechanism and chemical safety of nonintentional chemical substances (NICS) present in chlorine-treated water containing organic contaminants. Undesirable compounds, i.e., NICS, may be formed under certain conditions when chlorine reacts with organic matter. The rate and extent of chlorine consumption with organics are strongly dependent on their chemical structures, particularly whether double bonds or sulfur and nitrogen atoms occur in the molecules. Organothiophosphorus pesticides (P=S type) are easily oxidized to their phosphorus compounds (P=O type) in chlorinated water containing HOCl as little as 0.5 mg/l, resulting in an increase in cholinesterase-inhibitory activity. Chlorination of phenols in water also produces a series of highly chlorinated compounds, including chlorophenols, chloroquinones, chlorinated carboxylic acids, and polychlorinated phenoxyphenols (PCPPs). In some of these chloroquinones, 2,6-dichloroalkylsemiquinones exhibit a strong mutagenic response as do positive controls used in the Ames test. 2-phenoxyphenols in these PCPPs are particularly interesting, as they are present in the chlorine-treated phenol solution and they are also precursors (predioxins) of the highly toxic chlorinated dioxins. Polynuclear aromatic hydrocarbons (PAHs) were found to undergo chemical changes due to hypochlorite reactions to give chloro-substituted PAHs, oxygenated (quinones) and hydroxylated (phenols) compounds, but they exhibit a lower mutagenic response. In addition, field work was performed in river water and drinking water to obtain information on chemical distribution and their safety, and the results are compared with those obtained in the model chlorination experiments.

Synthesis and evaluation of novel opioid ligands with a C-homomorphinan skeleton.

PubMed

Ishikawa, Kyoko; Mochizuki, Yusuke; Hirayama, Shigeto; Nemoto, Toru; Nagai, Kenichiro; Itoh, Kennosuke; Fujii, Hideaki

2016-05-15

As the reports about C-homomorphinans with the seven-membered C-ring are much fewer than those of morphinan derivatives with a six-membered C-ring, we attempted to synthesize C-homomorphinan derivatives and to evaluate their opioid activities. C-Homomorphinan 5 showed sufficient binding affinities to the opioid receptors. C-Homomorphinan derivatives possessing the δ address moiety such as indole (NTI-type), quinoline, or benzylidene (BNTX-type) functionalities showed the strongest binding affinities for the δ receptor among the three types of opioid receptors, which indicated that the C-homomorphinan skeleton sufficiently functions as a message-part in the ligand. Although NTI-type compound 8 and quinoline compound 9 with C-homomorphinan scaffold exhibited lower affinities and selectivities for the δ receptor than the corresponding morphinan derivatives did, both the binding affinity and selectivity for the δ receptor of BNTX-type compound 12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound 12 was the most selective δ receptor antagonist among the tested compounds. Copyright © 2016 Elsevier Ltd. All rights reserved.

Anti-staphylococcal, anti-HIV and cytotoxicity studies of four South African medicinal plants and isolation of bioactive compounds from Cassine transvaalensis (Burtt. Davy) codd.

PubMed

Mthethwa, Ningy S; Oyedeji, Bola A O; Obi, Larry C; Aiyegoro, Olayinka A

2014-12-18

Medicinal plants represent an important opportunity to rural communities in Africa, as a source of affordable medicine and as a source of income. Increased patient awareness about safe usage is important as well as more training with regards to traditional medicine. The aim of this study was to evaluate the ethnomedicinal prowess of some indigenous South African plants commonly used in Eastern Cape Province of South Africa for the treatment of skin and respiratory tract infections, HIV and their toxicity potential. Cassine transvaalensis, Vangueria infausta, Croton gratissimus and Vitex ferruginea were tested for antibacterial activities against Staphylococcus aureus and Staphylococcus epidermidis using Kirby-Bauer disk diffusion and minimum inhibition concentration (MIC). Cytotoxic and anti-HIV-1 activities of plants were tested using MTT Assay (3- (Dimethylthiozole-2-yl-2,5-diphenyltetrazolium bromide)) and anti- HIV-1iib assay. In search of bioactive lead compounds, Cassine transvaalensis which was found to be the most active plant extract against the two Staphylocoous bacteria was subjected to various chromatographic. Thin layer chromatography, Column chromatography and Nuclear Magnetic Resonance (NMR), (1H-1H, 13C-13C, in DMSO_d6, Bruker 600 MHz) were used to isolate and characterize 3-Oxo-28-hydroxylbetuli-20(29)-ene and 3,28-dihydroxylbetuli-20(29)-ene bioactive compounds from C. transvaalensis. The four plants studied exhibited bioactive properties against the test isolates. The zones of inhibition ranged between 16 mm to 31 mm for multi-drug resistant staphylococci species. MIC values varied between 0.6 and 0.02 μg/ml. C. gratissimus and C. transvaalensis exhibited the abilities to inhibit HIV-1iib. Two bioactive compounds were isolated from C. transvaalensis. Data from this study reveals the use of these plant by traditional healers in the Eastern Cape. Furthermore, C. transvaalensis and C. gratissimus were found to be more active as against HIV-1iib. While C. transvaalensis was most active against the two Staphylococcus bacteria.

Structural and numerical chromosome aberration inducers in liver micronucleus test in rats with partial hepatectomy.

PubMed

Itoh, Satoru; Hattori, Chiharu; Nagata, Mayumi; Sanbuissho, Atsushi

2012-08-30

The liver micronucleus test is an important method to detect pro-mutagens such as active metabolites not reaching bone marrow due to their short lifespan. We have already reported that dosing of the test compound after partial hepatectomy (PH) is essential to detect genotoxicity of numerical chromosome aberration inducers in mice [Mutat. Res. 632 (2007) 89-98]. In naive animals, the proportion of binucleated cells in rats is less than half of that in mice, which suggests a species difference in the response to chromosome aberration inducers. In the present study, we investigated the responses to structural and numerical chromosome aberration inducers in the rat liver micronucleus test. Two structural chromosome aberretion inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used in the present study. PH was performed a day before or after the dosing of the test compound in 8-week old male F344 rats and hepatocytes were isolated 4 days after the PH. As a result, diethylnitrosamine and 1,2-dimethylhydrazine, structural chromosome aberration inducers, exhibited significant increase in the incidence of micronucleated hepatocyte (MNH) when given either before and after PH. Colchicine and carbendazim, numerical chromosome aberration inducers, did not result in any toxicologically significant increase in MNH frequency when given before PH, while they exhibited MNH induction when given after PH. It is confirmed that dosing after PH is essential in order to detect genotoxicity of numerical chromosome aberration inducers in rats as well as in mice. Regarding the species difference, a different temporal response to colchicine was identified. Colchicine increased the incidence of MNH 4 days after PH in rats, although such induction in mice was observed 8-10 days after PH. Copyright © 2012 Elsevier B.V. All rights reserved.

Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives.

PubMed

Liu, Jinbing; Chen, Changhong; Wu, Fengyan; Zhao, Liangzhong

2013-07-01

A series of chalcones and their derivatives were synthesized, and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant inhibitory activity, and four compounds exhibited more potent tyrosinase inhibitory activity than the reference standard inhibitor kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one). Specifically, 1-(-1-(4-methoxyphen- yl)-3-phenylallylidene)thiosemicarbazide (18) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 0.274 μM. The inhibition mechanism analysis of 1-(-1-(2,4-dihydroxyphenyl)-3-phenylallylidene) thiosemicarbazide (16) and 1-(-1-(4-methoxyphenyl)-3-phenylallylidene) thiosemicarbazide (18) demonstrated that the inhibitory effects of the two compounds on the tyrosinase were irreversible. Preliminary structure activity relationships' analysis suggested that further development of such compounds might be of interest. © 2013 John Wiley & Sons A/S.

Azide derivatized anticancer agents of Vitamin K 3: X-ray structural, DSC, resonance spectral and API studies

NASA Astrophysics Data System (ADS)

Badave, Kirti; Patil, Yogesh; Gonnade, Rajesh; Srinivas, Darbha; Dasgupta, Rajan; Khan, Ayesha; Rane, Sandhya

2011-12-01

Compound 1 [1-imino (acetyl hydrazino)-Vitamin K 3], displays valence tautomerically related electronic isomers as Form I and Form II. Form I exhibits 2D packing fragment with 1D ribbon chains of N-H⋯O hydrogen bonds and shows EPR silent features. While Form II is EPR active and exhibits biradical nature with double quantum transitions at g = 2.0040. 1H NMR of compound 2, [1-imino (hydrazino carboxylate)-Vitamin K 3] and Form II exhibit π delocalization via resonance assisted H-bonding [RAHB] effect compared to Form I. Molecular interactions in Form I and II are visualized by DSC. The electronic structures of compounds 1 and 2 have been correlated to their API values by measuring anticancer activities, mitochondrial potentials and DNA shearing patterns. Form II and compound 2 indicate mitochondria mediated apoptosis (˜75% cell death) while Form I causes 35% cell death.

Adsorption of organic stormwater pollutants onto activated carbon from sewage sludge.

PubMed

Björklund, Karin; Li, Loretta Y

2017-07-15

Adsorption filters have the potential to retain suspended pollutants physically, as well as attracting and chemically attaching dissolved compounds onto the adsorbent. This study investigated the adsorption of eight hydrophobic organic compounds (HOCs) frequently detected in stormwater - including four polycyclic aromatic hydrocarbons (PAHs), two phthalates and two alkylphenols - onto activated carbon produced from domestic sewage sludge. Adsorption was studied using batch tests. Kinetic studies indicated that bulk adsorption of HOCs occurred within 10 min. Sludge-based activated carbon (SBAC) was as efficient as tested commercial carbons for adsorbing HOCs; adsorption capacities ranged from 70 to 2800 μg/g (C initial  = 10-300 μg/L; 15 mg SBAC in 150 mL solution; 24 h contact time) for each HOC. In the batch tests, the adsorption capacity was generally negatively correlated to the compounds' hydrophobicity (log K ow ) and positively associated with decreasing molecule size, suggesting that molecular sieving limited adsorption. However, in repeated adsorption tests, where competition between HOCs was more likely to occur, adsorbed pollutant loads exhibited strong positive correlation with log K ow . Sewage sludge as a carbon source for activated carbon has great potential as a sustainable alternative for sludge waste management practices and production of a high-capacity adsorption material. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bioactive Compounds from Macroalgae in the New Millennium: Implications for Neurodegenerative Diseases

PubMed Central

Barbosa, Mariana; Valentão, Patrícia; Andrade, Paula B.

2014-01-01

Marine environment has proven to be a rich source of structurally diverse and complex compounds exhibiting numerous interesting biological effects. Macroalgae are currently being explored as novel and sustainable sources of bioactive compounds for both pharmaceutical and nutraceutical applications. Given the increasing prevalence of different forms of dementia, researchers have been focusing their attention on the discovery and development of new compounds from macroalgae for potential application in neuroprotection. Neuroprotection involves multiple and complex mechanisms, which are deeply related. Therefore, compounds exerting neuroprotective effects through different pathways could present viable approaches in the management of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. In fact, several studies had already provided promising insights into the neuroprotective effects of a series of compounds isolated from different macroalgae species. This review will focus on compounds from macroalgae that exhibit neuroprotective effects and their potential application to treat and/or prevent neurodegenerative diseases. PMID:25257784

Bioactive compounds from macroalgae in the new millennium: implications for neurodegenerative diseases.

PubMed

Barbosa, Mariana; Valentão, Patrícia; Andrade, Paula B

2014-09-25

Marine environment has proven to be a rich source of structurally diverse and complex compounds exhibiting numerous interesting biological effects. Macroalgae are currently being explored as novel and sustainable sources of bioactive compounds for both pharmaceutical and nutraceutical applications. Given the increasing prevalence of different forms of dementia, researchers have been focusing their attention on the discovery and development of new compounds from macroalgae for potential application in neuroprotection. Neuroprotection involves multiple and complex mechanisms, which are deeply related. Therefore, compounds exerting neuroprotective effects through different pathways could present viable approaches in the management of neurodegenerative diseases, such as Alzheimer's and Parkinson's. In fact, several studies had already provided promising insights into the neuroprotective effects of a series of compounds isolated from different macroalgae species. This review will focus on compounds from macroalgae that exhibit neuroprotective effects and their potential application to treat and/or prevent neurodegenerative diseases.

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.

Growth Media Affect Assessment of Antimicrobial Activity of Plant-Derived Polyphenols.

PubMed

Xu, Xin; Ou, Zhen M; Wu, Christine D

2018-01-01

This study aimed to investigate the effects of different microbial growth media on the laboratory assessment of antimicrobial activity of natural polyphenolic compounds. The inhibition of the tea polyphenol EGCG on growth of selected oral microorganisms was evaluated in complex media and a protein-free chemically defined medium (CDM). Other antimicrobial agents (polyphenolic grape seed extract, plant alkaloid berberine, methyl salicylate, and chlorhexidine gluconate) were also tested in the study. The presence of proteins and their effects on the antimicrobial activity of EGCG were investigated by the addition of BSA to the CDM. The MICs of EGCG against test oral microorganisms were 4 to 64 times higher in complex media than in CDM. The polyphenolic grape seed extract exhibited similar discrepancies. However, the MICs of the nonpolyphenolic compounds (berberine, methyl salicylate, and chlorhexidine) were not significantly different between the two growth media. The MIC of EGCG against S. mutans UA159 in CDM with added BSA was 16 times higher than that in CDM alone. Therefore, nonproteinaceous CDM should be used to avoid interference of proteins with the active ingredients when testing the antimicrobial activity of plant-derived polyphenolic compounds against microorganisms. This will also minimize the discrepancies noted in results obtained by different investigators.

Synthesis and structure-activity relationship studies of novel [6,6,5] tricyclic oxazolidinone derivatives as potential antibacterial agents.

PubMed

Xue, Tao; Ding, Shi; Guo, Bin; Chu, Wenjing; Wang, Hui; Yang, Yushe

2015-01-01

In our previous Letter, we reported the discovery of a novel benzoxazinyl-oxazolidinone antibacterial candidate 2. In order to identify a potential backup compound, extensive modifications on the B/C ring and C3 side chain were undertaken. A series of novel [6,6,5] tricyclic analogues were synthesized and their in vitro antibacterial activities were tested against a panel of susceptible and resistant Gram-positive pathogens. Among of them, benzothiazinyl-oxazolidinones with acetamide or thioamide as C3 side chains exhibited moderate to good antibacterial activity, such as compounds 54, 58, 59 and 63. In vitro liver microsomal stability was further evaluated and the results manifested that compounds 54 and 58 were both metabolically stable in rat and human liver microsomes. Additionally, insights gained from this investigation should provide directions for the further research of new oxazolidinone antibiotics. Copyright © 2015 Elsevier Ltd. All rights reserved.

Environmentally relevant concentrations of tramadol and citalopram alter behaviour of an aquatic invertebrate.

PubMed

Buřič, M; Grabicová, K; Kubec, J; Kouba, A; Kuklina, I; Kozák, P; Grabic, R; Randák, T

2018-05-14

Environmental pollution by pharmaceutically active compounds, used in quantities similar to those of pesticides and other organic micropollutants, is increasingly recognized as a major threat to the aquatic environment. These compounds are only partly removed from wastewaters and, despite their low concentrations, directly and indirectly affect behaviour of freshwater organisms in natural habitats. The aim of this study was to behaviourally assess the effects of an opioid painkiller (tramadol) and antidepressant drug (citalopram) on behaviour patterns of a clonal model species, marbled crayfish. Animals exposed to environmentally relevant concentrations of both tested compounds (∼1 μg l -1 ) exhibited significantly lower velocity and shorter distance moved than controls. Crayfish exposed to tramadol spent more time in shelters. Results were obtained by a simple and rapid method recommended as suitable for assessment of behaviour in aquatic organisms exposed to single pollutants and combinations. Copyright © 2018 Elsevier B.V. All rights reserved.

Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents.

PubMed

Suryadevara, Praveen Kumar; Racherla, Kishore Kumar; Olepu, Srinivas; Norcross, Neil R; Tatipaka, Hari Babu; Arif, Jennifer A; Planer, Joseph D; Lepesheva, Galina I; Verlinde, Christophe L M J; Buckner, Frederick S; Gelb, Michael H

2013-12-01

New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC50 <1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T. cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives as potential anticonvulsants.

PubMed

Madaiah, Malavalli; Prashanth, Maralekere K; Revanasiddappa, Hosakere D; Veeresh, Bantal

2013-03-01

New 3-[(2,4-dioxo-1,3,8-triazaspiro[4.6]undec-3-yl)methyl]benzonitrile derivatives 8-37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure-activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11, 18, 31, and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two-electron donor. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The impact of hybridization on the volatile and sensorial profile of Ocimum basilicum L.

PubMed

da Costa, Andréa Santos; Arrigoni-Blank, Maria de Fátima; da Silva, Maria Aparecida Azevedo Pereira; Alves, Mércia Freitas; Santos, Darlisson de Alexandria; Alves, Péricles Barreto; Blank, Arie Fitzgerald

2014-01-01

The aim of the present study was to investigate the volatile and sensorial profile of basil (Ocimum basilicum L.) by quantitative descriptive analysis (QDA) of the essential oil of three hybrids ("Cinnamon" × "Maria Bonita," "Sweet Dani" × "Cinnamon," and "Sweet Dani" × "Maria Bonita"). Twelve descriptive terms were developed by a selected panel that also generated the definition of each term and the reference samples. The data were subjected to ANOVA, Tukey's test, and principal component analysis. The hybrid "Cinnamon" × "Maria Bonita" exhibited a stronger global aroma that was less citric than the other samples. Hybridization favored the generation of novel compounds in the essential oil of the hybrid "Sweet Dani" × "Maria Bonita," such as canfora and (E)-caryophyllene; (E)-caryophyllene also was a novel compound in the hybrid "Sweet Dani" × "Cinnamon"; this compound was not present in the essential oils of the parents.

A novel and selective poly (ADP-ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.

PubMed

Ta, Lauren E; Schmelzer, James D; Bieber, Allan J; Loprinzi, Charles L; Sieck, Gary C; Brederson, Jill D; Low, Philip A; Windebank, Anthony J

2013-01-01

Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice. An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment. Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

Design, synthesis and structure-activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression.

PubMed

Mahesh, Radhakrishnan; Devadoss, Thangaraj; Pandey, Dilip Kumar; Bhatt, Shvetank; Yadav, Shushil Kumar

2010-11-15

A novel series of quinoxalin-2-carboxamides were designed based on the ligand-based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by spectral data. The target new chemical entities were evaluated for their 5-HT(3) receptor antagonisms in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methyl-5-HT, which was expressed in the form of pA(2) value. All the synthesized compounds showed antagonism towards 5-HT(3) receptor; based on this result, a structure-activity relationship was derived, which reveals that the aromatic residue in 5-HT(3) receptor antagonists may have hydrophobic interaction with 5-HT(3) receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA(2) values exhibited good anti-depressant-like activity as compared to the vehicle-treated group. Copyright © 2010 Elsevier Ltd. All rights reserved.

Scyphostatin, a neutral sphingomyelinase inhibitor from a discomycete, Trichopeziza mollissima: taxonomy of the producing organism, fermentation, isolation, and physico-chemical properties.

PubMed

Nara, F; Tanaka, M; Hosoya, T; Suzuki-Konagai, K; Ogita, T

1999-06-01

We performed experiments to screen for neutral sphingomyelinase inhibitors using rat brain microsomes as an enzyme source. Among more than 10,000 microbial extracts tested, a mycelial extract of Trichopeziza mollissima SANK 13892 exhibited potent inhibitory activity. The active compound, scyphostatin, was purified by a series of chromatographies. Scyphostatin inhibited the enzyme with an IC50 value of 1.0 microM.

New acylated clionasterol glycosides from Valeriana officinalis.

PubMed

Pullela, Srinivas V; Choi, Young Whan; Khan, Shabana I; Khan, Ikhlas A

2005-10-01

The chloroform extract of Valeriana officinalis led to the isolation of clionasterol-3-O-beta-D-glucopyranoside and a mixture of 6'-O-acyl-beta-D-glucosyl-clionasterols. The acyl moieties were identified as hexadecanoyl, 8 E,11 E-octadecadienoyl and 14-methylpentadecanoyl by alkaline hydrolysis followed by GC-MS analysis. The isolated compounds did not exhibit any anti-inflammatory, anticancer or cytotoxic activity when tested in a variety of in vitro cell-based assays.

Hydrogel tissue construct-based high-content compound screening.

PubMed

Lam, Vy; Wakatsuki, Tetsuro

2011-01-01

Current pharmaceutical compound screening systems rely on cell-based assays to identify therapeutic candidates and potential toxicities. However, cells grown on 2D substrata or in suspension do not exhibit the mechanical or physiological properties of cells in vivo. To address this limitation, the authors developed an in vitro, high-throughput, 3D hydrogel tissue construct (HTC)-based assay system to quantify cell and tissue mechanical properties and multiple parameters of physiology. HTC mechanics was quantified using an automated device, and physiological status was assessed using spectroscopy-based indicators that were read on microplate readers. To demonstrate the application of this system, the authors screened 4 test compounds--rotenone (ROT), cytochalasin D (CD), 2,4-dinitrophenol (DNP), and Rho kinase inhibitor (H-1152)--for their ability to modulate HTC contractility without affecting actin integrity, mitochondrial membrane potential (MMP), or viability. All 4 compounds dose-dependently reduced HTC contractility. However, ROT was toxic, DNP dissipated MMP, and CD reduced both intracellular F-actin and viability. H-1152 was found to be the best candidate compound since it reduced HTC contractility with minimal side effects. The authors propose that their HTC-based assay system can be used to screen for compounds that modulate HTC contractility and assess the underlying physiological mechanism(s) of compound activity and toxicity.

Comparison of EMIT II, CEDIA, and DPC RIA assays for the detection of lysergic acid diethylamide in forensic urine samples.

PubMed

Wiegand, Russell F; Klette, Kevin L; Stout, Peter R; Gehlhausen, Jay M

2002-10-01

In an effort to determine a practical, efficient, and economical alternative for the use of a radioimmunoassay (RIA) for the detection of lysergic acid diethylamide (LSD) in human urine, the performance of two photometric immunoassays (Dade Behring EMIT II and Microgenics CEDIA) and the Diagnostics Products Corp. (DPC) RIA were compared. Precision, accuracy, and linearity of the 3 assays were determined by testing 60 replicates (10 for RIA) at 5 different concentrations below and above the 500-pg/mL LSD cut-off. The CEDIA and RIA exhibited better accuracy and precision than the EMIT II immunoassay. In contrast, the EMIT II and CEDIA demonstrated superior linearity r2 = 0.9809 and 0.9540, respectively, as compared with the RIA (r2 = 0.9062). The specificity of the three assays was assessed using compounds that have structural and chemical properties similar to LSD, common over-the-counter products, prescription drugs and some of their metabolites, and other drugs of abuse. Of the 144 compounds studied, the EMIT II cross-reacted with twice as many compounds as did the CEDIA and RIA. Specificity was also assessed in 221 forensic human urine specimens that previously screened positive for LSD by the EMIT II assay. Of these, only 11 tested positive by CEDIA, and 3 were positive by RIA. This indicated a comparable specificity performance between CEDIA and RIA. This also was consistent with a previously reported high false-positive rate of EMIT II (low specificity). Each of the immunoassays correctly identified LSD in 23 out of 24 human urine specimens that had previously been found to contain LSD by gas chromatography-mass spectrometry at a cut-off concentration of 200 pg/mL. The CEDIA exhibited superior precision, accuracy, and decreased cross-reactivity to compounds other than LSD as compared with the EMIT II assay and does not necessitate the handling of radioactive materials.

A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus.

PubMed

Tajiri, Naoki; De La Peña, Ike; Acosta, Sandra A; Kaneko, Yuji; Tamir, Sharon; Landesman, Yosef; Carlson, Robert; Shacham, Sharon; Borlongan, Cesar V

2016-04-01

Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug-like inhibitors of XPO1, with potent anti-cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors. Here, we report that the SINE compounds (KPT-350 or KPT-335) sequestered TBI-induced neuroinflammation-related proteins (NF-(k)B, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF-α (20 ng/mL)-induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non-treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague-Dawley rats treated post-injury with SINE compounds exhibited significant reductions in TBI-induced behavioral and histological deficits. Animals that received KPT-350 orally starting at 2 h post-TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100-200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT-350 dosing, and throughout the 18-day post-TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT-350 reduced cortical core impact area and peri-impact cell death compared to vehicle treatment (P's < 0.05). Both in vitro and in vivo experiments revealed that KPT-350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF-(k)B expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI. © 2016 John Wiley & Sons Ltd.

5-(Furan-2-yl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one oxime (6f), a new synthetic compound, causes human fibrosarcoma HT-1080 cell apoptosis by disrupting tubulin polymerisation and inducing G2/M arrest.

PubMed

Zuo, Daiying; Pang, Lili; Shen, Jiwei; Guan, Qi; Bai, Zhaoshi; Zhang, Huijuan; Li, Yao; Lu, Guodong; Zhang, Weige; Wu, Yingliang

2017-06-01

In the current study, we synthesized a series of new compounds targeting tubulin and tested their anti-proliferative activities. Among these new synthetic com-pounds, 5-(furan-2-yl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one oxime (6f) exhibited significant anti-proliferative activity against different human cancer cell lines including human gastric adenocarcinoma SGC-7901, human non-small cell lung cancer A549, and human fibrosarcoma HT-1080. As a result, 6f was selected to further test the sensitivity to different cancer cell lines including human cervical cancer cell line HeLa, human breast cancer cell line MCF-7, non-small cell lung cancer cell line A549, human liver carcinoma cell line HepG-2, human oral squamous cell carcinoma cell lines KB, SGC-7901 and HT-1080. Among these cell lines, HT-1080 and HeLa are the most sensitive. Therefore, HT-1080 was selected to further explore the properties of anti-proliferative activity and the underlying mechanisms. Our data proved that 6f exhibited strong anti-proliferative effects against HT-1080 cells in a time- and dose-dependent manner. We showed that the growth inhibitory effect of 6f in HT-1080 cells was related with microtubule depolymerisation. Molecular docking studies revealed that 6f interacted and bound efficiently with the colchicine-binding site of tubulin. In addition, 6f treatment induced G2/M cell cycle arrest dose-dependently and subsequently induced cell apoptosis. Western blot study indicated that upregulation of cyclin B1 and p-cdc2 was related with G2/M arrest. 6f-induced cell apoptosis was associated with both mitochondrial and death receptor pathway. In conclusion, our data showed that 6f, among the newly synthetic compounds, exhibited highest anti-proliferative activity by disrupting the microtubule polymerisation, causing G2/M arrest and subsequently inducing cell apoptosis in HT-1080 cells. Hence, 6f is a promising microtubule depolymerising agent for the treatment of various cancers especially human fibrosarcoma.

Novel amide and sulphonamide derivatives of 6-(piperazin-1-yl)phenanthridine as potent Mycobacterium tuberculosis H37Rv inhibitors.

PubMed

Naidu, Kalaga Mahalakshmi; Nagesh, Hunsur Nagendra; Singh, Manjeet; Sriram, Dharmarajan; Yogeeswari, Perumal; Gowri Chandra Sekhar, Kondapalli Venkata

2015-03-06

A series of thirty three novel 6-(piperazin-1-yl)phenanthridine amide and sulphonamide analogues were synthesized, characterized and screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv strain. These compounds exhibited minimum inhibitory concentration (MIC) between 1.56 and ≥50 μg/mL. Out of these derivatives, few compounds 6l, 6r, 7b, 7f, 7g and 7k exhibited moderate activity (MIC = 6.25 μg/mL) and compounds 6b, 6e, 6k, 6n, 7h, 7i and 7n displayed good activity (MIC = 3.13 μg/mL), whereas compounds 6m, 6s and 7d exhibited excellent anti-tubercular activity (MIC = 1.56 μg/mL). In addition, MTT assay was accomplished on the active analogues of the series against mouse macrophage (RAW 264.7) cells to evaluate the toxicity profile of the newly synthesized compounds and selectivity index of the compounds was determined. Additionally, compounds 6b and 7d were docked to the ATPase domain of M. tuberculosis GyrB protein to know the interaction profile and structures of compounds 6b and 7d were further substantiated through single crystal XRD. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

New Whitening Constituents from Taiwan-Native Pyracantha koidzumii: Structures and Tyrosinase Inhibitory Analysis in Human Epidermal Melanocytes.

PubMed

Lin, Rong-Dih; Chen, Mei-Chuan; Liu, Yan-Ling; Lin, Yi-Tzu; Lu, Mei-Kuang; Hsu, Feng-Lin; Lee, Mei-Hsien

2015-12-02

Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata) Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9) and 3,4-dihydroxy-5-methoxybiphenyl-2'-O-β-d-glucopyranoside (13), as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia-associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver-Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics.

New Whitening Constituents from Taiwan-Native Pyracantha koidzumii: Structures and Tyrosinase Inhibitory Analysis in Human Epidermal Melanocytes

PubMed Central

Lin, Rong-Dih; Chen, Mei-Chuan; Liu, Yan-Ling; Lin, Yi-Tzu; Lu, Mei-Kuang; Hsu, Feng-Lin; Lee, Mei-Hsien

2015-01-01

Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata) Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9) and 3,4-dihydroxy-5-methoxybiphenyl-2ʹ-O-β-d-glucopyranoside (13), as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia-associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver–Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics. PMID:26633381

Compositions and methods related to serotonin 5-HT1A receptors

DOEpatents

Mukherjee, Jogeshwar; Saigal, Neil

2010-06-08

Contemplated substituted arylpiperazinyl compounds, and most preferably ¹⁸F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with ¹⁸F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

Compositions and methods related to serotonin 5-HT1A receptors

DOEpatents

Mukherjee, Jogeshwar [Irvine, CA; Saigal, Neil [Fresno, CA; Saigal, legal representative, Harsh

2012-09-25

Contemplated substituted arylpiperazinyl compounds, and most preferably .sup.18F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with .sup.18F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

Compositions and methods related to serotonin 5-HT1A receptors

DOEpatents

Mukherjee, Jogeshwar; Saigal, Neil; Saigal, legal representative, Harsh

2012-09-25

Contemplated substituted arylpiperazinyl compounds, and most preferably ¹⁸F-Mefway, exhibit desirable in vitro and in vivo binding characteristics to the 5-HT1A receptor. Among other advantageous parameters, contemplated compounds retain high binding affinity, display optimal lipophilicity, and are radiolabeled efficiently with ¹⁸F-fluorine in a single step. Still further, contemplated compounds exhibit high target to non-target ratios in receptor-rich regions both in vitro and in vivo, and selected compounds can be effectively and sensitively displaced by serotonin, thus providing a quantitative tool for measuring 5-HT1A receptors and serotonin concentration changes in the living brain.

Anti-tumour-promoting and thermal-induced protein denaturation inhibitory activities of β-sitosterol and lupeol isolated from Diospyros lotus L.

PubMed

Rauf, Abdur; Uddin, Ghias; Khan, Haroon; Raza, Muslim; Zafar, Muhammad; Tokuda, Harukuni

2016-01-01

In this study, the anti-tumour-promoting and thermal-induced protein denaturation inhibitory activities of β-sitosterol (1) and lupeol (2), isolated from Diospyros lotus L., were explored. Compound 1 showed a marked concentration-dependent inhibition against 12-O-tetradecanoylphorbol-13-acetate (20 ng/32 pmol)-induced Epstein-Barr virus early antigen activation in Raji cells with IC50 of 270 μg/ml, without significant toxicity (70% viability). Compound 2 showed significant anti-tumour-promoting effect with IC50 of 412 μg/ml, without significant toxicity (60% viability). In heat-induced protein denaturation assay, compound 1 exhibited a concentration-dependent attenuation with a maximum effect of 73.5% at 500 μg/ml with EC50 of 117 μg/ml, while compound 2 exhibited a maximum effect of 59.2% at 500 μg/ml with EC50 of 355 μg/ml. Moreover, in silico docking studies against the phosphoinositide 3-kinase enzyme also show the inhibitory potency of these compounds. In short, both the compounds exhibited a marked anti-tumour-promoting and potent inhibitory effect on thermal-induced protein denaturation.

Synthesis of biologically active N-methyl derivatives of amidines and cyclized five-membered products of amidines with oxalyl chloride.

PubMed

Sondhi, Sham M; Dinodia, Monica; Jain, Shubhi; Kumar, Ashok

2008-12-01

A series of substituted N-methylisonicotinamidine (2a-f), N-methylpyrazine-2-carboxamidine (2g-i) derivatives were synthesized by reaction of amidine derivatives (1a-i) with methyl iodide in presence of triethylamine. Five-membered condensed dihydroimidazolylbenzenesulfonamide derivatives (3a-i) were obtained by the reaction of amidine derivatives (1a-i) with acylating agent oxalyl chloride. All the compounds, i.e. 2a-i and 3a-i were purified by crystallization. Structures of all the synthesized compounds are supported by correct IR, (1)H NMR, mass spectral and analytical data. Anti-inflammatory activity evaluation was carried out using carrageenan-induced paw oedema assay and compounds 2e, 3a and 3d exhibited good anti-inflammatory activity (44%, 31% and 37% activity at 50 mg/kg p.o., respectively). Analgesic activity evaluation was carried out using acetic acid writhing assay and compounds 2a and 3f gave 75% activity each at 100 mg/kg p.o.; on the other hand compounds 3a and 3d exhibited 60% analgesic activity each at 50 mg/kg p.o. Compounds 3a and 3d exhibited good anti-inflammatory and analgesic activities.

Complete genome sequence of Campylobacter jejuni RM1246-ERRC that exhibits resistance to Quaternary Ammonium Compounds

USDA-ARS?s Scientific Manuscript database

Campylobacter jejuni strain RM1246-ERRC is a clinical isolate. In laboratory experiments RM1246-ERRC exhibited resistance to the antimicrobial effects of quaternary ammonium compounds (QACs) when compared to other C. jejuni strains. The chromosome of RM1246-ERRC was determined to be 1,659,694 bp w...

A composite docking approach for the identification and characterization of ectosteric inhibitors of cathepsin K.

PubMed

Law, Simon; Panwar, Preety; Li, Jody; Aguda, Adeleke H; Jamroz, Andrew; Guido, Rafael V C; Brömme, Dieter

2017-01-01

Cathepsin K (CatK) is a cysteine protease that plays an important role in mammalian intra- and extracellular protein turnover and is known for its unique and potent collagenase activity. Through studies on the mechanism of its collagenase activity, selective ectosteric sites were identified that are remote from the active site. Inhibitors targeting these ectosteric sites are collagenase selective and do not interfere with other proteolytic activities of the enzyme. Potential ectosteric inhibitors were identified using a computational approach to screen the druggable subset of and the entire 281,987 compounds comprising Chemical Repository library of the National Cancer Institute-Developmental Therapeutics Program (NCI-DTP). Compounds were scored based on their affinity for the ectosteric site. Here we compared the scores of three individual molecular docking methods with that of a composite score of all three methods together. The composite docking method was up to five-fold more effective at identifying potent collagenase inhibitors (IC50 < 20 μM) than the individual methods. Of 160 top compounds tested in enzymatic assays, 28 compounds revealed blocking of the collagenase activity of CatK at 100 μM. Two compounds exhibited IC50 values below 5 μM corresponding to a molar protease:inhibitor concentration of <1:12. Both compounds were subsequently tested in osteoclast bone resorption assays where the most potent inhibitor, 10-[2-[bis(2-hydroxyethyl)amino]ethyl]-7,8-diethylbenzo[g]pteridine-2,4-dione, (NSC-374902), displayed an inhibition of bone resorption with an IC50-value of approximately 300 nM and no cell toxicity effects.

A composite docking approach for the identification and characterization of ectosteric inhibitors of cathepsin K

PubMed Central

Law, Simon; Panwar, Preety; Li, Jody; Aguda, Adeleke H.; Jamroz, Andrew; Guido, Rafael V. C.

2017-01-01

Cathepsin K (CatK) is a cysteine protease that plays an important role in mammalian intra- and extracellular protein turnover and is known for its unique and potent collagenase activity. Through studies on the mechanism of its collagenase activity, selective ectosteric sites were identified that are remote from the active site. Inhibitors targeting these ectosteric sites are collagenase selective and do not interfere with other proteolytic activities of the enzyme. Potential ectosteric inhibitors were identified using a computational approach to screen the druggable subset of and the entire 281,987 compounds comprising Chemical Repository library of the National Cancer Institute-Developmental Therapeutics Program (NCI-DTP). Compounds were scored based on their affinity for the ectosteric site. Here we compared the scores of three individual molecular docking methods with that of a composite score of all three methods together. The composite docking method was up to five-fold more effective at identifying potent collagenase inhibitors (IC50 < 20 μM) than the individual methods. Of 160 top compounds tested in enzymatic assays, 28 compounds revealed blocking of the collagenase activity of CatK at 100 μM. Two compounds exhibited IC50 values below 5 μM corresponding to a molar protease:inhibitor concentration of <1:12. Both compounds were subsequently tested in osteoclast bone resorption assays where the most potent inhibitor, 10-[2-[bis(2-hydroxyethyl)amino]ethyl]-7,8-diethylbenzo[g]pteridine-2,4-dione, (NSC-374902), displayed an inhibition of bone resorption with an IC50-value of approximately 300 nM and no cell toxicity effects. PMID:29088253

Bioactivity-guided isolation of polyacetylenes with inhibitory activity against NO production in LPS-activated RAW264.7 macrophages from the rhizomes of Atractylodes macrocephala.

PubMed

Yao, Chun-Mei; Yang, Xiu-Wei

2014-02-03

The rhizome of Atractylodes macrocephala (Compositae) is one of the most well-known traditional Chinese medicine in China, Japan and Korea, which has a long history of use for the treatment of splenic asthenia, edema, anorexia, and excessive perspiration, etc. As active compounds of anti-inflammatory activity of this medicinal plant have not been fully elucidated, the aim of this study was to isolate and identify the active constituents inhibiting nitric oxide (NO) production from the rhizomes of A. macrocephala. Inhibitory activity against NO production in lipopolysaccharide-activated RAW264.7 macrophages was evaluated by Griess reaction. Fifteen polyacetylenes were isolated from the active ethyl acetate extract using activity-guided screening. The structures of all compounds were elucidated by spectroscopic methods and comparison with published data. The compounds were further tested for their inhibitory activity against NO production. Seven new polyacetylenes, named atractylodemaynes A-G (1-7), along with eight known ones (8-15) were isolated. Compound 14 was isolated for the first time from the rhizomes of A. macrocephala. The study showed that the tested compounds exhibited inhibitory activity against NO production in a dose-dependent manner. Among them, compounds 10, 11 and 12 had relatively stronger inhibitory effect with IC50 values of 28, 23 and 19μM, respectively. The results demonstrated that the polyacetylenes might greatly contribute to the anti-inflammatory activity of the rhizomes of A. macrocephala. © 2013 Elsevier Ireland Ltd. All rights reserved.

Synthesis and pharmacological characterization of novel xanthine carboxylate amides as A2A adenosine receptor ligands exhibiting bronchospasmolytic activity.

PubMed

Yadav, Rakesh; Bansal, Ranju; Rohilla, Suman; Kachler, Sonja; Klotz, Karl-Norbert

2016-04-01

The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a new series of selective ligands of the adenosine A2A receptors exhibiting bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the adenosine receptor (AR) binding affinities of the newly synthesized xanthines have also been studied. The compounds displayed moderate to potent binding affinities toward various adenosine receptor subtypes when evaluated through radioligand binding studies. However, most of the compounds showed the maximum affinity for the A2A subtype, some with high selectivity versus all other subtypes. Xanthine carboxylate amide 13b with a diethylaminoethylamino moiety at the para-position of the 8-phenylxanthine scaffold was identified as the most potent A2A adenosine receptor ligand with Ki=0.06μM. Similarly potent and highly A2A-selective are the isovanillin derivatives 16a and 16d. In addition, the newly synthesized xanthine derivatives showed good in vivo bronchospasmolytic activity when tested in guinea pigs. Copyright © 2016 Elsevier Inc. All rights reserved.

Bioactivities and chemical constituents of a Vietnamese medicinal plant Che Vang, Jasminum subtriplinerve Blume (Oleaceae).

PubMed

Ngan, Dai Hue; Hoai, Ho Thi Cam; Huong, Le Mai; Hansen, Poul Erik; Vang, Ole

2008-01-01

Five crude extracts were made from leaves and stems of Jasminum subtriplinerve Blume (Oleaceae) and investigated for antimicrobial, antioxidant and cytotoxic activities. The extractions were done with petroleum ether, ethyl acetate, ethanol, methanol or water. All extracts exhibited anti-bacterial activity except the water fraction. On the other hand, all extracts exhibit antioxidant activity except the petroleum ether fraction using the DPPH radical scavenging assay. Only the petroleum ether fraction showed a cytotoxicity activity against tested cell-lines, Hep-G2 and RD with IC(50) values of 19.2 and 20 microg mL(-1), respectively. From the petroleum ether and ethyl acetate extracts, two triterpenes namely 3beta-acetyl-oleanolic acid and lup-20-en-3beta-ol and a sterol, stigmast-5-en-3beta-ol were isolated. The structure of those compounds were elucidated by spectrometric methods IR, MS, 1D-NMR, 2D-NMR and simulated ACD/NMR spectra. The data presented here indicate that J. subtriplinerve do contain compounds with interesting biological activity.

Phytochemical properties and anti-proliferative activity of Olea europaea L. leaf extracts against pancreatic cancer cells.

PubMed

Goldsmith, Chloe D; Vuong, Quan V; Sadeqzadeh, Elham; Stathopoulos, Costas E; Roach, Paul D; Scarlett, Christopher J

2015-07-17

Olea europaea L. leaves are an agricultural waste product with a high concentration of phenolic compounds; especially oleuropein. Oleuropein has been shown to exhibit anti-proliferative activity against a number of cancer types. However, they have not been tested against pancreatic cancer, the fifth leading cause of cancer related death in Western countries. Therefore, water, 50% ethanol and 50% methanol extracts of Corregiola and Frantoio variety Olea europaea L. leaves were investigated for their total phenolic compounds, total flavonoids and oleuropein content, antioxidant capacity and anti-proliferative activity against MiaPaCa-2 pancreatic cancer cells. The extracts only had slight differences in their phytochemical properties, and at 100 and 200 μg/mL, all decreased the viability of the pancreatic cancer cells relative to controls. At 50 μg/mL, the water extract from the Corregiola leaves exhibited the highest anti-proliferative activity with the effect possibly due to early eluting HPLC peaks. For this reason, olive leaf extracts warrant further investigation into their potential anti-pancreatic cancer benefits.

Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.

PubMed

Camps, Pelayo; Formosa, Xavier; Galdeano, Carles; Gómez, Tània; Muñoz-Torrero, Diego; Scarpellini, Michele; Viayna, Elisabet; Badia, Albert; Clos, M Victòria; Camins, Antoni; Pallàs, Mercè; Bartolini, Manuela; Mancini, Francesca; Andrisano, Vincenza; Estelrich, Joan; Lizondo, Mònica; Bidon-Chanal, Axel; Luque, F Javier

2008-06-26

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.

Antinociceptive effects of the extracts of Xylopia parviflora bark and its alkaloidal components in experimental animals.

PubMed

Nishiyama, Yumi; Moriyasu, Masataka; Ichimaru, Momoyo; Iwasa, Kinuko; Kato, Atsushi; Mathenge, Simon G; Chalo Mutiso, Patrick B; Juma, Francis D

2010-01-01

In the present study, we attempted to elucidate the antinociceptive activity of Xylopia parviflora bark using the acetic acid-induced writhing test, hot plate test, and formalin test in mice. The MeOH extract (100 and 200 mg/kg, administered intraperitoneally (i.p.)) had an antinociceptive effect demonstrated by its inhibitory effects on writhing number induced by acetic acid. Three alkaloidal fractions exhibited significant antinociceptive effects in three animal models; the chloroform-soluble fraction, including secondary and tertiary alkaloids, exhibited the strongest effect. This result supported its use in folk medicine as an analgesic agent. We tested the main alkaloids of these fractions for their antinociceptive effects to clarify the active components. (+)-Corytuberine (6.3 and 12.5 mg/kg, i.p.) showed very strong activity, had a significant antinociceptive effect in the acetic acid-induced writhing test (with 49.4 and 98.9% reduction of writhes), in the hot plate test, and in the formalin test (with 55.4 and 90.6% inhibition during the first phase, and 73.9 and 99.9% during the second phase, respectively). (+)-Glaucine (12.5 and 25 mg/kg, i.p.) showed strong activity in three animal models, too. The activity of these compounds was also observed following oral administration in the acetic acid-induced writhing test.

An exploratory study on the peroxyl-radical-scavenging activity of 2,6-dimethyl-5-hepten-2-ol and its heterocyclic analogues

NASA Astrophysics Data System (ADS)

Stobiecka, Agnieszka; Sikora, Magdalena; Bonikowski, Radosław; Kula, Józef

2016-03-01

The structural properties and radical scavenging activity of 2,6-dimethyl-5-hepten-2-ol (1) and its new heterocyclic analogues, i.e. 2-methyl-4-(5-methylfuran-2-yl)-butan-2-ol (2) and 2-methyl-4-(5-methylthiophen-2-yl)-butan-2-ol (3) and have been studied by using the experimental and theoretical methods for the first time. Activity of title compounds against the peroxyl radical was determined by using standard fluorimetric test, i.e. the Oxygen Radical Absorbance Capacity assay (ORACFL). Furthermore, the electron-donating ability of odorants has been evaluated by using colorimetric ABTS assay. According to the experimental results obtained from the ORACFL test 2,6-dimethyl-5-hepten-2-ol was characterized by the highest activity in comparison with the novel counterparts. Nevertheless, all investigated compounds exhibited pronounced anti-peroxyl radical activity comparable to that exerted by the one of the most prominent antioxidant among the monoterpene alcohols, i.e. by linalool. On the other hand, the title compounds exerted relatively low capacity to quench the radical cation of ABTS. Theoretical calculations based on the Density Functional Theory (DFT) method with the hybrid functional B3LYP were carried out in order to investigate selected structural and electronic properties including the geometrical parameters as well as the energy of frontier molecular orbitals of parent molecules and the resulting radicals. Furthermore, the possible mechanism of peroxyl-radical-scavenging has been determined by using the thermodynamic descriptors such as the bond dissociation enthalpies (BDEs) and ionization potentials (IPs). These theoretical data pointed out the relevance of HAT mechanism in the peroxyl-radical-scavenging exhibited by 2,6-dimethyl-5-hepten-2-ol and its new heterocyclic analogues in polar and non-polar medium.

Gersemiols A-C and Eunicellol A, Diterpenoids from the Arctic Soft Coral Gersemia fruticosa.

PubMed

Angulo-Preckler, Carlos; Genta-Jouve, Grégory; Mahajan, Nipun; de la Cruz, Mercedes; de Pedro, Nuria; Reyes, Fernando; Iken, Katrin; Avila, Conxita; Thomas, Olivier P

2016-04-22

Three new diterpenes named gersemiols A-C (1-3) and a new eunicellane diterpene, eunicellol A (4), have been isolated together with the known sesquiterpene (+)-α-muurolene (5) from the Arctic soft coral Gersemia fruticosa. The name gersemiane was assigned to the rare and unnamed diterpene skeleton of compounds 1-3 corresponding to 4-isopropyl-1,5,8a-trimethyltetradecahydrophenanthrene. The chemical structures were elucidated on the basis of extensive spectroscopic analysis (HR-ESIMS, 1D and 2D NMR) as well as coupling constant calculations for the determination of the relative configurations. All compounds were tested for their antimicrobial activity against several bacteria and fungi and eunicellol A was found to exhibit moderate and selective antibacterial activity.

Bio-important antipyrine derived Schiff bases and their transition metal complexes: Synthesis, spectroscopic characterization, antimicrobial, anthelmintic and DNA cleavage investigation

NASA Astrophysics Data System (ADS)

Manjunath, M.; Kulkarni, Ajaykumar D.; Bagihalli, Gangadhar B.; Malladi, Shridhar; Patil, Sangamesh A.

2017-01-01

Spectroscopic (IR, NMR, UV-vis, ESR, ESI-mass), magnetic and TGA studies suggests octahedral geometry for all the CoII, NiII and CuII complexes of the Schiff bases, derived from 4-aminoantipyrine and 8-formyl-7-Hydroxy-4-methylcoumarin/5-formyl-6-hydroxycoumarin, coordinated through ONO donor sites. Antibacterial (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi), antifungal (Aspergillus niger, Aspergillus flavus and Cladosporium) and DNA cleavage properties of the metal complexes are investigated. The results suggested that some of the synthesized compounds are potential antimicrobials. The synthesized compounds tested for their anthelmintic activities and it was found that CoII and NiII complexes exhibited good anthelmintic properties.

Quantitative carbon detector for enhanced detection of molecules in foods, pharmaceuticals, cosmetics, flavors, and fuels.

PubMed

Beach, Connor A; Krumm, Christoph; Spanjers, Charles S; Maduskar, Saurabh; Jones, Andrew J; Dauenhauer, Paul J

2016-03-07

Analysis of trace compounds, such as pesticides and other contaminants, within consumer products, fuels, and the environment requires quantification of increasingly complex mixtures of difficult-to-quantify compounds. Many compounds of interest are non-volatile and exhibit poor response in current gas chromatography and flame ionization systems. Here we show the reaction of trimethylsilylated chemical analytes to methane using a quantitative carbon detector (QCD; the Polyarc™ reactor) within a gas chromatograph (GC), thereby enabling enhanced detection (up to 10×) of highly functionalized compounds including carbohydrates, acids, drugs, flavorants, and pesticides. Analysis of a complex mixture of compounds shows that the GC-QCD method exhibits faster and more accurate analysis of complex mixtures commonly encountered in everyday products and the environment.

Lipid encapsulated phenolic compounds by fluidization

USDA-ARS?s Scientific Manuscript database

Phenolic compounds exhibit antioxidant and antimicrobial activities with applications as functional food and feed additives. Ferulic acid, a phenolic compound present in grain crops and lignocellulose biomass, was encapsulated with saturated triglycerides using a laboratory fluidizer. Stability of t...

Phosphorescent organic light emitting diodes with high efficiency and brightness

DOEpatents

Forrest, Stephen R; Zhang, Yifan

2015-11-12

An organic light emitting device including a) an anode; b) a cathode; and c) an emissive layer disposed between the anode and the cathode, the emissive layer comprising an organic host compound and a phosphorescent compound exhibiting a Stokes Shift overlap greater than 0.3 eV. The organic light emitting device may further include a hole transport layer disposed between the emissive layer and the anode; and an electron transport layer disposed between the emissive layer and the cathode. In some embodiments, the phosphorescent compound exhibits a phosphorescent lifetime of less than 10 .mu.s. In some embodiments, the concentration of the phosphorescent compound ranges from 0.5 wt. % to 10 wt. %.

Synthesis of Chrysogeside B from Halotolerant Fungus Penicillium and Its Antimicrobial Activities Evaluation

NASA Astrophysics Data System (ADS)

Liu, Ruiquan; Wang, Lei; Li, Qibo; Liao, Min; Yang, Zhikun; Huang, Yun; Lv, Cong; Zheng, Bing; Zhong, Jiangchun; Bian, Qinghua; Wang, Min; Liu, Shangzhong

2017-04-01

Chrysogeside B, a natural cerebroside, was efficiently synthesized from commercial feedstocks. The bioassays showed that compounds 4, 5 and 6 exhibited enhanced biological activities compared Chrysogeside B. Further studies revealed that free hydroxyl groups and glycosidic bond have significant impact on the antimicrobial activities. The synthesis of Chrysogeside B and analogues designed to allow identification of the features of this glycolipid required for recognition by tested bacteria and Hela cells is described.

Pharmacological evaluation of halogenated and non-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles as D(2) and 5-HT(2A) receptor ligands.

PubMed

Tomić, Mirko; Vasković, Djurdjica; Tovilović, Gordana; Andrić, Deana; Penjišević, Jelena; Kostić-Rajačić, Sladjana

2011-05-01

Five groups of previously synthesized and initially screened non-substituted and 4-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles were estimated for their in-vitro binding affinities at the rat D(2) , 5-HT(2A) , and α(1) -adrenergic receptors. Among all these compounds, 2-methoxyphenyl and 2-chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4-halogenation of benzimidazoles reveal that substitution with bromine may greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5-HT(2A)/D(2) pK(i) binding ratios slightly above or less than 1, while only 4-chloro-6-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1H-benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non-cataleptic action in rats and prevents d-amphetamine-induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A new class of nitrosoureas. 4. Synthesis and antitumor activity of disaccharide derivatives of 3,3-disubstituted 1-(2-chloroethyl)-1-nitrosoureas.

PubMed

Tsujihara, K; Ozeki, M; Morikawa, T; Kawamori, M; Akaike, Y; Arai, Y

1982-04-01

A series of 33 N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of N-substituted glycosylamines has been prepared and tested for antitumor activities. The compounds were obtained by reaction of glycosylamines with isocyanate, followed by nitrosation with N2O4. Structure-activity relationships of these trisubstituted nitrosoureas were investigated by varying the N-substituents and disaccharide groups and by comparing them with the corresponding disubstituted analogues. A large number of the nitrosoureas bearing a maltosyl group exhibited strong antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma, and 60-day survivors against leukemia L1210 were found at the optimal dose for these derivatives. In contrast, the lactosyl and the melibiosyl derivatives were almost inactive. The most interesting compound in this series, the 3-isobutyl-3-maltosyl derivative (37), was tested against leukemia L1210 by single and multiple treatment. Its therapeutic ratio (96.3) obtained by multiple treatment is 3 times larger than that (31.5) obtained by single treatment, suggesting a possible clinical utility of 37 by multiple treatment. The favorable effect of a maltosyl moiety in this class of compounds is discussed.

Serendipitous discovery of potent human head and neck squamous cell carcinoma anti-cancer molecules: A fortunate failure of a rational molecular design.

PubMed

Zagni, Chiara; Pistarà, Venerando; Oliveira, Luciana A; Castilho, Rogerio M; Romeo, Giovanni; Chiacchio, Ugo; Rescifina, Antonio

2017-12-01

Histone deacetylase inhibitors (HDACis) play an important role as valuable drugs targeted to cancer therapy: several HDACis are currently being tested in clinical trials. Two new potential HDACis 1a and 1d, characterized by the presence of a biphenyl-4-sulfonamide group as a connection unit between the N-{4-[(E)-(2-formylhydrazinylidene)methyl]-3-hydroxyphenyl} and the 2-hydroxy-N-(trifluoroacetyl)benzamide moiety, respectively, as two zinc-binding group (ZBG), have been designed, synthesized and tested for their biological activity. Surprisingly, compounds 1a and 12, this last exclusively obtained in place of 1d, exhibited a very low HDAC inhibitory activity. A serendipitous assay of these two compounds, conducted on three chemoresistant cell lines of head and neck squamous cell carcinoma (HNSCC), showed their antiproliferative activity at low nanomolar concentrations, better than cisplatin. In vitro, biological assays indicated that compounds 1a and 12 are able to increase acetylation of histone H3 and to interfere with the PI3K/Akt/mTOR pathway by inducing the accumulation of PTEN protein. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

GC and GC/MS Analysis of Essential Oil Composition of the Endemic Soqotraen Leucas virgata Balf.f. and Its Antimicrobial and Antioxidant Activities

PubMed Central

Mothana, Ramzi A.; Al-Said, Mansour S.; Al-Yahya, Mohammed A.; Al-Rehaily, Adnan J.; Khaled, Jamal M.

2013-01-01

Leucas virgata Balf.f. (Lamiaceae) was collected from the Island Soqotra (Yemen) and its essential oil was obtained by hydrodistillation. The chemical composition of the oil was investigated by GC and GC-MS. Moreover, the essential oil was evaluated for its antimicrobial activity against two Gram-positive bacteria, two Gram-negative bacteria, and one yeast species by using broth micro-dilution assay for minimum inhibitory concentrations (MIC) and antioxidant activity by measuring the scavenging activity of the DPPH radical. The investigation led to the identification of 43 constituents, representing 93.9% of the total oil. The essential oil of L. virgata was characterized by a high content of oxygenated monoterpenes (50.8%). Camphor (20.5%) exo-fenchol (3.4%), fenchon (5.4%), and borneol (3.1%) were identified as the main components. Oxygenated sesquiterpenes were found as the second major group of compounds (21.0%). β-Eudesmol (6.1%) and caryophyllene oxide (5.1%) were the major compounds among oxygenated sesquiterpenes. The results of the antimicrobial assay showed that the oil exhibited a great antibacterial activity against the tested S. aureus, B. subtilis, and E. coli. No activity was found against P. aeruginosa and C. albicans. Moreover, the DPPH-radical scavenging assay exhibited only a moderate antioxidant activity (31%) for the oil at the highest concentration tested (1 mg/mL). PMID:24284402

Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents.

PubMed

Sabbah, Dima A; Hishmah, Bayan; Sweidan, Kamal; Bardaweel, Sanaa; AlDamen, Murad; Zhong, Haizhen A; Abu Khalaf, Reema; Hasan Ibrahim, Ameerah; Al-Qirim, Tariq; Abu Sheikha, Ghassan; Mubarak, Mohammad S

2018-01-01

Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has been highlighted as a therapeutic target for anticancer drug design. Target compounds were designed to address the effect of different substitution patterns at the N atom of the carboxamide moiety on the bioactivity of this series. Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon carcinoma (HCT-116), and Glide docking studies. A new series of N-substituted- 4-hydroxy-2-quinolone-3-carboxamides was prepared and characterized by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising PI3Kα inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and 18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kα and caspase-3 showed an agreement between the predicted binding affinity (ΔGobsd) and IC50 values of the derivatives for the caspase-3 model. Furthermore, Glide docking studies against PI3Kα demonstrated that the newly synthesized compounds accommodate PI3Kα kinase catalytic domain and form H-bonding with key binding residues. The series exhibited a potential PI3Kα inhibitory activity in HCT-116 cell line. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The effects of ultraviolet radiation on photosynthetic performance, growth and sunscreen compounds in aeroterrestrial biofilm algae isolated from building facades.

PubMed

Karsten, U; Lembcke, S; Schumann, R

2007-03-01

The effects of artificial ultraviolet radiation [UVR; 8 W m(-2) ultraviolet-A (UVA), 0.4 W m(-2) ultraviolet-B (UVB)] on photosynthetic performance, growth and the capability to synthesise mycosporine-like amino acids (MAAs) was investigated in the aeroterrestrial green algae Stichococcus sp. and Chlorella luteoviridis forming biofilms on building facades, and compared with the responses of two green algae, from soil (Myrmecia incisa) and brackish water (Desmodesmus subspicatus). All species exhibited decreasing quantum efficiency (Fv/Fm) after 1-3 days exposure to UVR. After 8-12 days treatment, however, all aeroterrestrial isolates exhibited full recovery under UVA and UVA/B. In contrast, D. subspicatus showed only 80% recovery after treatment with UVB. While Stichococcus sp. and C. luteoviridis exhibited a broad tolerance in growth under all radiation conditions tested, M. incisa showed a significant decrease in growth rate after exposure to UVA and UVA/B. Similarly D. subspicatus grew with a reduced rate under UVA, but UVA/B led to full inhibition. Using HPLC, an UV-absorbing MAA (324 nm-MAA) was identified in Stichococcus sp. and C. luteoviridis. While M. incisa contained a specific 322 nm-MAA, D. subspicatus lacked any trace of such compounds. UV-exposure experiments indicated that all MAA-containing species are capable of synthesizing and accumulating these compounds, thus supporting their function as an UV-sunscreen. All data well explain the conspicuous ecological success of aeroterrestrial green algae in biofilms on facades. Biosynthesis and accumulation of MAAs under UVR seem to result in a reduced UV-sensitivity of growth and photosynthesis, which consequently may enhance survival in the environmentally harsh habitat.

Computational discovery of stable M2A X phases

NASA Astrophysics Data System (ADS)

Ashton, Michael; Hennig, Richard G.; Broderick, Scott R.; Rajan, Krishna; Sinnott, Susan B.

2016-08-01

The family of layered Mn +1A Xn compounds provides a large class of materials with applications ranging from magnets to high-temperature coatings to nuclear cladding. In this work, we employ a density-functional-theory-based discovery approach to identify a large number of thermodynamically stable Mn +1A Xn compounds, where n =1 , M =Sc, Ti, V, Cr, Zr, Nb, Mo, Hf, Ta; A =Al, Si, P, S, Ga, Ge, As, Cd, In, Sn, Tl, Pb; and X =C, N. We calculate the formation energy for 216 pure M2A X compounds and 10 314 solid solutions, (MM') 2(A A') (X X') , relative to their competing phases. We find that the 49 experimentally known M2A X phases exhibit formation energies of less than 30 meV/atom. Among the 10 530 compositions considered, 3140 exhibit formation energies below 30 meV/atom, most of which have yet to be experimentally synthesized. A significant subset of 301 compositions exhibits strong exothermic stability in excess of 100 meV/atom, indicating favorable synthesis conditions. We identify empirical design rules for stable M2A X compounds. Among the metastable M2A X compounds are two Cr-based compounds with ferromagnetic ordering and expected Curie temperatures around 75 K. These results can serve as a map for the experimental design and synthesis of different M2A X compounds.

HR-LC-MS based analysis of two antibacterial metabolites from a marine sponge symbiont Streptomyces pharmamarensis ICN40.

PubMed

Joseph, Francis-Joseph Rosemary Sharmila; Iniyan, Appadurai Muthamil; Vincent, Samuel Gnana Prakash

2017-10-01

On the effort to screen antibiotics against Methicillin resistant Staphylococcus aureus (MRSA), an actinomycete strain which can produce bactericidal compound was isolated from a marine sponge of Kanyakumari Coast, India. Two anti-MRSA compounds (PVI401 and PVI402) were isolated from the fermentation plates of Streptomyces pharmamarensis ICN40. TLC bioautography analysis yielded two active spots with Rf value of 0.75 (PVI401) and 0.8 (PVI402) from the crude extract. Both the compounds were characterized by HR-LC-MS analysis. LC-MS based de-replication analysis found out the compound PVI401 with an exact mass of 376.09435 Da and PVI402 with an exact mass of 273.26795 Da were found to be unidentified. Antibacterial spectrum showed significant minimal inhibitory concentration as 0.5 μg/ml of PVI401 and 2 μg/ml of PVI402 against MRSA. The whole organism zebrafish safety evaluation exhibited the compound PVI402 is safe upto 1 mg/ml 40 μg/ml of PVI401 exhibited thrombosis in cardiac chamber and this compound exhibited 44 μg/ml of LC 50 against HepG2 hepatic carcinoma cell line. Both the compounds may be identified further for its structural novelty and clinical studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Potential osteogenic activity of ethanolic extract and oxoflavidin isolated from Pholidota articulata Lindley.

PubMed

Sharma, Chetan; Dixit, Manisha; Singh, Rohit; Agrawal, Manali; Mansoori, Mohd Nizam; Kureel, Jyoti; Singh, Divya; Narender, Tadigoppula; Arya, Kamal Ram

2015-07-21

Pholidota articulata Lindley (PA) locally known as Hadjojen (bone jointer) belongs to family Orchidaceae is used for healing fractures in folklore tradition of Kumaon region of Uttarakhand, Himalaya, India. Bone is a dynamic organ and is constantly being remodeled in order to facilitate growth and repair. This process requires the involvement of bone forming osteoblast and bone resorbing osteoclast cells, which function in generating and mineralizing bone, giving strength and rigidity to the skeletal system. Present study was aimed to determine the therapeutic potential of ethanolic extract of PA and its isolated compound oxoflavidin, by characterizing their fracture healing properties. Ovariectomized (Ovx) estrogen deficient adult female Balb/c mice were used for in vivo evaluation of osteogenic or bone healing potential of ethanolic extract of PA. Further, its isolated compounds were tested for their osteogenic efficacy using alkaline phosphatase assay and mineralization assay in vitro in mice calvarial osteoblasts. The ethanolic extract of PA exhibited significant restoration of trabecular micro-architecture in both femoral and tibial bones. Additionally, treatment with PA extract led to better bone quality and devoid of any uterine estrogenicity in ovariectomized estrogen deficient mice. One of the isolated compound, oxoflavidin enhanced ALP activity (a marker of osteoblast differentiation), mineral nodule formation and mRNA levels of osteogenic markers like BMP-2, Type 1 Collagen, RUNX-2 and osteocalcin. These results warrant that ethanolic extract of PA and it's pure compound oxoflavidin have fracture healing properties. The extract and oxoflavidin exhibit a strong threapeutical potential for the treatment and management of postmenopausal osteoporosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Antinociceptive Activity of Borreria verticillata: In vivo and In silico Studies

PubMed Central

Silva, Rosa H. M.; Lima, Nathália de Fátima M.; Lopes, Alberto J. O.; Vasconcelos, Cleydlenne C.; de Mesquita, José W. C.; de Mesquita, Ludmilla S. S.; Lima, Fernando C. V. M.; Ribeiro, Maria N. de S.; Ramos, Ricardo M.; Cartágenes, Maria do Socorro de S.; Garcia, João B. S.

2017-01-01

Borreria verticillata (L.) G. Mey. known vassourinha has antibacterial, antimalarial, hepatoprotective, antioxidative, analgesic, and anti-inflammatory, however, its antinociceptive action requires further studies. Aim of the study evaluated the antinociceptive activity of B. verticillata hydroalcoholic extract (EHBv) and ethyl acetate fraction (FAc) by in vivo and in silico studies. In vivo assessment included the paw edema test, writhing test, formalin test and tail flick test. Wistar rats and Swiss mice were divided into 6 groups and given the following treatments oral: 0.9% NaCl control group (CTRL), 10 mg/kg memantine (MEM), 10 mg/kg indomethacin (INDO), 500 mg/kg EHBv (EHBv 500), 25 mg/kg FAc (FAc 25) and 50 mg/kg FAc (FAc 50). EHBv, FAc 25 and 50 treatments exhibited anti-edematous and peripheral antinociceptive effects. For in silico assessment, compounds identified in FAc were subjected to molecular docking with COX-2, GluN1a and GluN2B. Ursolic acid (UA) was the compound with best affinity parameters (binding energy and inhibition constant) for COX-2, GluN1a, GluN2B, and was selected for further analysis with molecular dynamics (MD) simulations. In MD simulations, UA exhibited highly frequent interactions with residues Arg120 and Glu524 in the COX-2 active site and NMDA, whereby it might prevent COX-2 and NMDA receptor activation. Treatment with UA 10 mg/Kg showed peripheral and central antinociceptive effect. The antinociceptive effect of B. verticillata might be predominantly attributed to peripheral actions, including the participation of anti-inflammatory components. Ursolic acid is the main active component and seems to be a promising source of COX-2 inhibitors and NMDA receptor antagonists. PMID:28588488

Polyketide-Terpene Hybrid Metabolites from an Endolichenic Fungus Pestalotiopsis sp.

PubMed Central

Ding, Gang; Wang, Hai-Ying; Guo, Yu-Hua; Shang, Hai

2017-01-01

Five new polyketide-terpene hybrid metabolites (1–5) with highly functionalized groups, together with six known derivatives (6–11), were isolated from the endolichenic fungus Pestalotiopsis sp. Their structures were elucidated by extensive NMR experiments including 1H, 13C, HMQC, COSY, and HMBC. The relative configurations of the new compounds were determined by analysis of coupling constants and ROESY correlations. The absolute configurations especially the secondary alcohol at C-15 in 1 and secondary alcohol at C-14 in 5 were established via the CD experiments of the in situ formed [Rh2(OCOCF3)4] complex with the acetonide derivatives. These compounds were tested for their inhibition activity against six plant pathogens. Compounds 1 and 5 exhibited pronounced efficiency against Fusarium oxysporum, and compounds 5 and 6 potently inhibited Fusarium gramineum with MIC value of 8 µg/mL, which revealed the plausible ecological role of endolichenic fungus in providing chemical protection for its host lichen in the fungus-plant relationship. The biosynthetic pathway of compounds 1–11 was postulated for the first time, which paved the way for its further biosynthesis research. PMID:28593175

Facile one-pot multicomponent synthesis and molecular docking studies of steroidal oxazole/thiazole derivatives with effective antimicrobial, antibiofilm and hemolytic properties.

PubMed

Ansari, Anam; Ali, Abad; Asif, Mohd; Rauf, Mohd Ahmar; Owais, Mohammad; Shamsuzzaman

2018-06-01

A series of steroidal oxazole and thiazole derivatives have been synthesized employing thiosemicarbazide/semicarbazide hydrochloride and ethyl 2-chloroacetoacetate with a simple and facile one-pot multicomponent reaction pathway. The antimicrobial activity of newly synthesized compounds were evaluated against four bacterial strains namely Gram-negative (Escherichia coliand Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Listeria monocytogenes) in addition to pathogenic fungi (Candida albicans and Cryptococcus neoformans). Bioactivity assay manifested that most of the compounds exhibited good antimicrobial activity. To provide additional insight into antimicrobial activity, the compounds were also tested for their antibiofilm activity against S. aureus biofilm. Moreover, molecular docking study shows binding of compounds with amino acid residues of DNA gyrase and glucosamine-6-phosphate synthase (promising antimicrobial target) through hydrogen bonding interactions. Hemolytic activity have been also investigated to ascertain the effect of compounds over RBC lysis and results indicate good prospects for biocompatibility. The expedient synthesis of steroidal heterocycles, effective antibacterial and antifungal behavior against various clinically relevant human pathogens, promising biocompatibility offer opportunities for further modification and potential applications as therapeutic agents. Copyright © 2018 Elsevier Inc. All rights reserved.

In vitro acetylcholinesterase activity of peptide derivatives isolated from two species of Leguminosae.

PubMed

Alves, Clayton Q; Lima, Luciano S; David, Jorge M; Lima, Marcos V B; David, Juceni P; Lima, Fernanda W M; Pedroza, Kelly C M C; Queiroz, Luciano P

2013-07-01

Cratylia mollis Martius ex Benth. and Cenostigma macrophyllum Tul. (Leguminosae) are both endemic Brazilian plants and they are used by the natives as medicinal plants, and the leaves of C. mollis are also employed as forage for cattle during the dry season of region. Isolation of the compounds responsible for the acetylcholinesterase (AChE) inhibition from the CHCl3 active extract. Two peptidic compounds were isolated by chromatographic techniques from the CHCl3 extract of the leaves of C. mollis and C. macrophyllum. They were identified by spectrometric data analysis (MS and NMR) and they were subjected to AChE inhibition employing Ellman's test. The peptides were identified as N-benzoylphenylalaninoyl-phenlyalaninolacetate (aurentiamide acetate) (1) and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2). Both peptides 1 and 2 exhibit AChE inhibition, with IC50 values equal to 111.34 µM and 137.6 µM, respectively. Compound 1 (aurentiamide acetate) has rarely been isolated from the Leguminosae family, and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2) is a compound that has never previously been isolated from this family. Compound 1 is shown to be a potent inhibitor of AChE, with IC50 values similar to the physostigmine control (141.51 µM).

Efficient synthesis and antimicrobial activity of some novel S-β-d-glucosides of 5-aryl-1,2,4-triazole-3-thiones derivatives.

PubMed

Ji, Dan; Lu, JunRui; Lu, BoWei; Xin, ChunWei; Mu, JiangBei; Li, JianFa; Peng, ChunYong; Bao, XiuRong

2013-04-01

A series of 3-S-β-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,2,4-triazole, Schiff base and glucosides. The structures of the target compounds have been characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS. All the newly synthesized compounds have been evaluated for their antimicrobial activities in vitro against Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8099) as well as Monilia albican (ATCC 10231). The bioactive assay showed that most of the tested compounds displayed variable inhibitory effects on the growth of the Gram-positive bacterial strain (Staphylococcus aureus), Gram-negative bacterial strains (Escherichia coli) and fungal strains (Monilia albican). All the target compounds exhibited better antifungal activity than antibacterial activity. Especially, compounds 6b, 6c, 6f, 6j, 6k and 6l showed excellent activity against fungus Monilia albican with MIC values of 16 μg/mL. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis, pH dependent photometric and electrochemical investigation, redox mechanism and biological applications of novel Schiff base and its metallic derivatives

NASA Astrophysics Data System (ADS)

Rauf, Abdur; Shah, Afzal; Khan, Abdul Aziz; Shah, Aamir Hassan; Abbasi, Rashda; Qureshi, Irfan Zia; Ali, Saqib

2017-04-01

A novel Schiff base, 1-((2, 4-dimethylphenylimino)methyl)naphthalen-2-ol abbreviated as (HL) and its four metallic complexes were synthesized and confirmed by 1H and 13C NMR, FTIR, TGA and UV-Visible spectroscopy. Schiff base was also characterized by X-ray analysis. The photometric and electrochemical responses of all the synthesized compounds were investigated in a wide pH range. Structures of the compounds were optimized computationally for the evaluation of different physico-chemical parameters. On the basis of electrochemical results the redox mechanistic pathways of the compounds were proposed. The cytotoxicity analysis on Hela cells revealed that HL and its complexes inhibit cell growth as revealed from their IC50 values (HL):106.7 μM, (L2VO): 40.66 μM, (L2Sn): 5.92 μM, (L2Zn): 42.82 and (L2Co): 107.68 μM. The compounds were tested for anti-diabetic, triglyceride, cholesterol, anti-microbial, anti-fungal and enzyme inhibition activities. The results revealed that HL and its complexes are promising new therapeutic options as these compounds exhibit strong activity against cancer cells, diabetics, fungal and microbial inhibition.

Ultrasound-assisted synthesis, anticonvulsant activity, and docking study of indole-appended thiazolidin-4-ones.

PubMed

Nikalje, Anna Pratima G; Shaikh, Sameer I; Mulay, Abhineet; Khan, Firoz A K; Sangshetti, Jaiprakash N; Shaikh, Shoaib

2014-10-01

Two series of novel indolyl thiazolidin-4-one derivatives 4a-j and 5a-j were obtained by an ecofriendly synthetic protocol by treating a mixture of Schiff's bases (0.01 mol) with thioglycolic acid or thiolactic acid (0.01 mol) and anhydrous zinc chloride in catalytic amount in DMF as solvent under ultrasound irradiation, using an ultrasound synthesizer with a synthetic solid probe. The structures of the synthesized compounds were confirmed by IR, (1) H NMR, (13) C NMR, MS, and elemental analysis. The anticonvulsant activity and neurotoxicity of the newly synthesized compounds were established by MES and sc-PTZ model and by rotarod test, respectively, in vivo using mouse models. The actophotometer was used for the screening of behavioral activity. The compounds exhibited promising anticonvulsant activity; especially, the compounds showed maximum protection in the MES model at a dose of 100 mg/kg. Further, docking studies of the synthesized compounds were performed against the sodium channel receptor and showed good binding interactions with the receptor. A computational study was carried out to highlight the pharmacophore distance mapping, log p determination, and pharmacokinetic parameters. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, Characterisation, Molecular Docking, Anti-microbial and Anti-diabetic Screening of Substituted 4-indolylphenyl-6-arylpyrimidine-2-imine Derivatives.

PubMed

Ramya, Veerasamy; Vembu, Santhirakasu; Ariharasivakumar, Ganesan; Gopalakrishnan, Manathusamy

2017-09-01

The purpose of the research is to synthesise a novel series of (E)-2-(4-(1H-indol-3-yl)-6-p-substituted phenylpyrimidin-2-yl)dimethylguanidine derivatives since 3-(1H-indol-3-yl)-1-p-substituted phenylprop-2-en-1-one and evaluate their molecular docking studies, antimicrobial, and anti-diabetic activities. Among all the synthesized compounds ( 11a-g ), compound 11a exhibits excellent CDOCKER energy (-11.36 kcal/mol). The entire compounds ( 11a-g ) confirm very good antimicrobial activity towards the tested microorganisms. In the in vitro anti-diabetic studies, compounds (11a, 11c, and 11g) confirm higher alpha-amylase and alpha-glucosidase inhibition activity. In the in vivo anti-diabetic activities, the synthesized compounds (11a-g) (10 mg/kg, p.o.) investigated by the streptozotocin (60 mg/kg, ip) -nicotinamide (120 mg/kg, p.o.) - induced model in adult male albino Wistar rat and these derivatives show considerable fasting blood glucose level when compared to metformin hydrochloride a potent and well-known anti-diabetic drug as a reference. © Georg Thieme Verlag KG Stuttgart · New York.

The antibacterial activity of compounds isolated from oakmoss against Legionella pneumophila and other Legionella spp.

PubMed

Nomura, Harue; Isshiki, Yasunori; Sakuda, Keisuke; Sakuma, Katsuya; Kondo, Seiichi

2012-01-01

Oakmoss is a natural fragrance ingredient exhibiting highly specific, potent antibacterial activity against Legionella pneumophila, a causative agent of severe water-bone pneumonia. In the present study, the antibacterial activity of individual compounds isolated from oakmoss was investigated against L. pneumophila and other Legionella spp. A total of 18 known compounds and two minor novel compounds (i.e., 3-methoxy-5-methylphenyl-2,4-dihydroxy-6-methylbenzoate (compound 9) and 8-(2,4-dihydroxy-6-(2-oxoheptyl)-phenoxy)-6-hydroxy-3-pentyl-1H-isochromen-1-one (compound 20)) were purified from oakmoss. The minimum inhibitory concentrations (MICs) against clinical and environmental isolates of L. pneumophila, L. bozemanii, L. micdadei, L. longbeachae, and L. dumoffii for 11 of the 20 compounds were less than 100 µg/mL (range 0.8-64.0 µg/mL). Novel compounds 9 and 20 exhibited potent antibacterial activity against L. pneumophila strains (MIC ranges of 1.3-8.0 µg/mL and 3.3-13.3 µg/mL, respectively) and also against four other Legionella species (MIC ranges of 0.8-8.0 µg/mL and 3.3-21.3 µg/mL, respectively). Time-kill assays indicated that compounds 9 and 20 kill bacteria at a concentration equivalent to 2×MIC after 1 h and 6 h co-incubations, respectively. While oakmoss and the purified components exhibited antibacterial activity against Legionella spp., they were not active against other Gram-negative and -positive bacteria such as Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus.

Antibacterial activity of tannins isolated from Sapium baccatum extract and use for control of tomato bacterial wilt.

PubMed

Vu, Thuy Thu; Kim, Hun; Tran, Vu Khac; Vu, Hoang Dinh; Hoang, Tien Xuan; Han, Jae Woo; Choi, Yong Ho; Jang, Kyoung Soo; Choi, Gyung Ja; Kim, Jin-Cheol

2017-01-01

In the search for new antibacterial agents from natural sources, we revealed that a crude methanol extract of Sapium baccatum was highly active against Ralstonia solanacearum, a causal agent of a serious disease called bacterial wilt of tomato. The bioassay-guided fractionation of this extract resulted in the isolation of seven known active compounds, including gallic acid, methyl gallate, corilagin, tercatain, chebulagic acid, chebulinic acid, and quercetin 3-O-α-L-arabinopyranoside. Their chemical structures were determined by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. An in vitro antibacterial bioassay using a broth microdilution method revealed that, except for quercetin 3-O-α-L-arabinopyranoside (MIC = 250 μg/mL), the isolated compounds exhibited strong antibacterial activity against R. solanacearum (MIC = 26-52 μg/mL). Among the seven compounds, methyl gallate exhibited the strongest broad-spectrum activity against most of the plant pathogenic bacteria tested (MIC = 26-250 μg/mL). In the in vivo experiments, the crude extract of S. baccatum at 2000 and 1000 μg/mL reduced the development of tomato bacterial wilt by 83 and 63%, respectively, under greenhouse conditions after 14 days of infection. The results suggested that the extracts of S. baccatum or isolated tannins could be used as natural bactericides for the control of bacterial wilt of tomato.

Supramolecular approach to enantioselective DNA recognition using enantiomerically resolved cationic 4-amino-1,8-naphthalimide-based Tröger's bases.

PubMed

Banerjee, Swagata; Bright, Sandra A; Smith, Jayden A; Burgeat, Jeremy; Martinez-Calvo, Miguel; Williams, D Clive; Kelly, John M; Gunnlaugsson, Thorfinnur

2014-10-03

The synthesis and photophysical studies of two cationic Tröger's base (TB)-derived bis-naphthalimides 1 and 2 and the TB derivative 6, characterized by X-ray crystallography, are presented. The enantiomers of 1 and 2 are separated by cation-exchange chromatography on Sephadex C25 using sodium (-)-dibenzoyl-l-tartarate as the chiral mobile phase. The binding of enantiomers with salmon testes (st)-DNA and synthetic polynucleotides are studied by a variety of spectroscopic methods including UV/vis absorbance, circular dichroism, linear dichroism, and ethidium bromide displacement assays, which demonstrated binding of these compounds to the DNA grooves with very high affinity (K ∼ 10(6) M(-1)) and preferential binding of (-)-enantiomer. In all cases, binding to DNA resulted in a significant stabilization of the double-helical structure of DNA against thermal denaturation. Compound (±)-2 and its enantiomers possessed significantly higher binding affinity for double-stranded DNA compared to 1, possibly due to the presence of the methyl group, which allows favorable hydrophobic and van der Waals interactions with DNA. The TB derivatives exhibited marked preference for AT rich sequences, where the binding affinities follow the order (-)-enantiomer > (±) > (+)-enantiomer. The compounds exhibited significant photocleavage of plasmid DNA upon visible light irradiation and are rapidly internalized into malignant cell lines.

Antibacterial activity of tannins isolated from Sapium baccatum extract and use for control of tomato bacterial wilt

PubMed Central

Vu, Thuy Thu; Kim, Hun; Tran, Vu Khac; Vu, Hoang Dinh; Hoang, Tien Xuan; Han, Jae Woo; Choi, Yong Ho; Jang, Kyoung Soo; Choi, Gyung Ja

2017-01-01

In the search for new antibacterial agents from natural sources, we revealed that a crude methanol extract of Sapium baccatum was highly active against Ralstonia solanacearum, a causal agent of a serious disease called bacterial wilt of tomato. The bioassay-guided fractionation of this extract resulted in the isolation of seven known active compounds, including gallic acid, methyl gallate, corilagin, tercatain, chebulagic acid, chebulinic acid, and quercetin 3-O-α-L-arabinopyranoside. Their chemical structures were determined by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. An in vitro antibacterial bioassay using a broth microdilution method revealed that, except for quercetin 3-O-α-L-arabinopyranoside (MIC = 250 μg/mL), the isolated compounds exhibited strong antibacterial activity against R. solanacearum (MIC = 26–52 μg/mL). Among the seven compounds, methyl gallate exhibited the strongest broad-spectrum activity against most of the plant pathogenic bacteria tested (MIC = 26–250 μg/mL). In the in vivo experiments, the crude extract of S. baccatum at 2000 and 1000 μg/mL reduced the development of tomato bacterial wilt by 83 and 63%, respectively, under greenhouse conditions after 14 days of infection. The results suggested that the extracts of S. baccatum or isolated tannins could be used as natural bactericides for the control of bacterial wilt of tomato. PMID:28742863

Synthesis of novel 1,2,3-triazole based benzoxazolinones: their TNF-α based molecular docking with in-vivo anti-inflammatory, antinociceptive activities and ulcerogenic risk evaluation.

PubMed

Haider, Saqlain; Alam, M Sarwar; Hamid, Hinna; Shafi, Syed; Nargotra, Amit; Mahajan, Priya; Nazreen, Syed; Kalle, Arunasree M; Kharbanda, Chetna; Ali, Yakub; Alam, Aftab; Panda, Amulya K

2013-01-01

A library of novel bis-heterocycles containing benzoxazolinone based 1,2,3-triazoles has been synthesized using click chemistry approach. The compound 3f exhibited potent selective COX-2 inhibition of 59.48% in comparison to standard drug celecoxib (66.36% inhibition). The compound 3i showed significant (p < 0.001, 50.95%), TNF-α inhibitory activity as compared to indomethacin (p < 0.001, 64.01%). The results of the carrageenan induced hind paw oedema showed that compounds 3a, 3f, 3i, 3o, and 3e exhibited potent anti-inflammatory activity in comparison to Indomethacin. The molecular docking studies revealed that 3i exhibits strong inhibitory effect due to the extra stability of the complex because of an extra π-π bond. The histopathology report showed that none of the compounds caused gastric ulceration. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazines.

PubMed

Matosiuk, Dariusz; Fidecka, Sylwia; Antkiewicz-Michaluk, Lucyna; Lipkowski, Janusz; Dybala, Izabela; Koziol, Anna E

2002-09-01

Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo-[1,2-a][1,3,5]triazines (C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents--phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1H)-dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazine (C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD(50) > 2000 mg kg(-1) i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg(-1)) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid mu receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT(2) and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar') at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT(2) expressed in the binding assay test. Copyright 2002 Editions scienctifiques et médicales Elsevier SAS

Algicidal activity of marine Alteromonas sp. KNS-16 and isolation of active compounds.

PubMed

Cho, Ji Young

2012-01-01

The KNS-16 algicidal strain was isolated from a harmful alga bloom (HAB) area and identified as Alteromonas sp. based on 16S rDNA sequencing. The KNS-16 strain was found to control HABs by producing algicidal compounds in an indirect interaction. Four active compounds were isolated from KNS-16 culture, and their structures were analyzed by interpreting nuclear magnetic resonance and mass spectroscopy data. The structures were identified as 2-undecen-1'-yl-4-quinolone (1), 2-undecyl-4-quinolone (2), 3-hexyl-6-pentyl-4-hydroxyl-2H-pyran-2-one (3), and 6-heptyl-3-hexyl-4-hydroxyl-2H-pyran-2-one (4). Compound 1 was most active against HABs such as Heterosigma akashiwo, Cochlodinium polykrikoides, and Alexandrium tamarense with LC(50) values of 0.5-1.1 µg/mL. The four compounds exhibited high LC(50) values against aquaculture algae such as Tetaselmis suecica, Isochrysis galbana, and Pavlova lutheri at 39-66 µg/mL. Based on toxicity tests on the brine shrimp Artemia salina and the rotifer Brachionus rotundiformis, the four compounds showed ranges of 409-608 and 189-224 µg/mL of LC(50) for the two organisms, respectively. The LC(50) values for juvenile fish of Sebastes schlegelii were 284-304 µg/mL.

Open innovation for phenotypic drug discovery: The PD2 assay panel.

PubMed

Lee, Jonathan A; Chu, Shaoyou; Willard, Francis S; Cox, Karen L; Sells Galvin, Rachelle J; Peery, Robert B; Oliver, Sarah E; Oler, Jennifer; Meredith, Tamika D; Heidler, Steven A; Gough, Wendy H; Husain, Saba; Palkowitz, Alan D; Moxham, Christopher M

2011-07-01

Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy. To address this issue, Eli Lilly and Company launched the Phenotypic Drug Discovery Initiative (PD(2)), a model of open innovation whereby external research groups can submit compounds for testing in a panel of Lilly phenotypic assays. This communication describes the statistical validation, operations, and initial screening results from the first PD(2) assay panel. Analysis of PD(2) submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD(2) have confirmed hit rates from 1.6% to 10%, with the majority of active compounds exhibiting acceptable potency and selectivity. Phenotypic lead generation strategies, in conjunction with novel chemical diversity obtained via open-source initiatives such as PD(2), may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery.

Rational Design and Synthesis of New, High Efficiency, Multipotent Schiff Base-1,2,4-triazole Antioxidants Bearing Butylated Hydroxytoluene Moieties.

PubMed

Yehye, Wageeh A; Abdul Rahman, Noorsaadah; Saad, Omar; Ariffin, Azhar; Abd Hamid, Sharifah Bee; Alhadi, Abeer A; Kadir, Farkaad A; Yaeghoobi, Marzieh; Matlob, Abdulsalam A

2016-06-28

A new series of multipotent antioxidants (MPAOs), namely Schiff base-1,2,4-triazoles attached to the oxygen-derived free radical scavenging moiety butylated hydroxytoluene (BHT) were designed and subsequently synthesized. The structure-activity relationship (SAR) of the designed antioxidants was established alongside the prediction of activity spectra for substances (PASS). The antioxidant activities of the synthesized compounds 4-10 were tested by the DPPH bioassay. The synthesized compounds 4-10 inhibited stable DPPH free radicals at a level that is 10(-4) M more than the well-known standard antioxidant BHT. Compounds 8-10 with para-substituents were less active than compounds 4 and 5 with trimethoxy substituents compared to those with a second BHT moiety (compounds 6 and 7). With an IC50 of 46.13 ± 0.31 µM, compound 6 exhibited the most promising in vitro inhibition at 89%. Therefore, novel MPAOs containing active triazole rings, thioethers, Schiff bases, and BHT moieties are suggested as potential antioxidants for inhibiting oxidative stress processes and scavenging free radicals, hence, this combination of functions is anticipated to play a vital role in repairing cellular damage, preventing various human diseases and in medical therapeutic applications.

Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure.

PubMed

Keskin, O; Bahar, I; Jernigan, R L; Beutler, J A; Shoemaker, R H; Sausville, E A; Covell, D G

2000-04-01

An analysis of the growth inhibitory potency of 122 anticancer agents available from the National Cancer Institute anticancer drug screen is presented. Methods of singular value decomposition (SVD) were applied to determine the matrix of distances between all compounds. These SVD-derived dissimilarity distances were used to cluster compounds that exhibit similar tumor growth inhibitory activity patterns against 60 human cancer cell lines. Cluster analysis divides the 122 standard agents into 25 statistically distinct groups. The first eight groups include structurally diverse compounds with reactive functionalities that act as DNA-damaging agents while the remaining 17 groups include compounds that inhibit nucleic acid biosynthesis and mitosis. Examination of the average activity patterns across the 60 tumor cell lines reveals unique 'fingerprints' associated with each group. A diverse set of structural features are observed for compounds within these groups, with frequent occurrences of strong within-group structural similarities. Clustering of cell types by their response to the 122 anticancer agents divides the 60 cell types into 21 groups. The strongest within-panel groupings were found for the renal, leukemia and ovarian cell panels. These results contribute to the basis for comparisons between log(GI(50)) screening patterns of the 122 anticancer agents and additional tested compounds.

Assembly of three new POM-based Ag(I) coordination polymers with antibacterial and photocatalytic properties

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

Lu, Xin-Xin; Luo, Yu-Hui; Lu, Chen

Three new silver coordination polymers, namely, {Ag_3(bpy)_6[PW_1_2O_4_0]} (1), {Ag_5(H_2biim)_2(Hbiim-NO_2)_2[PW_1_2O_4_0]} (2), {Ag_7(pytz)_4[PW_1_2O_4_0]} (3) (bpy=2,2′-bipyridine, H{sub 2}biim=2,2′-biimidazole, pytz=4-(1H-tetrazol-5-yl)pyridine), have been synthesized under hydrothermal condition. Compound 1 shows a 3D supramolecular framework based on 0D moieties. Compound 2 exhibits an attractive 2D biologic screw axis. Compound 3 displays a 3D structure, which consists of Ag(I)···π interactions, π···π stacking and weak Ag···Ag interactions. It is noteworthy that nitration happens to compound 2 during the hydrothermal condition, which is quite rare. Through contrasting the antibacterial activities of gram negative and gram positive bacteria, we find compounds 1–3 have better antibacterial property in gram negative bacteriamore » than gram positive bacteria. In addition, compounds 1–3 also exhibit efficiency of photocatalytic decomposition of organic dyes. Those compounds may be used as potential multifunctional materials in wastewater treatment, because they not only can kill bacteria but also degrade organic pollutants. - Highlights: • Three new silver coordination polymers have been synthesized under hydrothermal condition. • Due to different coordination modes of rigid N-donor ligands, structures of the title compounds vary from 0D to 3D frameworks. • It is noteworthy that nitration happens to compound 2 during the hydrothermal condition, which is quite rare. • In addition, these compounds exhibit efficiency of photocatalytic decomposition of dyes and antibacterial activities.« less

Electronic tongue for nitro and peroxide explosive sensing.

PubMed

González-Calabuig, Andreu; Cetó, Xavier; Del Valle, Manel

2016-06-01

This work reports the application of a voltammetric electronic tongue (ET) towards the simultaneous determination of both nitro-containing and peroxide-based explosive compounds, two families that represent the vast majority of compounds employed either in commercial mixtures or in improvised explosive devices. The multielectrode array was formed by graphite, gold and platinum electrodes, which exhibited marked mix-responses towards the compounds examined; namely, 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), pentaerythritol tetranitrate (PETN), 2,4,6-trinitrotoluene (TNT), N-methyl-N,2,4,6-tetranitroaniline (Tetryl) and triacetone triperoxide (TATP). Departure information was the set of voltammograms, which were first analyzed by means of principal component analysis (PCA) allowing the discrimination of the different individual compounds, while artificial neural networks (ANNs) were used for the resolution and individual quantification of some of their mixtures (total normalized root mean square error for the external test set of 0.108 and correlation of the obtained vs. expected concentrations comparison graphs r>0.929). Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Synthetic antimicrobial peptides as agricultural pesticides for plant-disease control.

PubMed

Montesinos, Emilio; Bardají, Eduard

2008-07-01

There is a need of antimicrobial compounds in agriculture for plant-disease control, with low toxicity and reduced negative environmental impact. Antimicrobial peptides are produced by living organisms and offer strong possibilities in agriculture because new compounds can be developed based on natural structures with improved properties of activity, specificity, biodegradability, and toxicity. Design of new molecules has been achieved using combinatorial-chemistry procedures coupled to high-throughput screening systems and data processing with design-of-experiments (DOE) methodology to obtain QSAR equation models and optimized compounds. Upon selection of best candidates with low cytotoxicity and moderate stability to protease digestion, anti-infective activity has been evaluated in plant-pathogen model systems. Suitable compounds have been submitted to acute toxicity testing in higher organisms and exhibited a low toxicity profile in a mouse model. Large-scale production can be achieved by solution organic or chemoenzymatic procedures in the case of very small peptides, but, in many cases, production can be performed by biotechnological methods using genetically modified microorganisms (fermentation) or transgenic crops (plant biofactories).

Headspace, volatile and semi-volatile organic compounds diversity and radical scavenging activity of ultrasonic solvent extracts from Amorpha fruticosa honey samples.

PubMed

Jerković, Igor; Marijanović, Zvonimir; Kezić, Janja; Gugić, Mirko

2009-07-27

Volatile organic compounds of Amorpha fruticosa honey samples were isolated by headspace solid-phase microextraction (HS-SPME) and ultrasonic solvent extraction (USE), followed by gas chromatography and mass spectrometry analyses (GC, GC-MS), in order to obtain complementary data for overall characterization of the honey aroma. The headspace of the honey was dominated by 2-phenylethanol (38.3-58.4%), while other major compounds were trans- and cis-linalool oxides, benzaldehyde and benzyl alcohol. 2-Phenylethanol (10.5-16.8%) and methyl syringate (5.8-8.2%) were the major compounds of ultrasonic solvent extracts, with an array of small percentages of linalool, benzene and benzoic acid derivatives, aliphatic hydrocarbons and alcohols, furan derivatives and others. The scavenging ability of the series of concentrations of the honey ultrasonic solvent extracts and the corresponding honey samples was tested by a DPPH (1,1-diphenyl-2-picrylhydrazyl) assay. Approximately 25 times lower concentration ranges (up to 2 g/L) of the extracts exhibited significantly higher free radical scavenging potential with respect to the honey samples.

Discovery of new anti-depressants from structurally novel 5-HT3 receptor antagonists: design, synthesis and pharmacological evaluation of 3-ethoxyquinoxalin-2-carboxamides.

PubMed

Mahesh, Radhakrishnan; Devadoss, Thangaraj; Pandey, Dilip Kumar; Bhatt, Shvetank

2011-02-15

A novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT(3) receptor antagonist using ligand-based approach. The desired carboxamides were synthesized from the key intermediate, 3-ethoxyquinoxalin-2-carboxylic acid by coupling with appropriate amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The 5-HT(3) receptor antagonism was evaluated in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methy-5-HT, which was expressed in the form of pA(2) values. Compound 6h (3-ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-yl)methanone was found to be the most active compound, which expressed a pA(2) value of 7.7. In forced swim test, the compounds with higher pA(2) value exhibited good anti-depressant-like activity and compounds with lower pA(2) value failed to show activity as compared to the vehicle-treated group. Copyright © 2010 Elsevier Ltd. All rights reserved.

An acetate prodrug of a pyridinol-based vitamin E analogue.

PubMed

Khdour, Omar M; Lu, Jun; Hecht, Sidney M

2011-11-01

To investigate of an approach to stabilize a novel pyridinol based α-tocopherol analogue (1) as a prodrug by acetylation of its phenol moiety. Biochemical indicators of oxidative stress in mitochondria were utilized to gain insight into the cytoprotective mechanism(s) of compound 1 acetate. Oxygen free radical scavenging activity was measured using DCF probe in a cultured cell model system that had been placed under oxidative stress. Lipid peroxidation was examined both in a cell-free system and in oxidatively stressed cultured cells. The bioenergetic parameters of mitochondria were evaluated by measuring mitochondrial membrane potential (Δψ(m)) and the MPT. The present results suggest strongly that the antioxidant efficacy of compound 1 can be improved by using it as a prodrug. The tested prodrug has shown to be activated as a function of time, presumably due to susceptibility to enzymatic hydrolysis, and exhibits an antioxidant effect in time-dependent manner, providing a compound that is more effective than α-tocopherol acetate with regard to all protective properties studied. An effective approach to stabilize compound 1 was realized by using its acetate as a prodrug.

Imaging flow cytometry for the screening of compounds that disrupt the Plasmodium falciparum digestive vacuole.

PubMed

Chia, Wan Ni; Lee, Yan Quan; Tan, Kevin Shyong-Wei

2017-01-01

Malaria, despite being one of the world's oldest infectious diseases, remains difficult to eradicate because the parasite is rapidly developing resistance to frontline chemotherapies. Previous studies have shown that the parasite exhibits features resembling programmed cell death upon treatment with drugs that disrupt its digestive vacuole (DV), providing a phenotypic readout that can be detected using the imaging flow cytometer. Large compound collections can thus be screened to identify drugs that are able to disrupt the DV of the malaria parasite using this high-content high-throughput screening platform. As a proof-of-concept, 4440 compounds were screened using this platform in 4months and 254 hits (5.7% hit rate) were obtained. Additionally, 25 compounds (0.6% top hit rate) were observed to retain potent DV disruption activity that was comparable to the canonical DV disruptive drug chloroquine when tested at a ten-fold lower concentration from the original screen. This pilot study demonstrates the robustness and high-throughput capability of the imaging flow cytometer and we report herein the methodology of this screening assay. Copyright © 2016 Elsevier Inc. All rights reserved.

Synthesis and Characterization of a Novel Phenolic Lipid for Use as Potential Lipophilic Antioxidant and as a Prodrug of Butyric Acid.

PubMed

Kaki, Shiva Shanker; Kunduru, Konda Reddy; Kanjilal, Sanjit; Narayana Prasad, Rachapudi Badari

2015-01-01

Ferulic acid was modified to produce a novel phenolipid containing butyl chains. Ferulic acid was esterified with butanol to produce butyl ferulate which was further dihydroxylated followed by esterification with butyric anhydride to produce the phenolipid containing butyric acid. IR, NMR and MS techniques confirmed the structure of the synthesized structured lipophilic phenolic compound. The synthesized compound was tested for in vitro antioxidant and antimicrobial activities. The produced phenolipid showed moderate antioxidant activity in DPPH (2, 2-diphenyl-1-picrylhydrazyl) radical scavenging assay but in linoleic acid oxidation method, it exhibited good activity compared with the parent compound and the reference compounds. The prepared derivative could find applications as antioxidant in lipophilic systems and also as a potential prodrug of butyric acid. It also showed antibacterial effect against the four bacterial strains studied. The drug-likeness properties of the prepared molecule calculated were in the acceptable ranges according to Lipinski's rule of 5 and suggest that it has potential to cross the blood-brain barrier.

Marine Inspired 2-(5-Halo-1H-indol-3-yl)-N,N-dimethylethanamines as Modulators of Serotonin Receptors: An Example Illustrating the Power of Bromine as Part of the Uniquely Marine Chemical Space.

PubMed

Ibrahim, Mohamed A; El-Alfy, Abir T; Ezel, Kelly; Radwan, Mohamed O; Shilabin, Abbas G; Kochanowska-Karamyan, Anna J; Abd-Alla, Howaida I; Otsuka, Masami; Hamann, Mark T

2017-08-09

In previous studies, we have isolated several marine indole alkaloids and evaluated them in the forced swim test (FST) and locomotor activity test, revealing their potential as antidepressant and sedative drug leads. Amongst the reported metabolites to display such activities was 5-bromo- N , N -dimethyltryptamine. Owing to the importance of the judicious introduction of halogens into drug candidates, we synthesized two series built on a 2-(1 H -indol-3-yl)- N , N -dimethylethanamine scaffold with different halogen substitutions. The synthesized compounds were evaluated for their in vitro and in vivo antidepressant and sedative activities using the mouse forced swim and locomotor activity tests. Receptor binding studies of these compounds to serotonin (5-HT) receptors were conducted. Amongst the prepared compounds, 2-(1 H -indol-3-yl)- N , N -dimethyl-2-oxoacetamide ( 1a ), 2-(5-bromo-1 H -indol-3-yl)- N , N -dimethyl-2-oxoacetamide ( 1d ), 2-(1 H -indol-3-yl)- N , N -dimethylethanamine ( 2a ), 2-(5-chloro-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2c ), 2-(5-bromo-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2d ), and 2-(5-iodo-1 H -indol-3-yl)- N , N -dimethylethanamine ( 2e ) have been shown to possess significant antidepressant-like action, while compounds 2c , 2d , and 2e exhibited potent sedative activity. Compounds 2a , 2c , 2d , and 2e showed nanomolar affinities to serotonin receptors 5-HT 1A and 5-HT₇. The in vitro data indicates that the antidepressant action exerted by these compounds in vivo is mediated, at least in part, via interaction with serotonin receptors. The data presented here shows the valuable role that bromine plays in providing novel chemical space and electrostatic interactions. Bromine is ubiquitous in the marine environment and a common element of marine natural products.

Impact of yeast starter formulations on the production of volatile compounds during wine fermentation.

PubMed

Romano, Patrizia; Pietrafesa, Rocchina; Romaniello, Rossana; Zambuto, Marianna; Calabretti, Antonella; Capece, Angela

2015-01-01

The most diffused starter formulation in winemaking is actually represented by active dry yeast (ADY). Spray-drying has been reported as an appropriate preservation method for yeast and other micro-organisms. Despite the numerous advantages of this method, the high air temperatures used can negatively affect cell viability and the fermentative performance of dried cells. In the present study, 11 wine S. cerevisiae strains (both indigenous and commercial) were submitted to spray-drying; different process conditions were tested in order to select the conditions allowing the highest strain survival. The strains exhibited high variability for tolerance to spray-drying treatment. Selected strains were tested in fermentation at laboratory scale in different formulations (free fresh cells, free dried cells, immobilized fresh cells and immobilized dried cells), in order to assess the influence of starter formulation on fermentative fitness of strains and aromatic quality of wine. The analysis of volatile fraction in the experimental wines produced by selected strains in different formulations allowed identification of > 50 aromatic compounds (alcohols, esters, ketones, aldehydes and terpenes). The results obtained showed that the starter formulation significantly influenced the content of volatile compounds. In particular, the wines obtained by strains in dried forms (as both free and immobilized cells) contained higher numbers of volatile compounds than wines obtained from fresh cells. Copyright © 2014 John Wiley & Sons, Ltd.

Evaluation of Aromatic Plants and Compounds Used to Fight Multidrug Resistant Infections

PubMed Central

Perumal Samy, Ramar; Manikandan, Jayapal; Al Qahtani, Mohammed

2013-01-01

Traditional medicine plays a vital role for primary health care in India, where it is widely practiced to treat various ailments. Among those obtained from the healers, 78 medicinal plants were scientifically evaluated for antibacterial activity. Methanol extract of plants (100 μg of residue) was tested against the multidrug resistant (MDR) Gram-negative and Gram-positive bacteria. Forty-seven plants showed strong activity against Burkholderia pseudomallei (strain TES and KHW) and Staphylococcus aureus, of which Tragia involucrata L., Citrus acida Roxb. Hook.f., and Aegle marmelos (L.) Correa ex Roxb. showed powerful inhibition of bacteria. Eighteen plants displayed only a moderate effect, while six plants failed to provide any evidence of inhibition against the tested bacteria. Purified compounds showed higher antimicrobial activity than crude extracts. The compounds showed less toxic effect to the human skin fibroblasts (HEPK) cells than their corresponding aromatic fractions. Phytochemical screening indicates that the presence of various secondary metabolites may be responsible for this activity. Most of the plant extracts contained high levels of phenolic or polyphenolic compounds and exhibited activity against MDR pathogens. In conclusion, plants are promising agents that deserve further exploration. Lead molecules available from such extracts may serve as potential antimicrobial agents for future drug development to combat diseases caused by the MDR bacterial strains as reported in this study. PMID:24223059

HPTLC and magnetochromatography of new complexes of carboxylates with transition metals or rare earth elements and their ligands - study of lipophilicity.

PubMed

Malinowska, Irena; Wronka, Agnieszka; Ferenc, Wiesława

2017-05-01

Nineteen new complexes of carboxylates with transition and rare elements as central ions and their ligands were characterized by chromatographic analyses. The parameter of relative lipophilicity (R M0 ) of the tested compounds was determined experimentally by the reversed-phase high-performance thin layer chromatography method with mixtures of various organic modifiers (acetonitrile, acetone, dioxane) and water as a mobile phase. The extrapolated R M0 values were compared with the logP values calculated from the molecular structures of tested solutes. Similarities between the lipophilicity indices were analysed by principal component analysis and linear regression. Thin-layer chromatography combined with a magnetic field has been proposed as a complementary method for determination of lipophilicity of the investigated compounds. The chromatograms in the field and outside it were developed simultaneously in two identical chromatographic chambers. One of them was placed in the external magnetic field of 0.4 T inductivity. We proved that chelation causes a drastic change in compound lipophilicity, but all complexes did not exhibit enhanced activity as compared with the parent ligand. Also in the magnetic field the retention of some complexes changed, which means that the presence of the field influences the physicochemical properties of the compounds and their interactions with the stationary phase. Copyright © 2016 John Wiley & Sons, Ltd.

Monitoring the biodegradability of bisphenol A and its metabolic intermediates by manometric respirometry tests.

PubMed

Ferro Orozco, A M; Contreras, E M; Zaritzky, N E

2016-11-01

As a result of its wide usage in the production of polycarbonate plastics and epoxy resins, bisphenol A (BPA) is commonly detected in wastewaters. Recently, BPA became a major concern because its adverse effects as an endocrine disruptor. In this work, the biodegradation kinetics of BPA and its metabolic intermediates 4-hydroxyacetophenone (4HAP), 4-hydroxybenzaldehyde (4HB) and 4-hydroxybenzoic acid (4HBA) by BPA-acclimated activated sludge was studied using manometric respirometry (BOD) tests. For all the tested compounds, BOD curves exhibited two phases. In the first one, a fast increase of the oxygen consumption (OC) due to the active oxidation of the substrate was obtained. Then, when the substrate was exhausted, the endogenous respiration produced a slower increase of OC. A standard Monod-model with biomass growth was used to represent the OC profiles as a function of time. For all the tested compounds, a good agreement between the proposed model and the experimental data was obtained. According to their biodegradation rates, the tested compounds can be ordered as follows: BPA < 4HAP ≪ 4HB < 4HBA. Because the oxidation rate of BPA by BPA-acclimated activated sludge limits the rate of the whole biodegradation pathway, the accumulation of metabolic intermediates 4HAP, 4HB, and 4HBA would be negligible. To calculate the dissolved oxygen (DO) concentration (C) during the BOD tests, the oxygen transfer coefficient (k L a) of the BOD bottles was obtained using the sulfite method. Finally, a simple procedure to calculate the minimum DO concentration (C min ) based on BOD data was developed. Calculation results demonstrated that under the tested conditions, C values were high enough as not to be the limiting substrate for the microbial growth.

Two new Cu{sup I} compounds with zwitterionic tetrazolate ligand: In situ synthesis, crystal structures, luminescence and photocatalytic properties

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

Zhang, Jian-Yong; Xing, Yuan-Yuan; Wang, Qing-Wei

2015-12-15

Two 2D new Cu(I) coordination polymers, namely [Cu{sub 2}(mpTZ){sub 2}Br{sub 2}]·H{sub 2}O (1), and [Cu{sub 2}(mpTZ){sub 2}N{sub 3}]ClO{sub 4} (2) (mpTZ=N-methyl-4-pyridinium tetrazolate) have been synthesized under solvothermal conditions, in which the mpTZ ligands and Cu{sup I} ions were obtained through in situ [2+3] cycloaddition reaction and reduction reaction of Cu{sup II} salts, respectively. Both compounds have been structural characterized by single crystal X-ray diffraction, FT-IR, PXRD and EA. Compound 1 exhibits a 2D neutral coordination network, in which the Cu{sup I} ions are bridged by η{sub 3}−1, 2, 4-tetrazolate into 2D sheet. In compound 2, the Cu{sup I} ions aremore » linked by azide (in µ{sub 3}−1, 1, 3 bridging mode) and tetrazolate (in η{sub 3}−1, 2, 3 bridging mode) anions into 2D positively charged sheet, extended along the bc plane. Both compounds 1 and 2 exhibit intense bluish green luminescence in the solid state. Photocatalytic performances of the two compounds for the degradation of methylene blue (MB) under visible light were also investigated and the MB degradation in the presence of 1 was nearly complete (99%) after 150 min. - Graphical abstract: Two Cu{sup I}CPs have been solvothermally synthesized through the in situ [2+3] cycloaddition and metal reduction reaction. Both compounds exhibit intense luminescence and high photocatalytic degradation under visible light. - Highlights: • Two new Cu{sup I}-based CPs are solvothermally synthesized through in situ [2+3] cycloaddition reaction and metal reduction reaction. • Both compounds exhibit strong luminescence and photocatalytic degradation of methylene blue (MB) under visible light. • The MB degradation in the presence of 1 is nearly complete (99%) after 150 min.« less

Synergistic Interactions of Eugenol-tosylate and Its Congeners with Fluconazole against Candida albicans.

PubMed

Ahmad, Aijaz; Wani, Mohmmad Younus; Khan, Amber; Manzoor, Nikhat; Molepo, Julitha

2015-01-01

We previously reported the antifungal properties of a monoterpene phenol "Eugenol" against different Candida strains and have observed that the addition of methyl group to eugenol drastically increased its antimicrobial potency. Based on the results and the importance of medicinal synthetic chemistry, we synthesized eugenol-tosylate and its congeners (E1-E6) and tested their antifungal activity against different clinical fluconazole (FLC)- susceptible and FLC- resistant C. albicans isolates alone and in combination with FLC by determining fractional inhibitory concentration indices (FICIs) and isobolograms calculated from microdilution assays. Minimum inhibitory concentration (MIC) results confirmed that all the tested C. albicans strains were variably susceptible to the semi-synthetic derivatives E1-E6, with MIC values ranging from 1-62 μg/ml. The test compounds in combination with FLC exhibited either synergy (36%), additive (41%) or indifferent (23%) interactions, however, no antagonistic interactions were observed. The MICs of FLC decreased 2-9 fold when used in combination with the test compounds. Like their precursor eugenol, all the derivatives showed significant impairment of ergosterol biosynthesis in all C. albicans strains coupled with down regulation of the important ergosterol biosynthesis pathway gene-ERG11. The results were further validated by docking studies, which revealed that the inhibitors snugly fitting the active site of the target enzyme, mimicking fluconazole, may well explain their excellent inhibitory activity. Our results suggest that these compounds have a great potential as antifungals, which can be used as chemosensitizing agents with the known antifungal drugs.

Design, synthesis, and evaluation of resveratrol derivatives as Aß(₁-₄₂) aggregation inhibitors, antioxidants, and neuroprotective agents.

PubMed

Lu, Chuanjun; Guo, Yueyan; Li, Jianheng; Yao, Meicun; Liao, Qiongfeng; Xie, Zhiyong; Li, Xingshu

2012-12-15

A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM. Copyright © 2012 Elsevier Ltd. All rights reserved.

Identification of an annonaceous acetogenin mimetic, AA005, as an AMPK activator and autophagy inducer in colon cancer cells.

PubMed

Liu, Yong-Qiang; Cheng, Xin; Guo, Liang-Xia; Mao, Chan; Chen, Yi-Jie; Liu, Hai-Xia; Xiao, Qi-Cai; Jiang, Sheng; Yao, Zhu-Jun; Zhou, Guang-Biao

2012-01-01

Annonaceous acetogenins, a large family of naturally occurring polyketides isolated from various species of the plant genus Annonaceae, have been found to exhibit significant cytotoxicity against a variety of cancer cells. Previous studies showed that these compounds could act on the mitochondria complex-I and block the corresponding electron transport chain and terminate ATP production. However, more details of the mechanisms of action remain ambiguous. In this study we tested the effects of a set of mimetics of annonaceous acetogenin on some cancer cell lines, and report that among them AA005 exhibits the most potent antitumor activity. AA005 depletes ATP, activates AMP-activated protein kinase (AMPK) and inhibits mTOR complex 1 (mTORC1) signal pathway, leading to growth inhibition and autophagy of colon cancer cells. AMPK inhibitors compound C and inosine repress, while AMPK activator AICAR enhances, AA005-caused proliferation suppression and subsequent autophagy of colon cancer cells. AA005 enhances the ATP depletion and AMPK activation caused by 2-deoxyglucose, an inhibitor of mitochondrial respiration and glycolysis. AA005 also inhibits chemotherapeutic agent cisplatin-triggered up-regulation of mTOR and synergizes with this drug in suppression of proliferation and induction of apoptosis of colon cancer cells. These data indicate that AA005 is a new metabolic inhibitor which exhibits therapeutic potentials in colon cancer.

High-energy coordination polymers (CPs) exhibiting good catalytic effect on the thermal decomposition of ammonium dinitramide

NASA Astrophysics Data System (ADS)

Li, Xin; Han, Jing; Zhang, Sheng; Zhai, Lianjie; Wang, Bozhou; Yang, Qi; Wei, Qing; Xie, Gang; Chen, Sanping; Gao, Shengli

2017-09-01

High-energy coordination polymers (CPs) not only exhibit good energetic performances but also have a good catalytic effect on the thermal decomposition of energetic materials. In this contribution, two high-energy CPs Cu2(DNBT)2(CH3OH)(H2O)3·3H2O (1) and [Cu3(DDT)2(H2O)2]n (2) (H2DNBT = 3,3‧-dinitro-5,5‧-bis(1H-1,2,4-triazole and H3DDT = 4,5-bis(1H-tetrazol-5-yl)-2H-1,2,3-triazole) were synthesized and structurally characterized. Furthermore, 1 was thermos-dehydrated to produce Cu2(DNBT)2(CH3OH)(H2O)3 (1a). The thermal decomposition kinetics of 1, 1a and 2 were studied by Kissinger's method and Ozawa's method. Thermal analyses and sensitivity tests show that all compounds exhibit high thermal stability and low sensitivity for external stimuli. Meanwhile, all compounds have large positive enthalpy of formation, which are calculated as being (1067.67 ± 2.62) kJ mol-1 (1), (1464.12 ± 3.12) kJ mol-1 (1a) and (3877.82 ± 2.75) kJ mol-1 (2), respectively. The catalytic effects of 1a and 2 on the thermal decomposition of ammonium dinitramide (ADN) were also investigated.

Synthesis, evaluation and molecular docking studies of amino acid derived N-glycoconjugates as antibacterial agents.

PubMed

Baig, Noorullah; Singh, Rajnish Prakash; Chander, Subhash; Jha, Prabhat Nath; Murugesan, Sankaranarayanan; Sah, Ajay K

2015-12-01

Six amino acid derived N-glycoconjugates of d-glucose were synthesized, characterized and tested for antibacterial activity against G(+)ve (Bacillus cereus) as well as G(-)ve (Escherichia coli and Klebsiella pneumoniae) bacterial strains. All the tested compounds exhibited moderate to good antibacterial activity against these bacterial strains. The results were compared with the antibacterial activity of standard drug Chloramphenicol, where results of A5 (Tryptophan derived glycoconjugates) against E. coli and A4 (Isoleucine derived glycoconjugates) against K. pneumoniae bacterial strains are comparable with the standard drug molecule. In silico docking studies were also performed in order to understand the mode of action and binding interactions of these molecules. The docking studies revealed that, occupation of compound A5 at the ATP binding site of subunit GyrB (DNA gyrase, PDB ID: 3TTZ) via hydrophobic and hydrogen bonding interactions may be the reason for its significant in vitro antibacterial activity. Copyright © 2015 Elsevier Inc. All rights reserved.

Isolation and identification of lipopeptide antibiotics from Paenibacillus elgii B69 with inhibitory activity against methicillin-resistant Staphylococcus aureus.

PubMed

Ding, Rui; Wu, Xue-Chang; Qian, Chao-Dong; Teng, Yi; Li, Ou; Zhan, Zha-Jun; Zhao, Yu-Hua

2011-12-01

Two lipopeptide antibiotics, pelgipeptins C and D, were isolated from Paenibacillus elgii B69 strain. The molecular masses of the two compounds were both determined to be 1,086 Da. Mass-spectrometry, amino acid analysis and NMR spectroscopy indicated that pelgipeptin C was the same compound as BMY-28160, while pelgipeptin D was identified as a new antibiotic of the polypeptin family. These two peptides were active against all the tested microorganisms, including antibiotic-resistant pathogenic bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA). Time-kill assays demonstrated that pelgipeptin D exhibited rapid and effective bactericidal action against MRSA at 4×MIC. Based on acute toxicity test, the intraperitoneal LD50 value of pelgipeptin D was slightly higher than that of the structurally related antimicrobial agent polymyxin B. Pelgipeptins are highly potent antibacterial and antifungal agents, particularly against MRSA, and warrant further investigation as possible therapeutic agents for bacteria infections resistant to currently available antibiotics.

Comparative study of the antioxidant activities of some lipase-catalyzed alkyl dihydrocaffeates synthesized in ionic liquid.

PubMed

Gholivand, Somayeh; Lasekan, Ola; Tan, Chin Ping; Abas, Faridah; Wei, Leong Sze

2017-06-01

The solubility limitations of phenolic acids in many lipidic environments are now greatly improved by their enzymatic esterification in ionic liquids (ILs). Herein, four different ILs were tested for the esterification of dihydrocaffeic acid with hexanol and the best IL was selected for the synthesis of four other n-alkyl esters with different chain-lengths. The effect of alkyl chain length on the anti-oxidative properties of the resulted purified esters was investigated using β-carotene bleaching (BCB) and free radical scavenging method DPPH and compared with butylated hydroxytoluene (BHT) as reference compound. All four esters (methyl, hexyl, dodecyl and octadecyl dihydrocaffeates) exhibited relatively strong radical scavenging abilities. The scavenging activity of the test compounds was in the following order: methyl ester>hexyl ester⩾dodecyl ester>octadecyl ester>BHT while the order for the BCB anti-oxidative activity was; BHT>octadecyl ester>dodecyl ester>hexyl ester>methyl ester. Copyright © 2016 Elsevier Ltd. All rights reserved.

Exploiting the pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors.

PubMed

La Motta, Concettina; Sartini, Stefania; Mugnaini, Laura; Salerno, Silvia; Simorini, Francesca; Taliani, Sabrina; Marini, Anna Maria; Da Settimo, Federico; Lavecchia, Antonio; Novellino, Ettore; Antonioli, Luca; Fornai, Matteo; Blandizzi, Corrado; Del Tacca, Mario

2009-03-26

A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure-activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors.

Ameliorating effect of new constituents from the hooks of Uncaria rhynchophylla on scopolamine-induced memory impairment.

PubMed

Shin, Suk-Chul; Lee, Dong-Ung

2013-07-01

To study the chemical constituents and their anti-amnesic effect from the hooks of Uncaria rhynchophylla. The isolation of compounds was performed by chromatographic techniques and their structures were identified on the basis of spectral analysis. Their ameliorating effects on scopolamine-induced memory impairment in vivo using a Morris water-maze task and passive avoidance task system were evaluated. Activity-guided fractionation of the total extracts resulted in the isolation of four constituents, trans-anethole (1), p-anisaldehyde (2), estragole (3), and 3-oxo-olean-12-en-28-oic acid (4), which were found for the first time from this plant. Compound 1 exhibited a better memory enhancing effect than tacrine, a positive agent, at the same dose in the passive avoidance test and a similar property in the water-maze test, and its action may be mediated, in part, by the acetylcholine enhancing cholinergic nervous system. Copyright © 2013 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Synthesis and antifungal evaluation of PCA amide analogues.

PubMed

Qin, Chuan; Yu, Di-Ya; Zhou, Xu-Dong; Zhang, Min; Wu, Qing-Lai; Li, Jun-Kai

2018-04-18

To improve the physical and chemical properties of phenazine-1-carboxylic acid (PCA) and find higher antifungal compounds, a series of PCA amide analogues were designed and synthesized and their structures were confirmed by 1 H NMR, HRMS, and X-ray. Most compounds showed some antifungal activities in vitro. Particularly, compound 3d exhibited inhibition effect against Pyriculariaoryzac Cavgra with EC 50 value of 28.7 μM and compound 3q exhibited effect against Rhizoctonia solani with EC 50 value of 24.5 μM, more potently active than that of the positive control PCA with its EC 50 values of 37.3 μM (Pyriculariaoryzac Cavgra) and 33.2 μM (Rhizoctonia solani), respectively.

Extracellular enzymatic activities and physiological profiles of yeasts colonizing fruit trees.

PubMed

Molnárová, Jana; Vadkertiová, Renáta; Stratilová, Eva

2014-07-01

Yeasts form a significant and diverse part of the phyllosphere microbiota. Some yeasts that inhabit plants have been found to exhibit extracellular enzymatic activities. The aim of the present study was to investigate the ability of yeasts isolated from leaves, fruits, and blossoms of fruit trees cultivated in Southwest Slovakia to produce extracellular enzymes, and to discover whether the yeasts originating from these plant organs differ from each other in their physiological properties. In total, 92 strains belonging to 29 different species were tested for: extracellular protease, β-glucosidase, lipase, and polygalacturonase activities; fermentation abilities; the assimilation of xylose, saccharose and alcohols (methanol, ethanol, glycerol); and for growth in a medium with 33% glucose. The black yeast Aureobasidium pullulans showed the largest spectrum of activities of all the species tested. Almost 70% of the strains tested demonstrated some enzymatic activity, and more than 90% utilized one of the carbon compounds tested. Intraspecies variations were found for the species of the genera Cryptococcus and Pseudozyma. Interspecies differences of strains exhibiting some enzymatic activities and utilizing alcohols were also noted. The largest proportion of the yeasts exhibited β-glucosidase activity and assimilated alcohols independently of their origin. The highest number of strains positive for all activities tested was found among the yeasts associated with leaves. Yeasts isolated from blossoms assimilated saccharose and D-xylose the most frequently of all the yeasts tested. The majority of the fruit-inhabiting yeasts grew in the medium with higher osmotic pressure. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes.

PubMed

Girennavar, Basavaraj; Poulose, Shibu M; Jayaprakasha, Guddadarangavvanahally K; Bhat, Narayan G; Patil, Bhimanagouda S

2006-04-15

Bioactive compounds present in grapefruit juice are known to increase the bioavailability of certain medications by acting as potent CYP 3A4 inhibitors. An efficient technique has been developed for isolation and purification of three furocoumarins. The isolated compounds have been tested for the inhibition of human CYP 1B1 isoform using specific substrates. Grapefruit juice was extracted with ethyl acetate (EtOAc) and the dried extract was loaded onto silica gel column chromatography. Further, column fractions were subjected to preparative HPLC to obtain three compounds. The purity of these compounds was analyzed by HPLC and structures were determined by NMR studies. The identified compounds, bergamottin, 6',7'-dihydroxybergamottin (DHB), and paradisin-A, were tested for their inhibitory effects on hydroxylase and O-dealkylase activities of human cytochrome P450 isoenzymes CYP 3A4 and CYP 1B1. Paradisin-A was found to be a potent CYP 3A4 inhibitor with an IC50 of 1.2 microM followed by DHB and bergamottin. All three compounds showed a substantial inhibitory effect on CYP 3A4 below 10 microM. Inhibitory effects on CYP 1B1 exhibited a greater variation due to the specificity of substrates. Paradisin A showed an IC50 of 3.56+/-0.12 microM for the ethoxy resorufin O-dealkylase (EROD) activity and 33.56+/-0.72 microM for the benzyloxy resorufin (BROD). DHB and bergamottin showed considerable variations for EROD and BROD activities with an IC50 of 7.17 microM and 13.86 microM, respectively.

Discovery of Indeno[1,2-c]quinoline Derivatives as Potent Dual Antituberculosis and Anti-Inflammatory Agents.

PubMed

Tseng, Chih-Hua; Tung, Chun-Wei; Wu, Chen-Hsin; Tzeng, Cherng-Chyi; Chen, Yen-Hsu; Hwang, Tsong-Long; Chen, Yeh-Long

2017-06-16

A series of indeno[1,2- c ]quinoline derivatives were designed, synthesized and evaluated for their anti-tuberculosis (anti-TB) and anti-inflammatory activities. The minimum inhibitory concentration (MIC) of the newly synthesized compound was tested against Mycobacterium tuberculosis H 37 R V . Among the tested compounds, ( E )- N '-[6-(4-hydroxypiperidin-1-yl)-11 H -indeno[1,2- c ]quinolin-11-ylidene]isonicotino-hydrazide ( 12 ), exhibited significant activities against the growth of M. tuberculosis (MIC values of 0.96 μg/mL) with a potency approximately equal to that of isoniazid (INH), an anti-TB drug. Important structure features were analyzed by quantitative structure-activity relationship (QSAR) analysis to give better insights into the structure determinants for predicting the anti-TB activity. The anti-inflammatory activity was induced by superoxide anion generation and neutrophil elastase (NE) release using the formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils method. Results indicated that compound 12 demonstrated a potent dual inhibitory effect on NE release and superoxide anion generation with IC 50 values of 1.76 and 1.72 μM, respectively. Our results indicated that compound 12 is a potential lead compound for the discovery of dual anti-TB and anti-inflammatory drug candidates. In addition, 6-[3-(hydroxymethyl)piperidin-1-yl]-9-methoxy-11 H -indeno[1,2- c ]quinolin-11-one ( 4g ) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC 50 values of 0.46 and 0.68 μM, respectively, and is a potential lead compound for the discovery of anti-inflammatory drug candidates.

Graph Theoretical Analysis, In Silico Modeling, Synthesis, Anti-Microbial and Anti-TB Evaluation of Novel Quinoxaline Derivatives.

PubMed

Saravanan, Govindaraj; Selvam, Theivendren Panneer; Alagarsamy, Veerachamy; Kunjiappan, Selvaraj; Joshi, Shrinivas D; Indhumathy, Murugan; Kumar, Pandurangan Dinesh

2018-05-01

We designed to synthesize a number of 2-(2-(substituted benzylidene) hydrazinyl)-N-(4-((3-(phenyl imino)-3,4-dihydro quinoxalin-2(1 H)-ylidene)amino) phenyl) acetamide S1-S13: with the hope to obtain more active and less toxic anti-microbial and anti-TB agents. A series of novel quinoxaline Schiff bases S1-S13: were synthesized from o-phenylenediamine and oxalic acid by a multistep synthesis. In present work, we are introducing graph theoretical analysis to identify drug target. In the connection of graph theoretical analysis, we utilised KEGG database and Cytoscape software. All the title compounds were evaluated for their in-vitro anti-microbial activity by using agar well diffusion method at three different concentration levels (50, 100 and 150 µg/ml). The MIC of the compounds was also determined by agar streak dilution method. The identified study report through graph theoretical analysis were highlights that the key virulence factor for pathogenic mycobacteria is a eukaryotic-like serine/threonine protein kinase, termed PknG. All compounds were found to display significant activity against entire tested bacteria and fungi. In addition the synthesized scaffolds were screened for their in vitro antituberculosis (anti-TB) activity against Mycobacterium tuberculosis (Mtb) strain H 37 Ra using standard drug Rifampicin. A number of analogs found markedly potent anti-microbial and anti-TB activity. The relationship between the functional group variation and the biological activity of the evaluated compounds were well discussed. The observed study report was showing that the compound S6: (4-nitro substitution) exhibited most potent effective anti-microbial and anti-TB activity out of various tested compounds. © Georg Thieme Verlag KG Stuttgart · New York.

Rhipicephalus (Boophilus) microplus in the western-central region of Rio Grande do Sul, Brazil: multiresistant tick.

PubMed

Machado, Fabrício Amadori; Pivoto, Felipe Lamberti; Ferreira, Maiara Sanitá Tafner; Gregorio, Fabiano de Vargas; Vogel, Fernanda Silveira Flores; Sangioni, Luís Antônio

2014-01-01

The aim of the present study was to assess the acaricide resistance of tick populations in the western-central region of Rio Grande do Sul (Brazil), which has not previously been reported. Fifty-four cattle farms were visited and specimens of Rhipicephalus (Boophilus) microplus were collected and subjected to the adult immersion test, using nine commercial acaricides in the amidine, pyrethroid and organophosphate groups. Climatic data, including monthly precipitation, were recorded. The results from the present study demonstrated that seven of the acaricides analyzed presented mean efficacy values of less than 95%, with large differences among the products tested. Nine of them exhibited satisfactory and unsatisfactory acaricide results on at least one farm. In conclusion, the farms located in the western-central region of Rio Grande do Sul, Brazil, exhibited populations of R. (Boophilus) microplus with variable degrees of susceptibility to different acaricides, thus suggesting that resistance to the active compounds exists. It is suggested that treatment protocols should be implemented at the beginning of winter and summer, using the acaricides that showed efficacy in the adult immersion test.

Copper(II) complexes with 4-(1H-1, 2, 4-trizol-1-ylmethyl) benzoic acid: Syntheses, crystal structures and antifungal activities

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

Xiong, Pingping; Li, Jie; Bu, Huaiyu, E-mail: 7213792@qq.com

2014-07-01

Reaction of Cu(II) with an asymmetric semi-rigid organic ligand 4-(1H-1, 2, 4-trizol-1-ylmethyl) benzoic acid (HL), yielded five compounds, [Cu{sub 0.5}L]{sub n} (1), [Cu(HL){sub 2}Cl{sub 2}]{sub n} (2), [Cu(HL){sub 2}Cl{sub 2}(H{sub 2}O)] (3), [Cu(L){sub 2}(H{sub 2}O)]{sub n} (4) and [Cu(L)(phen)(HCO{sub 2})]{sub n} (5), which have been fully characterized by infrared spectroscopy, elemental analysis, and single-crystal X-ray diffraction. As for compounds 1, 2 and 5, Cu(II) is bridged through HL, Cl{sup -}, and formic acid, respectively, featuring 1D chain-structure. In compound 3, Cu(II) with hexahedral coordination sphere is assembled through hydrogen-bonding into 3D supramolecular framework. In compound 4, 1D chain units –Cu–O–Cu–O–more » are ligand-bridged into a 3D network. All compounds were tested on fungi (Fusarium graminearum, Altemaria solani, Macrophoma kawatsukai, Alternaria alternata and Colletotrichum gloeosporioides). Compound 1 exhibits a better antifungal effect compared to other compounds. An effect of structure on the antifungal activity has also been correlated. - Graphical abstract: Copper(II) compounds with 4-(1H-1, 2, 4-trizol-1-ylmethyl) benzoic acid, were prepared, structurally characterized and investigated for antifungal activity. - Highlights: • The title compounds formed by thermodynamics and thermokinetics. • The five compounds show higher inhibition percentage than reactants. • The structure effect on the antifungal activity.« less

Agelasine F from a Philippine Agelas sp. sponge exhibits in vitro antituberculosis activity.

PubMed

Mangalindan, G C; Talaue, M T; Cruz, L J; Franzblau, S G; Adams, L B; Richardson, A D; Ireland, C M; Concepcion, G P

2000-05-01

Marine sponge samples were collected in Baler, Aurora, Philippines, and extracts were tested for in vitro antituberculosis activity. An orange Agelas sp. sponge yielded the known compound, agelasine F, which inhibited some drug resistant strains of Mycobacterium tuberculosis in vitro at concentrations as low as 3.13 micrograms/ml. Activity against M. tuberculosis residing within macrophages required concentrations of 13-22 micrograms/ml which was below the IC50 for Vero cells (34 micrograms/ml).

Spectroscopic analysis of phenolic compounds for food and feed formulations

USDA-ARS?s Scientific Manuscript database

Phenolic compounds exhibit several bioactive properties including anti-oxidant, anti-microbial, and anti-fungal characteristics with potential applications as additives in functional food and feed formulations. Phenolic compounds occur in plants as secondary metabolites and may be recovered as a co-...

Anticancer potential of new steroidal thiazolidin-4-one derivatives. Mechanisms of cytotoxic action and effects on angiogenesis in vitro.

PubMed

Živković, Marijana B; Matić, Ivana Z; Rodić, Marko V; Novaković, Irena T; Krivokuća, Ana M; Sladić, Dušan M; Krstić, Natalija M

2017-11-01

The synthesis and cytotoxic activities determination of new steroidal mono- and bis(thiazolidin-4-ones) 4a-f and 5a-f have been performed. Their anticancer action was also evaluated in comparison to previously synthesized and reported corresponding steroidal thiosemicarbazones. All compounds were obtained as stereoisomeric mixtures with different configuration (E or Z) in the hydrazone moiety at the C-3 position. After several consecutive crystallizations diastereomerically pure major (E)-isomers of mono-thiazolidin-4-ones were isolated. The structure and stereochemistry of 2,4-thiazolidinedione,2-[(17-oxoandrost-4-en-3-ylidene)hydrazone] were confirmed by X-ray analysis. A pathway for the formation of thiazolidin-4-one ring was proposed. The steroid thiazolidinone derivatives examined in this study exerted selective concentration-dependent cytotoxic activities on six tested malignant cell lines. Ten out of twelve examined compounds exhibited strong cytotoxic effects on K562 cells (IC 50 values from 8.5μM to 14.9μM), eight on HeLa cells (IC 50 values ranging from 8.9μM to 15.1μM) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC 50 values from 12.7μM to 25.6μM) than cisplatin (21.5μM) which served as a positive control. Eight of these ten compounds showed high selectivity in the cytotoxic action against HeLa and K562 cancer cell lines when compared with normal human fibroblasts MRC-5 and normal human PBMC. The study of mechanisms of the anticancer activity of the two selected compounds, mono- and bis(thiazolidin-4-one) derivatives of 19-norandrost-4-ene-3,17-dione 4a and 5a, revealed that both of these compounds induced apoptosis in HeLa cells through extrinsic and intrinsic signalling pathways. Treatment of EA.hy926 cells with sub-toxic concentrations of these compounds led to the inhibition of cell connecting and sprouting, and tube formation. The synthesized compounds exhibited poor antioxidant activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficient Synthesis and Bioactivity of Novel Triazole Derivatives.

PubMed

Hu, Boyang; Zhao, Hanqing; Chen, Zili; Xu, Chen; Zhao, Jianzhuang; Zhao, Wenting

2018-03-21

Triazole pesticides are organic nitrogen-containing heterocyclic compounds, which contain 1,2,3-triazole ring. In order to develop potential glucosamine-6-phosphate synthase (GlmS) inhibitor fungicides, forty compounds of triazole derivatives were synthesized in an efficient way, thirty nine of them were new compounds. The structures of all the compounds were confirmed by high resolution mass spectrometer (HRMS), ¹H-NMR and 13 C-NMR. The fungicidal activities results based on means of mycelium growth rate method indicated that some of the compounds exhibited good fungicidal activities against P. CapasiciLeonian , Sclerotinia sclerotiorum (Lib.) de Bary, Pyricularia oryzae Cav. and Fusarium oxysporum Schl. F.sp. vasinfectum (Atk.) Snyd. & Hans. at the concentration of 50 µg/mL, especially the inhibitory rates of compounds 1-d and 1-f were over 80%. At the same time, the preliminary studies based on the Elson-Morgan method indicated that the compounds exhibited some inhibitory activity toward glucosamine-6-phosphate synthase (GlmS). These compounds will be further studied as potential antifungal lead compounds. The structure-activity relationships (SAR) were discussed in terms of the effects of the substituents on both the benzene and the sugar ring.

Design, synthesis and biological evaluation of novel ring-opened cromakalim analogues with relaxant effects on vascular and respiratory smooth muscles and as stimulators of elastin synthesis.

PubMed

Bouhedja, Mourad; Peres, Basile; Fhayli, Wassim; Ghandour, Zeinab; Boumendjel, Ahcène; Faury, Gilles; Khelili, Smail

2018-01-20

Two new series of ring-opened analogues of cromakalim bearing sulfonylurea moieties (series A: with N-unmethylated sulfonylureas, series B: with N-methylated sulfonylureas) were synthesized and tested as relaxants of vascular and respiratory smooth muscles (rat aorta and trachea, respectively). Ex vivo biological evaluations indicated that the most active compounds, belonging to series B, displayed a marked vasorelaxant activity on endothelium-intact aortic rings and the trachea. A majority of series B compounds exhibited a higher vasorelaxant activity (EC 50  < 22 μM) than that of the reference compound diazoxide (EC 50  = 24 μM). Interestingly, several tested compounds of series B also presented stronger relaxant effects on the trachea than the reference compound cromakalim (EC 50  = 124 μM), in particular compounds B4, B7 and B16 (EC 50  < 10 μM). By contrast, series A derivatives were poorly active on aortic rings (EC 50  > 57 μM for all, and EC 50  > 200 μM for a majority of them), but some of them showed an interesting relaxing effect on trachea (i.e. A15 and A33, EC 50  = 30 μM). The most potent compounds of both series, i.e. A15, A33 and B16, tested on aortic rings in the presence of glibenclamide or 80 mM KCl, suggested that they acted as voltage-gated Ca 2+ channel blockers, like verapamil, instead of being ATP-potassium channel activators, as is cromakalim, the parent molecule. Further investigations on cultured vascular smooth muscle cells showed a strong stimulating effect on elastin synthesis, especially compound B16, which was more active at 20 μM than diazoxide, a reference ATP-sensitive potassium channel activator. Taken together, our results show that the N-methylation of the sulfonylurea moieties of ring-opened cromakalim analogues led to new compounds blocking calcium-gated channels, which had a major impact on the arterial and tracheal activities as well as selectivity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives.

PubMed

Lino, Cleudiomar Inácio; Gonçalves de Souza, Igor; Borelli, Beatriz Martins; Silvério Matos, Thelma Tirone; Santos Teixeira, Iasmin Natália; Ramos, Jonas Pereira; Maria de Souza Fagundes, Elaine; de Oliveira Fernandes, Philipe; Maltarollo, Vinícius Gonçalves; Johann, Susana; de Oliveira, Renata Barbosa

2018-05-10

In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 μM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Evaluation of Clove Oil, Icaridin, and Transfluthrin for Spatial Repellent Effects in Three Tests Systems Against the Aedes aegypti (Diptera: Culicidae).

PubMed

Nentwig, G; Frohberger, S; Sonneck, R

2017-01-01

One essential oil (clove oil), one skin repellent (icaridin), and one insecticide (transfluthrin) were tested for spatial repellent effects against non-blood-fed female Aedes aegypti (L.) mosquitoes. The compounds were tested in acetone dilution series using a Y-olfactometer, a double cage system, and a double room system. All compounds exhibited spatial repellent effects at certain concentrations. Clove oil required relative high dosages to cause high effects (Y-olfactometer 6 mg, double cage 60 mg, and double room 1,200 mg). The dosages to achieve comparable results with icaridin were lower (Y-olfactometer and double cage 1 mg, and double room 150 mg). For transfluthrin, the equivalent dosages were lower again (Y-olfactometer 0.003 mg, double cage 0.03 mg, and double room 0.1 mg). Furthermore, these results reveal a correlation between the size of the test system and the effective dosage. Averaged for the three compounds, the quantity for the double room was 21-fold higher than for the double cage, which required again a 9-fold higher dosage than the Y-olfactometer. An establishment of a screening cascade is discussed starting with the Y-olfactometer (high throughput rate), followed by the double cage system and ending with the double room system as the most nearest to practical conditions. Furthermore, the testing of existing repellent products to validate the double room test, the role of sublethal dosages concerning insecticides including possible upcoming of resistance after exposure, the delayed action and impact on blood feeding and oviposition are exemplified. © The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of flavonol and its dimethoxy derivatives on paclitaxel-induced peripheral neuropathy in mice.

PubMed

Sayeli, Vijaykumar; Nadipelly, Jagan; Kadhirvelu, Parimala; Cheriyan, Binoy Varghese; Shanmugasundaram, Jaikumar; Subramanian, Viswanathan

2018-04-13

Peripheral neuropathy is the dose limiting side effect of many anticancer drugs. Flavonoids exhibit good antinociceptive effect in animal models. Their efficacy against different types of nociception has been documented. The present study investigated the effect of flavonol (3-hydroxy flavone), 3',4'-dimethoxy flavonol, 6,3'-dimethoxy flavonol, 7,2'-dimethoxy flavonol and 7,3'-dimethoxy flavonol against paclitaxel-induced peripheral neuropathy in mice. A single dose of paclitaxel (10 mg/kg, i.p.) was administered to induce peripheral neuropathy in mice and the manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later by employing Von Frey hair aesthesiometer test, acetone bubble test and hot water tail immersion test, respectively. The test compounds were prepared as a suspension in 0.5% carboxymethyl cellulose and were administered s.c. in various doses (25, 50, 100 and 200 mg/kg). The above behavioral responses were assessed prior to and 30 min after drug treatment. In addition, the effect of test compounds on proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β) and free radicals was investigated by using suitable in vitro assays. A dose-dependent attenuation of tactile allodynia, cold allodynia and thermal hyperalgesia was evidenced in mice treated with flavonol derivatives. The test compounds inhibited TNF-α, IL-1β and free radicals in a concentration-dependent manner. These results revealed that flavonol and its dimethoxy derivatives ameliorated the manifestations of paclitaxel-induced peripheral neuropathy in mice. The inhibition of proinflammatory cytokines and free radicals could contribute to this beneficial effect.

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

Ding, Ling; Zhong, Jie-Cen; Qiu, Xing-Tai

Two series of lanthanide-carboxylates, [Ln(2,2′-dtba)(2,2′-Hdtba)(EtOH)]{sub n} (I:Ln=Eu(1a), Dy(1b)) and [Ln(2,2′-dtba)(2,2′-Hdtba)(4,4′-bpy){sub 0.5}]{sub n} (II:Ln=Eu(2a), Dy(2b), Tb(2c) 2,2′-H{sub 2}dtba=2,2′-dithiodibenzoic acid, 4,4′-bpy=4,4′-bipyridine) have been synthesized under hydrothermal conditions. Interestingly, the H{sub 2}dtba organic ligand was generated by in situ S–S reaction of 2-mercaptobenzoic acid. Compounds I and II possess different 2D layered structures based on similar 1D [Ln(2,2′-dtba)]{sup +} chains. Photoluminescence studies reveal that compounds I and II exhibit strong lanthanide characteristic emission bands. Remarkably, Compounds 1b and 2a both exhibit good photocatalytic activity for degradation of Rhodamine-B (Rh-B) under the simulated sunlight irradiation. - Graphical abstract: Two series of lanthanide-carboxylates have beenmore » in situ synthesized under hydrothermal conditions. The lanthanide-carboxylates exhibit strong lanthanide characteristic emission bands and good photocatalytic activity for degradation of Rhodamine-B. - Highlights: • 2D layered lanthanide-carboxylates with 2,2′-dithiodibenzoic acid. • In situ S–S reaction of 2-mercaptobenzoic acid under hydrothermal condition. • The Emission spectra of I and II exhibit the characteristic transition of lanthanide ions. • Compounds 1b and 2a exhibit good photocatalytic activity for degradation of Rhodamine-B.« less

Phytotoxicity of vulpia residues: III. Biological activity of identified allelochemicals from Vulpia myuros.

PubMed

An, M; Pratley, J E; Haig, T

2001-02-01

Twenty compounds identified in vulpia (Vulpia myuros) residues as allelochemicals were individually and collectively tested for biological activity. Each exhibited characteristic allelochemical behavior toward the test plant, i.e., inhibition at high concentrations and stimulation or no effect at low concentrations, but individual activities varied. Allelopathins present in large quantities, such as syringic, vanillic, and succinic acids, possessed low activity, while those present in small quantities, such as catechol and hydrocinnamic acid, possessed strong inhibitory activity. The concept of a phytotoxic strength index was developed for quantifying the biological properties of each individual allelopathin in a concise, comprehensive, and meaningful format. The individual contribution of each allelopathin, assessed by comparing the phytotoxic strength index to the overall toxicity of vulpia residues, was variable according to structure and was influenced by its relative proportion in the residue. The majority of compounds possessed low or medium biological activity and contributed most of the vulpia phytotoxicity, while compounds with high biological activity were in the minority and only present at low concentration. Artificial mixtures of these pure allelochemicals also produced phytotoxicity. There were additive/synergistic effects evident in the properties of these mixtures. One such mixture, formulated from allelochemicals found in the same proportions as occur in vulpia extract, produced stronger activity than another formulated from the same set of compounds but in equal proportions. These results suggest that the exploration of the relative composition of a cluster of allelopathins may be more important than simply focusing on the identification of one or two compounds with strong biological activity and that synergism is fundamental to the understanding of allelopathy.

Detection of Aryl Hydrocarbon Receptor Activation by Some Chemicals in Food Using a Reporter Gene Assay

PubMed Central

Amakura, Yoshiaki; Tsutsumi, Tomoaki; Yoshimura, Morio; Nakamura, Masafumi; Handa, Hiroshi; Matsuda, Rieko; Teshima, Reiko; Watanabe, Takahiro

2016-01-01

The purpose of this study was to examine whether a simple bioassay used for the detection of dioxins (DXNs) could be applied to detect trace amounts of harmful DXN-like substances in food products. To identify substances with possible DXN-like activity, we assessed the ability of various compounds in the environment to bind the aryl hydrocarbon receptor (AhR) that binds specifically to DXNs. The compounds tested included 19 polycyclic aromatic hydrocarbons (PAHs), 20 PAH derivatives (nitrated, halogenated, and aminated derivatives), 23 pesticides, six amino acids, and eight amino acid metabolites. The AhR binding activities (AhR activity) of these compounds were measured using the chemical activated luciferase gene expression (CALUX) reporter gene assay system. The majority of the PAHs exhibited marked AhR activity that increased in a concentration-dependent manner. Furthermore, there was a positive link between AhR activity and the number of aromatic rings in the PAH derivatives. Conversely, there appeared to be a negative correlation between AhR activity and the number of chlorine residues present on halogenated PAH derivatives. However, there was no correlation between AhR activity and the number and position of substituents among nitrated and aminated derivatives. Among the pesticides tested, the indole-type compounds carbendazim and thiabendazole showed high levels of activity. Similarly, the indole compound tryptamine was the only amino acid metabolite to induce AhR activity. The results are useful in understanding the identification and characterization of AhR ligands in the CALUX assay. PMID:28231110

Toxicity evaluation of 2-hydroxybiphenyl and other compounds involved in studies of fossil fuels biodesulphurisation.

PubMed

Alves, L; Paixão, S M

2011-10-01

The acute toxicity of some compounds used in fossil fuels biodesulphurisation studies, on the respiration activity, was evaluated by Gordonia alkanivorans and Rhodococcus erythropolis. Moreover, the effect of 2-hydroxybiphenyl on cell growth of both strains was also determined, using batch (chronic bioassays) and continuous cultures. The IC₅₀ values obtained showed the toxicity of all the compounds tested to both strains, specially the high toxicity of 2-HBP. These results were confirmed by the chronic toxicity data. The toxicity data sets highlight for a higher sensitivity to the toxicant by the strain presenting a lower growth rate, due to a lower cells number in contact with the toxicant. Thus, microorganisms exhibiting faster generation times could be more resistant to 2-HBP accumulation during a BDS process. The physiological response of both strains to 2-HBP pulse in a steady-state continuous culture shows their potential to be used in a future fossil fuel BDS process. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis and biological evaluation of 2-arylimino-3-pyridin-thiazolineone derivatives as antibacterial agents.

PubMed

Cai, Ming-Guang; Wu, Yang; Chang, Jun

2016-05-15

With an intention to find more potent antibacterial agents, four halogen disubstituted thiazolineone derivatives (2a-d), five halogen monosubstituted thiazolineone derivatives (2e-i), and eleven 2-arylimino-3-pyridin-thiazolineone derivatives (2j-t) were synthesized and screened for their antibacterial activity, bactericidal activity, cytotoxicity, and erythrocyte hemolysis. Most of the synthesized derivatives showed antibacterial activity in inhibiting the growth of S. epidermidis and MRSA, and exhibited safety in the cytotoxicity study on the Vero cells and hemolytic activities test on healthy human erythrocytes. 2-Arylimino-3-pyridin-thiazolineone derivatives not only improved the clog P, but also showed potent antibacterial activity in inhibiting the growth of S. epidermidis and MRSA. In particularly, several compounds (2f, 2i, 2r and 2t) showed bactericidal activity, in which compound 2r displayed the best inhibitory capacity among the synthesized compounds, and further druggability research is on going. Copyright © 2016 Elsevier Ltd. All rights reserved.

Nanoliposomes for encapsulation and delivery of the potential antitumoral methyl 6-methoxy-3-(4-methoxyphenyl)-1 H-indole-2-carboxylate

NASA Astrophysics Data System (ADS)

Abreu, Ana S.; Castanheira, Elisabete Ms; Queiroz, Maria-João Rp; Ferreira, Paula Mt; Vale-Silva, Luís A.; Pinto, Eugénia

2011-08-01

A potential antitumoral fluorescent indole derivative, methyl 6-methoxy-3-(4-methoxyphenyl)-1 H-indole-2-carboxylate, was evaluated for the in vitro cell growth inhibition on three human tumor cell lines, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), and NCI-H460 (non-small cell lung cancer), after a continuous exposure of 48 h, exhibiting very low GI50 values for all the cell lines tested (0.25 to 0.33 μM). This compound was encapsulated in different nanosized liposome formulations, containing egg lecithin (Egg-PC), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylglycerol (DPPG), DSPC, cholesterol, dihexadecyl phosphate, and DSPE-PEG. Dynamic light scattering measurements showed that nanoliposomes with the encapsulated compound are generally monodisperse and with hydrodynamic diameters lower than 120 nm, good stability and zeta potential values lower than -18 mV. Dialysis experiments allowed to monitor compound diffusion through the lipid membrane, from DPPC/DPPG donor liposomes to NBD-labelled lipid/DPPC/DPPG acceptor liposomes.

Design, synthesis, and biological evaluation of prenylated chalcones as 5-LOX inhibitors.

PubMed

Reddy, Nimmanapalli P; Aparoy, Polamarasetty; Reddy, T Chandra Mohan; Achari, Chandrani; Sridhar, P Ramu; Reddanna, Pallu

2010-08-15

Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen-Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC(50) at 4 microM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI(50) at 9 microM) on breast cancer cell line, MCF-7. Copyright 2010 Elsevier Ltd. All rights reserved.

NQR Line Broadening Due to Crystal Lattice Imperfections and Its Relationship to Shock Sensitivity

NASA Astrophysics Data System (ADS)

Caulder, S. M.; Buess, M. L.; Garroway, A. N.; Miller, P. J.

2004-07-01

The hydrodynamic hot spot model is used to explain the difference between shock sensitive and shock insensitive explosives. Among the major factors that influence the shock sensitivity of energetic compounds are the quality and particle size of the energetic crystals used to formulate the cast plastic bonded explosive. As do all energetic compounds, RDX and HMX exhibit internal crystal defects the magnitude and type of which depend on the manufacturing process used to synthesize and re-crystallize the energetic compound. Nuclear Quadrupole Resonance (NQR) spectroscopy was used to determine the crystal quality of RDX, HMX and CL-20 obtained from various manufacturers. The NQR experimental results are discussed. Cast plastic bonded explosives were made using the RDX and HMX obtained from the various manufacturers and subsequently subjected to the NOL large-scale gap test (LSGT). The results of the LSGT are discussed and correlated with the NQR results. A relationship between the crystal defect density and shock initiation pressure of the plastic bonded explosive is developed and discussed.

The Impact of Hybridization on the Volatile and Sensorial Profile of Ocimum basilicum L.

PubMed Central

da Costa, Andréa Santos; Arrigoni-Blank, Maria de Fátima; da Silva, Maria Aparecida Azevedo Pereira; Alves, Mércia Freitas; Santos, Darlisson de Alexandria; Alves, Péricles Barreto; Blank, Arie Fitzgerald

2014-01-01

The aim of the present study was to investigate the volatile and sensorial profile of basil (Ocimum basilicum L.) by quantitative descriptive analysis (QDA) of the essential oil of three hybrids (“Cinnamon” × “Maria Bonita,” “Sweet Dani” × “Cinnamon,” and “Sweet Dani” × “Maria Bonita”). Twelve descriptive terms were developed by a selected panel that also generated the definition of each term and the reference samples. The data were subjected to ANOVA, Tukey's test, and principal component analysis. The hybrid “Cinnamon” × “Maria Bonita” exhibited a stronger global aroma that was less citric than the other samples. Hybridization favored the generation of novel compounds in the essential oil of the hybrid “Sweet Dani” × “Maria Bonita,” such as canfora and (E)-caryophyllene; (E)-caryophyllene also was a novel compound in the hybrid “Sweet Dani” × “Cinnamon”; this compound was not present in the essential oils of the parents. PMID:24558334

Activity of bis(7-hydroxycoumarin) Mannich bases against bovine viral diarrhoea virus.

PubMed

Ibrahim, Munjed M; Mazzei, Mauro; Delogu, Ilenia; Szabó, Róbert; Sanna, Giuseppina; Loddo, Roberta

2016-10-01

Some Mannich bases of 7-hydroxycoumarins (3-6) with piperazine or other amines bearing two secondary amine groups were prepared and tested against viruses representative of RNA families. All compounds were symmetrical and possessed two identical coumarin moieties with respect to one diamine. In the series of 7-hydroxy derivatives, 3a was endowed with a significant activity against BVDV. Then, some of these double Mannich bases were alkylated and acylated. Among the propyloxy derivatives, only 3f showed a modest activity against BVDV. Among the acyl derivatives, the p-nitrobenzoyl derivative 3i emerged as the most active compound; in this series, the p-nitrobenzoyl derivative 3j also exhibited good action against BVDV and modest activity against CVB-5. On the whole, the compounds presented here show some differences, with respect to previous studies in terms of SAR from similar Mannich bases of 7-hydroxycoumarin. Copyright © 2016 Elsevier B.V. All rights reserved.

Potential allelopathic azaphilones produced by the endophytic Chaetomium globosum TY1 inhabited in Ginkgo biloba using the one strain-many compounds method.

PubMed

Wang, Dacheng; Zhang, Yamei; Li, Xiang; Pan, Hongyu; Chang, Mengyuan; Zheng, Tianyu; Sun, Jinzhu; Qiu, Daren; Zhang, Mingzhe; Wei, Dongsheng; Qin, Jianchun

2017-03-01

On the basis of the one strain-many compounds strategy, seven azaphilones, including Chaetomugilin A (1), D (2), S (3), I (4), J (5), Q (6) and O (7), were isolated from the endophytic Chaetomium globosum TY1. Their structures were identified by NMR and HRESIMS spectrometry data. All azaphilones were evaluated for plant growth regulation using eight species of herbaceous plant seeds seedling growth bioassay, which showed the plant growth influence of the seedling. Among these compounds tested, Chaetomugilin O (7) with tetrahydrofuran exhibited higher response index and lower IC 50 values than positive control glyphosate, a broad-spectrum systemic herbicide. 1-3 also showed better or similar inhibit activity to glyphosate. The structure-allelopathic activity relationship analysis of these isolated azaphilones indicates that both tetrahydrofuran and tetrahydrofuran combine with lactones ring groups give potent inhibition of seedling growth. Chaetomugilin O and Chaetomugilin A, D, S could be used to develop natural eco-friendly herbicides.

Novel 4-Thiazolidinone Derivatives as Anti-Infective Agents: Synthesis, Characterization, and Antimicrobial Evaluation.

PubMed

Gupta, Amit; Singh, Rajendra; Sonar, Pankaj K; Saraf, Shailendra K

2016-01-01

A series of new 4-thiazolidinone derivatives was synthesized, characterized by spectral techniques, and screened for antimicrobial activity. All the compounds were evaluated against five Gram-positive bacteria, two Gram-negative bacteria, and two fungi, at concentrations of 50, 100, 200, 400, 800, and 1600 µg/mL, respectively. Minimum inhibitory concentrations of all the compounds were also determined and were found to be in the range of 100-400 µg/mL. All the compounds showed moderate-to-good antimicrobial activity. Compounds 4a [2-(4-fluoro-phenyl)-3-(4-methyl-5,6,7,8-tetrahydro-quinazolin-2-yl)-thiazolidin-4-one] and 4e [3-(4,6-dimethyl-pyrimidin-2-yl)-2-(2-methoxy-phenyl)-thiazolidin-4-one] were the most potent compounds of the series, exhibiting marked antimicrobial activity against Pseudomonas fluorescens, Staphylococcus aureus, and the fungal strains. Thus, on the basis of results obtained, it may be concluded that synthesized compounds exhibit a broad spectrum of antimicrobial activity.

Synthesis, characterization and molecular docking studies of substituted 4-coumarinylpyrano[2,3-c]pyrazole derivatives as potent antibacterial and anti-inflammatory agents.

PubMed

Chougala, Bahubali M; Samundeeswari, S; Holiyachi, Megharaja; Shastri, Lokesh A; Dodamani, Suneel; Jalalpure, Sunil; Dixit, Sheshagiri R; Joshi, Shrinivas D; Sunagar, Vinay A

2017-01-05

A green, eco-friendly and efficient protocol has been developed and synthesized a series of coumarin based pyrano[2,3-c]pyrazole derivatives (3) by multi-component reaction (MCR). Unexpected 3-coumarinyl-3-pyrazolylpropanoic acids (4) have been isolated by the reaction of compound (3) in acidic conditions. Further, intramolecular cyclization of compounds (4) leads to C 4 C 4 chromons (9) and these compounds were screened for their biological activities using array of techniques. Most of the compounds exhibited promising antibacterial activity, in particular Gram-positive bacteria. The anti-inflammatory assay was evaluated against protein denaturation as well as HRBC membrane stabilization methods and compounds exhibit excellent anti-inflammatory activity in both methods. Molecular docking study has been performed for all the synthesized compounds with S. aureus dihydropteroate synthetase (DHPS) and results obtained are quite promising. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Synthesis of isatin thiosemicarbazones derivatives: in vitro anti-cancer, DNA binding and cleavage activities.

PubMed

Ali, Amna Qasem; Teoh, Siang Guan; Salhin, Abdussalam; Eltayeb, Naser Eltaher; Khadeer Ahamed, Mohamed B; Abdul Majid, A M S

2014-05-05

New derivatives of thiosemicarbazone Schiff base with isatin moiety were synthesized L1-L6. The structures of these compounds were characterized based on the spectroscopic techniques. Compound L6 was further characterized by XRD single crystal. The interaction of these compounds with calf thymus (CT-DNA) exhibited high intrinsic binding constant (k(b)=5.03-33.00×10(5) M(-1)) for L1-L3 and L5 and (6.14-9.47×10(4) M(-1)) for L4 and L6 which reflect intercalative activity of these compounds toward CT-DNA. This result was also confirmed by the viscosity data. The electrophoresis studies reveal the higher cleavage activity of L1-L3 than L4-L6. The in vitro anti-proliferative activity of these compounds against human colon cancer cell line (HCT 116) revealed that the synthesized compounds (L3, L6 and L2) exhibited good anticancer potency. Copyright © 2014 Elsevier B.V. All rights reserved.

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

Dong, Wen-Wen; Xia, Liang; Peng, Zhen

Under solvothermal conditions, the reactions of Co{sup II}/Zn{sup II} ions with bent ligand 3-(pyridin-4-yl)-5-(pyrazin-2-yl)-1H-1,2,4-triazole (4-Hpzpt) afford two compounds {[M(4-pzpt)_2] guest}{sub n} (guest=H{sub 2}O, M=Co{sup II} (1), Zn{sup II} (2)). Both compounds are the thermally and hydrolytically robust 4-connected 3D NbO framework, which formed by double helical chains to give rise to 1D hollow nanochannel with uncoordinated nitrogens completely exposed on the pore surface. Compound 1 exhibits improved N{sub 2}, CO{sub 2} and H{sub 2} uptake capacities, while compound 2 displays the strong luminescent emission with obvious red shift. - Graphical abstract: Two 2-fold interpenetrated NbO-type MOFs with 1D nanochannel weremore » synthesized. Compound 1 exhibits improved N{sub 2}, CO{sub 2} and H{sub 2} uptake capacities, while compound 2 displays the strong fluorescent emission with obvious red shift. Display Omitted.« less

Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.

PubMed

Huang, Wenlin; Zhang, Zhongsheng; Barros-Álvarez, Ximena; Koh, Cho Yeow; Ranade, Ranae M; Gillespie, J Robert; Creason, Sharon A; Shibata, Sayaka; Verlinde, Christophe L M J; Hol, Wim G J; Buckner, Frederick S; Fan, Erkang

2016-11-29

A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC 50 s of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Polybenzimidazole compounds, polymeric media, and methods of post-polymerization modifications

DOEpatents

Klaehn, John R [Idaho Falls, ID; Peterson, Eric S [Idaho Falls, ID; Wertsching, Alan K [Idaho Falls, ID; Orme, Christopher J [Shelley, ID; Luther, Thomas A [Idaho Falls, ID; Jones, Michael G [Pocatello, ID

2007-08-21

A PBI compound includes imidazole nitrogens at least a portion of which are substituted with an organic-inorganic hybrid moiety. At least 85% of the imidazole nitrogens may be substituted. The organic-inorganic hybrid moiety may be an organosilane moiety, for example, (R)Me.sub.2SiCH.sub.2-- where R is selected from among methyl, phenyl, vinyl, and allyl. The PBI compound may exhibit similar thermal properties in comparison to the unsubstituted PBI. The PBI compound may exhibit a solubility in an organic solvent greater than the solubility of the unsubstituted PBI. The PBI compound may be included in separatory media. A substituted PBI synthesis method may include providing a parent PBI in a less than 5 wt % solvent solution. Substituting may occur at about room temperature and/or at about atmospheric pressure. Substituting may use at least 5 equivalents in relation to the imidazole nitrogens to be substituted or, preferably, about 15.

Synthesis and Anticancer Mechanism Investigation of Dual Hsp27 and Tubulin Inhibitors

PubMed Central

Zhong, Bo; Chennamaneni, Snigdha; Lama, Rati; Yi, Xin; Geldenhuys, Werner J.; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; Su, Bin

2013-01-01

Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development. PMID:23767669

Polybenzimidazole compounds

DOEpatents

Klaehn, John R.; Peterson, Eric S.; Wertsching, Alan K.; Orme, Christopher J.; Luther, Thomas A.; Jones, Michael G.

2010-08-10

A PBI compound that includes imidazole nitrogens, at least a portion of which are substituted with an organic-inorganic hybrid moiety. At least 85% of the imidazole nitrogens may be substituted. The organic-inorganic hybrid moiety may be an organosilane moiety, for example, (R)Me.sub.2SiCH.sub.2--, where R is selected from among methyl, phenyl, vinyl, and allyl. The PBI compound may exhibit similar thermal properties in comparison to the unsubstituted PBI. The PBI compound may exhibit a solubility in an organic solvent greater than the solubility of the unsubstituted PBI. The PBI compound may be included in separatory media. A substituted PBI synthesis method may include providing a parent PBI in a less than 5 wt % solvent solution. Substituting may occur at about room temperature and/or at about atmospheric pressure. Substituting may use at least five equivalents in relation to the imidazole nitrogens to be substituted or, preferably, about fifteen equivalents.

Comparison of toxicity of class-based organic chemicals to algae and fish based on discrimination of excess toxicity from baseline level.

PubMed

Li, Jin J; Tai, Hong W; Yu, Yang; Wen, Yang; Wang, Xiao H; Zhao, Yuan H

2015-07-01

Toxicity data to fish and algae were used to investigate excess toxicity between species. Results show that chemicals exhibiting excess toxicity to fish also show excess toxicity to algae for most of the compounds. This indicates that they share the same mode of action between species. Similar relationships between logKOW and toxicities to fish and algae for baseline and less inert compounds suggest that they have similar critical body residues in the two species. Differences in excess toxicity for some compounds suggest that there is a difference of physiological structure and metabolism between fish and algae. Some reactive compounds (e.g. polyamines) exhibit greater toxic effects for algae than those for fish because of relatively low bio-uptake potential of these hydrophilic compounds in fish as compared with that in algae. Esters exhibiting greater toxicity in fish than that in algae indicate that metabolism can affect the discrimination of excess toxicity from baseline level. Algae growth inhibition is a very good surrogate for fish lethality. This is not only because overall toxicity sensitivity to algae is greater than that to fish, but also the excess toxicity calculated from algal toxicity can better reflect reactivity of compounds with target molecules than fish toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Design, synthesis, and taste evaluation of a high-intensity umami-imparting oxazole-based compound.

PubMed

Amino, Yusuke; Tahara, Yu-Ki; Yamada, Kei; Nakazawa, Masakazu; Tagami, Uno; Tajima, Takaho; Kuroda, Motonaka

2017-09-01

Umami taste is imparted predominantly by monosodium glutamate (MSG) and 5'-ribonucleotides. Recently, several different classes of hydrophobic umami-imparting compounds, the structures of which are quite different from MSG, have been reported. To obtain a novel umami-imparting compound, N-cinnamoyl phenethylamine was chosen as the lead compound, and a rational structure-optimization study was conducted on the basis of the pharmacophore model of previously reported compounds. The extremely potent umami-imparting compound 2-[[[2-[(1E)-2-(1,3-benzodioxol-5-yl)ethenyl]-4-oxazolyle]methoxy]methyl]pyridine, which exhibits 27,000 times the umami taste of MSG, was found. Its terminal pyridine residue and linear structure are suggested to be responsible for its strong activity. The time taken to reach maximum taste intensity exhibited by it, as determined by the time-intensity method, is 22.0 s, whereas the maximum taste intensity of MSG occurs immediately. This distinct difference in the time-course taste profile may be due to the hydrophobicity and strong receptor affinity of the new compound.

Potential of the octanol-water partition coefficient (logP) to predict the dermal penetration behaviour of amphiphilic compounds in aqueous solutions.

PubMed

Korinth, Gintautas; Wellner, Tanja; Schaller, Karl Heinz; Drexler, Hans

2012-11-23

Aqueous amphiphilic compounds may exhibit enhanced skin penetration compared with neat compounds. Conventional models do not predict this percutaneous penetration behaviour. We investigated the potential of the octanol-water partition coefficient (logP) to predict dermal fluxes for eight compounds applied neat and as 50% aqueous solutions in diffusion cell experiments using human skin. Data for seven other compounds were accessed from literature. In total, seven glycol ethers, three alcohols, two glycols, and three other chemicals were considered. Of these 15 compounds, 10 penetrated faster through the skin as aqueous solutions than as neat compounds. The other five compounds exhibited larger fluxes as neat applications. For 13 of the 15 compounds, a consistent relationship was identified between the percutaneous penetration behaviour and the logP. Compared with the neat applications, positive logP were associated with larger fluxes for eight of the diluted compounds, and negative logP were associated with smaller fluxes for five of the diluted compounds. Our study demonstrates that decreases or enhancements in dermal penetration upon aqueous dilution can be predicted for many compounds from the sign of logP (i.e., positive or negative). This approach may be suitable as a first approximation in risk assessments of dermal exposure. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Design, synthesis, antiviral activity and mode of action of phenanthrene-containing N-heterocyclic compounds inspired by the phenanthroindolizidine alkaloid antofine.

PubMed

Yu, Xiuling; Wei, Peng; Wang, Ziwen; Liu, Yuxiu; Wang, Lizhong; Wang, Qingmin

2016-02-01

The phenanthroindolizidine alkaloid antofine and its analogues have excellent antiviral activity against tobacco mosaic virus (TMV). To simplify the structure and the synthesis of the phenanthroindolizidine alkaloid, a series of phenanthrene-containing N-heterocyclic compounds (compounds 1 to 33) were designed and synthesised, based on the intermolecular interaction of antofine and TMV RNA, and systematically evaluated for their anti-TMV activity. Most of these compounds exhibited good to reasonable anti-TMV activity. The optimum compounds 5, 12 and 21 displayed higher activity than the lead compound antofine and commercial ribavirin. Compound 12 was chosen for field trials of antiviral efficacy against TMV, and was found to exhibit better activity than control plant virus inhibitors. Compounds 5 and 12 were chosen for mode of action studies. The changes in fluorescence intensity of compounds 5 and 12 on separated TMV RNA showed that these small molecules can also bind to TMV RNA, but the mode is very different from that of antofine. The compounds combining phenanthrene and an N-heterocyclic ring could maintain the anti-TMV activity of phenanthroindolizidines, but their modes of action are different from that of antofine. The present study lays a good foundation for us to find more efficient anti-plant virus reagents. © 2015 Society of Chemical Industry.

Anti-inflammatory, anti-tumor-promoting, and cytotoxic activities of constituents of marigold (Calendula officinalis) flowers.

PubMed

Ukiya, Motohiko; Akihisa, Toshihiro; Yasukawa, Ken; Tokuda, Harukuni; Suzuki, Takashi; Kimura, Yumiko

2006-12-01

Ten oleanane-type triterpene glycosides, 1-10, including four new compounds, calendulaglycoside A 6'-O-methyl ester (2), calendulaglycoside A 6'-O-n-butyl ester (3), calendulaglycoside B 6'-O-n-butyl ester (5), and calendulaglycoside C 6'-O-n-butyl ester (8), along with five known flavonol glycosides, 11-15, were isolated from the flowers of marigold (Calendula officinalis). Upon evaluation of compounds 1-9 for inhibitory activity against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, all of the compounds, except for 1, exhibited marked anti-inflammatory activity, with ID50 values of 0.05-0.20 mg per ear. In addition, when 1-15 were evaluated against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA, compounds 1-10 exhibited moderate inhibitory effects (IC50 values of 471-487 mol ratio/32 pmol TPA). Furthermore, upon evaluation of the cytotoxic activity against human cancer cell lines in vitro in the NCI Developmental Therapeutics Program, two triterpene glycosides, 9 and 10, exhibited their most potent cytotoxic effects against colon cancer, leukemia, and melanoma cells.

Efficient Electrochemical Synthesis, Antimicrobial and Antiinflammatory Activity of 2–amino-5-substituted- 1,3,4-oxadiazole Derivatives

PubMed Central

Kumar, S.; Srivastava, D. P.

2010-01-01

An efficient electrochemical method for the preparation of 2-amino-5-substituted-1,3,4-oxadiazoles (4a-k) at platinum anode through the electrooxidation of semicarbazone (3a-k) at controlled potential electrolysis has been reported in the present study. The electrolysis was carried out in the acetic acid solvent and lithium perchlorate was used as supporting electrolyte. The products were characterized by IR,1H-NMR,13C-NMR, mass spectra and elemental analysis. The synthesized compounds were screened for their in vitro growth inhibiting activity against different strains of bacteria viz., Klebsilla penumoniae, Escherichia coli, Bassilus subtilis and Streptococcus aureus and antifungal activity against Aspergillus niger and Crysosporium pannical and results have been compared with the standard antibacterial streptomycin and antifungal griseofulvin. Compounds exhibits significant antibacterial activity and antifungal activity. Compounds 4a and g exhibited equal while 4c, d, i and j slightly less antibacterial activity than standard streptomycin. Compounds 4a and g exhibited equal while 4b, c, d, f and i displayed slightly less antifungal activity than standard griseofulvins. PMID:21218056

Design, synthesis and structure-activity relationship study of wollamide B; a new potential anti TB agent

PubMed Central

Laqua, Katja; Walkowska, Anna Maria; Cunningham, Fraser; Martinez-Martinez, Maria Santos; Cuevas-Zurita, Juan Carlos; Ballell-Pages, Lluís; Imming, Peter

2017-01-01

Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 μM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness. Among the 25 synthesized wollamides five of them showed potent activities with MICs ≤ 3.1 μM and found to be nontoxic against human HepG2 cells up to 100 μM. The results of the in vitro ADME profiling revealed the remarkable plasma stability and very good aqueous solubility of the class in general while the metabolic stability was found to be moderate to low. Of particular note, compounds 7c (MIC = 1.1 μM) and 13c (0.6 μM) that exhibited good balance of antimycobacterial activity vs. optimal pharmacokinetic properties could be used as a new lead for further development. PMID:28423019

Anti-aging activities of extracts from Tunisian medicinal halophytes and their aromatic constituents

PubMed Central

Jdey, A.; Falleh, H.; Ben Jannet, S.; Mkadmini Hammi, K.; Dauvergne, X.; Magné, C.; Ksouri, R.

2017-01-01

Six medicinal halophytes widely represented in North Africa and commonly used in traditional medicine were screened for pharmacological properties to set out new promising sources of natural ingredients for cosmetic or nutraceutical applications. Thus, Citrullus colocynthis, Cleome arabica, Daemia cordata, Haloxylon articulatum, Pituranthos scoparius and Scorzonera undulata were examined for their in vitro antioxidant (DPPH scavenging and superoxide anion-scavenging, β-carotene bleaching inhibition and iron-reducing tests), antibacterial (microdilution method, against four human pathogenic bacteria) and anti-tyrosinase activities. Besides, their aromatic composition was determined by RP-HPLC. H. articulatum shoot extracts exhibited the strongest antioxidant activity and inhibited efficiently the growth of Salmonella enterica and Escherichia coli. P. scoparius and C. arabica inhibited slightly monophenolase, whereas H. articulatum was the most efficient inhibitor of diphenolase activity. Furthermore, H. articulatum exhibited the highest aromatic content (3.4 % DW), with dopamine as the major compound. These observations suggest that shoot extract of H. articulatum, and to a lesser extent of C. arabica, could be used as antioxidant, antibiotic as well as new natural skin lightening agents. Also, possible implication of aromatic compounds in anti-tyrosinase activity is discussed. PMID:28827992

Anti-aging activities of extracts from Tunisian medicinal halophytes and their aromatic constituents.

PubMed

Jdey, A; Falleh, H; Ben Jannet, S; Mkadmini Hammi, K; Dauvergne, X; Magné, C; Ksouri, R

2017-01-01

Six medicinal halophytes widely represented in North Africa and commonly used in traditional medicine were screened for pharmacological properties to set out new promising sources of natural ingredients for cosmetic or nutraceutical applications. Thus, Citrullus colocynthis , Cleome arabica , Daemia cordata , Haloxylon articulatum , Pituranthos scoparius and Scorzonera undulata were examined for their in vitro antioxidant (DPPH scavenging and superoxide anion-scavenging, β -carotene bleaching inhibition and iron-reducing tests), antibacterial (microdilution method, against four human pathogenic bacteria) and anti-tyrosinase activities. Besides, their aromatic composition was determined by RP-HPLC. H. articulatum shoot extracts exhibited the strongest antioxidant activity and inhibited efficiently the growth of Salmonella enterica and Escherichia coli . P. scoparius and C. arabica inhibited slightly monophenolase, whereas H. articulatum was the most efficient inhibitor of diphenolase activity. Furthermore, H. articulatum exhibited the highest aromatic content (3.4 % DW), with dopamine as the major compound. These observations suggest that shoot extract of H. articulatum , and to a lesser extent of C. arabica , could be used as antioxidant, antibiotic as well as new natural skin lightening agents. Also, possible implication of aromatic compounds in anti-tyrosinase activity is discussed.

Screening for bioactivity of Mutinus elegans extracts

NASA Astrophysics Data System (ADS)

Gajendiran, A.; Cyriac, RE; Abraham, J.

2017-11-01

Mutinus elegans is a species of fungi that is commonly called as Elegant Stinkhorn. The aim of this study was to screen the crude extracts of the fungus for phytochemical analysis, antimicrobial activity, antioxidant assay and anticancer activity. Extraction of the fungal sample in Soxhlet apparatus was done with n-hexane and methanol as the solvent. Stock solutions of the crude methanol extract were prepared and used for microbiological assay. Thin layer chromatography was performed in order to determine the number of active components in n-hexane, and methanol solvent system for the fungus Mutinus elegans. Further, antioxidant assay was performed using DPPH radical scavenging assay. The fungal sample was then tested for cytotoxicity assay against MG63 osteosarcoma cell lines. The antimicrobial assay of Mutinus elegans extract exhibited activity against five pathogens. The zone of inhibition was measured with respect to standard antibiotics. Gas chromatography and Mass spectrometry (GC/MS analysis), revealed the presence of dibromo-tetradecan-1-ol-acetate, 2-myristynoyl-glycinamide, fumaric acid, and cyclohexylmethyldecyl ester compounds were presented in methanol and n-hexane extract of Mutinus elegans. The present study concludes the presence of bioactive compound in the extract which exhibited antimicrobial and antioxidant activity in Mutinus elegans.

Structure-odor relationships of linalool, linalyl acetate and their corresponding oxygenated derivatives

NASA Astrophysics Data System (ADS)

Elsharif, Shaimaa; Banerjee, Ashutosh; Buettner, Andrea

2015-10-01

Linalool 1 is an odorant that is commonly perceived as having a pleasant odor, but is also known to elicit physiological effects such as inducing calmness and enhancing sleep. However, no comprehensive studies are at hand to show which structural features are responsible for these prominent effects. Therefore, a total of six oxygenated derivatives were synthesized from both 1 and linalyl acetate 2, and were tested for their odor qualities and relative odor thresholds (OTs) in air. Linalool was found to be the most potent odorant among the investigated compounds, with an average OT of 3.2 ng/L, while the 8-hydroxylinalool derivative was the least odorous compound with an OT of 160 ng/L; 8-carboxylinalool was found to be odorless. The odorant 8-oxolinalyl acetate, which has very similar odor properties to linalool, was the most potent odorant besides linalool, exhibiting an OT of 5.9 ng/L. By comparison, 8-carboxylinalyl acetate had a similar OT (6.1 ng/L) as its corresponding 8-oxo derivative but exhibited divergent odor properties (fatty, greasy, musty). Overall, oxygenation on carbon 8 had a substantial effect on the aroma profiles of structural derivatives of linalool and linalyl acetate.

Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine▿ †‡

PubMed Central

Kumar, Sanjay; Das, Sajal Kumar; Dey, Sumanta; Maity, Pallab; Guha, Mithu; Choubey, Vinay; Panda, Gautam; Bandyopadhyay, Uday

2008-01-01

A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (KD = 12 to 20 μM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H2O2, and hydroxyl radical (·OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (ΔΨm) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of ·OH may be mainly responsible for the antimalarial effect of AASMP since ·OH scavengers such as mannitol, as well as spin trap α-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial. PMID:18025110

Anti-vRE and anti-MRSA activities of new quinolones and their synergism with commercial antibiotics. Part 2.

PubMed

Sakagami, Yoshikazu; Komemushi, Sadao; Tsukamoto, Goro; Kondo, Hirosato; Yoshikawa, Akiko; Muraoka, Osamu

2008-09-01

Anti-VRE and anti-MRSA activities of new quinolone derivatives [The two quinolone derivatives are 8- [3-[(ethylamino) methyl]-1-pyrrodinyl] -7-fluoro-9, 1-[(N-methylimino)methano]-5-oxo-5H-thiazolo[3,2-a]quinolone-4-carboxylic acid (compound A) and 7-fluoro-8-morpholino-9,1-[(N-methylimino) methanol-5-oxo-5H-thiazolo [3,2-a] quinolone-4-carboxylic acid (compound B)] and their synergism with commercial antibiotics were investigated. Compound A exhibited potent antibacterial activity against VRE and MRSA among the five new quinolone compounds tested, and showed superior activity to pefloxacin, ofloxacin and levofloxacin, which are clinically in use these days. With respect to the anti-VRE activity, compound A showed synergism with fosfomycin (FOM), and partial synergism with ampicillin (ABPC), gentaicin (GM), minocycline (MINO) and vancomycin hydrochloride (VCM). Partial synergism in anti-VRE activity was also observed between compound B and GM, MINO, FOM and VCM. Compound A also showed synergism with MINO and FOM in anti-MASA activity. Partial synergism was observed with ABPC, GM and VCM. Synergism with ABPC was not detected in anti-MRSA activity. On the other hand, the synergism of compound B with FOM, and the partial synergisms with ABPC, GM and MINO were also found against MRSA. No synergism with ABPC was found against MRSA. These results suggested that compound A and B could possibly reduce the daily administration dose of these antibiotics in the treatment of nosocomial infections, and also reduce the possibility of the occurrence of nosocomial infections caused by VRE and/or MRSA.

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

Gilchrist, Kristin H., E-mail: kgilchrist@rti.org; Lewis, Gregory F.; Gay, Elaine A.

Microelectrode arrays (MEAs) recording extracellular field potentials of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) provide a rich data set for functional assessment of drug response. The aim of this work is the development of a method for a systematic analysis of arrhythmia using MEAs, with emphasis on the development of six parameters accounting for different types of cardiomyocyte signal irregularities. We describe a software approach to carry out such analysis automatically including generation of a heat map that enables quick visualization of arrhythmic liability of compounds. We also implemented signal processing techniques for reliable extraction of the repolarization peak formore » field potential duration (FPD) measurement even from recordings with low signal to noise ratios. We measured hiPS-CM's on a 48 well MEA system with 5 minute recordings at multiple time points (0.5, 1, 2 and 4 h) after drug exposure. We evaluated concentration responses for seven compounds with a combination of hERG, QT and clinical proarrhythmia properties: Verapamil, Ranolazine, Flecainide, Amiodarone, Ouabain, Cisapride, and Terfenadine. The predictive utility of MEA parameters as surrogates of these clinical effects were examined. The beat rate and FPD results exhibited good correlations with previous MEA studies in stem cell derived cardiomyocytes and clinical data. The six-parameter arrhythmia assessment exhibited excellent predictive agreement with the known arrhythmogenic potential of the tested compounds, and holds promise as a new method to predict arrhythmic liability. - Highlights: • Six parameters describing arrhythmia were defined and measured for known compounds. • Software for efficient parameter extraction from large MEA data sets was developed. • The proposed cellular parameter set is predictive of clinical drug proarrhythmia.« less

Synthesis of 2-acylated and sulfonated 4-hydroxycoumarins: In vitro urease inhibition and molecular docking studies.

PubMed

Rashid, Umer; Rahim, Fazal; Taha, Muhammad; Arshad, Muhammad; Ullah, Hayat; Mahmood, Tariq; Ali, Muhammad

2016-06-01

Sixteen 4-hydroxycoumarin derivatives were synthesized, characterized through EI-MS and (1)H NMR and screened for urease inhibitory potential. Three compounds exhibited better urease inhibition than the standard inhibitor thiourea (IC50=21±0.11μM) while other four compounds exhibited good to moderate inhibition with IC50 values between 29.45±1.1μM and 69.53±0.9μM. Structure activity relationship was established on the basis of molecular docking studies, which helped to predict the binding interactions of the most active compounds. Copyright © 2016 Elsevier Inc. All rights reserved.

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum.

PubMed

Gomes, Marcelo N; Alcântara, Laura M; Neves, Bruno J; Melo-Filho, Cleber C; Freitas-Junior, Lucio H; Moraes, Carolina B; Ma, Rui; Franzblau, Scott G; Muratov, Eugene; Andrade, Carolina Horta

2017-06-01

Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC 50 in the range of 6.2-10.98μM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50μM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis, spectral characterization, crystal structure and molecular docking study of 2,7-diaryl-1,4-diazepan-5-ones

NASA Astrophysics Data System (ADS)

Sethuvasan, S.; Sugumar, P.; Maheshwaran, V.; Ponnuswamy, M. N.; Ponnuswamy, S.

2016-07-01

In this study, a series of variously substituted r-2,c-7-diaryl-1,4-diazepan-5-ones 9-16 have been synthesized using Schmidt rearrangement and are characterized by IR, mass and 1D & 2D NMR spectral data. The proton NMR coupling constant and estimated dihedral angles reveal that the compounds 9-16 prefer a chair conformation with equatorial orientation of alkyl and aryl groups. Single crystal X-ray structure has been solved for compounds 9 and 11 which also indicates the preference for distorted chair conformation with equatorial orientation of substituents. The compounds 9-16 have been docked with the structure of Methicillin-resistant Staphylococcus aureus (MRSA) and the results demonstrate that compound 10 is having better docking score and glide energy than others and it is comparable to co-crystal ligand. Furthermore, all the compounds have been evaluated for their antibacterial and antioxidant activities. All the compounds show moderate antibacterial activity and only 11 exhibits better activity against S. aures and Escherichia coli. The compounds 11, 13 and 14 exhibit half of the antioxidant power when compared to the BHT and the remaining compounds show moderate activity.

Hemolytic and cytotoxic properties of saponin purified from Holothuria leucospilota sea cucumber

PubMed Central

Soltani, Mozhgan; Parivar, Kazem; Baharara, Javad; Kerachian, Mohammad Amin; Asili, Javad

2014-01-01

Background: Holothuroids (sea cucumbers) are members of the phylum echinodermata, which produce saponins. Saponins exhibit a wide spectrum of pharmacological and biological activities. In this study, we isolated the crude saponins from the body wall of the dominant Iranian species of sea cucumber, Holothuria leucospilota (H. leucospilota). The purpose of this study was to confirm the presence of saponins in the Persian Gulf H. leucospilota and study the hemolytic and cytotoxic activities of these compounds. Methods: The body wall of sea cucumber was dried and powdered and the crude saponins were isolated using various solvents. The crude saponins were further purified by column chromatography using HP-20 resin. The foam test, Thin Layer Chromatography (TLC), hemolytic assay, and Fourier Transform Infrared Spectroscopy (FTIR) confirmed the presence of saponins. Cytotoxicity was analyzed using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay on A549 cells, a human lung cancer cell line. Results: The foam test, hemolytic assay, and TLC supported the presence of saponin compounds in the 80% ethanol fraction of H. leucospilota. The infrared (IR) spectrum of the extract showed hydroxyl (-OH), alkyl (C-H), ether (C-O) and ester (–C=O) absorption characteristic of teriterpenoid saponins. The C-O-C absorption indicated glycoside linkages to the sapogenins. The crude saponin extracted from sea cucumber was cytotoxic to A549 cells. Conclusion: The 80% ethanol fraction of saponin isolated from H. leucospilota exhibited hemolytic activity and offers promise as an anti-cancer candidate. PMID:26989736

Hemolytic and cytotoxic properties of saponin purified from Holothuria leucospilota sea cucumber.

PubMed

Soltani, Mozhgan; Parivar, Kazem; Baharara, Javad; Kerachian, Mohammad Amin; Asili, Javad

2014-10-01

Holothuroids (sea cucumbers) are members of the phylum echinodermata, which produce saponins. Saponins exhibit a wide spectrum of pharmacological and biological activities. In this study, we isolated the crude saponins from the body wall of the dominant Iranian species of sea cucumber, Holothuria leucospilota (H. leucospilota). The purpose of this study was to confirm the presence of saponins in the Persian Gulf H. leucospilota and study the hemolytic and cytotoxic activities of these compounds. The body wall of sea cucumber was dried and powdered and the crude saponins were isolated using various solvents. The crude saponins were further purified by column chromatography using HP-20 resin. The foam test, Thin Layer Chromatography (TLC), hemolytic assay, and Fourier Transform Infrared Spectroscopy (FTIR) confirmed the presence of saponins. Cytotoxicity was analyzed using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay on A549 cells, a human lung cancer cell line. The foam test, hemolytic assay, and TLC supported the presence of saponin compounds in the 80% ethanol fraction of H. leucospilota. The infrared (IR) spectrum of the extract showed hydroxyl (-OH), alkyl (C-H), ether (C-O) and ester (-C=O) absorption characteristic of teriterpenoid saponins. The C-O-C absorption indicated glycoside linkages to the sapogenins. The crude saponin extracted from sea cucumber was cytotoxic to A549 cells. The 80% ethanol fraction of saponin isolated from H. leucospilota exhibited hemolytic activity and offers promise as an anti-cancer candidate.

Synthesis, crystal structure, and biological evaluation of a series of phloretin derivatives.

PubMed

Wang, Li; Li, Zheng-Wei; Zhang, Wei; Xu, Rui; Gao, Fei; Liu, Yang-Feng; Li, Ya-Jun

2014-10-13

A one-step synthesis of phloretin derivatives 2-11 from phloretin in good to excellent yields is reported. Their structures were characterized by 1H-NMR, 13C-NMR and MS, and the structures of 8 and 11 were determined by X-ray diffraction analysis. A mechanism for the formation of 9-11 is proposed. Compared with the anticancer drug docetaxel, phloretin, phloretin derivatives and phlorizin exhibited moderate cytotoxicity toward the MDA-MB-231, SPC-A1, A549, MCF-7 and EC109 cell lines. Among all of the tested compounds, 7 exhibited the strongest cytotoxicity toward the five cell lines and was more active than docetaxel in MDA-MB-231 cells. Our findings suggest that these derivatives hold great promise for further development as anticancer agents.

Bacteriological profiling of diphenylureas as a novel class of antibiotics against methicillin-resistant Staphylococcus aureus

PubMed Central

Younis, Waleed; Ezzat, Hany G.; Peters, Christine E.; AbdelKhalek, Ahmed; Cooper, Bruce; Pogliano, Kit; Pogliano, Joe; Mayhoub, Abdelrahman S.; Seleem, Mohamed N.

2017-01-01

Bacterial resistance to antibiotics remains an imposing global public health challenge. Of the most serious pathogens, methicillin-resistant Staphylococcus aureus (MRSA) is problematic given strains have emerged that exhibit resistance to several antibiotic classes including β-lactams and agents of last resort such as vancomycin. New antibacterial agents composed of unique chemical scaffolds are needed to counter this public health challenge. The present study examines two synthetic diphenylurea compounds 1 and 2 that inhibit growth of clinically-relevant isolates of MRSA at concentrations as low as 4 µg/mL and are non-toxic to human colorectal cells at concentrations up to 128 μg/mL. Both compounds exhibit rapid bactericidal activity, completely eliminating a high inoculum of MRSA within four hours. MRSA mutants exhibiting resistance to 1 and 2 could not be isolated, indicating a low likelihood of rapid resistance emerging to these compounds. Bacterial cytological profiling revealed the diphenylureas exert their antibacterial activity by targeting bacterial cell wall synthesis. Both compounds demonstrate the ability to resensitize vancomycin-resistant Staphylococcus aureus to the effect of vancomycin. The present study lays the foundation for further investigation and development of diphenylurea compounds as a new class of antibacterial agents. PMID:28797064

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2.

PubMed

Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R; Janganati, Venumadhav; Dwoskin, Linda P; Crooks, Peter A

2017-12-15

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [ 3 H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [ 3 H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [ 3 H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [ 3 H]DA uptake at VMAT2, Ki changes in the nanomolar range (K i  = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K i  = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K i  = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Copyright © 2017 Elsevier Ltd. All rights reserved.

A full mass spectrum evaluation of semivolatile organic compounds measured during the Southern Oxidant and Aerosol Study in Alabama, USA, 2013

NASA Astrophysics Data System (ADS)

Holzinger, Rupert; Khan, Anwar; Misztal, Pawel; Goldstein, Allen

2016-04-01

A serial 3-stage denuder system has been developed and for the first time deployed during the Southern Oxidant and Aerosol Study (SOAS) in Centreville, Alabama, USA, for one month during the summer of 2013. Volatile organic compounds (VOCs) were collected on an activated carbon denuder and thermally desorbed to be measured with PTR-MS (PTR-TOF800, Ionicon Analytik GmbH). Comparison with a second PTR-MS instrument operated under standard conditions at the same site revealed poor recovery for the majority of the VOCs while individual species measured by the different PTR-MS systems still exhibited excellent correlation. Semivolatile organic compounds (SVOCs) in the gas phase were collected and thermally desorbed on a denuder coated with Methylsiloxane (Agilent DB-1). More than 100 SVOCs have been detected at levels in the range 0.05-3 pmmol/mol and only a few species exhibited maximum mixing ratios above 5 pmol/mol. Many of the detected species exhibited a clear diurnal profile while the concentration of some was clearly dominated by pollution events. Carboxylic acids, (oxidized) polycyclic aromatic compounds, and monoterpene oxidation products were compound groups that provided most of the mass and a typical total concentration of the measured burden of SVOCs was 5 microgram per cubic meter.

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.

Fungi treated with small chemicals exhibit increased antimicrobial activity against facultative bacterial and yeast pathogens.

PubMed

Zutz, Christoph; Bandian, Dragana; Neumayer, Bernhard; Speringer, Franz; Gorfer, Markus; Wagner, Martin; Strauss, Joseph; Rychli, Kathrin

2014-01-01

For decades, fungi have been the main source for the discovery of novel antimicrobial drugs. Recent sequencing efforts revealed a still high number of so far unknown "cryptic" secondary metabolites. The production of these metabolites is presumably epigenetically silenced under standard laboratory conditions. In this study, we investigated the effect of six small mass chemicals, of which some are known to act as epigenetic modulators, on the production of antimicrobial compounds in 54 spore forming fungi. The antimicrobial effect of fungal samples was tested against clinically facultative pathogens and multiresistant clinical isolates. In total, 30 samples of treated fungi belonging to six different genera reduced significantly growth of different test organisms compared to the untreated fungal sample (growth log reduction 0.3-4.3). For instance, the pellet of Penicillium restrictum grown in the presence of butyrate revealed significant higher antimicrobial activity against Staphylococcus (S.) aureus and multiresistant S. aureus strains and displayed no cytotoxicity against human cells, thus making it an ideal candidate for antimicrobial compound discovery. Our study shows that every presumable fungus, even well described fungi, has the potential to produce novel antimicrobial compounds and that our approach is capable of rapidly filling the pipeline for yet undiscovered antimicrobial substances.

Fungi Treated with Small Chemicals Exhibit Increased Antimicrobial Activity against Facultative Bacterial and Yeast Pathogens

PubMed Central

Zutz, Christoph; Bandian, Dragana; Neumayer, Bernhard; Speringer, Franz; Wagner, Martin; Strauss, Joseph

2014-01-01

For decades, fungi have been the main source for the discovery of novel antimicrobial drugs. Recent sequencing efforts revealed a still high number of so far unknown “cryptic” secondary metabolites. The production of these metabolites is presumably epigenetically silenced under standard laboratory conditions. In this study, we investigated the effect of six small mass chemicals, of which some are known to act as epigenetic modulators, on the production of antimicrobial compounds in 54 spore forming fungi. The antimicrobial effect of fungal samples was tested against clinically facultative pathogens and multiresistant clinical isolates. In total, 30 samples of treated fungi belonging to six different genera reduced significantly growth of different test organisms compared to the untreated fungal sample (growth log reduction 0.3–4.3). For instance, the pellet of Penicillium restrictum grown in the presence of butyrate revealed significant higher antimicrobial activity against Staphylococcus (S.) aureus and multiresistant S. aureus strains and displayed no cytotoxicity against human cells, thus making it an ideal candidate for antimicrobial compound discovery. Our study shows that every presumable fungus, even well described fungi, has the potential to produce novel antimicrobial compounds and that our approach is capable of rapidly filling the pipeline for yet undiscovered antimicrobial substances. PMID:25121102

Cytotoxic pregnane steroids from the seeds of Cipadessa baccifera (Roth.) Miq.

PubMed

Zhao, Lei; Zhang, Ping; Su, Xiao-Jie; Zhang, Bing

2017-03-01

A chemical investigation of the 80% ethanol extract of the seeds of Cipadessa baccifera (Roth.) Miq. led to the isolation of five new pregnane steroids, 17α,18,20S-trihydroxy-pregn-4-en-3,16-dione (1), 18-hydoxy-pregn-4,17(20)-trans-dien-3,16-dione (2), 3β,18-dihydroxy-pregn-5,17(20)-trans-dien-16-one (3), 2α,3β,4β,18-tetrahydroxy-pregn-5,17(20)-trans-dien-16-one (4), and 2α,3β,4β,17α,18,20S-hexahydroxy-pregn-5-en-16-one (5), along with two known compounds, 17α,20S-dihydroxy-pregn-4-en-3,16-dione (6) and 3β-hydroxy-pregn-5,17-dien-16-one (7). Structural elucidation of all the compounds was accomplished by spectral methods such as 1D and 2D NMR, IR, UV, and HRESIMS. The isolated compounds were tested in vitro for cytotoxic activities against seven tumor cell lines. As a result, pregnane-type steroids 1, 5 and 6 exhibited cytotoxicity with IC 50 values <20μM against all tested tumor cell lines except meningioma cells (BEN-MEN-1). Copyright © 2017 Elsevier B.V. All rights reserved.

A Rare Class of New Dimeric Naphthoquinones from Diospyros lotus have Multidrug Reversal and Antiproliferative Effects

PubMed Central

Rauf, Abdur; Uddin, Ghias; Siddiqui, Bina S.; Molnár, Joseph; Csonka, Ákos; Ahmad, Bashir; Szabó, Diana; Farooq, Umar; Khan, Ajmal

2015-01-01

Three new dimeric naphthoquinones, 5,4′-dihydroxy-1′-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,5′,8′-tetraone (1), 5′,8′-dihydroxy-5-methoxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (2) and 8,5′,8′-trihydroxy-6,6′-dimethyl-7,3′-binaphthyl-1,4,1′,4′-tetraone (3), were isolated from the roots of Diospyros lotus. Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR, such as HSQC, HMBS, NOESY, and J-resolved. Compounds 1–3 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein through use of the rhodamine-123 exclusion screening test on human ABCB1 gene transfected L5178Y mouse T-cell lymphoma. Compounds 1–3 were also assessed for their antiproliferative and cytotoxic effects on L5178 and L5178Y mouse T-cell lymphoma lines. Both 1 and 2 exhibited promising antiproliferative and MDR-reversing effects in a dose-dependent manner. The effects of the tested compounds on the activity of doxorubicin were observed to vary from slight antagonism to antagonism. PMID:26732580

Experimental and computational approaches of a novel methyl (2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)sulfonamido]methyl}-3-(4-chlorophenyl)prop-2-enoate: A potential antimicrobial agent and an inhibition of penicillin-binding protein

NASA Astrophysics Data System (ADS)

Murugavel, S.; Vetri velan, V.; Kannan, Damodharan; Bakthadoss, Manickam

2016-07-01

The title compound methyl(2E)-2-{[N-(2-formylphenyl) (4-methylbenzene)sulfonamido]methyl}-3-(4-chlorophenyl) prop-2-enoate (MFMSC) has been synthesized and single crystals were grown by slow evaporation solution growth technique at room temperature. Structural and vibrational spectroscopic studies were carried out by using single crystal X-ray diffraction, FT-IR and NMR spectral analysis together with DFT method using GAUSSIAN'03 software. The detailed interpretation of the vibrational spectra has been carried out by VEDA program. NBO analysis, Mulliken charge analysis, HOMO-LUMO, MEP, Global chemical reactivity descriptors and thermodynamic properties have been analyzed. The hyperpolarisability calculation reveals the present material has a reasonably good propensity for nonlinear optical activity. The obtained antimicrobial activity results indicate that the compound shows good to moderate activity against all tested bacterial and fungal pathogens. A computational study was also carried out to predict the drug-likeness and ADMET properties of the title compound. Due to the different potential biological activity of the title compound, molecular docking study is also reported and the compound might exhibit inhibitory activity against penicillin-binding protein PBP-2X.

Secondary Metabolites from the Culture of the Marine Sponge-Associated Fungi Talaromyces tratensis and Sporidesmium circinophorum.

PubMed

Buttachon, Suradet; May Zin, War War; Dethoup, Tida; Gales, Luís; Pereira, José A; Silva, Artur M S; Kijjoa, Anake

2016-06-01

Wortmin (1), meso-1,4-bis(4-methoxybenzyl)-2,3-butanediol (2), and a new isocoumarin derivative tratenopyrone (3) were isolated from the marine sponge-associated fungus Talaromyces tratensis KUFA 0091. A new diphenyl ether derivative, circinophoric acid (4), was isolated, together with the previously reported anthraquinones catenarin and physcion, the benzophenone monomethylsoluchrin, and β-ergosterol-5,8-endoperoxide, from the marine sponge-associated fungus Sporidesmium circinophorum KUFA 0043. The structures of the new compounds were established based on an extensive analysis of 1D and 2D NMR spectra, and, in the case of compounds 2-4, also by X-ray analysis. All of the isolated compounds were tested for their antibacterial activity against Gram-positive and Gram-negative bacteria, and multidrug-resistant isolates from the environment, as well as for their anti-quorum sensing based on the pigment production of Chromobacterium violaceum ATCC 31523. None of the compounds exhibited either antibacterial (MIC > 256 µg/mL) or anti-quorum sensing activities. The compounds were also inactive in the antifungal (MIC > 512 µg/mL) and cancer cell line (GI50 > 150 µM) assays. Georg Thieme Verlag KG Stuttgart · New York.

Enzymatic synthesis of 1,3-dihydroxyphenylacetoyl-sn-glycerol: Optimization by response surface methodology and evaluation of its antioxidant and antibacterial activities.

PubMed

Kharrat, Nadia; Aissa, Imen; Dgachi, Youssef; Aloui, Fatma; Chabchoub, Fakher; Bouaziz, Mohamed; Gargouri, Youssef

2017-12-01

In this study, the enzymatic synthesis of phenylacetoyl glycerol ester was carried out as a response to the increasing consumer demand for natural compounds. 1,3-dihydroxyphenylacetoyl-sn-Glycerol (1,3-di-HPA-Gly), labeled as "natural" compound with interesting biological properties, has been successfully synthesized for the first time in good yield by a direct esterification of glycerol (Gly) with p-hydroxyphenylacetic acid (p-HPA) using immobilized Candida antarctica lipase as a biocatalyst. Spectroscopic analyses of purified esters showed that the glycerol was mono- or di-esterified on the primary hydroxyl group. These compounds were evaluated for their antioxidant activity using two different tests. The glycerol di-esters (1,3-di-HPA-Gly) showed a higher antiradical capacity than that of the butyl hydroxytoluene. Furthermore, compared to the p-HPA, synthesized ester (1,3-di-HPA-Gly) exhibited the most antibacterial effect mainly against Gram + bacteria. Among synthesized esters the 1,3-di-HPA-Gly was most effective as antioxidant and antibacterial compound. These findings could be the basis for a further exploitation of the new compound, 1,3-di-HPA-Gly, as antioxidant and antibacterial active ingredient in the cosmetic and pharmaceutical fields. Copyright © 2017. Published by Elsevier Inc.

Design, Synthesis and Antifungal Activity Evaluation of New Thiazolin-4-ones as Potential Lanosterol 14α-Demethylase Inhibitors

PubMed Central

Stana, Anca; Vodnar, Dan C.; Tamaian, Radu; Pîrnău, Adrian; Vlase, Laurian; Ionuț, Ioana; Oniga, Ovidiu; Tiperciuc, Brînduşa

2017-01-01

Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with α-monochloroacetic acid or ethyl α-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR (infrared spectra), 1H NMR (proton nuclear magnetic resonance), 13C NMR (carbon nuclear magnetic resonance) and MS (mass spectrometry) data were consistent with the assigned structures. The synthesized thiazolin-4-one derivatives were tested for antifungal properties against several strains of Candida and all compounds exhibited efficient anti-Candida activity, two of them (9b and 10) being over 500-fold more active than fluconazole. Furthermore, the compounds’ lipophilicity was assessed and the compounds were subjected to in silico screening for prediction of their ADME-Tox properties (absorbtion, distribution, metabolism, excretion and toxicity). Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. The results of the in vitro antifungal activity screening, docking study and ADME-Tox prediction revealed that the synthesized compounds are potential anti-Candida agents that might act by inhibiting the fungal lanosterol 14α-demethylase and can be further optimized and developed as lead compounds. PMID:28106743

Aryloxyalkanoic Acids as Non-Covalent Modifiers of the Allosteric Properties of Hemoglobin

PubMed Central

Omar, Abdelsattar M.; Mahran, Mona A.; Ghatge, Mohini S.; Bamane, Faida H. A.; Ahmed, Mostafa H.; El-Araby, Moustafa E.; Abdulmalik, Osheiza; Safo, Martin K.

2017-01-01

Hemoglobin (Hb) modifiers that stereospecifically inhibit sickle hemoglobin polymer formation and/or allosterically increase Hb affinity for oxygen have been shown to prevent the primary pathophysiology of sickle cell disease (SCD), specifically, Hb polymerization and red blood cell sickling. Several such compounds are currently being clinically studied for the treatment of SCD. Based on the previously reported non-covalent Hb binding characteristics of substituted aryloxyalkanoic acids that exhibited antisickling properties, we designed, synthesized and evaluated 18 new compounds (KAUS II series) for enhanced antisickling activities. Surprisingly, select test compounds showed no antisickling effects or promoted erythrocyte sickling. Additionally, the compounds showed no significant effect on Hb oxygen affinity (or in some cases, even decreased the affinity for oxygen). The X-ray structure of deoxygenated Hb in complex with a prototype compound, KAUS-23, revealed that the effector bound in the central water cavity of the protein, providing atomic level explanations for the observed functional and biological activities. Although the structural modification did not lead to the anticipated biological effects, the findings provide important direction for designing candidate antisickling agents, as well as a framework for novel Hb allosteric effectors that conversely, decrease the protein affinity for oxygen for potential therapeutic use for hypoxic- and/or ischemic-related diseases. PMID:27529207

Synthesis, characterization and in silico designing of diethyl-3-methyl-5-(6-methyl-2-thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido) thiophene-2,4-dicarboxylate derivative as anti-proliferative and anti-microbial agents.

PubMed

Malani, Kalpesh; Thakkar, Sampark S; Thakur, Mukund Chandra; Ray, Arabinda; Doshi, Hiren

2016-10-01

A series of eight compounds diethyl-3-methyl-5-(6-methyl-2-thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamido) thiophene-2,4-dicarboxilate (KM10-17) analogues have been prepared by conventional methods and characterized by IR, Mass, NMR and elemental analysis. In silico docking studies on Human topoisomerase IIbeta (PDB Id: 3QX3) have been performed for all molecules (KM10-17) synthesized. The compounds were tested for in vitro anti-proliferative activity on VERO and 786-O cell lines. Out of all the synthesized compounds, KM11 &KM16 showed moderate activity on both cell lines. In vitro anti-microbial activity was also checked against Bacillus subtilis (BS), Staphylococcus aurous (SA), Pseudomonas aeruginosa (PA), Escherichia coli (EC) and Candida albicans (CA) by well diffusion method. The compound KM11 was found to have highest zone of inhibition against BS, SA, PA and EC. The molecules KM13 and KM16 exhibited good activity against CA. The compounds KM14 and KM16 indicated good zone of inhibition against BS. Copyright © 2016 Elsevier Inc. All rights reserved.

SAR study on N2,N4-disubstituted pyrimidine-2,4-diamines as effective CDK2/CDK9 inhibitors and antiproliferative agents† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ra01440j

PubMed Central

Jing, Liandong; Tang, Yanbo; Goto, Masuo; Lee, Kuo-Hsiung

2018-01-01

Cyclin-dependent kinases (CDKs) are pivotal kinases in cell cycle transition and gene transcription. A series of N2,N4-diphenylpyrimidine-2,4-diamines were previously identified as potent CDK2/CDK9 inhibitors. To explore the SAR of this structural prototype, twenty-four novel N2,N4-disubstituted pyrimidine-2,4-diamines were designed and synthesized. Among them, twenty-one compounds exhibited potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems, and the most potent CDK2 and CDK9 inhibitors, 3g and 3c, showed IC50 values of 83 nM and 65 nM respectively. Most of these compounds displayed significant inhibition against the tested tumor cell lines in the SRB assay, and in particular, remained active against the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometer analysis of compounds 2a, 2d and 3b in MDA-MB-231 cells indicated that these compounds induced cell cycle arrest in G2/M phase. Docking studies on compound 3g were performed, which provided conducive clues for further molecular optimization. PMID:29682280

Identification of Small-Molecule Frequent Hitters of Glutathione S-Transferase-Glutathione Interaction.

PubMed

Brenke, Jara K; Salmina, Elena S; Ringelstetter, Larissa; Dornauer, Scarlett; Kuzikov, Maria; Rothenaigner, Ina; Schorpp, Kenji; Giehler, Fabian; Gopalakrishnan, Jay; Kieser, Arnd; Gul, Sheraz; Tetko, Igor V; Hadian, Kamyar

2016-07-01

In high-throughput screening (HTS) campaigns, the binding of glutathione S-transferase (GST) to glutathione (GSH) is used for detection of GST-tagged proteins in protein-protein interactions or enzyme assays. However, many false-positives, so-called frequent hitters (FH), arise that either prevent GST/GSH interaction or interfere with assay signal generation or detection. To identify GST-FH compounds, we analyzed the data of five independent AlphaScreen-based screening campaigns to classify compounds that inhibit the GST/GSH interaction. We identified 53 compounds affecting GST/GSH binding but not influencing His-tag/Ni(2+)-NTA interaction and general AlphaScreen signals. The structures of these 53 experimentally identified GST-FHs were analyzed in chemoinformatic studies to categorize substructural features that promote interference with GST/GSH binding. Here, we confirmed several existing chemoinformatic filters and more importantly extended them as well as added novel filters that specify compounds with anti-GST/GSH activity. Selected compounds were also tested using different antibody-based GST detection technologies and exhibited no interference clearly demonstrating specificity toward their GST/GSH interaction. Thus, these newly described GST-FH will further contribute to the identification of FH compounds containing promiscuous substructures. The developed filters were uploaded to the OCHEM website (http://ochem.eu) and are publicly accessible for analysis of future HTS results. © 2016 Society for Laboratory Automation and Screening.

An in vitro comparative study of the antioxidant activity and SIRT1 modulation of natural compounds.

PubMed

Fusi, Jonathan; Bianchi, Sara; Daniele, Simona; Pellegrini, Silvia; Martini, Claudia; Galetta, Fabio; Giovannini, Luca; Franzoni, Ferdinando

2018-05-01

Oxidative stress arises from an imbalance between the production of free radicals and antioxidant defences. Several studies have suggested that dietary antioxidants (such as polyphenols and berberine) may counteract oxidative stress through the involvement of the Sirtuin 1/Adenosine Monophosphate-Activated Protein Kinase (SIRT1/AMPK) pathway. The aim of this study was to evaluate the direct and specific antioxidant activity of some natural compounds, as well as their ability to modulate the expression of SIRT1 and the activation of AMPK. Quercetin, tyrosol, ferulic acid, catechin, berberine and curcumin were evaluated for their specific and direct antioxidant activity with TOSC assay. Their ability to modulate SIRT1 and AMPK was assessed by immunoblotting assay, while their cytotoxicity by CellTiter-Blue Cell Viability Assay. No statistically significant decrease (p > 0.05) in the number of viable cells was found upon challenging with the natural compounds. Quercetin exhibited the highest antioxidant activity against peroxyl radical and peroxinitrate derivates, while curcumin showed the best anti-hydroxyl activity with respect to the other compounds and, most importantly, respect to the reference antioxidants. Finally, all the tested compounds significantly increased the SIRT1 expression and the activation of AMPK. Our results clearly disclose the specific antioxidant activity of these natural compounds and their ability to increase SIRT1 expression and AMPK activation. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

The potential of anti-malarial compounds derived from African medicinal plants, part I: a pharmacological evaluation of alkaloids and terpenoids

PubMed Central

2013-01-01

Traditional medicine caters for about 80% of the health care needs of many rural populations around the world, especially in developing countries. In addition, plant-derived compounds have played key roles in drug discovery. Malaria is currently a public health concern in many countries in the world due to factors such as chemotherapy faced by resistance, poor hygienic conditions, poorly managed vector control programmes and no approved vaccines. In this review, an attempt has been made to assess the value of African medicinal plants for drug discovery by discussing the anti-malarial virtue of the derived phytochemicals that have been tested by in vitro and in vivo assays. This survey was focused on pure compounds derived from African flora which have exhibited anti-malarial properties with activities ranging from “very active” to “weakly active”. However, only the compounds which showed anti-malarial activities from “very active” to “moderately active” are discussed in this review. The activity of 278 compounds, mainly alkaloids, terpenoids, flavonoids, coumarines, phenolics, polyacetylenes, xanthones, quinones, steroids, and lignans have been discussed. The first part of this review series covers the activity of 171 compounds belonging to the alkaloid and terpenoid classes. Data available in the literature indicated that African flora hold an enormous potential for the development of phytomedicines for malaria. PMID:24330395

High-throughput cardiac safety evaluation and multi-parameter arrhythmia profiling of cardiomyocytes using microelectrode arrays.

PubMed

Gilchrist, Kristin H; Lewis, Gregory F; Gay, Elaine A; Sellgren, Katelyn L; Grego, Sonia

2015-10-15

Microelectrode arrays (MEAs) recording extracellular field potentials of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) provide a rich data set for functional assessment of drug response. The aim of this work is the development of a method for a systematic analysis of arrhythmia using MEAs, with emphasis on the development of six parameters accounting for different types of cardiomyocyte signal irregularities. We describe a software approach to carry out such analysis automatically including generation of a heat map that enables quick visualization of arrhythmic liability of compounds. We also implemented signal processing techniques for reliable extraction of the repolarization peak for field potential duration (FPD) measurement even from recordings with low signal to noise ratios. We measured hiPS-CM's on a 48 well MEA system with 5minute recordings at multiple time points (0.5, 1, 2 and 4h) after drug exposure. We evaluated concentration responses for seven compounds with a combination of hERG, QT and clinical proarrhythmia properties: Verapamil, Ranolazine, Flecainide, Amiodarone, Ouabain, Cisapride, and Terfenadine. The predictive utility of MEA parameters as surrogates of these clinical effects were examined. The beat rate and FPD results exhibited good correlations with previous MEA studies in stem cell derived cardiomyocytes and clinical data. The six-parameter arrhythmia assessment exhibited excellent predictive agreement with the known arrhythmogenic potential of the tested compounds, and holds promise as a new method to predict arrhythmic liability. Copyright © 2015 Elsevier Inc. All rights reserved.

Total phenolic compounds, flavonoids, and radical scavenging activity of 21 selected tropical plants.

PubMed

Mustafa, R A; Abdul Hamid, A; Mohamed, S; Bakar, F Abu

2010-01-01

Free radical scavenging activity of 21 tropical plant extracts was evaluated using 1,1-diphenyl-2-picrylhydrazyl assay (DPPH). Total phenolic compounds and flavonoids were determined using Folin-Ciocalteu and HPLC, respectively. Results of the study revealed that all the plants tested exhibited excellent antioxidant activity with IC(50) in the range of 21.3 to 89.6 microg/mL. The most potent activity was demonstrated by Cosmos caudatus (21.3 microg/mL) and Piper betle (23.0 microg/mL) that are not significantly different than that of -tocopherol or BHA. L. inermis extract was found to consist of the highest concentration of phenolics, catechin, epicatechin, and naringenin. High content of quercetin, myricetin, and kaempferol were identified in Vitex negundo, Centella asiatica, and Sesbania grandiflora extracts, respectively. Luteolin and apigenin, on the other hand, were found in Premna cordifolia and Kaempferia galanga extracts. Strong correlation (R = 0.8613) between total phenolic compounds and total flavonoids (R = 0.8430) and that of antioxidant activity of the extracts were observed. The study revealed that phenolic, in particular flavonoids, may be the main contributors to the antioxidant activity exhibited by the plants. Potent antioxidant from natural sources is of great interest to replace the use of synthetic antioxidants. In addition, some of the plants have great potential to be used in the development of functional ingredients/foods that are currently in demand for the health benefits associated with their use.

Vertical Stratification of Peat Pore Water Dissolved Organic Matter Composition in a Peat Bog in Northern Minnesota

NASA Astrophysics Data System (ADS)

Tfaily, Malak M.; Wilson, Rachel M.; Cooper, William T.; Kostka, Joel E.; Hanson, Paul; Chanton, Jeffrey P.

2018-02-01

We characterized dissolved organic matter (DOM) composition throughout the peat column at the Marcell S1 forested bog in northern Minnesota and tested the hypothesis that redox oscillations associated with cycles of wetting and drying at the surface of the fluctuating water table correlate with increased carbon, sulfur, and nitrogen turn over. We found significant vertical stratification of DOM molecular composition and excitation-emission matrix parallel factor analysis components within the peat column. In particular, the intermediate depth zone ( 50 cm) was identified as a zone where maximum decomposition and turnover is taking place. Surface DOM was dominated by inputs from surface vegetation. The intermediate depth zone was an area of high organic matter reactivity and increased microbial activity with diagenetic formation of many unique compounds, among them polycyclic aromatic compounds that contain both nitrogen and sulfur heteroatoms. These compounds have been previously observed in coal-derived compounds and were assumed to be responsible for coal's biological activity. Biological processes triggered by redox oscillations taking place at the intermediate depth zone of the peat profile at the S1 bog are assumed to be responsible for the formation of these heteroatomic PACs in this system. Alternatively, these compounds could stem from black carbon and nitrogen derived from fires that have occurred at the site in the past. Surface and deep DOM exhibited more similar characteristics, compared to the intermediate depth zone, with the deep layer exhibiting greater input of microbially degraded organic matter than the surface suggesting that the entire peat profile consists of similar parent material at different degrees of decomposition and that lateral and vertical advection of pore water from the surface to the deeper horizons is responsible for such similarities. Our findings suggest that molecular composition of DOM in peatland pore water is dynamic and is a function of ecosystem activity, water table, redox oscillation, and pore water advection.

Vertical Stratification of Peat Pore Water Dissolved Organic Matter Composition in a Peat Bog in Northern Minnesota: Pore Water DOM composition in a peat bog

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

Tfaily, Malak M.; Wilson, Rachel M.; Cooper, William T.

We characterized dissolved organic matter (DOM) composition throughout the peat column at the Marcell S1 forested bog in northern Minnesota and tested the hypothesis that redox oscillations associated with cycles of wetting and drying at the surface of the fluctuating water table correlate with increased carbon, sulfur and nitrogen turn over. We found significant vertical stratification of DOM molecular composition and EEM-PARAFAC components within the peat column. In particular the intermediate depth zone (~ 50 cm) was identified as a zone where maximum decomposition and turnover is taking place. Surface DOM was dominated by inputs from surface vegetation. The intermediate-depthmore » zone was an area of high organic matter reactivity and increased microbial activity with diagenetic formation of many unique compounds, among them polycyclic aromatic compounds (PAC) that contain both nitrogen and sulfur heteroatoms. These compounds have been previously observed in coal-derived compounds and were assumed to be responsible for coal's biological activity. Biological processes triggered by redox oscillations taking place at the intermediate depth zone of the peat profile at the S1 bog are assumed to be responsible for the formation of these heteroatomic PACs in this system. Alternatively these compounds could stem from black carbon and nitrogen derived from fires that have occurred at the site in the past. Surface and deep DOM exhibited more similar characteristics, compared to the intermediate-depth zone, with the deep layer exhibiting greater input of microbially degraded organic matter than the surface suggesting that the entire peat profile consists of similar parent material at different degrees of decomposition and that lateral and vertical advection of pore water from the surface to the deeper horizons is responsible for such similarities. Our findings suggest that molecular composition of DOM in peatland pore water is dynamic and is a function of ecosystem activity, water table and redox oscillation and porewater advection.« less

DFT studies of the vibrational spectra of salicylic acid and related compounds

USDA-ARS?s Scientific Manuscript database

Compounds that exhibit intra- and intermolecular hydrogen bonds can have infrared and Raman spectra that show evidences of these hydrogen bonds. In modeling the vibrational spectra of such compounds, the addition of explicit hydrogen bonding species (e.g. solvent molecules) can often improve agreeme...

Isolation and identification of ingredients inducing cancer cell death from the seeds of Alpinia galanga, a Chinese spice.

PubMed

Zeng, Qiao-hui; Lu, Chuan-Li; Zhang, Xue-wu; Jiang, Jian-Guo

2015-02-01

This study was carried out to isolate ingredients from the seeds of a Chinese spice (Alpinia galangal) and to evaluate their cytotoxic activity on cancer cell lines. Isolation and purification of the phytochemical constituents were conducted using silica gel, Sephadex LH-20 and ODS columns. After extraction using 95% ethanol, the total extracts were re-extracted, resulting in petroleum ether (PE), ethyl acetate (EA) and water fractions, respectively. Activity tests showed that the EA fraction exhibited obvious (p < 0.05) protective effects on H2O2 damaged PC-12 cells at 20 μg mL(-1), and showed much higher (p < 0.05) cytotoxic activity on cancer cell lines than other fractions. Five compounds, 1'-S-1'-acetoxyeugenol acetate (I), 1'-S-1'-acetoxychavicol acetate (II), 2-propenal, 3-[4-(acetyloxy)-3-methoxyphenyl] (III), isocoronarin D (IV) and caryolane-1, 9β-diol (V), were obtained from the EA fraction and identified by HPLC, UV, MS, and NMR spectroscopic analyses. Compounds III and V were isolated from A. galangal for the first time. Moreover, compounds I, II, IV and V were the main active ingredients for inducing death of the tested cancer cells, and their IC50 values ranged from 60 to 90 μg mL(-1), indicating that these compounds possessed a wide anti-cancer capability. Therefore, A. galangal seeds could be a potential source of healthy food for tumor prevention.