Synthesis of pyrido[1,2-a]benzimidazoles and other fused imidazole derivatives with a bridgehead nitrogen atom

NASA Astrophysics Data System (ADS)

Begunov, Roman S.; Ryzvanovich, Galina A.

2013-01-01

Main methods for the synthesis of fused imidazole derivatives with a bridgehead nitrogen atom are systematically considered and summarized. The reaction mechanisms that underlie the methods for the synthesis of pyrido[1,2-a]benzimidazoles and related compounds are described. Biological properties and mechanisms of the biological activity of fused azaheterocycles are discussed. The bibliography includes 152 references.

Lipase-Catalyzed Kinetic Resolution of Novel Antifungal N-Substituted Benzimidazole Derivatives.

PubMed

Łukowska-Chojnacka, Edyta; Staniszewska, Monika; Bondaryk, Małgorzata; Maurin, Jan K; Bretner, Maria

2016-04-01

A series of new N-substituted benzimidazole derivatives was synthesized and their antifungal activity against Candida albicans was evaluated. The chemical step included synthesis of appropriate ketones containing benzimidazole ring, reduction of ketones to the racemic alcohols, and acetylation of alcohols to the esters. All benzimidazole derivatives were obtained with satisfactory yields and in relatively short times. All synthesized compounds exhibit significant antifungal activity against Candida albicans 900028 ATCC (% cell inhibition at 0.25 μg concentration > 98%). Additionally, racemic mixtures of alcohols were separated by lipase-catalyzed kinetic resolution. In the enzymatic step a transesterification reaction was applied and the influence of a lipase type and solvent on the enantioselectivity of the reaction was studied. The most selective enzymes were Novozyme SP 435 and lipase Amano AK from Pseudomonas fluorescens (E > 100). © 2016 Wiley Periodicals, Inc.

Design and Synthesis of Mannich bases as Benzimidazole Derivatives as Analgesic Agents.

PubMed

Datar, Prasanna A; Limaye, Saleel A

2015-01-01

Mannich bases were selected for 2D QSAR study to derive meaningful relationship between the structural features and analgesic activity. Using the knowledge of important features a novel series was designed to obtain improved analgesic activity. A series of novel Mannich bases 1-(N-substituted amino)methyl]-2-substituted benzimidazole derivatives were synthesized and were screened for analgesic activity. Some of these compounds showed promising analgesic activity when compared with the standard drug diclofenac sodium.

Cellular distribution, purification and electrophoretic properties of malate dehydrogenase in Trichuris ovis and inhibition by benzimidazoles and pyrimidine derivatives.

PubMed

Sanchez-Moreno, M; Ortega, J E; Valero, A

1989-12-01

High levels of malate dehydrogenase were found in Trichuris ovis. Two molecular forms of the enzyme, of different cellular location and electrophoretic pattern, were isolated and purified. The activity of soluble malate dehydrogenase was greater than that of mitochondrial malate dehydrogenase. Both forms also displayed different electrophoretic profiles in comparison with purified extracts from goat (Capra hircus) liver. Substrate concentration directly affected enzyme activity. Host and parasite malate dehydrogenase activity were both inhibited by a series of benzimidazoles and pyrimidine-derived compounds, some of which markedly reduced parasite enzyme activity, but not host enzyme activity. Percentage inhibition by some pyrimidine derivatives was greater than that produced by benzimidazoles.

Recent Development of Benzimidazole-Containing Antibacterial Agents.

PubMed

Song, Di; Ma, Shutao

2016-04-05

Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole-based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In vitro activity of new N-benzyl-1H-benzimidazol-2-amine derivatives against cutaneous, mucocutaneous and visceral Leishmania species.

PubMed

Nieto-Meneses, Rocío; Castillo, Rafael; Hernández-Campos, Alicia; Maldonado-Rangel, Armando; Matius-Ruiz, Jeferson B; Trejo-Soto, Pedro Josué; Nogueda-Torres, Benjamín; Dea-Ayuela, Ma Auxiliadora; Bolás-Fernández, Francisco; Méndez-Cuesta, Carlos; Yépez-Mulia, Lilián

2018-01-01

The identification of specific therapeutic targets and the development of new drugs against leishmaniasis are urgently needed, since chemotherapy currently available for its treatment has several problems including many adverse side effects. In an effort to develop new antileishmanial drugs, in the present study a series of 28 N-benzyl-1H-benzimidazol-2-amine derivatives was synthesized and evaluated in vitro against Leishmania mexicana promastigotes. Compounds 7 and 8 with the highest antileishmanial activity (micromolar) and lower cytotoxicity than miltefosine and amphotericin B were selected to evaluate their activity against L. braziliensis 9and L. donovani, species causative of mucocutaneous and visceral leishmaniasis, respectively. Compound 7 showed significantly higher activity against L. braziliensis promastigotes than compound 8 and slightly lower than miltefosine. Compounds 7 and 8 had IC 50 values in the micromolar range against the amastigote of L. mexicana and L. braziliensis. However, both compounds did not show better activity against L. donovani than miltefosine. Compound 8 showed the highest SI against both parasite stages of L. mexicana. In addition, compound 8 inhibited 68.27% the activity of recombinant L. mexicana arginase (LmARG), a therapeutic target for the treatment of leishmaniasis. Docking studies were also performed in order to establish the possible mechanism of action by which this compound exerts its inhibitory effect. Compound 8 shows promising potential for the development of more potent antileishmanial benzimidazole derivatives. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis and exploration of QSAR model of 2-methyl-3-[2-(2-methylprop-1-en-1-yl)-1H-benzimidazol-1-yl]pyrimido[1,2-a]benzimidazol-4(3H)-one as potential antibacterial agents.

PubMed

Sharma, Pratibha; Kumar, Ashok; Sharma, Manisha; Singh, Jitendra; Bandyopadhyay, Prabal; Sathe, Manisha; Kaushik, M P

2012-04-01

Present communication deals with the synthesis of novel 2-methyl-3-[2-(2-methylprop-1-en-1-yl)-1H-benzimidazol-1-yl]pyrimido[1,2-a]benzimidazol-4(3H)-one derivatives under phase transfer catalysis (PTC) conditions using benzyl triethyl ammonium chloride (BTEAC) as PTC. It also elicits the studies on in vitro antimicrobial evaluation of synthesized compounds against a representative genera of gram-negative and gram-positive bacteria i.e., Bacillus subtilis, Staphylococcus aureus, Pseudomonas diminuta and Escherichia coli. All the compounds have been found to manifest profound antimicrobial activity. Moreover, extensive quantitative structure-activity relationship (QSAR) studies have been performed to deduce a correlation between molecular descriptors under consideration and the elicited biological activity. A tri-parametric QSAR model has been generated upon rigorous statistical treatment.

Comparison of Conventional and Microwave-assisted Synthesis of Benzimidazole Derivative from Citronellal in Kaffir lime oil (Citrus hystrix DC.)

NASA Astrophysics Data System (ADS)

Warsito, W.; Noorhamdani, A. S.; Suratmo; Dwi Sapri, R.; Alkaroma, D.; Azhar, A. Z.

2018-04-01

Simple method has been used for the synthesis of benzimidazole derivative from citronellal in kaffir lime oil under microwave irradiation. These compounds were synthesized also by conventional heating for comparison. In addtion, microwave-assited synthesis was also compared between using to dichloromethane and methanol solvents with variation of reaction time for 30 to 70 minutes and 4 to 12 h for conventional heating. The 2-citronellyl benzimidazole compound synthesized were characterised by FT-IR, GC-MS, 1H and 13C NMR spectroscopy. Comparison between conventional and microwave-assisted synthesis was done by comparing between correlation of reaction time and percentage yield. The time optimum of microwave-assisted and conventional synthesis using dichloromethane solvent respectively at 60 minutes (yield 19.23%) and 8 hours (yield 11.54%). In addition, microwave-assited synthesis increasing 157.81 times compared by conventional heating. While using methanol solvent tends to increase linearly however the percentage of yield only 0.77 times of synthesis using dichloromethane solvent.

Structure of HIV-1 nonnucleoside reverse transcriptase inhibitors derivatives of N-benzyl-benzimidazole with different substituents in position 4

NASA Astrophysics Data System (ADS)

Ziółkowska, Natasza E.; Michejda, Christopher J.; Bujacz, Grzegorz D.

2010-01-01

The constant development of new drugs against HIV-1 is necessary due to global expansion of AIDS and HIV-1 drug resistance. Nonnucleoside reverse transcriptase inhibitors of HIV-1 (NNRTIs) are potentially effective and nontoxic drugs in AIDS therapy. The crystal structures of six nonnucleoside inhibitors of HIV-1 reverse transcriptase (RT) derivatives of N-benzyl-benzimidazole are reported here. The investigated compounds belong to the group of so called "butterfly like" inhibitors with characteristic two π-electron moieties with an angled orientation. The structural data show the influence of the substituents of the benzimidazole ring on the geometry of the molecule and correlation between the structure of the inhibitor and its biological activity.

2-Aryl benzimidazoles: Synthesis, In vitro α-amylase inhibitory activity, and molecular docking study.

PubMed

Adegboye, Akande Akinsola; Khan, Khalid Mohammed; Salar, Uzma; Aboaba, Sherifat Adeyinka; Kanwal; Chigurupati, Sridevi; Fatima, Itrat; Taha, Mohammad; Wadood, Abdul; Mohammad, Jahidul Isalm; Khan, Huma; Perveen, Shahnaz

2018-04-25

Despite of many diverse biological activities exhibited by benzimidazole scaffold, it is rarely explored for the α-amylase inhibitory activity. For that purpose, 2-aryl benzimidazole derivatives 1-45 were synthesized and screened for in vitro α-amylase inhibitory activity. Structures of all synthetic compounds were deduced by various spectroscopic techniques. All compounds revealed inhibition potential with IC 50 values of 1.48 ± 0.38-2.99 ± 0.14 μM, when compared to the standard acarbose (IC 50  = 1.46 ± 0.26 μM). Limited SAR suggested that the variation in the inhibitory activities of the compounds are the result of different substitutions on aryl ring. In order to rationalize the binding interactions of most active compounds with the active site of α-amylase enzyme, in silico study was conducted. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Antibacterial activity of head-to-head bis-benzimidazoles.

PubMed

Moreira, Joao B; Mann, John; Neidle, Stephen; McHugh, Timothy D; Taylor, Peter W

2013-10-01

Symmetric bis-benzimidazole (BBZ) conjugates were profiled for activity against a range of Gram-positive and Gram-negative bacteria. para-Substituted ethoxy, amino and methoxy derivatives displayed potent bacteriostatic activity against meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, streptococci and Listeria monocytogenes. Moderate to good activity was also found against mycobacteria; two compounds were strongly active against logarithmic phase and hypoxia-induced latent Mycobacterium tuberculosis. No compound displayed significant activity towards Gram-negative bacteria. Only high concentrations of antibacterial BBZs showed cytotoxic effects towards fibroblasts, and the most active compound was well tolerated by zebrafish embryos. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Effect of substituted benzimidazoles on acid secretion in isolated and enriched guinea pig parietal cells.

PubMed Central

Sewing, K F; Harms, P; Schulz, G; Hannemann, H

1983-01-01

The inhibitory effect of the three benzimidazole derivatives timoprazole, picoprazole, and omeprazole on histamine and dbcAMP stimulated 14C-aminopyrine accumulation (= H+ secretion) has been studied in isolated and enriched guinea-pig parietal cells. All compounds tested inhibited H+ secretion in a concentration dependent manner with IC50 values of 8.5 +/- 1.9 mumol/l for timoprazole, 3.9 +/- 0.7 mumol/l for picoprazole, and 0.13 +/- 0.03 mumol/l for omeprazole. The IC50 of timoprazole, when dbcAMP was used as a stimulus, did not differ significantly from that of histamine stimulation. The type of inhibition was of a non-competitive nature. The full acid response to histamine after temporary exposure of the cells to the benzimidazoles could be restored by washing the cells twice; this suggests that the inhibition is reversible. The data - among others - indicate that the properties of the benzimidazoles described here would allow these compounds to be used as effective antisecretagogues. PMID:6303916

Synthesis, crystal structure, spectroscopic characterization, Hirshfeld surface analysis, and DFT calculations of 1,4-dimethyl-2-oxo-pyrimido[1,2-a]benzimidazole hydrate

NASA Astrophysics Data System (ADS)

El Bakri, Youness; Anouar, El Hassane; Ramli, Youssef; Essassi, El Mokhtar; Mague, Joel T.

2018-01-01

Imidazopyrimidine derivatives are organic synthesized compounds with a pyrimido[1,2-a]benzimidazole as basic skeleton. They are known for their various biological properties and as an important class of compounds in medicinal chemistry. A new 1,4-dimethyl-2-oxo-pyrimido[1,2-a]benzimidazole hydrate derivative of the tilted group has been synthesized and characterized by spectroscopic techniques NMR and FT-IR; and by a single crystal X-ray diffraction. The X-ray results showed that the tricyclic core of the title compound, C12H11N3O·H2O, is almost planar. The molecules stack along the a-axis direction in head-to- tail fashion through π-stacking interactions involving all three rings. The stacks are tied together by direct Csbnd H⋯O hydrogen bonds and by Osbnd H⋯O, Osbnd N⋯N and Csbnd H⋯O hydrogen bonds with the lattice water. DFT calculations at B3LYP/6-311++G(d,p) in gas phase an polarizable continuum model have been carried out to predict the spectral and geometrical data of the tilted compound. The obtained results showed relatively good correlations between the predicted and experimental data with correlation coefficients higher than 98%.

QSAR Analysis of 2-Amino or 2-Methyl-1-Substituted Benzimidazoles Against Pseudomonas aeruginosa

PubMed Central

Podunavac-Kuzmanović, Sanja O.; Cvetković, Dragoljub D.; Barna, Dijana J.

2009-01-01

A set of benzimidazole derivatives were tested for their inhibitory activities against the Gram-negative bacterium Pseudomonas aeruginosa and minimum inhibitory concentrations were determined for all the compounds. Quantitative structure activity relationship (QSAR) analysis was applied to fourteen of the abovementioned derivatives using a combination of various physicochemical, steric, electronic, and structural molecular descriptors. A multiple linear regression (MLR) procedure was used to model the relationships between molecular descriptors and the antibacterial activity of the benzimidazole derivatives. The stepwise regression method was used to derive the most significant models as a calibration model for predicting the inhibitory activity of this class of molecules. The best QSAR models were further validated by a leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. To confirm the predictive power of the models, an external set of molecules was used. High agreement between experimental and predicted inhibitory values, obtained in the validation procedure, indicated the good quality of the derived QSAR models. PMID:19468332

α-Amino Acid Derived Benzimidazole-Linked Rhodamines: A Case of Substitution Effect at the Amino Acid Site toward Spiro Ring Opening for Selective Sensing of Al3+ Ions.

PubMed

Majumdar, Anupam; Mondal, Subhendu; Daniliuc, Constantin G; Sahu, Debashis; Ganguly, Bishwajit; Ghosh, Sourav; Ghosh, Utpal; Ghosh, Kumaresh

2017-08-07

α-Amino acid derived benzimidazole-linked rhodamines have been synthesized, and their metal ion sensing properties have been evaluated. Experimentally, l-valine- and l-phenylglycine-derived benzimidazole-based rhodamines 1 and 2 selectively recognize Al 3+ ion in aqueous CH 3 CN (CH 3 CN/H 2 O 4/1 v/v, 10 mM tris HCl buffer, pH 7.0) over the other cations by exhibiting color and "turn-on" emission changes. In contrast, glycine-derived benzimidazole 3 remains silent in the recognition event and emphasizes the role of α-substitution of amino acid undertaken in the design. The fact has been addressed on the basis of the single-crystal X-ray structures and theoretical calculations. Moreover, pink 1·Al 3+ and 2·Al 3+ ensembles selectively sensed F - ions over other halides through a discharge of color. Importantly, compounds 1 and 2 are cell permeable and have been used as imaging reagents for the detection of Al 3+ uptake in human lung carcinoma cell line A549.

Synthesis and Tuberculostatic Activity Evaluation of Novel Benzazoles with Alkyl, Cycloalkyl or Pyridine Moiety.

PubMed

Krause, Malwina; Foks, Henryk; Augustynowicz-Kopeć, Ewa; Napiórkowska, Agnieszka; Szczesio, Małgorzata; Gobis, Katarzyna

2018-04-23

Compounds possessing benzimidazole system exhibit significant antituberculous activity. In order to examine how structure modifications affect tuberculostatic activity, a series of benzazole derivatives were synthesized and screened for their antitubercular activity. The compounds 1 ⁻ 20 were obtained by the reaction between o -diamine, o -aminophenol, or o -aminothiophenol with carboxylic acids or thioamides. The newly synthesized compounds were characterized by IR, ¹H-NMR, 13 C-NMR spectra, and elemental analysis. Synthesized benzazoles were evaluated for their tuberculostatic activity toward Mycobacterium tuberculosis strains. Quantum chemical calculations were performed to study the molecular geometry and the electronic structure of benzimidazoles GK-151B, 4 , 6 , and benzoxazole 11 , using the Gaussian 03W software (Gaussian, Inc., Wallingford, CT, USA). Three-dimensional structure of benzimidazoles 1 ⁻ 3 , MC-9, and GK-151B was determined by ab initio calculation using Gamess-US software. The activity of the received benzimidazoles was moderate or good. All of the benzoxazoles and benzothiazoles demonstrated much lower activity. Benzoxazoles were less active by about 50 times, and benzothiazole by 100 times than the benzimidazole analogs. Quantum chemical calculations showed differences in the distribution of electrostatic potential in the benzazole system of benzimidazoles and benzoxazoles. Three-dimensional structure calculations revealed how the parity of the alkyl substituent at the C2 position impacts the activity. Benzimidazole system is essential for the antituberculosis activity that is associated with the presence of the imine nitrogen atom in N-1 position. Its replacement by an oxygen or sulfur atom results in a decrease of the activity. The parity of the alkyl substituent at the C-2 position also modifies the activity.

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

PubMed

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

2017-06-01

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

Facile synthesis, structural elucidation and spectral analysis of pyrrole 4-imidazole derivatives

NASA Astrophysics Data System (ADS)

Singh, R. N.; Rawat, Poonam; Baboo, Vikas

2015-12-01

In this work pyrrole 4-imidazole derivatives (3A-3D): benzimidazoles and pyrrole 4-imidazoline have been synthesized by condensation, cyclization and oxidation of ethyl 4-formyl-3,5-dimethyl-1H-pyrrole carboxylate and phenylene diamine derivatives/ethylene diamine. The structure of these biheterocyclic compounds have been derived by elemental and spectroscopic - IR, UV, MS, 1H and 13C NMR analysis as well as theoretical study. The static first hyperpolarizability, β0 values for pyrrole 4-imidazole derivatives, (3A-3D) have been calculated as 10.901 × 10-31, 19.607 × 10-31, 40.323 × 10-31, 5.686 × 10-31 esu, respectively. The gradual increase in β0 value of synthesized pyrrole-benzimidazole derivatives from 3A to 3C is due to addition of acceptors -Cl atom in 3B to -NO2 group in 3C on benzimidazole side. The experimental absorption spectra found to be in UV region and the high β0 values show that the synthesized pyrrole-imidazoles are suitable as non-linear optical (NLO) materials.

Virus-directed enzyme prodrug therapy and the assessment of the cytotoxic impact of some benzimidazole derivatives.

PubMed

Szewczuk, Michał; Boguszewska, Karolina; Żebrowska, Marta; Balcerczak, Ewa; Stasiak, Marta; Świątkowska, Maria; Błaszczak-Świątkiewicz, Katarzyna

2017-07-01

Virus-directed enzyme prodrug therapy is one of the major strategy of increasing cytotoxicity of bioreductive agents. This research intended to examine new selected benzimidazole derivatives as a substrate for nitroreductase, the enzyme involved in nitroreduction which is responsible to the production of cytotoxic metabolites. In this way, the selectivity and strength of cytotoxicity can be raised. The effect of benzimidazoles on virus transfected cells and non-virus transfected cells A549 cell line was established by Annexin V + propidium iodide test, western blot, and polymerase chain reaction analysis of specific pro- and anti-apoptotic proteins in the corresponding gene expression and additionally nitroreductase gene expression. Our results proved the pro-apoptotic properties of all tested compounds in normoxia and hypoxia, especially according to virused A549 cells where the time of exposition was reduced from 48 to 4 h. In this shorten period of time, the strongest activity was shown by N-oxide compounds with nitro-groups. The apoptosis was confirmed by generation of BAX gene and protein and reduction of BCL2 gene and protein.

Benzimidazoles as new scaffold of sirtuin inhibitors: green synthesis, in vitro studies, molecular docking analysis and evaluation of their anti-cancer properties.

PubMed

Yoon, Yeong Keng; Ali, Mohamed Ashraf; Wei, Ang Chee; Shirazi, Amir Nasrolahi; Parang, Keykavous; Choon, Tan Soo

2014-08-18

Two series of novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. Among the newly synthesized compounds, compound 4j displayed the best inhibitory activity for SIRT1 (IC50 = 54.21 μM) as well as for SIRT2 (IC50 = 26.85 μM). Cell proliferation assay showed that compound 4j possessed good antitumor activity against three different types of cancer cells derived from colon (HCT-116), breast (MDA-MB-468) and blood-leukemia (CCRF-CEM) with cell viability of 40.0%, 53.2% and 27.2% respectively at 50 μM. Docking analysis of representative compound 4j into SIRT2 indicated that the interaction with receptor was primarily due to hydrogen bonding and π-π stacking interactions. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Nonpeptidic angiotensin II AT₁ receptor antagonists derived from 6-substituted aminocarbonyl and acylamino benzimidazoles.

PubMed

Zhang, Jun; Wang, Jin-Liang; Yu, Wei-Fa; Zhou, Zhi-Ming; Tao, Wen-Chang; Wang, Yi-Cheng; Xue, Wei-Zhe; Xu, Di; Hao, Li-Ping; Han, Xiao-Feng; Fei, Fan; Liu, Ting; Liang, Ai-Hua

2013-11-01

Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT₁ receptor antagonists. Compounds 6f, 6g, 11e, 11f, 11g, and 12 showed nanomolar AT₁ receptor binding affinity and high AT₁ receptor selectivity over AT₂ receptor in a preliminary pharmacological evaluation. Among them, the two most active compounds 6f (AT₁ IC₅₀ = 3 nM, AT₂ IC₅₀ > 10,000 nM, PA₂ = 8.51) and 11g (AT₁ IC₅₀ = 0.1 nM, AT₂ IC₅₀ = 149 nM, PA₂ = 8.43) exhibited good antagonistic activity in isolated rabbit aortic strip functional assay. In addition, they were orally active AT₁ receptor antagonists in spontaneous hypertensive rats. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

[Inhibitory effect of benzimidazole derivatives on cholinesterases of animals in the presence of different substrates].

PubMed

Basova, N E; Kormilitsyn, B N; Perchenok, A Iu; Rosengart, E V; Saakov, V S; Suvorov, A A

2014-01-01

Specifically synthesized group of benzimidazole derivatives possessing varying degrees of delocalization of the positive charge in the cation group of the molecule has been studied in order to search for potential cholinergically active compounds and to study the role of the Coulomb interaction in cholinesterase catalysis. These compounds were reversible inhibitors of cholinesterase (ChE) of human erythrocytes, horse serum, brain of the frog Rana temporaria and visual ganglia of the Pacific squid Todarodes pacificus in the presence of acetylthiocholine iodide and propionylthiocholine iodide as substrates. The differences in the nature of reversible inhibitory effect were observed. The effect of the inhibitor structure and substrate nature, specific for each of the studied inhibitors, on the character of the process of reversible inhibition was found.

One-pot microwave assisted synthesis under green chemistry conditions, antioxidant screening, and cytotoxicity assessments of benzimidazole Schiff bases and pyrimido[1,2-a]benzimidazol-3(4H)-ones.

PubMed

Neochoritis, Constantinos G; Zarganes-Tzitzikas, Tryfon; Tsoleridis, Constantinos A; Stephanidou-Stephanatou, Julia; Kontogiorgis, Christos A; Hadjipavlou-Litina, Dimitra J; Choli-Papadopoulou, Theodora

2011-01-01

The synthesis of a number of benzimidazole Schiff bases 3 and 3-oxo-pyrimido[1,2-a]benzimidazoles 4 in excellent yields by a one-step sequence from the reaction of 2-aminobenzimidazole under green chemistry conditions is described. Structural assignments of the new compounds as well as complete assignment of (1)H and (13)C NMR signals have been unambiguously achieved based on the analysis of their (1)H and (13)C NMR (1D and 2D), IR, MS and elemental analysis data. To the synthesized Schiff bases the E-configuration was assigned on the basis of comparison of experimental and calculated (DFT) (13)C NMR chemical shifts. Compounds 3 and 4 were evaluated as inhibitors of lipoxygenase (LOX) and of lipid peroxidation (LPO). All the tested derivatives showed inhibition of lipid peroxidation, whereas most of them were found to have higher activation than the reference compound trolox; The Schiff bases 3e, 3h, and 3i, and the pyrimidobenzimidazoles 4a, 4e and 4f were found to be the most potent. The most potent LOX inhibitor within the subset of Schiff bases was found compound 3i, followed by 3f, whereas compounds 4a and 4g were found the most potent of the 3-oxo-pyrimido[1,2-a]benzimidazole group. Moreover, some cytotoxicity assessments were undertaken, whereupon it was found that Schiff base 3i and pyrimidobenzimidazoles 4e and 4f did not exhibit cytotoxicity at similar concentrations resembling thus the inhibitory activity of lipid peroxidation. The most cytotoxic Schiff base and pyrimidobenzimidazole were found to be 3d and 4c, respectively. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Theoretical DFT, vibrational and NMR studies of benzimidazole and alkyl derivatives

NASA Astrophysics Data System (ADS)

Infante-Castillo, Ricardo; Rivera-Montalvo, Luis A.; Hernández-Rivera, Samuel P.

2008-04-01

Benzimidazoles are heterocyclic compounds that have awaked great interest during the last few years because of their proven biological activity as antiviral, antimicrobial, and antitumoral agents. For this reason, the development of a systematic FT-IR, FT-Raman and NMR study of 1-substituted compounds in 2-methylbenzimidazole constitutes a significant tool in understanding the molecular dynamics and the structural parameters that govern their behavior. Two new 1-alkyl-2-methylbenzimidazoles compounds were synthesized from reaction of 2-methylbenzimidazole with primary and secondary alkyl halides using a strong base as a catalyst. These compounds were purified and characterized by elemental analysis and different spectroscopic methods. The comparative analysis of vibrational modes of benzimidazole and its alkyl derivatives show that regions of absorption are very similar in all of them. However, changes are produced at low frequencies specifically in the C-H out of plane deformations, ring breathing and ring skeletal vibrations. The ring out-of plane bending modes shift by 10-15 cm -1 in some cases as results of alkyl substitution. The theoretical calculated spectra, using Density Functional Theory (DFT) approximation, and experimental results were consistent with each other. The GIAO method was used to calculate absolute shieldings, which agree consistently with those measured by 1H and 13C NMR. The consistency and efficiency of the GIAO 13C and 1H NMR calculations were thoroughly checked by the analysis of statistical parameters concerning computed and experimental 13C and 1H NMR chemical shift values of the studied compounds.

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors.

PubMed

Rastija, Vesna; Agić, Dejan; Tomiš, Sanja; Nikolič, Sonja; Hranjec, Marijana; Grace, Karminski-Zamola; Abramić, Marija

2015-01-01

A molecular modeling study is performed on series of benzimidazol-based inhibitors of human dipeptidyl peptidase III (DPP III). An eight novel compounds were synthesized in excellent yields using green chemistry approach. This study is aimed to elucidate the structural features of benzimidazole derivatives required for antagonism of human DPP III activity using Quantitative Structure-Activity Relationship (QSAR) analysis, and to understand the mechanism of one of the most potent inhibitor binding into the active site of this enzyme, by molecular dynamics (MD) simulations. The best model obtained includes S3K and RDF045m descriptors which have explained 89.4 % of inhibitory activity. Depicted moiety for strong inhibition activity matches to the structure of most potent compound. MD simulation has revealed importance of imidazolinyl and phenyl groups in the mechanism of binding into the active site of human DPP III.

Synthesis of benzimidazole derivatives as potent β-glucuronidase inhibitors.

PubMed

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

2015-08-01

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

A benzimidazole derivative (RCB20) in vitro induces an activation of energetic pathways on Taenia crassiceps (ORF strain) cysticerci.

PubMed

Fraga, Carolina Miguel; da Costa, Tatiane Luiza; de Castro, Ana Maria; Reynoso-Ducoing, Olivia; Ambrosio, Javier; Hernández-Campos, Alicia; Castillo, Rafael; Vinaud, Marina Clare

2017-01-01

Human cysticercosis caused by Taenia crassiceps is unusual; however, it is an useful experimental model for cysticercosis studies. Benzimidazole derivatives are important antihelminthic drugs widely used against helminths. A novel compound 6-chloro-5-(1-naphthyloxy) -2-(trifluoromethyl)-1H-benzimidazole (RCB20) is a benzimidazole derivative less polar and more lipophilic. The aim of this study was to detect the effect of the RCB20 on the in vitro energetic metabolism of T. crassiceps cysticerci. For this, products of the metabolism both produced and secreted/excreted (S/E) by the parasite were detected through spectrophotometry and high performance liquid chromatography after exposure to 6.5 and 13 μM of RCB20 and albendazole sulfoxide (ABZSO). There was a gradual increase in the concentrations of glucose not uptaken by parasites exposed to both concentrations RCB20 and ABZSO. There was a higher concentration of all the organic acids related to the tricarboxilic acid cycle int the parasites exposed to RCB20. The structural differences between RCB20 and ABZSO result in different targets within the parasite and in a greater induction of the energetic pathways, such as the glycolysis and the TCA cycle. RCB20 is a good candidate as a substitute for anthelminthic benzimidazoles due to a differentiated site of action with similar outcome. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors.

PubMed

Can, Nafiz Öncü; Çevik, Ulviye Acar; Sağlık, Begüm Nurpelin; Özkay, Yusuf; Atlı, Özlem; Baysal, Merve; Özkay, Ümide Demir; Can, Özgür Devrim

2017-08-19

The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1 H -benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds ( n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, ¹H-NMR, 13 C-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds ( 2b and 2j ) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b , 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases.

Mannich-Benzimidazole Derivatives as Antioxidant and Anticholinesterase Inhibitors: Synthesis, Biological Evaluations, and Molecular Docking Study.

PubMed

Alpan, Ayşe Selcen; Sarıkaya, Görkem; Çoban, Güneş; Parlar, Sülünay; Armagan, Güliz; Alptüzün, Vildan

2017-07-01

A series of Mannich bases of benzimidazole derivatives having a phenolic group were designed to assess their anticholinesterase and antioxidant activities. The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated in vitro by using Ellman's method. According to the activity results, all of the compounds exhibited moderate to good AChE inhibitory activity (except for 2a), with IC 50 values ranging from 0.93 to 10.85 μM, and generally displayed moderate BuChE inhibitory activity. Also, most of the compounds were selective against BuChE. Compound 4b was the most active molecule on the AChE enzyme and also selective. In addition, we investigated the antioxidant effects of the synthesized compounds against FeCl 2 /ascorbic acid-induced oxidative stress in the rat brain in vitro, and the activity results showed that most of the compounds are effective as radical scavengers. Molecular docking studies and molecular dynamics simulations were also carried out. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel multi-targeted agents for Alzheimer's disease: Synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles.

PubMed

Ozadali-Sari, Keriman; Tüylü Küçükkılınç, Tuba; Ayazgok, Beyza; Balkan, Ayla; Unsal-Tan, Oya

2017-06-01

The present study describes the synthesis, pharmacological evaluation (BChE/AChE inhibition, Aβ antiaggregation, and neuroprotective effects), and molecular modeling studies of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazole derivatives. The alkyl-substituted derivatives exhibited selective inhibition on BChE with varying efficiency. Compounds 3b and 3d were found to be the most potent inhibitors of BChE with IC 50 values of 5.18 and 5.22μM, respectively. The kinetic studies revealed that 3b is a partial non-competitive BChE inhibitor. Molecular modeling studies also showed that the alkyl-substituted derivatives were able to reach the catalytic anionic site of the BChE. The compounds with an inhibitory effect on BChE were subsequently screened for their Aβ antiaggregating and neuroprotective activities. Compounds 3a and 3b exerted a potential neuroprotective effect against H 2 O 2 and Aβ-induced cytotoxicity in SH-SY5Y cells. Collectively, 3b was found as the most promising compound for the development of multi-target directed ligands against Alzheimer's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis and characterization of 2-substituted benzimidazoles and their evaluation as anticancer agent

NASA Astrophysics Data System (ADS)

Azam, Mohammad; Khan, Azmat Ali; Al-Resayes, Saud I.; Islam, Mohammad Shahidul; Saxena, Ajit Kumar; Dwivedi, Sourabh; Musarrat, Javed; Trzesowska-Kruszynska, Agata; Kruszynski, Rafal

2015-05-01

In this work, we report a series of benzimidazole derivatives synthesized from benzene-1,2-diamine and aryl-aldehydes at room temperature. The synthesized compounds have been characterized on the basis of elemental analysis and various spectroscopic studies viz., IR, 1H- and 13C-NMR, ESI-MS as well by X-ray single X-ray crystallographic study. Interaction of these compounds with CT-DNA has been examined with fluorescence experiments and showed significant binding ability. All the synthesized compounds have been screened for their antitumor activities against various human cancer cell lines viz., Human breast adenocarcinoma cell line (MCF-7), Human leukemia cell line (THP-1), Human prostate cancer cell lines (PC-3) and adenocarcinomic human alveolar basal epithelial cell lines (A-549). Interestingly, all the compounds showed significant anticancer activity.

Synthesis and β-glucuronidase inhibitory potential of benzimidazole derivatives.

PubMed

Khan, Khalid Mohammed; Khan, Momin; Ambreen, Nida; Rahim, Fazal; Naureen, Shagufta; Perveen, Shahnaz; Choudhary, M Iqbal; Voelter, Wolfgang

2012-05-01

Benzimidazole derivatives 1-24 have been synthesized and their in vitro β-glucuronidase inhibitory activitiy was evaluated. Compounds 15 (IC50=6.33+/-0.40 μM), 7 (IC50=22.0+/-0.33 μM), 2 (IC50=23.1+/-1.78 μM), 17 (IC50=23.9+/-1.46 μM), and 3 (IC50=33.8+/-1.61 μM) showed more potent β-glucuronidase inhibitory activity than the standard (D-saccharic acid 1,4 lactone, IC50=48.4+/-1.25 μM). This study has identified a new series of potential β-glucuronidase inhibitors. A structure-activity relationship has also been studied.

Structural Studies on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design

DTIC Science & Technology

2008-02-01

via virtual screening. These compounds include small molecules – transition state analogues and benzimidazoles . We have determined the crystal...project period. It has been established that benzimidazole compounds are good zinc chealators and since botulinum neurotoxin catalytic domains are zinc...endopeptidases we first selected a subset of compounds containing benzimidazole moieties. We pulled out nearly 9000 compound containing both

Conjugation of Benzylvanillin and Benzimidazole Structure Improves DNA Binding with Enhanced Antileukemic Properties

PubMed Central

Al-Mudarris, Ban A.; Chen, Shih-Hsun; Liang, Po-Huang; Osman, Hasnah; Jamal Din, Shah Kamal Khan; Abdul Majid, Amin M. S.

2013-01-01

Benzyl-o-vanillin and benzimidazole nucleus serve as important pharmacophore in drug discovery. The benzyl vanillin (2-(benzyloxy)-3-methoxybenzaldehyde) compound shows anti-proliferative activity in HL60 leukemia cancer cells and can effect cell cycle progression at G2/M phase. Its apoptosis activity was due to disruption of mitochondrial functioning. In this study, we have studied a series of compounds consisting of benzyl vanillin and benzimidazole structures. We hypothesize that by fusing these two structures we can produce compounds that have better anticancer activity with improved specificity particularly towards the leukemia cell line. Here we explored the anticancer activity of three compounds namely 2-(2-benzyloxy-3-methoxyphenyl)-1H-benzimidazole, 2MP, N-1-(2-benzyloxy-3-methoxybenzyl)-2-(2-benzyloxy-3-methoxyphenyl)-1H-benzimidazole, 2XP, and (R) and (S)-1-(2-benzyloxy-3-methoxyphenyl)-2, 2, 2-trichloroethyl benzenesulfonate, 3BS and compared their activity to 2-benzyloxy-3-methoxybenzaldehyde, (Bn1), the parent compound. 2XP and 3BS induces cell death of U937 leukemic cell line through DNA fragmentation that lead to the intrinsic caspase 9 activation. DNA binding study primarily by the equilibrium binding titration assay followed by the Viscosity study reveal the DNA binding through groove region with intrinsic binding constant 7.39 µM/bp and 6.86 µM/bp for 3BS and 2XP respectively. 2XP and 3BS showed strong DNA binding activity by the UV titration method with the computational drug modeling showed that both 2XP and 3BS failed to form any electrostatic linkages except via hydrophobic interaction through the minor groove region of the nucleic acid. The benzylvanillin alone (Bn1) has weak anticancer activity even after it was combined with the benzimidazole (2MP), but after addition of another benzylvanillin structure (2XP), stronger activity was observed. Also, the combination of benzylvanillin with benzenesulfonate (3BS) significantly improved the anticancer activity of Bn1. The present study provides a new insight of benzyl vanillin derivatives as potential anti-leukemic agent. PMID:24260527

Laser action benzimidazoles in various aggregate states

NASA Astrophysics Data System (ADS)

Gruzinskii, V. V.; Degtiarenko, K. M.; Shalaev, V. K.; Kopylova, T. N.; Verkhovskii, V. S.; Tarasenko, V. F.; Melchenko, S. V.

1983-04-01

Lasing has been obtained in solutions of benzimidazole (Bi) derivatives: 2-phenyl-Bi (with the band maximum lambda-r-max = 341-347 nm), 2-n-tolyl-Bi (344 nm), and 2-(4'-biphenilyl) Bi (366-374 nm). It is found that compounds of this class provide a basis for laser radiation covering a wide region of the spectrum. Lasing has been obtained on the vapors of 2-(4'-biphenilyl) Bi (361.2 nm) and 2-(n-tolyl) Bi (336.5 nm) with a pentane stabilizer of the excited states. High volatility, photostability, and lasing in wide ranges of concentration determine the efficiency of using this new class of compounds (chain arylbenzimidazoles) in lasers using the vapors of complex molecules.

Novel product ions of 2-aminoanilide and benzimidazole Ag(I) complexes using electrospray ionization with multi-stage tandem mass spectrometry.

PubMed

Johnson, Byron S; Burinsky, David J; Burova, Svetlana A; Davis, Roman; Fitzgerald, Russ N; Matsuoka, Richard T

2012-05-15

The 2-aminoaniline scaffold is of significant value to the pharmaceutical industry and is embedded in a number of pharmacophores including 2-aminoanilides and benzimidazoles. A novel application of coordination ion spray mass spectrometry (CIS-MS) for interrogating the silver ion (Ag(+)) complexes of a homologous series of these compounds using multi-stage tandem mass spectrometry is described. Unlike the ubiquitous alkali metal ion complexes, Ag(+) complexes of 2-aminoanilides and benzimidazoles were found to yield [M - H](+) ions in significant abundance via gas-phase elimination of the metal hydride (AgH) resulting in unique product ion cascades. Sample introduction was by liquid chromatography with mass spectrometry analysis performed on a hybrid linear ion trap/orbitrap instrument capable of high-resolution measurements. Rigorous structural characterization by multi-stage tandem mass spectrometry using [M +  H](+), [M - H](-) and [M - H](+) precursor ions derived from ESI and CIS experiments was performed for the homologous series of 2-aminoanilide and benzimidazole compounds. A full tabular comparison of structural information resulting from these product ion cascades was produced. Multi-stage tandem mass spectrometry of [M - H](+) ions resulting from Ag(+) complexes of 2-aminoanilides and benzimidazoles in CIS-MS experiments produced unique product ion cascades that exhibited complementary structural information to that obtained from tandem mass spectrometry of [M  +  H](+) and [M - H](-) ions by electrospray ionization (ESI). These observations may be broadly applicable to other compounds that are observed to form Ag(+) complexes and eliminate AgH. Copyright © 2012 John Wiley & Sons, Ltd.

Synthesis, antibacterial activity, synergistic effect, cytotoxicity, docking and molecular dynamics of benzimidazole analogues.

PubMed

Srivastava, Ritika; Gupta, Sunil K; Naaz, Farha; Singh, Anuradha; Singh, Vishal K; Verma, Rajesh; Singh, Nidhi; Singh, Ramendra K

2018-05-24

A series of 2-Cl-benzimidazole derivatives was synthesized and assessed for antibacterial activity. Antibacterial results indicated that compounds 2d, 2e, 3a, 3b, 3c, 4d and 4e showed promising activity against B. cerus, S. aureus and P. aeruginosa (MIC: 6.2 μg/mL) and excellent efficacy against E. coli (MIC: 3.1 μg/mL). Furthermore, compounds 3d and 3e displayed better activity (MIC: 3.1 μg/mL) than the reference drugs chloramphenicol and cycloheximide against gram positive and gram negative bacterial strains. The compounds 3d-e also showed better activity than the reference drug paromomycin against B. cerus and P. aeruginosa and showed similar inhibition pattern against S. aureus and E. coli. (MIC: 3.1 μg/mL). Studies on fractional inhibitory concentration (FIC) determination of compounds 1a-e, 2a-c, 4a-c and the reference antibiotic via combination approach revealed a synergistic effect as the MIC values were lowered up to 1 / 8 th to 1 / 33 rd of the original MIC. In-vitro cytotoxicity study indicated that 2-Cl-benzimidazole derivatives showed less toxicity than the reference used against PBM, CEM and Vero cell lines. Docking studies and MD simulations of compounds on bacterial protein (eubacterial ribosomal decoding A site, PDB: 1j7t) have been conducted to find the possible mode of action of the molecules. In silico ADMET evaluations of compounds 3d and 3e showed promising results comparable to the reference drugs used in this study. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Trisubstituted Benzimidazole Cell Division Inhibitor with Efficacy against Mycobacterium tuberculosis

PubMed Central

Knudson, Susan E.; Awasthi, Divya; Kumar, Kunal; Carreau, Alexandra; Goullieux, Laurent; Lagrange, Sophie; Vermet, Hélèn; Ojima, Iwao; Slayden, Richard A.

2014-01-01

Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73±0.24 Log10 CFU and 2.68±Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy. PMID:24736743

Synthesis and characterization of 2-substituted benzimidazoles and their evaluation as anticancer agent.

PubMed

Azam, Mohammad; Khan, Azmat Ali; Al-Resayes, Saud I; Islam, Mohammad Shahidul; Saxena, Ajit Kumar; Dwivedi, Sourabh; Musarrat, Javed; Trzesowska-Kruszynska, Agata; Kruszynski, Rafal

2015-05-05

In this work, we report a series of benzimidazole derivatives synthesized from benzene-1,2-diamine and aryl-aldehydes at room temperature. The synthesized compounds have been characterized on the basis of elemental analysis and various spectroscopic studies viz., IR, (1)H- and (13)C-NMR, ESI-MS as well by X-ray single X-ray crystallographic study. Interaction of these compounds with CT-DNA has been examined with fluorescence experiments and showed significant binding ability. All the synthesized compounds have been screened for their antitumor activities against various human cancer cell lines viz., Human breast adenocarcinoma cell line (MCF-7), Human leukemia cell line (THP-1), Human prostate cancer cell lines (PC-3) and adenocarcinomic human alveolar basal epithelial cell lines (A-549). Interestingly, all the compounds showed significant anticancer activity. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthesis and Anti-inflammatory Evaluation of Novel Benzimidazole and Imidazopyridine Derivatives

PubMed Central

2012-01-01

Sepsis, an acute inflammatory disease, remains the most common cause of death in intensive care units. A series of benzimidazole and imidazopyridine derivatives were synthesized and screened for anti-inflammatory activities, and the imidazopyridine series showed excellent inhibition of the expression of inflammatory cytokines in LPS-stimulated macrophages. Compounds X10, X12, X13, X14, and X15 inhibited TNF-α and IL-6 release in a dose-dependent manner, and X12 showed no cytotoxicity in hepatic cells. Furthermore, X12 exhibited a significant protection against LPS-induced septic death in mouse models. Together, these data present a series of new imidazopyridines with potential therapeutic effects in acute inflammatory diseases. PMID:24900565

Synthesis and Anti-inflammatory Evaluation of Novel Benzimidazole and Imidazopyridine Derivatives.

PubMed

Chen, Gaozhi; Liu, Zhiguo; Zhang, Yali; Shan, Xiaoou; Jiang, Lili; Zhao, Yunjie; He, Wenfei; Feng, Zhiguo; Yang, Shulin; Liang, Guang

2013-01-10

Sepsis, an acute inflammatory disease, remains the most common cause of death in intensive care units. A series of benzimidazole and imidazopyridine derivatives were synthesized and screened for anti-inflammatory activities, and the imidazopyridine series showed excellent inhibition of the expression of inflammatory cytokines in LPS-stimulated macrophages. Compounds X10, X12, X13, X14, and X15 inhibited TNF-α and IL-6 release in a dose-dependent manner, and X12 showed no cytotoxicity in hepatic cells. Furthermore, X12 exhibited a significant protection against LPS-induced septic death in mouse models. Together, these data present a series of new imidazopyridines with potential therapeutic effects in acute inflammatory diseases.

Involvement of conformational isomerism in the complexity of the crystal network of 1-(4-nitrophenyl)-1H-1,3-benzimidazole derivatives driven by C-H...A (A = NO2, Npy and π) and orthogonal Npy...NO2 and ONO...Csp2 interactions.

PubMed

García-Aranda, Mónica I; Gómez-Castro, Carlos Z; García-Báez, Efrén V; Gómez, Yolanda Gómez Y; Castrejón-Flores, José L; Padilla-Martínez, Itzia I

2018-04-01

A detailed structural analysis of the benzimidazole nitroarenes 1-(4-nitrophenyl)-1H-1,3-benzimidazole, C 13 H 9 N 3 O 2 , (I), 1-(4-nitrophenyl)-2-phenyl-1H-1,3-benzimidazole, C 19 H 13 N 3 O 2 , (II), and 2-(3-methylphenyl)-1-(4-nitrophenyl)-1H-1,3-benzimidazole, C 20 H 15 N 3 O 2 , (III), has been performed. They are nonplanar structures whose crystal arrangement is governed by Csp 2 -H...A (A = NO 2 , N py and π) hydrogen bonding. The inherent complexity of the supramolecular arrangements of compounds (I) (Z' = 2) and (II) (Z' = 4) into tapes, helices and sheets is the result of the additional participation of π-π NO2 and n-π* (n = O and N py ; π* = Csp 2 and N NO2 ) interactions that contribute to the stabilization of the equi-energetic conformations adopted by each of the independent molecules in the asymmetric unit. In contrast, compound (III) (Z' = 1) is self-paired, probably due to the effect of the steric demand of the methyl group on the crystal packing. Theoretical ab initio calculations confirmed that the presence of the arene ring at the benzimidazole 2-position increases the rotational barrier of the nitrobenzene ring and also supports the electrostatic nature of the orthogonal ONO...Csp 2 and N py ...NO 2 interactions.

Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.

PubMed

Chino, Ayaka; Masuda, Naoyuki; Amano, Yasushi; Honbou, Kazuya; Mihara, Takuma; Yamazaki, Mayako; Tomishima, Masaki

2014-07-01

In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition. Copyright © 2014. Published by Elsevier Ltd.

Synthesis, electronic properties, antioxidant and antibacterial activity of some new benzimidazoles.

PubMed

Mavrova, Anelia Ts; Yancheva, Denitsa; Anastassova, Neda; Anichina, Kamelya; Zvezdanovic, Jelena; Djordjevic, Aleksandra; Markovic, Dejan; Smelcerovic, Andrija

2015-10-01

Two groups of benzimidazole derivatives were synthesized using as precursors 5(6)-substituted 2-mercapto-benzimidazol-thiols and their antioxidant activity was investigated using TBA-MDA test. In the group of 1,3-disubstituted-benzimidazol-2-imines the highest lipid peroxidation inhibition effect 74.04% (IC₅₀=141.89 μg/mL) revealed ethyl [3-(2-ethoxy-2-oxoethyl)-2-imino-5-benzoyl-2,3-dihydro-1H-benzimdazol-1-yl]acetate 12 while in the group of 2-substituted-1,3-thiazolo[3,2-a]benzimidazolones the highest inhibition effect showed 2-(4-fluorobenzylidene)-7-(phenylcarbonyl)[1,3]thiazolo[3,2-a]benzimidazol-3(2H)-one 17 90.76% (IC₅₀=53.70 μg/mL). In order to estimate the capability of the studied benzimidazoles to act as radical scavengers the structure of the most active derivative within the both subseries was optimized at B3LYP/6-311++G(∗∗) level and the respective bond dissociation enthalpies were calculated. The appropriate models for the HAT and SET-mechanism of the antioxidant activity were proposed. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and three Gram-negative bacteria (Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and Salmonella abony NCTC 6017). 1,3-Diphenylpropyl-5-methyl-1,3-dihydro-2H-benzimidazol-2-imine 14 exhibited significant activity against B. subtilis, S. aureus, S. abony and E. coli (with MIC values of 0.125, 0.016, 0.50 and 0.50mg/mL, respectively). The group of thiazolobenzimidazolones did not reveal antibacterial activity against the tested strains. Copyright © 2015. Published by Elsevier Ltd.

A Practical Green Synthesis and Biological Evaluation of Benzimidazoles Against Two Neglected Tropical Diseases: Chagas and Leishmaniasis.

PubMed

Bandyopadhyay, Debashis; Samano, Selina; Villalobos-Rocha, Juan Carlos; Sanchez-Torres, Luvia Enid; Nogueda-Torres, Benjamin; Rivera, Gildardo; Banik, Bimal K

2017-01-01

Antimicrobial resistance is an ever-increasing problem throughout the world and has already reached severe proportions. Two very common neglected tropical diseases are Chagas' disease and leishmaniasis. Chagas' disease is a severe health problem, mainly in Latin America, causing approximately 50000 deaths a year and millions of people are infected. About 25-30% of the patients infected with Trypanosoma cruzi develop the chronic form of the disease. On the other hand, Leishmaniasis represents complex diseases with an important clinical and epidemiological diversity. It is endemic in 88 countries 72 of which are developing countries and it has been estimated that are 12 million people infected and 350 million are in areas with infection risk. On this basis, research on organic compounds that can be used against these two diseases is an important target. A very simple, green, and efficient protocol is developed in which bismuth nitrate pentahydrate is employed as a Lewis acid catalyst in aqueous media under microwave irradiation for the synthesis of various 2-aryl substituted benzimidazoles from aldehydes and o-phenylenediamine. Other salient features of this protocol include milder conditions, atom-economy, easy extraction, and no wastes. Nine 1H-benzimidazole derivatives (1-9) with substituents at positions 2 and 5 were synthesized and the structure of the compounds was elucidated by spectroscopic methods. The compounds were screened to identify whether they posses pharmacological activity against Chagas' disease and leishmaniasis. Compound 8 showed better activity than the control Nifurtimox against INC-5 Trypanosoma cruzi strain whereas compounds 3 and 9 have demonstrated potent leshmanicidal activity. A systematic green synthetic procedure and in vitro biological evaluation of nine 1H-benzimidazoles are described. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Microwave-assisted Synthesis of Benzimidazole Derivatives from Citronellal in Kaffir Lime (Citrus hystrix DC.) Oil

NASA Astrophysics Data System (ADS)

Sapri Ramadhan, Dwi; Warsito; Dhiaul Iftitah, Elvina

2018-01-01

Benzimidazoles are an important group of heterocyclic aromatic organic compound in the field of medicinal chemistry. It plays a very important role in pharmacological activity such as, analgesic, antiinflammatory, antibacterial, anti ungal, anti iral, antithelmenthic, anti convulsant, antihypertensive, and antiulcer. The synthesis of benzimidazole derivative under microwave irradiation of citronellal as raw material which is extracted from Citrus hystrix DC. (kaffir lime) leaves. The reaction using methanol and dichloromethane as solvent with variation of reaction time at 30, 40, 50, 60, and 70 minutes and mole ratio of citronellal to 1,2-phenylenediamine, 1:1, 1:1.5, and 1:2, respectively. Synthesis products was characterized by FT-IR and GC-MS. The optimum reaction time was obtained at 60 minutes in the present of dichloromethane and 1:2 mole ratio of citronellal to 1,2-phenylenediamine. The yield of the product is 42.19%. Structure of the synthesized compound were assigned on spectrum bands for C=N str at 1661 cm-1, C-N str at 1271 cm-1, C=C str of benzene ring at 1622 and 1456 cm-1 and C=C str of alkene at 1379 cm-1. GC-MS analysis showed single peak with retention time of 15.339 minute and m/z 242.

[Research of imidazo[1,2-a]benzimidazole derivatives. XXX. Synthesis and properties of (imidazo[1,2-a]benzimidazolyl-2)acetic acid derivatives].

PubMed

Anisimova, V A; Tolpygin, I E; Spasov, A A; Serdiuk, T S; Sukhov, A G

2011-01-01

Ethyl esters of (9-subtituted-imidazo[1,2-a]benzimidazolyl-2)acetic acids were synthesized. The chemical properties of these esters (hydrolysis, decarboxylation, hydrazinolysis) and biological activity (fungicidal, antimicrobial, antiarrhythmic activity, and also affects on the brain rhythmogenesis) of the prepared compounds were studied.

Graph theoretical analysis, insilico modeling, design, and synthesis of compounds containing benzimidazole skeleton as antidepressant agents.

PubMed

Theivendren, Panneerselvam; Subramanian, Arumugam; Murugan, Indhumathy; Joshi, Shrinivas D; More, Uttam A

2017-05-01

In this study, drug target was identified using KEGG database and network analysis through Cytoscape software. Designed series of novel benzimidazoles were taken along with reference standard Flibanserin for insilico modeling. The novel 4-(1H-benzo[d]imidazol-2-yl)-N-(substituted phenyl)-4-oxobutanamide (3a-j) analogs were synthesized and evaluated for their antidepressant activity. Reaction of 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanoic acid (1) with 4-(1H-benzo [d] imidazol-2-yl)-4-oxobutanoyl chloride (2) furnished novel 4-(1H-benzo [d] imidazol-2-yl)-N-(substituted phenyl)-4-oxobutanamide (3a-j). All the newly synthesized compounds were characterized by IR, 1 H-NMR, and mass spectral analysis. The antidepressant activities of synthesized derivatives were compared with standard drug clomipramine at a dose level of 20 mg/kg. Among the derivatives tested, most of the compounds were found to have potent activity against depression. The high level of activity was shown by the compounds 3d, 3e, 3i, and it significantly reduced the duration of immobility time at the dose level of 50 mg/kg. © 2016 John Wiley & Sons A/S.

Inhibitory effects of benzimidazole containing new phenolic Mannich bases on human carbonic anhydrase isoforms hCA I and II.

PubMed

Gul, Halise Inci; Yazici, Zehra; Tanc, Muhammet; Supuran, Claudiu T

2016-12-01

New phenolic mono and bis Mannich bases incorporating benzimidazole, such as 2-(aminomethyl)-4-(1H-benzimidazol-2-yl)phenol and 2,6-bis(aminomethyl)-4-(1H-benzimidazol-2-yl)phenol were synthesized starting from 4-(1H-benzimidazol-2-yl)phenol. Amines used for the synthesis included dimethylamine, pyrrolidine, piperidine, N-methylpiperazine and morpholine. The CA inhibitory properties of these compounds were tested on the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and hCA II. These new compounds, as many phenols show moderate CA inhibitory properties.

Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of anti-MRSA and anti-VRE agents.

PubMed

Hu, Laixing; Kully, Maureen L; Boykin, David W; Abood, Norman

2009-03-01

A new class of novel bis-benzimidazole diamidine compounds have been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Anti-MRSA and anti-VRE activities of the most potent compound 1 were more active than Vancomycin. The mechanism of action for this class of compounds appears to be different from existing antibiotics. Bis-benzimidazole diamidine compounds have potential for further investigation as a new class of potent anti-MRSA and anti-VRE agents.

Design, synthesis and biological evaluation of berberine-benzimidazole hybrids as new type of potentially DNA-targeting antimicrobial agents.

PubMed

Jeyakkumar, Ponmani; Zhang, Ling; Avula, Srinivasa Rao; Zhou, Cheng-He

2016-10-21

A series of novel berberine-benzimidazole derivatives were conveniently and efficiently synthesized and characterized by NMR, IR, MS and HRMS spectra. Most of the prepared compounds showed effective antimicrobial activities in contrast with clinical norfloxacin, chloromycin and fluconazole. Especially, compound 5d exhibited good anti-MRSA, anti-Escherichia coli, and anti-Salmonella typhi activity with low MIC values of 2-8 μg/mL, which were comparable or even superior to reference drugs. The preliminarily interactive investigation revealed that the most active compound 5d could effectively intercalate into DNA to form 5d-DNA complex and cleavage DNA by agarose gel electrophoresis experiments. It was also found that compound 5d was able to efficiently permeabilize the membranes of both Gram-positive (MRSA) and Gram-negative (E. coli DH52) bacteria. Experiments and molecular docking both showed that human serum albumin (HSA) could effectively transport compound 5d and hydrophobic interactions and hydrogen bonds play important roles in the association of compound 5d with HSA. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Triaryl Benzimidazoles as a New Class of Antibacterial Agents against Resistant Pathogenic Microorganisms.

PubMed

Picconi, Pietro; Hind, Charlotte; Jamshidi, Shirin; Nahar, Kazi; Clifford, Melanie; Wand, Matthew E; Sutton, J Mark; Rahman, Khondaker Miraz

2017-07-27

A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.

Diversity-Oriented Synthesis of Coumarin-Linked Benzimidazoles via a One-Pot, Three-Step, Intramolecular Knoevenagel Cyclization.

PubMed

Yao, Po-Hsin Eric; Kumar, Sunil; Liu, Yu-Li; Fang, Chiu-Ping; Liu, Chia-Chen; Sun, Chung-Ming

2017-04-10

Diversity-oriented synthesis of coumarin-linked benzimidazoles from N-(2-aminophenyl)-2-cyanoacetamide was achieved via a one-pot, three-step sequential reaction in excellent yields. In situ intramolecular cyclization of the cyanoacetamide afforded benzimidazoles which subsequently underwent a Knoevenagel condensation of the 2-cyanomethylbenzimidazoles with salicylaldehydes promoted by triethylamine to reach the target compounds. An important intermediate, 2-(2-imino-2H-chromen-3-yl)-1H-benzimidazole was characterized by X-ray analysis and further hydrolyzed to 2-(coumarin-3-yl)benzimidazole in acidic condition. Among the synthesized compounds, some were found to be promising inhibitors of porcine kidney d-amino acid oxidase (pkDAO).

Photophysical processes of some benzimidazole derivatives

NASA Astrophysics Data System (ADS)

Chen, Zhaobin; Zhang, Caihong; Feng, Liheng

2005-11-01

The photophysical properties of N-(α-naphthyl)-benzimidazole (α-NABI), N-(β-naphthyl)-benzimidazole (β-NABI) and N-(α-pyridyl)-benzimidazole (α-PYBI) were studied and α-NYBI exhibit intramolecular charge transfer fluorescence in polar solvents. The fluorescence of benzimidazoles can be quenched by acetic acid and the existence of exciplexes was observed between the benzimidazole derivatives and acetic acid. Particularly, the maximum emission peak of solution of α-PYBI in mixed solvent, ether and acetic acid, presents obvious red-shift with the increase of concentration of acetic acid in the mixed solvent.

Effect of a novel benzimidazole derivative in experimental Schistosoma mansoni infection.

PubMed

El Bialy, Serry A; Taman, Amira; El-Beshbishi, Samar N; Mansour, Basem; El-Malky, Mohamed; Bayoumi, Waleed A; Essa, Hassan M

2013-12-01

Currently, praziquantel is the only drug of choice for treatment of schistosomiasis. Reports of praziquantel resistance raise concerns about future control of the disease. Therefore, the search for new schistosomicidal drugs is eminent. In this study, the effect of a novel benzimidazole-derived compound (compound BTP-Iso) was assessed in mice harboring adult Schistosoma mansoni (Egyptian strain). Mice were treated 42 days p.i. with compound BTP-Iso using two treatment regimens (200 or 300 mg/kg). In both regimens, there were significant reductions in the number of recovered S. mansoni worms especially females and in immature ova, in addition to a significant reduction in the number and size of hepatic granulomata. A dose of 300 mg/kg resulted in a significant decrease in intestinal and hepatic tissue egg loads. Effect on schistosomes was confirmed by scanning electron microscopy, where adult worms recovered from mice treated with 200 mg/kg of compound BTP-Iso revealed tegumental alternations, characterised by swelling of tegumental ridges, bleb formation, and mild erosion in male worms; however in females, there were extensive erosion and destruction of the tegumental surface. These promising results may encourage future use of compound BTP-Iso in the treatment of schistosomiasis. However, more research is needed to detect the effect of compound BTP-Iso on early developmental stages of S. mansoni and on other species of human schistosomes.

Benzimidazole derivatives: selective fluorescent chemosensors for the picogram detection of picric acid.

PubMed

Xiong, Jin-Feng; Li, Jian-Xiao; Mo, Guang-Zhen; Huo, Jing-Pei; Liu, Jin-Yan; Chen, Xiao-Yun; Wang, Zhao-Yang

2014-12-05

1,3,5-Tri(1H-benzo[d]imidazol-2-yl)benzene derivatives, as a new kind of fluorescent chemosensor for the detection of nitroaromatic explosives, are designed and synthesized by simple N-hydrocarbylation. Among 16 obtained compounds, compound 4g has the best capability for detection of picric acid (PA), having good selectivity and high sensitivity. The detection of PA with 4g solution-coated paper strips at the picogram level is developed. A simple, portable, and low-cost method is provided for detecting PA in solution and contact mode.

Design and synthesis of positional isomers of 5 and 6-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles as possible antimicrobial and antitubercular agents.

PubMed

Ranjith, P Karuvalam; Rajeesh, P; Haridas, Karickal R; Susanta, Nayak K; Row, Tayur N Guru; Rishikesan, R; Kumari, N Suchetha

2013-09-15

In this Letter, we report the structure-activity relationship (SAR) studies on series of positional isomers of 5(6)-bromo-1-[(phenyl)sulfonyl]-2-[(4-nitrophenoxy)methyl]-1H-benzimidazoles derivatives 7(a-j) and 8(a-j) synthesized in good yields and characterized by (1)H NMR, (13)C NMR and mass spectral analyses. The crystal structure of 7a was evidenced by X-ray diffraction study. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, (Gram-positive), Escherichia coli and Klebsiella pneumoniae (Gram-negative), antifungal activity against Candida albicans, Aspergillus flavus and Rhizopus sp. and antitubercular activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, Mycobacterium fortuitum and MDR-TB strains. The synthesized compounds displayed interesting antimicrobial activity. The compounds 7b, 7e and 7h displayed significant activity against Mycobacterium tuberculosis H37Rv strain. Copyright © 2013 Elsevier Ltd. All rights reserved.

Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H₁-antihistamines for insomnia.

PubMed

Ravula, Satheesh Babu; Yu, Jinghua; Tran, Joe A; Arellano, Melissa; Tucci, Fabio C; Moree, Wilna J; Li, Bin-Feng; Petroski, Robert E; Wen, Jianyun; Malany, Siobhan; Hoare, Samuel R J; Madan, Ajay; Crowe, Paul D; Beaton, Graham

2012-01-01

The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis and quantitative structure activity relationship (QSAR) of arylidene (benzimidazol-1-yl)acetohydrazones as potential antibacterial agents.

PubMed

El-Kilany, Yeldez; Nahas, Nariman M; Al-Ghamdi, Mariam A; Badawy, Mohamed E I; El Ashry, El Sayed H

2015-01-01

Ethyl (benzimidazol-1-yl)acetate was subjected to hydrazinolysis with hydrazine hydrate to give (benzimidazol-1-yl)acetohydrazide. The latter was reacted with various aromatic aldehydes to give the respective arylidene (1H-benzimidazol-1-yl)acetohydrazones. Solutions of the prepared hydrazones were found to contain two geometric isomers. Similarly (2-methyl-benzimidazol-1-yl)acetohydrazide was reacted with various aldehydes to give the corresponding hydrazones. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens (A. tumefaciens), Erwinia carotovora (E. carotovora), Corynebacterium fascians (C. fascians) and Pseudomonas solanacearum (P. solanacearum). MIC result demonstrated that salicylaldehyde(1H-benzimidazol-1-yl)acetohydrazone (4) was the most active compound (MIC = 20, 35, 25 and 30 mg/L against A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively). Quantitative structure activity relationship (QSAR) investigation using Hansch analysis was applied to find out the correlation between antibacterial activity and physicochemical properties. Various physicochemical descriptors and experimentally determined MIC values for different microorganisms were used as independent and dependent variables, respectively. pMICs of the compounds exhibited good correlation (r = 0.983, 0.914, 0.960 and 0.958 for A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively) with the prediction made by the model. QSAR study revealed that the hydrophobic parameter (ClogP), the aqueous solubility (LogS), calculated molar refractivity, topological polar surface area and hydrogen bond acceptor were found to have overall significant correlation with antibacterial activity. The statistical results of training set, correlation coefficient (r and r (2)), the ratio between regression and residual variances (f, Fisher's statistic), the standard error of estimates and significant (s) gave reliability to the prediction of molecules with activity using QSAR models. However, QSAR equations derived for the MIC values against the tested bacteria showed negative contribution of molecular mass.

In Vitro and In Vivo Activities of Dicationic Diguanidino Compounds against Echinococcus multilocularis Metacestodes

PubMed Central

Küster, Tatiana; Kriegel, Nadja; Boykin, David W.; Stephens, Chad E.

2013-01-01

Alveolar echinococcosis (AE) is a disease predominantly affecting the liver, with metacestodes (larvae) of the tapeworm Echinococcus multilocularis proliferating and exhibiting tumor-like infiltrative growth. For many years, chemotherapeutical treatment against alveolar echinococcosis has relied on the benzimidazoles albendazole and mebendazole, which require long treatment durations and exhibit parasitostatic rather than parasiticidal efficacy. Although benzimidazoles have been and still are beneficial for the patients, there is clearly a demand for alternative and more efficient treatment options. Aromatic dications, more precisely a small panel of di-N-aryl-diguanidino compounds, were screened for efficacy against E. multilocularis metacestodes in vitro. Only those with a thiophene core group were active against metacestodes, while furans were not. The most active compound, DB1127, was further investigated in terms of in vivo efficacy in mice experimentally infected with E. multilocularis metacestodes. This diguanidino compound was effective against AE when administered intraperitoneally but not when applied orally. Thus, thiophene-diguanidino derivatives with improved bioavailability when administered orally could lead to treatment options against AE. PMID:23716058

New benzimidazoles and their antitumor effects with Aurora A kinase and KSP inhibitory activities.

PubMed

Abd El-All, Amira S; Magd-El-Din, Asmaa A; Ragab, Fatma A F; ElHefnawi, Mahmoud; Abdalla, Mohamed M; Galal, Shadia A; El-Rashedy, Ahmed A

2015-07-01

A newly synthesized series of anticancer compounds comprising thiazolo[3,2-a]pyrimidine derivatives 6a-q bearing a benzimidazole moiety was produced via a one-pot reaction of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-cyanoacetamide 5 with 2-aminothiazole and an appropriate aromatic aldehyde. Compound 7 was obtained via the reaction of 4-(1H-benzo[d]imidazol-2yl)benzenamide 1 with carbon disulphide and methyl iodide in the presence of concentrated aqueous solution of NaOH, then treated with o-phenylenediamine to give N-(4-1H-benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine 8. The structures of the newly synthesized compounds were confirmed by analytical and spectroscopic measurements (IR, MS, and (1) H NMR). The synthesized products were screened and studied for their in vitro antitumor activity against three human cancer cell lines (namely colorectal cancer cell line HCT116, human liver cancer cell line HepG2, and human ovarian cancer cell line A2780) and their Aurora A kinase and KSP inhibitory activities. All newly synthesized compounds revealed marked results comparable with the standard drug CK0106023. The compounds 6e and 6k of the thiazolopyrimidine derivatives were the most active compounds when tested against the three cell lines in comparison with the standard drug CK0106023, and showed potent dual KSP and Aurora A kinase inhibition. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optimization of the central linker of dicationic bis-benzimidazole anti-MRSA and anti-VRE agents.

PubMed

Hu, Laixing; Kully, Maureen L; Boykin, David W; Abood, Norman

2009-07-01

A series of bis-benzimidazole diamidine compounds containing different central linkers has been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Seven compounds have shown potent antibacterial activities. The anti-MRSA and anti-VRE activities of compound 1h were more potent than that of the lead compound 1a and vancomycin.

Crystal structures of HIV-1 nonnucleoside reverse transcriptase inhibitors: N-benzyl-4-methyl-benzimidazoles

NASA Astrophysics Data System (ADS)

Ziółkowska, Natasza E.; Michejda, Christopher J.; Bujacz, Grzegorz D.

2009-07-01

HIV-1 nonnucleoside reverse transcriptase inhibitors are potentially specific and effective drugs in AIDS therapy. The presence of two aromatic systems with an angled orientation in the molecule of the inhibitor is crucial for interactions with HIV-1 RT. The inhibitor drives like a wedge into the cluster of aromatic residues of RT HIV-1 and restrains the enzyme in a conformation that blocks the chemical step of nucleotide incorporation. Structural studies provide useful information for designing new, more active inhibitors. The crystal structures of four NNRTIs are presented here. The investigated compounds are derivatives of N-benzyl-4-methyl-benzimidazole with various aliphatic and aromatic substituents at carbon 2 positions and a 2,6-dihalogeno-substituted N-benzyl moiety. Structural data reported here show that the conformation of the investigated compounds is relatively rigid. Such feature is important for the nonnucleoside inhibitor binding to HIV-1 reverse transcriptase.

Structural optimization of N1-aryl-benzimidazoles for the discovery of new non-nucleoside reverse transcriptase inhibitors active against wild-type and mutant HIV-1 strains.

PubMed

Monforte, Anna Maria; De Luca, Laura; Buemi, Maria Rosa; Agharbaoui, Fatima E; Pannecouque, Christophe; Ferro, Stefania

2018-02-01

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of human immunodeficiency virus (HIV) infection. These regimens are extremely effective in suppressing virus replication. Recently, our research group identified some N 1 -aryl-2-arylthioacetamido-benzimidazoles as a novel class of NNRTIs. In this research work we report the design, the synthesis and the structure-activity relationship studies of new compounds (20-34) in which some structural modifications have been introduced in order to investigate their effects on reverse transcriptase (RT) inhibition and to better define the features needed to increase the antiviral activity. Most of the new compounds proved to be highly effective in inhibiting both RT enzyme at nanomolar concentrations and HIV-1 replication in MT4 cells with minimal cytotoxicity. Among them, the most promising N 1 -aryl-2-arylthioacetamido-benzimidazoles and N 1 -aryl-2-aryloxyacetamido-benzimidazoles were also tested toward a panel of single- and double-mutants strain responsible for resistance to NNRTIs, showing in vitro antiviral activity toward single mutants L100I, K103N, Y181C, Y188L and E138K. The best results were observed for derivatives 29 and 33 active also against the double mutants F227L and V106A. Computational approaches were applied in order to rationalize the potency of the new synthesized inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis of some N-substituted indole derivatives and their biological activities.

PubMed

el-Diwani, H; Nakkady, S S; Hishmat, O H; el-Shabrawy, O A; Mahmoud, S S

1992-03-01

Acylation of 2,3-diphenyl-5-methoxy-indole using ethyl chloroformate or chloroacetyl chloride in dimethylformamide and sodium hydride yielded the N-substituted derivatives 1 and 2, respectively. While Friedel-Crafts acylation using chloroacetyl chloride afforded di-4,6-chloroacetyl derivative 3, the reaction of the N-chloroacetyl derivative 2 with amines, hydrazines, urea, semicarbazide hydrochloride, thiophenol, benzimidazole-2-thiol, thiosemicarbazide, 2-mercaptoethanol and thioglycolic acid was studied. Several of the compounds were tested for their effect on arterial blood pressure, antiinflammatory and ulcerogenic activities.

Antiprotozoal activities of benzimidazoles and correlations with beta-tubulin sequence.

PubMed Central

Katiyar, S K; Gordon, V R; McLaughlin, G L; Edlind, T D

1994-01-01

Benzimidazoles have been widely used since the 1960s as anthelmintic agents in veterinary and human medicine and as antifungal agents in agriculture. More recently, selected benzimidazole derivatives were shown to be active in vitro against two protozoan parasites, Trichomonas vaginalis and Giardia lamblia, and clinical studies with AIDS patients have suggested that microsporidia are susceptible as well. Here, we first present in vitro susceptibility data for T. vaginalis and G. lamblia using an expanded set of benzimidazole derivatives. Both parasites were highly susceptible to four derivatives, including mebendazole, flubendazole, and fenbendazole (50% inhibitory concentrations of 0.005 to 0.16 microgram/ml). These derivatives also had lethal activity that was time dependent: 90% of T. vaginalis cells failed to recover following a 20-h exposure to mebendazole at 0.17 microgram/ml. G. lamblia, but not T. vaginalis, was highly susceptible to five additional derivatives. Next, we examined in vitro activity of benzimidazoles against additional protozoan parasites: little or no activity was observed against Entamoeba histolytica, Leishmania major, and Acanthamoeba polyphaga. Since the microtubule protein beta-tubulin has been identified as the benzimidazole target in helminths and fungi, potential correlations between benzimidazole activity and beta-tubulin sequence were examined. This analysis included partial sequences (residues 108 to 259) from the organisms mentioned above, as well as the microsporidia Encephalitozoon hellem and Encephalitozoon cuniculi and the sporozoan Cryptosporidium parvum. beta-tubulin residues Glu-198 and, in particular, Phe-200 are strong predictors of benzimidazole susceptibility; both are present in Encephalitozoon spp. but absent in C. parvum. PMID:7811023

Inhibition of partially purified K+/H+-ATPase from guinea-pig isolated and enriched parietal cells by substituted benzimidazoles.

PubMed Central

Beil, W.; Sewing, K. F.

1984-01-01

The cellular and subcellular distributions of adenosinetriphosphatases (ATPases) were examined in guinea-pig gastric mucosal cells. All cell types displayed Mg2+-ATPase and bicarbonate (HCO3-)-stimulated ATPase activity. K+-ATPase was located only in fractions derived from parietal cells. Differential and density-gradient centrifugation of material prepared from parietal cells revealed that K+-ATPase activity was located in a tubulo-vesicular membrane fraction. Enzyme activity was ten fold greater in this fraction than in a crude parietal cell homogenate. The substituted benzimidazoles, omeprazole and picoprazole, inhibited K+-ATPase (IC50 1.8 +/- 0.5 mumol l-1 and 3.1 +/- 0.4 mumol l-1, respectively). Detailed kinetic analysis indicated that these compounds were non-competitive and reversible inhibitors of the enzyme. In contrast cimetidine and verapamil were without effect on the enzyme. The relevance of the inhibition of K+-ATPase to the antisecretory activity of the benzimidazoles, in experimental animals and man, is discussed. PMID:6146367

Arbidol: a quarter-century after. Past, present and future of the original Russian antiviral

NASA Astrophysics Data System (ADS)

Balakin, K. V.; Filosa, R.; Lavrenov, S. N.; Mkrtchayn, A. S.; Nawrozkij, M. B.; Novakov, I. A.

2018-06-01

The present review is concerned with the synthesis and structure–activity relationship studies of Arbidol and its structural analogues. The latter are roughly divided into several unequal parts: indole- and benzofuran-based compounds, benzimidazole and imidazopyridine bioisosteres and ring-expanded quinoline derivatives. Much attention is focused on various types of antiviral activity of the above-mentioned Arbidol congeners, as well as of the parent compound itself. Features of Arbidol synthesis and metabolic changes are also discussed. The bibliography includes 166 references.

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.

Development of supported liquid membrane techniques for the monitoring of trace levels of organic pollutants in wastewaters and water purification systems

NASA Astrophysics Data System (ADS)

Msagati, Titus A. M.; Mamba, Bhekie B.

The supported liquid membrane (SLM) extraction technique has been developed and successfully used for the monitoring of trace quantities of ionisable organic contaminants, including 17β-estradiol and its metabolites, testosterones and their methyl ester derivatives, benzimidazole anthelmintic antibiotics and sulphonamides in aquatic systems. A number of parameters which control the mass transfer in the supported liquid membrane extraction process such as donor and acceptor pH, extraction time and the type of organic liquid membrane were optimised to enhance the efficiency of the liquid membrane in the removal of these compounds. The method developed gave very low detection limits (0.3 ng/l to 2.4 ng/l for 17β-estradiol and its metabolites; between 1 μg/l and 20 μg/l for sulphonamides; and between 0.1 ng/l and 10 ng/l for benzimidazole anthelmintic compounds). The SLM method showed good linearity, reproducibility and repeatability values and is therefore suitable for routine monitoring of such compounds in water and wastewater systems.

Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, As A New Class of Antitubercular Agents

PubMed Central

Kumar, Kunal; Awasthi, Divya; Lee, Seung-Yub; Zanardi, Ilaria; Ruzsicska, Bela; Knudson, Susan; Tonge, Peter J.; Slayden, Richard A.; Ojima, Iwao

2010-01-01

Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds do not show appreciable cytotoxicity (IC50 >200 μM) against Vero cells, which inhibit Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation. PMID:21126020

Novel trisubstituted benzimidazoles, targeting Mtb FtsZ, as a new class of antitubercular agents.

PubMed

Kumar, Kunal; Awasthi, Divya; Lee, Seung-Yub; Zanardi, Ilaria; Ruzsicska, Bela; Knudson, Susan; Tonge, Peter J; Slayden, Richard A; Ojima, Iwao

2011-01-13

Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds did not show appreciable cytotoxicity (IC(50) > 200 μM) against Vero cells, which inhibited Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation.

Synthesis of some novel phosphorylated and thiophosphorylated benzimidazoles and benzothiazoles and their evaluation for larvicidal potential to Aedes albopictus and Culex quinquefasciatus.

PubMed

Bandyopadhyay, Prabal; Sathe, Manisha; Tikar, Sachin N; Yadav, Ruchi; Sharma, Pratibha; Kumar, Ashok; Kaushik, M P

2014-07-01

Series of benzimidazole and benzothiazole linked phosphoramidates and phosphoramidothioates (5a-j) and benzimidazole linked phenylphosphoramidates and phenylphosphoramidothioates (10a-e) were synthesized. The title compounds were preliminary screened for mosquito larvicidal properties against Aedes albopictus and Culex quinquefasciatus at different concentration from 40 to 5 mg/L. Among the screened compounds three compounds revealed potential larvicidal effects with 100% mortality in the order of 10e>5j>5e. Compound 10e was found to be the most toxic compound to Ae. albopictus and Cx. quinquefasciatus. The LC50 of 10e against Ae. albopictus was found to be 6.42 and 5.25 mg/L at 24 and 48 h, respectively, whereas it was 7.01 and 3.88 mg/L, respectively in Cx. quinquefasciatus. Temephos was used as positive control. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

Mehboob, Shahila; Hevener, Kirk E.; Truong, Kent

Because of structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motifmore » of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.« less

Structural Studies on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design

DTIC Science & Technology

2009-02-01

compounds via virtual screening. These compounds include small molecules – transition state analogues and benzimidazoles . Since there is a commonality in...Crystal structure of BoNT/E has been determined helping us to understand the faster action of BoNT/E compared to BoNT/A. • A subset of benzimidazole

Progress in the pharmacological treatment of human cystic and alveolar echinococcosis: Compounds and therapeutic targets

PubMed Central

Siles-Lucas, Mar; Casulli, Adriano; Cirilli, Roberto

2018-01-01

Human cystic and alveolar echinococcosis are helmintic zoonotic diseases caused by infections with the larval stages of the cestode parasites Echinococcus granulosus and E. multilocularis, respectively. Both diseases are progressive and chronic, and often fatal if left unattended for E. multilocularis. As a treatment approach, chemotherapy against these orphan and neglected diseases has been available for more than 40 years. However, drug options were limited to the benzimidazoles albendazole and mebendazole, the only chemical compounds currently licensed for treatment in humans. To compensate this therapeutic shortfall, new treatment alternatives are urgently needed, including the identification, development, and assessment of novel compound classes and drug targets. Here is presented a thorough overview of the range of compounds that have been tested against E. granulosus and E. multilocularis in recent years, including in vitro and in vivo data on their mode of action, dosage, administration regimen, therapeutic outcomes, and associated clinical symptoms. Drugs covered included albendazole, mebendazole, and other members of the benzimidazole family and their derivatives, including improved formulations and combined therapies with other biocidal agents. Chemically synthetized molecules previously known to be effective against other infectious and non-infectious conditions such as anti-virals, antibiotics, anti-parasites, anti-mycotics, and anti-neoplastics are addressed. In view of their increasing relevance, natural occurring compounds derived from plant and fungal extracts are also discussed. Special attention has been paid to the recent application of genomic science on drug discovery and clinical medicine, particularly through the identification of small inhibitor molecules tackling key metabolic enzymes or signalling pathways. PMID:29677189

Syntheses and molecular structures of novel Ru(II) complexes with bidentate benzimidazole based ligands and their catalytic efficiency for oxidation of benzyl alcohol

NASA Astrophysics Data System (ADS)

Dayan, Osman; Tercan, Melek; Özdemir, Namık

2016-11-01

Five bidentate ligands derived from quinoline-2-carboxylic acid, i.e. 2-(1H-benzimidazol-2-yl)quinoline (L1), 2-(1-benzyl-1H-benzimidazol-2-yl)quinoline (L2), 2-[1-(2,3,5,6-tetramethylbenzyl)-1H-benzimidazol-2-yl]quinoline (L3), 2-[1-(4-chlorobenzyl)-1H-benzimidazol-2-yl]quinoline (L4), and 2-[1-(4-methylbenzyl)-1H-benzimidazol-2-yl]quinoline (L5) were synthesized. Treatment of L1-5 with [RuCl2(p-cymene)]2 and KPF6 afforded six-coordinate piano-stool Ru(II) complexes, namely, [RuCl(L1)(p-cymene)]PF6 (C1), [RuCl(L2)(p-cymene)]PF6 (C2), [RuCl(L3)(p-cymene)]PF6 (C3), [RuCl(L4)(p-cymene)]PF6 (C4), and [RuCl(L5)(p-cymene)]PF6 (C5). Synthesized compounds were characterized with different techniques such as 1H and 13C NMR, FT-IR, and UV-vis spectroscopy. The solid state structure of L1 and C3 was confirmed by single-crystal X-ray diffraction analysis. The single crystal structure of C3 verified coordination of L3 to the Ru(II) center. The Ru(II) center has a pseudo-octahedral three legged piano stool geometry. The complexes C1-5 were tested as catalysts for the catalytic oxidation of benzyl alcohol to benzaldehyde in the presence of periodic acid (H5IO6) (Substrate/Catalyst/Oxidant = 1/0.01/0.5). The best result was obtained with C2 (3 h→90%).

Syntheses, crystal structures and luminescent properties of two salts with 2-((1H-imidazol-1-yl)methyl)-1H-benzimidazole

NASA Astrophysics Data System (ADS)

Wang, Yong-Tao; Lü, Lin-Rui; Tang, Gui-Mei

2018-03-01

Two new benzimidazole salts, namely, [H2IBI]2+ 2X (X = NO3- (1), ClO4- (2) [IBI = 2-((1H-imidazol-1-yl)methyl)-1H-benzimidazole], were grown through reacting IBI and two different inorganic acids by slow evaporation method, respectively. Compounds 1 and 2 have been characterized by single-crystal X-ray diffraction, IR, UV-Vis, and thermogravimetric analyses (TGA). In both compounds, a set of hydrogen bonds (C/Nsbnd H⋯O) can be clearly observed, through which a three-dimensional framework will be generated. The luminescent spectra show the emission peaks in compounds 1 and 2 are found at 375 and 371 nm, respectively. By comparison with the free IBI, the emission maxima of compounds 1 and 2 are obviously red-shifted about 67 and 63 nm, respectively.

Photophysical Behavior and Computational Investigation of Novel 1,4-Bis(2-(2-Phenylpyrimido[1,2-a]Benzimidazol-4-Yl)Phenoxy)Butan (BPPB) Macromolecule.

PubMed

Saleh, Tamer S; Hussein, Mahmoud A; Osman, Osman I; Alamry, Khalid A; Mekky, Ahmed E M; Asiri, Abdullah M; El-Daly, Samy A

2016-09-01

A new macromolecule pyrimido[l,2-a]benzimidazole derivative named 1,4-bis(2-(2-phenylpyrimido[1,2-a]benzimidazol-4-yl)phenoxy)butan (BPPB) has been synthesized in accepted yield using microwave assistance. The new compound BPPB has been formed by the interaction of 3,3'-((butane-1,4-diylbis(oxy))bis(2,1-phenylene))bis(1-phenylprop-2-en-1-one) (3) with 2- aminobenzimidazole (4) in the presence of potassium hydroxide as a basic catalyst in dimethylformamide (DMF) under microwave radiation for 20 min. The chemical structure of this novel compound was elucidated by elemental and spectral techniques including: FT-IR, (1)H-NMR, (13)C-NMR and mass spectra. The electronic absorption and emission spectra of BPPB were measured in different solvents. BPPB displayed a solvatochromic effect of the emission spectrum that is reflected by red shifts of its fluorescence emission maxima on increasing the solvent polarity, indicating a change of electronic charge distribution upon excitation. BPPB crystalline solids gave excimer-like emission at 535 nm with a bandwidth of ca. 60 nm. Ground and excited states electronic geometry optimizations using density functional theory (DFT) and time-dependent density functional theory (TD-DFT), respectively, complemented these spectral findings. The intramolecular charge transfer was investigated by natural bond orbital (NBO) technique.

Seven organic salts assembled from hydrogen-bonds of N-H⋯O, O-H⋯O, and C-H⋯O between acidic compounds and bis(benzimidazole)

NASA Astrophysics Data System (ADS)

Jin, Shouwen; Liu, Hui; Gao, Xin Jun; Lin, Zhanghui; Chen, Guqing; Wang, Daqi

2014-10-01

Seven crystalline organic acid-base adducts derived from 1,4-bis(benzimidazol-2-yl)butane/1,2-bis(2-benzimidazolyl)-1,2-ethanediol and acidic components (picric acid, 2-hydroxy-5-(phenyldiazenyl)benzoic acid, 5-sulfosalicylic acid, oxalic acid, and 1,5-naphthalenedisulfonic acid) were prepared and characterized by the single crystal X-ray diffraction analysis, IR, mp, and elemental analysis. All of the seven compounds are organic salts involving proton transfer from the acidic components to the bis(benzimidazole). For the salt 3, although a competing carboxyl group is present, it has been observed that only the proton at the -SO3H group is deprotonized rather than the H at the COOH. While in the salt 7, both COOH and SO3H were ionized to exhibit a valence number of -2. For 4, the oxalic acid existed as unionized molecule, monoanion, and dianion simultaneously in one compound. All supramolecular architectures of the organic salts 1-7 involve extensive intermolecular N-H⋯O, O-H⋯O, and C-H⋯O hydrogen bonds as well as other noncovalent interactions. Since the potentially hydrogen bonding phenol group is present in the ortho position to the carboxyl group in 2, 3, and 7, it forms the more facile intramolecular O-H⋯O hydrogen bonding. The role of weak and strong noncovalent interactions in the crystal packing is ascertained. These weak interactions combined, all the complexes displayed 3D framework structure.

Biomimetics for Treating Biofilm-Embedded Infections

DTIC Science & Technology

2012-12-17

ethers and benzimidazoles . Among all three series, PMX519 series is the most studied. Several arylamides, hybrid arylurea/ethers and... benzimidazoles have improved activity/safety profiles relative to PMX519. Eight compounds were efficacious against S. aureus in vivo. The activity against Gram... benzimidazole PMX1405 was identified and proved to be active against E.coli in vivo. Arylamide 519 series. The arylamide series have been

Antiproliferative activity of amino substituted benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles explored by 2D and 3D cell culture system.

PubMed

Perin, Nataša; Bobanović, Kristina; Zlatar, Ivo; Jelić, Dubravko; Kelava, Vanja; Koštrun, Sanja; Marković, Vesna Gabelica; Brajša, Karmen; Hranjec, Marijana

2017-01-05

Benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles with amino chains on the different positions have been evaluated by 2D and 3D assays on the human breast cancer cells. Pentacyclic derivatives were synthesized by microwave assisted amination to study the influence of the thiophene substructure on antitumor activity in comparison to tetracyclic analogues. The results obtained from 2D assay reveals that the antitumor activity is strongly dependent on the nature and position of amino chains. Tetracyclic derivatives displayed selective activity on SK-BR-3 with the 2-amino substituted derivatives as the most active ones while pentacyclic derivatives 6-16 and 21-25 showed more pronounced activity on T-47D. The evaluation of antitumor activity in the 3D assay pointed out that some of the tetracyclic and pentacyclic amino substituted derivatives showed selective activity on the MDA-MB-231 cell line. Influence of physico-chemical properties of the compounds on antiproliferative activity have been investigated by multivariate statistical methods. As a measure of lipophilicity, experimental Chrom LogD values have been determined and number of structural parameters have been calculated for investigated compounds. Main factors contributing to the antiproliferative effect for both 2D and 3D cell cultures are found to be basicity, lipophilicity, molecular weight and number of H-bond donors. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Electronic spectra and DFT calculations of some pyrimido[1,2-a]benzimidazole derivatives

NASA Astrophysics Data System (ADS)

Elshakre, Mohamed E.; Moustafa, H.; Hassaneen, Huwaida. M. E.; Moussa, Abdelrahim. Z.

2015-06-01

Ground state properties of 2,4-diphenyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine, compound 1, and its derivatives are investigated experimentally and theoretically in Dioxane and DMF. The calculations show that all the studied compounds (1-7) are non-planar, resulting in a significant impact on the electronic and structural properties. The ground state properties of compounds 1-7 at B3LYP/6-311G (d, p) show that compound 5 has the lowest EHOMO, ELUMO, and ΔE indicating highest reactivity. Compound 7 is found to have the highest polarity. The observed UV spectra in Dioxane and DMF of compounds 1-4 show 2 bands, while compounds 5-7 show 4 bands in both solvents. Band maxima (λmax) and intensities of the spectra are found to have solvent dependence reflected as blue and red shifts. The theoretical spectra computed at TD-B3LYP/6-311G (d, p) in gas phase, Dioxane and DMF indicate a good agreement with the observed spectra.

Synthesis and photophysical characterizations of thermal-stable naphthalene benzimidazoles.

PubMed

Erten-Ela, Sule; Ozcelik, Serdar; Eren, Esin

2011-07-01

Microwave-assisted synthesis, photophysical and electrochemical properties of thermal-stable naphthalene benzimidazoles and naphthalimides are studied in this paper. Microwave-assisted synthesis of naphthalene benzimidazoles provide higher yields than the conventional thermal synthesis. Comparative photophysical properties of naphthalene benzimidazoles and naphthalimides are revealed that conjugation of electron-donating group onto naphthalimide moiety increases fluorescence quantum yields. Fluorophore-solvent interactions are also investigated using Lippert-Mataga equation for naphthalimides and naphthalene benzimidazoles. Thermal stabilities of naphthalene benzimidazoles are better than naphthalimides due to increased aromaticity. The experimental E(LUMO) levels of naphthalene benzimidazoles are found to be between 3.15 and 3.28 eV. Therefore, naphthalene benzimidazole derivatives consisting of anchoring groups are promising materials in organic dye sensitized solar cells. © Springer Science+Business Media, LLC 2011

Di(hydroxyphenyl)- benzimidazole monomers

NASA Technical Reports Server (NTRS)

Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G. (Inventor)

1993-01-01

Di(hydroxyphenyl)benzimidazole monomers were prepared from phenyl-hydroxybenzoate and aromatic bis(o-diamine)s. These monomers were used in the synthesis of soluble polybenzimidazoles. The reaction involved the aromatic nucleophilic displacement of various di(hydroxyphenyl)benzimidazole monomers with activated aromatic dihalides or activated aromatic dinitro compounds in the presence of an alkali metal base. These polymers exhibited lower glass transition temperatures, improved solubility, and better compression moldability over their commercial counterparts.

Activity of benzimidazoles against Dientamoeba fragilis (Trichomonadida, Monocercomonadidae) in vitro and correlation of beta-tubulin sequences as an indicator of resistance

PubMed Central

Stark, Damien; Barratt, Joel L.N.; Roberts, Tamalee; Marriott, Deborah; Harkness, John T.; Ellis, John

2014-01-01

Recently, Dientamoeba fragilis has emerged as a significant and common enteropathogen. The majority of patients with dientamoebiasis present with gastrointestinal complaints and chronic symptoms are common. Numerous studies have successfully demonstrated parasite clearance, coupled with complete resolution of clinical symptoms following treatment with various antiparasitic compounds. Despite this, there is very little in vitro susceptibility data available for the organism. Benzimidazoles are a class of antiparasitic drugs that are commonly used for the treatment of protozoan and helminthic infections. Susceptibility testing was undertaken on four D. fragilis clinical isolates against the following benzimidazoles: albendazole, flubendazole, mebendazole, nocodazole, triclabendazole and thiabendazole. The activities of the antiprotozoal compounds at concentrations ranging from 2 μg/mL to 500 μg/mL were determined via cell counts of D. fragilis grown in xenic culture. All tested drugs showed no efficacy. The beta-tubulin transcript was sequenced from two of the D. fragilis isolates and amino acid sequences predicted a susceptibility to benzimidazoles. This is the first study to report susceptibility profiles for benzimidazoles against D. fragilis, all of which were not active against the organism. This study also found that beta-tubulin sequences cannot be used as a reliable marker for resistance of benzimidazoles in D. fragilis. PMID:25148459

Benzimidazole-Based Antibacterial Agents Against F. tularensis

PubMed Central

Kumar, Kunal; Awasthi, Divya; Lee, Seung-Yub; Cummings, Jason E.; Knudson, Susan E.; Slayden, Richard A.; Ojima, Iwao

2013-01-01

Francisella tularensis is a highly virulent pathogenic bacterium. In order to identify novel potential antibacterial agents against F. tularensis, libraries of trisubstituted benzimidazoles were screened against F. tularensis LVS strain. In a preliminary screening assay, remarkably, 23 of 2,5,6- and 2,5,7-trisubstituted benzimidazoles showed excellent activity exhibiting greater than 90 % growth inhibition at 1 µg/mL. Among those hits, 21 compounds showed MIC90 values in the range of 0.35–48.6 µg/mL after accurate MIC determination. In ex-vivo efficacy assays, four of these compounds exhibited 2–3 Log reduction in colony forming units (CFU) per mL at concentrations of 10 and 50 µg/mL. PMID:23623254

On the Interpretation of the Influence of Substituents on the UV-Spectroscopic Properties of Benzimidazole and Indazole Derivatives (In German)

NASA Astrophysics Data System (ADS)

Fabian, Walter

1983-12-01

On the interpretation of the influence of substituents on the UV-spectroscopic properties of benzimidazole and indazole derivatives. The UV spectra of a series of substituted benzimidazoles and indazoles were calculated by means of semiempirical quantum chemical methods (PPP, CNDO/S-CI). The results of the PPP calculations were subjected to a configuration analysis. Using this method, the influence of the nature and position of substituents on the absorption characteristics could be rationalized.

Interaction of Benzimidazoles and Benzotriazole: Its Corrosion Protection Properties on Mild Steel in Hydrochloric Acid

NASA Astrophysics Data System (ADS)

Ramya, K.; Mohan, Revathi; Joseph, Abraham

2014-11-01

Synergistic hydrogen-bonded interaction of alkyl benzimidazoles and 1,2,3-benzotrizole and its corrosion protection properties on mild steel in hydrochloric acid at different temperatures have been studied using polarization, EIS, adsorption, surface studies, and computational methods. The extent of synergistic interaction increases with temperature. Quantum chemical approach is used to calculate some electronic properties of the molecules and to ascertain the synergistic interaction, inhibitive effect, and molecular structures. The corrosion inhibition efficiencies and the global chemical reactivity relate to some parameters, such as total energy, E HOMO, E LUMO, and gap energy (Δ E). 1,2,3-Benzotrizole interacts with benzimidazoles derivatives up to a bond length of approximately 1.99 Å. This interaction represents the formation of a hydrogen bond between the 1,2,3-benzotrizole and benzimidazoles. This synergistic interaction of 1,2,3-benzotrizole and benzimidazole derivatives offers extended inhibition efficiency toward mild steel in hydrochloric acid.

Institute for Advanced Pharmaceutical Sciences: Molecular Targets and Drug Screens to Combat Bioterrorism

DTIC Science & Technology

2008-12-01

evaluation of bis( benzimidazoles ), bis(benzoxazoles), and benzothiazoles. Bioorg. Med. Chem., 14, 6106-6119, (2006). (2) Chang, J., Zhao, K., Pan, S...evaluation of bis( benzimidazoles ), bis(benzoxazoles), and benzothiazoles. Bioorg. Med. Chem., 14, 6106-6119, (2006). (2) Chang, J., Zhao, K., Pan, S...benzoxazole, benzimidazole and bis- benzimidazole derivatives (Figure 1) and will test their efficacy against the Bacillus anthracis ∆ANR strain. N H N CO2H

Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation.

PubMed

Liu, Han-Bo; Gao, Wei-Wei; Tangadanchu, Vijai Kumar Reddy; Zhou, Cheng-He; Geng, Rong-Xia

2018-01-01

A series of novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents were designed, synthesized and characterized by IR, NMR and HRMS spectra. The biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Noticeably, compound 7d could effectively inhibit the growth of A. flavus, E. coli DH52 and MRSA with MIC values of 1, 1 and 8 μg/mL, respectively. Further studies revealed that pyrimidine derivative 7d could exhibit bactericidal mode of action against both Gram positive (S. aureus and MRSA) and Gram negative (P. aeruginosa) bacteria. The active molecule 7d showed low cell toxicity and did not obviously trigger the development of resistance in bacteria even after 16 passages. Furthermore, compound 7d was able to beneficially regulate reactive oxygen species (ROS) generation for an excellent safety profile. Molecular docking study revealed that compound 7d could bind with DNA gyrase by the formation of hydrogen bonds. The preliminary exploration for antimicrobial mechanism disclosed that compound 7d could effectively intercalate into calf thymus DNA to form a steady supramolecular complex, which might further block DNA replication to exert the powerful bioactivities. The binding investigation of compound 7d with human serum albumins (HSA) revealed that this molecule could be effectively transported by HSA. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Synthesis and Optical Properties of Excited-State Intramolecular Proton Transfer Active π-Conjugated Benzimidazole Compounds: Influence of Structural Rigidification by Ring Fusion.

PubMed

Takagi, Koji; Ito, Kaede; Yamada, Yoshihiro; Nakashima, Takuya; Fukuda, Ryoichi; Ehara, Masahiro; Masu, Hyuma

2017-12-01

Two excited-state intramolecular proton transfer (ESIPT) active benzimidazole derivatives (1 and 2) were synthesized by acid-catalyzed intramolecular cyclization. The steady-state fluorescence spectrum in THF revealed that ring-fused derivative 1 exhibits a dual emission, namely, the major emission was from the K* (keto) form (ESIPT emission) at 515 nm with a large Stokes shift of 11 100 cm -1 and the minor emission was from the E* (enol) form at below 400 nm. In contrast, the normal emission from the E* form was dominant and the fluorescence quantum yield was very low (Φ ∼ 0.002) for nonfused derivative 2. The time-resolved fluorescence spectroscopy of 1 suggested that ESIPT effectively occurs due to the restricted conformational transition to the S 1 -T ICT state, and the averaged radiative and nonradiative decay rate constants were estimated as ⟨k f ⟩ = 0.15 ns -1 and ⟨k nr ⟩ = 0.60 ns -1 , respectively. The fluorescence emission of 1 was influenced by the measurement conditions, such as solvent polarity and basicity, as well as the presence of Lewis base. The ESIPT process and solvatochromic behavior were nicely reproduced by the DFT/TDDFT calculation using the PCM model. In the single-crystal fluorescent spectra, the ESIPT emissions were exclusively observed for both fused and nonfused compounds as a result of hydrogen-bonding interactions.

Design, Synthesis and Evaluation of Novel 2,5,6-Trisubstituted Benzimidazoles Targeting FtsZ as Antitubercular Agents

PubMed Central

Park, Bora; Awasthi, Divya; Chowdhury, Soumya R.; Melief, Eduard H.; Kumar, Kunal; Knudson, Susan E.; Slayden, Richard A.; Ojima, Iwao

2014-01-01

Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63–12.5 μg/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the Kd of 5a with Mtb-FtsZ was determined to be 1.32 μM. PMID:24726304

Synthesis of substituted 2-(β-D-glucopyranosyl)-benzimidazoles and their evaluation as inhibitors of glycogen phosphorylase.

PubMed

Bokor, Éva; Szilágyi, Enikő; Docsa, Tibor; Gergely, Pál; Somsák, László

2013-11-15

Microwave assisted condensation of O-perbenzoylated C-(β-d-glucopyranosyl)formic acid with 1,2-diaminobenzenes in the presence of triphenylphosphite gave the corresponding O-protected 2-(β-d-glucopyranosyl)-benzimidazoles in moderate yields. O-Perbenzoylated C-(β-d-glucopyranosyl)formamide and -thioformamide were transformed into the corresponding ethyl C-(β-d-glucopyranosyl)formimidate and -thioformimidate, respectively, by Et3O·BF4. Treatment of the formimidate with 1,2-diaminobenzenes afforded O-protected 2-(β-d-glucopyranosyl)-benzimidazoles in good to excellent yields. Similar reaction of the thioformimidate gave these compounds in lower yields. The O-benzoyl protecting groups were removed by the Zemplén protocol. These test compounds were assayed against rabbit muscle glycogen phosphorylase (GP) b, the prototype of liver GP, the rate limiting enzyme of glycogen degradation. The best inhibitors were 2-(β-d-glucopyranosyl)-4-methyl-benzimidazole (Ki=2.8μM) and 2-(β-d-glucopyranosyl)-naphtho[2,3-d]imidazole (Ki=2.1μM) exhibiting a ∼3-4 times stronger binding than the unsubstituted parent compound. Copyright © 2013 Elsevier Ltd. All rights reserved.

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.

Aryl-substituted aminobenzimidazoles targeting the hepatitis C virus internal ribosome entry site

PubMed Central

Ding, Kejia; Wang, Annie; Boerneke, Mark A.; Dibrov, Sergey M.; Hermann, Thomas

2014-01-01

We describe the exploration of N1-aryl-substituted benzimidazoles as ligands for the hepatitis C virus (HCV) internal ribosome entry site (IRES) RNA. The design of the compounds was guided by the co-crystal structure of a benzimidazole viral translation inhibitor in complex with the RNA target. Structure-binding activity relationships of aryl-substituted benzimidazole ligands were established that were consistent with the crystal structure of the translation inhibitor complex. PMID:24856063

Activity of benzimidazoles against Dientamoeba fragilis (Trichomonadida, Monocercomonadidae) in vitro and correlation of beta-tubulin sequences as an indicator of resistance.

PubMed

Stark, Damien; Barratt, Joel L N; Roberts, Tamalee; Marriott, Deborah; Harkness, John T; Ellis, John

2014-01-01

Recently, Dientamoeba fragilis has emerged as a significant and common enteropathogen. The majority of patients with dientamoebiasis present with gastrointestinal complaints and chronic symptoms are common. Numerous studies have successfully demonstrated parasite clearance, coupled with complete resolution of clinical symptoms following treatment with various antiparasitic compounds. Despite this, there is very little in vitro susceptibility data available for the organism. Benzimidazoles are a class of antiparasitic drugs that are commonly used for the treatment of protozoan and helminthic infections. Susceptibility testing was undertaken on four D. fragilis clinical isolates against the following benzimidazoles: albendazole, flubendazole, mebendazole, nocodazole, triclabendazole and thiabendazole. The activities of the antiprotozoal compounds at concentrations ranging from 2 μg/mL to 500 μg/mL were determined via cell counts of D. fragilis grown in xenic culture. All tested drugs showed no efficacy. The beta-tubulin transcript was sequenced from two of the D. fragilis isolates and amino acid sequences predicted a susceptibility to benzimidazoles. This is the first study to report susceptibility profiles for benzimidazoles against D. fragilis, all of which were not active against the organism. This study also found that beta-tubulin sequences cannot be used as a reliable marker for resistance of benzimidazoles in D. fragilis. D. Stark et al., published by EDP Sciences, 2014

Eight supramolecular assemblies constructed from bis(benzimidazole) and organic acids through strong classical hydrogen bonding and weak noncovalent interactions

NASA Astrophysics Data System (ADS)

Jin, Shouwen; Wang, Daqi

2014-05-01

Eight crystalline organic acid-base adducts derived from alkane bridged bis(N-benzimidazole) and organic acids (2,4,6-trinitrophenol, p-nitrobenzoic acid, m-nitrobenzoic acid, 3,5-dinitrobenzoic acid, 5-sulfosalicylic acid and oxalic acid) were prepared and characterized by X-ray diffraction analysis, IR, mp, and elemental analysis. Of the eight compounds five are organic salts (1, 4, 6, 7 and 8) and the other three (2, 3, and 5) are cocrystals. In all of the adducts except 1 and 8, the ratio of the acid and the base is 2:1. All eight supramolecular assemblies involve extensive intermolecular classical hydrogen bonds as well as other noncovalent interactions. The role of weak and strong noncovalent interactions in the crystal packing is ascertained. These weak interactions combined, all the complexes displayed 3D framework structure. The results presented herein indicate that the strength and directionality of the classical N+-H⋯O-, O-H⋯O, and O-H⋯N hydrogen bonds (ionic or neutral) and other nonbonding associations between acids and ditopic benzimidazoles are sufficient to bring about the formation of cocrystals or organic salts.

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

PubMed

Mochizuki, Michiyo; Kori, Masakuni; Kobayashi, Katsumi; Yano, Takahiko; Sako, Yuu; Tanaka, Maiko; Kanzaki, Naoyuki; Gyorkos, Albert C; Corrette, Christopher P; Cho, Suk Young; Pratt, Scott A; Aso, Kazuyoshi

2016-03-24

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.

Synthesis of benzimidazoles by potassium tert-butoxide-promoted intermolecular cyclization reaction of 2-iodoanilines with nitriles.

PubMed

Xiang, Shi-Kai; Tan, Wen; Zhang, Dong-Xue; Tian, Xian-Li; Feng, Chun; Wang, Bi-Qin; Zhao, Ke-Qing; Hu, Ping; Yang, Hua

2013-11-14

The synthesis of benzimidazoles by intermolecular cyclization reaction of 2-iodoanilines with nitriles has been developed. These reactions proceeded without the aid of any transition metals or ligands and just using KOBu(t) as the base. A variety of substituted benzimidazole derivatives can be synthesized by the approach.

Modified tetrahalogenated benzimidazoles with CK2 inhibitory activity are active against human prostate cancer cells LNCaP in vitro.

PubMed

Schneider, Carolin C; Kartarius, Sabine; Montenarh, Mathias; Orzeszko, Andrzej; Kazimierczuk, Zygmunt

2012-07-15

A series of novel CK2 inhibitors, tetrahalogenated benzimidazoles carrying an aminoalkylamino group at position 2, has been prepared by nucleophilic substitution of the respective 2,4,5,6,7-pentabromobenzimidazoles and 2-bromo-4,5,6,7-tetraiodobenzimidazoles. The new derivatives as well as some previously obtained tetrahalogenobenzimidazoles, including 4,5,6,7-tetrabromobenzimidazole (TBI) and 4,5,6,7-tetraiodobenzimidazole (TIBI), were evaluated for activity against the hormone-sensitive human prostate cancer cell line LNCaP. The activity of 2-aminoalkylamino derivatives was notably higher (LD(50) 4.75-9.37 μM) than that of TBI and TIBI (LD(50) ≈ 20 μM). The determination of the LD(50) value identified the 2-aminoethylamino-4,5,6,7-tetraiodobenzimidazole with an additional methyl group at position 1 (6) as the most efficient compound (LD(50): 4.75 ± 1.02 μM). Interestingly, there was no clear correlation between cell viability and apoptosis induction indicating additional cell death mechanisms. Copyright © 2012 Elsevier Ltd. All rights reserved.

Antischistosomal Activity of Pyrido[1,2-a]benzimidazole Derivatives and Correlation with Inhibition of β-Hematin Formation.

PubMed

Okombo, John; Singh, Kawaljit; Mayoka, Godfrey; Ndubi, Ferdinand; Barnard, Linley; Njogu, Peter M; Njoroge, Mathew; Gibhard, Liezl; Brunschwig, Christel; Vargas, Mireille; Keiser, Jennifer; Egan, Timothy J; Chibale, Kelly

2017-06-09

The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit β-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 μM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between β-hematin inhibitory and antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most active compound in vivo showed 58.7 and 61.3% total and female worm burden reduction, respectively. Pharmacokinetic analysis suggested solubility-limited absorption and high hepatic clearance as possible contributors to the modest efficacy despite good in vitro activity. The PBIs evaluated in this report thus merit further optimization to improve their efficacy and to elucidate their possible mode of action.

Unusually Strong Binding to the DNA Minor Groove by a Highly Twisted Benzimidazole-Diphenylether: Induced Fit and Bound Water†

PubMed Central

Tanious, Farial A.; Laine, William; Peixoto, Paul; Bailly, Christian; Goodwin, Kristie D.; Lewis, Mark A.; Long, Eric C.; Georgiadis, Millie M.; Tidwell, Richard R.; Wilson, W. David

2008-01-01

RT29 is a dicationic diamidine derivative that does not obey the classical “rules” for shape and functional group placement that are expected to result in strong binding and specific recognition of the DNA minor groove. The compound contains a benzimidazole-diphenyl ether core that is flanked by the amidine cations. The diphenyl ether is highly twisted and gives the entire compound too much curvature to fit well to the shape of the minor groove. DNaseI footprinting, fluorescence intercalator displacement studies and circular dichroism spectra, however, indicate that the compound is an AT specific minor groove binding agent. Even more surprisingly, quantitative biosensor-surface plasmon resonance and isothermal titration calorimetric results indicate that the compound binds with exceptional strength to certain AT sequences in DNA with a large negative enthalpy of binding. Crystallographic results for the DNA complex of RT29 compared to calculated results for the free compound show that the compound undergoes significant conformational changes to enhance its minor groove interactions. In addition, a water molecule is incorporated directly into the complex to complete the compound-DNA interface and it forms an essential link between the compound and base pair edges at the floor of the minor groove. The calculated ΔCp value for complex formation is substantially less than the experimentally observed value in support of water being an intrinsic part of the complex with a major contribution to the ΔCp value. Both the induced fit conformational changes of the compound and the bound water are essential for strong binding to DNA by RT29. PMID:17506529

Antiviral Activity of a Small-Molecule Inhibitor of Filovirus Infection

DTIC Science & Technology

2010-05-01

one or two heterocyclic aromatic struc- tures (i.e., indole, benzofuran, benzimidazole , or benzothiophene) connected via an aliphatic linker or...tion of compound hits by high-throughput analysis. Using a ZEBOV-GFP assay, 2-(2-(5-(amino(imino)methyl)-1-benzofu- ran-2-yl)vinyl)-1H- benzimidazole -5

Structure-activity relationship of three synthesized benzimidazole-based oligosaccharides in human platelet activation.

PubMed

Chang, Yi; Hsu, Wen-Hsien; Yang, Wen-Bin; Jayakumar, Thanasekaran; Lee, Tzu-Yin; Sheu, Joen-Rong; Lu, Wan-Jung; Li, Jiun-Yi

2017-11-01

Antiplatelet agents have considerable benefits in the treatment of thromboembolic diseases; however, these agents still have substantial limitations due to their severe side-effects. In this study, the antiplatelet activity of three newly synthesized saccharide based benzimidazole derivatives, M3BIM, Malto-BIM and Melibio-BIM, in collagen and thrombin-stimulated human platelets in vitro was examined. Among the compounds tested, only compound M3BIM exerted concentration (20-60 µM)-dependent inhibitory effects against collagen (1 µg/ml) and thrombin (0.01 U/ml)-induced washed human platelet aggregation. Moreover, at a concentration of 60 µM, M3BIM distinctly abolished collagen-induced adenosine triphosphate (ATP) release and intracellular Ca2+ mobilization. Additionally, this compound attenuated the collagen-induced phosphorylation of p47, a marker of the activation of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK). However, Malto-BIM and Melibio-BIM were not effective in this regard. Moreover, the toxic effects of these compounds were evaluated using zebrafish embryo toxicity (ZET) assay, and the results revealed that all three compounds had no comparative cytotoxicity within the range of 25-200 µM. Overall, the results of this study provide evidence for the inhibitory effects of M3BIM on collagen-induced platelet aggregation in vitro compared to other imidazole derivatives. The presence of 1-imidazolyl moiety at one end with a longer chain length (three sugar moieties) may be mainly responsible for the observed effects of M3BIM. These results suggest that compound M3BIM may be used as a potential candidate for the treatment of aberrant platelet activation-related diseases as it inhibits the activation of p47 and p38 MAPK, and reduces ATP release and Ca2+ mobilization.

In Vitro Activity of wALADin Benzimidazoles against Different Life Cycle Stages of Plasmodium Parasites

PubMed Central

Lentz, Christian S.; Sattler, Julia M.; Fendler, Martina; Gottwalt, Simon; Halls, Victoria S.; Strassel, Silke; Arriens, Sandra; Hannam, Jeffrey S.; Specht, Sabine; Famulok, Michael; Mueller, Ann-Kristin; Hoerauf, Achim

2014-01-01

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates. PMID:25313210

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition.

PubMed

Igawa, Hideyuki; Takahashi, Masashi; Shirasaki, Mikio; Kakegawa, Keiko; Kina, Asato; Ikoma, Minoru; Aida, Jumpei; Yasuma, Tsuneo; Okuda, Shoki; Kawata, Yayoi; Noguchi, Toshihiro; Yamamoto, Syunsuke; Fujioka, Yasushi; Kundu, Mrinalkanti; Khamrai, Uttam; Nakayama, Masaharu; Nagisa, Yasutaka; Kasai, Shizuo; Maekawa, Tsuyoshi

2016-06-01

Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q-u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents.

PubMed

Park, Bora; Awasthi, Divya; Chowdhury, Soumya R; Melief, Eduard H; Kumar, Kunal; Knudson, Susan E; Slayden, Richard A; Ojima, Iwao

2014-05-01

Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 μg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 μg/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the Kd of 5a with Mtb-FtsZ was determined to be 1.32 μM. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparative experimental pharmacokinetics of benzimidazole derivatives.

PubMed

Sergeeva, S A; Gulyaeva, I L

2008-12-01

Comparative study of experimental kinetics of distribution of benzimidazole derivatives (bemithyl, etomerzole, and thietazole) in organs and tissues was carried out after single and course treatment. The drugs intensely passed into organs and tissues from the blood after treatment by all protocols. Specific features of drug distribution were detected; for example, splenic tissue selectively accumulated thietazole during course treatment.

Polybenzimidazoles Via Aromatic Nucleophilic Displacement

NASA Technical Reports Server (NTRS)

Connell, John W.; Hergenrother, Paul M.; Smith, Joseph G.

1994-01-01

Soluble polybenzimidazoles (PBI's) synthesized by nucleophilic displacement reaction of di(hydroxyphenyl)-benzimidazole monomers with activated aromatic difluoride compounds in presence of anhydrous potassium carbonate. These polymers exhibit good thermal, thermo-oxidative, and chemical stability, and high mechanical properties. Using benzimidazole monomers, more economical, and new PBI's processed more easily than commercial PBI, without loss of desirable physical properties.

Light fluorous-tagged traceless one-pot synthesis of benzimidazoles facilitated by microwave irradiation.

PubMed

Tseng, Chih-Chung; Tasi, Cheng-Hsun; Sun, Chung-Ming

2012-06-01

A novel protocol for rapid assemble of benzimidazole framework has been demonstrated. This method incorporated with light fluorous-tag provides a convenient method for diversification of benzimidazoles and for easy purification via fluorous solid-phase extraction (F-SPE) in a parallel manner. The key transformation of this study involves in situ reduction of aromatic nitro compound, amide formation, cyclization and aromatization promoted by microwave irradiation in a one-pot fashion. The strategy is envisaged to be applied for the establishment of drug-like small molecule libraries for high throughput screening.

Multistep divergent synthesis of benzimidazole linked benzoxazole/benzothiazole via copper catalyzed domino annulation.

PubMed

Liao, Jen-Yu; Selvaraju, Manikandan; Chen, Chih-Hau; Sun, Chung-Ming

2013-04-21

An efficient, facile synthesis of structurally diverse benzimidazole integrated benzoxazole and benzothiazoles has been developed. In a multi-step synthetic sequence, 4-fluoro-3-nitrobenzoic acid was converted into benzimidazole bis-heterocycles, via the intermediacy of benzimidazole linked ortho-chloro amines. The amphiphilic reactivity of this intermediate was designed to achieve the title compounds by the reaction of various acid chlorides and isothiocyanates in a single step through the in situ formation of ortho-chloro anilides and thioureas under microwave irradiation. A versatile one pot domino annulation reaction was developed to involve the reaction of benzimidazole linked ortho-chloro amines with acid chlorides and isothiocyanates. The initial acylation and urea formation followed by copper catalyzed intramolecular C-O and C-S cross coupling reactions furnished the angularly oriented bis-heterocycles which bear a close resemblance to the streptomyces antibiotic UK-1.

Design, synthesis and biological activity of 6-substituted carbamoyl benzimidazoles as new nonpeptidic angiotensin II AT₁ receptor antagonists.

PubMed

Zhang, Jun; Wang, Jin-Liang; Zhou, Zhi-Ming; Li, Zhi-Huai; Xue, Wei-Zhe; Xu, Di; Hao, Li-Ping; Han, Xiao-Feng; Fei, Fan; Liu, Ting; Liang, Ai-Hua

2012-07-15

A series of 6-substituted carbamoyl benzimidazoles were designed and synthesised as new nonpeptidic angiotensin II AT(1) receptor antagonists. The preliminary pharmacological evaluation revealed a nanomolar AT(1) receptor binding affinity for all compounds in the series, and a potent antagonistic activity in an isolated rabbit aortic strip functional assay for compounds 6f, 6g, 6h and 6k was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6g is an orally active AT(1) receptor antagonist with low toxicity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Research on differences between 2-(2‧-pyridyl)benzimidazole and 2-(4‧-pyridyl)benzimidazole based on terahertz time-domain spectroscopy

NASA Astrophysics Data System (ADS)

Song, Maojiang; Yang, Fei; Liu, Liping; Su, Caixia

2018-02-01

Due to the important pharmaceutical activities of benzimidazole derivatives, the differences between 2-(2‧-pyridyl)benzimidazole and 2-(4‧-pyridyl)benzimidazole were researched by terahertz time-domain spectroscopy and density functional theory systematically. Although the only difference between their molecular configurations is the different arrangement of nitrogen on pyridine ring, 2PBI and 4PBI have large differences in their experimental absorption spectra in the range of 0.2-2.5 THz, such as the amount, amplitude and frequency position of absorption peaks. The validity of these results was confirmed by the theoretical results simulated using density functional theory. The possible reasons of these differences originate from the different dihedral angles between benzimidazole ring and pyridine ring and the different hydrogen-bonding interactions within crystal cell.

Crystal structures and intermolecular interactions of two novel antioxidant triazolyl-benzimidazole compounds

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

Karayel, A., E-mail: matchlessjimmy@163.com, E-mail: yccaoh@hotmail.com; Özbey, S.; Ayhan-Kılcıgil, G.

2015-12-15

The crystal structures of 5-(2-(p-chlorophenylbenzimidazol-1-yl-methyl)-4-(3-fluorophenyl)-2, 4-dihydro-[1,2,4]-triazole-3-thione (G6C) and 5-(2-(p-chlorophenylbenzimidazol-1-yl-methyl)-4-(2-methylphenyl)-2, 4-dihydro-[1,2,4]-triazole-3-thione (G4C) have been determined by single-crystal X-ray diffraction. Benzimidazole ring systems in both molecules are planar. The triazole part is almost perpendicular to the phenyl and the benzimidazole parts of the molecules in order to avoid steric interactions between the rings. The crystal structures are stabilized by intermolecular hydrogen bonds between the amino group of the triazole and the nitrogen atom of benzimidazole of a neighboring molecule.

Synthesis and characterization of a novel long-alkyl-chain ester-substituted benzimidazole gelator and its octan-1-ol solvate.

PubMed

Geiger, H Cristina; Zick, Patricia L; Roberts, William R; Geiger, David K

2017-04-01

The synthesis of a novel benzimidazole derivative with a long-chain-ester substituent, namely methyl 8-[4-(1H-benzimidazol-2-yl)phenoxy]octanoate, (3), is reported. Ester (3) shows evidence of aggregation in solution and weak gelation ability with toluene. The octan-1-ol solvate, methyl 8-[4-(1H-benzimidazol-2-yl)phenoxy]octanoate octan-1-ol monosolvate, C 22 H 26 N 2 O 3 ·C 8 H 18 O, (4), exhibits a four-molecule hydrogen-bonded motif in the solid state, with N-H...O hydrogen bonds between benzimidazole molecules and O-H...N hydrogen bonds between the octan-1-ol solvent molecules and the benzimidazole unit. The alkyl chains of the ester and the octan-1-ol molecules are in unfolded conformations. The phenylene ring is canted by 10.27 (6)° from the plane of the benzimidazole ring system. H...C contacts make up 20.7% of the Hirshfeld surface coverage. Weak C-H...π interactions involving the benzimidazole alkyl chain and three aromatic rings are observed.

In vitro activity of wALADin benzimidazoles against different life cycle stages of Plasmodium parasites.

PubMed

Lentz, Christian S; Sattler, Julia M; Fendler, Martina; Gottwalt, Simon; Halls, Victoria S; Strassel, Silke; Arriens, Sandra; Hannam, Jeffrey S; Specht, Sabine; Famulok, Michael; Mueller, Ann-Kristin; Hoerauf, Achim; Pfarr, Kenneth M

2015-01-01

wALADin1 benzimidazoles are specific inhibitors of δ-aminolevulinic acid dehydratase from Wolbachia endobacteria of filarial nematodes. We report that wALADin1 and two derivatives killed blood stage Plasmodium falciparum in vitro (50% inhibitory concentrations, 39, 7.7, and 12.8 μM, respectively). One of these derivatives inhibited gliding motility of Plasmodium berghei ANKA infectious sporozoites with nanomolar affinity and blocked invasion into hepatocytes but did not affect intrahepatocytic replication. Hence, wALADin1 benzimidazoles are tools to study gliding motility and potential antiplasmodial drug candidates. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Synthesis, characterization, and antimicrobial activity of silver(I) and copper(II) complexes of phosphate derivatives of pyridine and benzimidazole.

PubMed

Kalinowska-Lis, Urszula; Szewczyk, Eligia M; Chęcińska, Lilianna; Wojciechowski, Jakub M; Wolf, Wojciech M; Ochocki, Justyn

2014-01-01

Two silver(I) complexes--[Ag(4-pmOpe)]NO₃}(n) and [Ag(2-bimOpe)₂]NO₃--and three copper(II) complexes--[Cu₄Cl₆O(2-bimOpe)₄], [CuCl₂(4-pmOpe)₂], and [CuCl₂(2-bis(pm)Ope]--were synthesized by reaction of silver(I) nitrate or copper(II) chloride with phosphate derivatives of pyridine and benzimidazole, namely diethyl (pyridin-4-ylmethyl)phosphate (4-pmOpe), 1H-benzimidazol-2-ylmethyl diethyl phosphate (2-bimOpe), and ethyl bis(pyridin-2-ylmethyl)phosphate (2-bis(pm)Ope). These compounds were characterized by ¹H, ¹³C, and ³¹P NMR as well as IR spectroscopy, elemental analysis, and ESIMS spectrometry. Additionally, molecular and crystal structures of {[Ag(4-pmOpe)]NO₃}n and [Cu₄Cl₆O(2-bimOpe)₄] were determined by single-crystal X-ray diffraction analysis. The antimicrobial profiles of synthesized complexes and free ligands against test organisms from the ATCC and clinical sources were determined. Silver(I) complexes showed good antimicrobial activities against Candida albicans strains (MIC values of ∼19 μM). [Ag(2-bimOpe)₂]NO₃ was particularly active against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus epidermidis, with MIC values of ∼5 and ∼10 μM, respectively. Neither copper(II) complexes nor the free ligands inhibited the growth of test organisms at concentrations below 500 μg mL⁻¹. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and Crystal Structures of Benzimidazole-2-thione Derivatives by Alkylation Reactions.

PubMed

El Ashry, El Sayed H; El Kilany, Yeldez; Nahas, Nariman M; Barakat, Assem; Al-Qurashi, Nadia; Ghabbour, Hazem A; Fun, Hoong-Kun

2015-12-22

Alkylated, benzylated and bromoalkylated benzimidazole-thione that intramolecularly heterocyclized to 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole were synthesized. The chemical structure of the synthesized product was characterized by Infra Red, ¹H-NMR, (13)C-NMR, and Mass spectroscopy. Furthermore, the molecular structures of 8 and 9 were confirmed by X-ray single crystallography in different space groups, Pbca and P2₁/c, respectively.

A novel series of N-acyl substituted indole-linked benzimidazoles and naphthoimidazoles as potential anti inflammatory, anti biofilm and anti microbial agents.

PubMed

Abraham, Rajan; Prakash, Periakaruppan; Mahendran, Karthikeyan; Ramanathan, Murugappan

2018-01-01

A novel N-acyl substituted indole-linked benzimidazoles and naphthoimidazoles were synthesized. Their chemical structures were confirmed using spectroscopic tools including 1 H NMR, 13 C NMR and CHN-elemental analyses. Anti inflammatory activity for all target compounds was evaluated in-vitro. The synthesized compounds hinder the biofilm formation and control the growth of the pathogen, Staphylococcus epidermis. Anti microbial activity of the compounds was evaluated against both Gram negative and Gram positive bacteria such as Staphylococcus aureus (MTCC 2940), Pseudomonas aeruginosa (MTCC424), Escherchia coli (MTCC 443) and Enterococcus fecalis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structure of five molecular salts assembled from noncovalent associations between organic acids, imidazole, benzimidazole, and 1-(2-(1H-benzimidazol-1-yl)ethyl)-1H-benzimidazole

NASA Astrophysics Data System (ADS)

Chen, Xuchong; Jin, Shouwen; Zhang, Huan; Xiao, Xiao; Liu, Bin; Wang, Daqi

2017-09-01

Cocrystallization of the imidazole derivatives, L1-L3, with a series of organic acids gave a total of five molecular salts with the compositions: (imidazole): (DL-10-camphorsulfonic acid) [(HL1+)·(cpsa-), cpsa- = DL-10-camphorsulfonate] (1), (imidazole): (3,5-dihydroxybenzoic acid) [(HL1+) · (3,5-dba-), 3,5-dba- = 3,5-dihydroxybenzoate] (2), (imidazole): (isophthalic acid): H2O [(HL1)+·(Hmpa)-·H2O, Hmpa- = hydrogenisophthalate] (3), (benzimidazole): (butane-1,2,3,4-tetracarboxylic acid) [(HL2+)·(H3bta -), H3bta- = trihydrogen butane-1,2,3,4-tetracarboxylate] (4), and (benzimidazole)2: 1-(2-(1H-benzimidazol-1-yl)ethyl)-1H-benzimidazole: (5-nitrosalicylic acid)2 [(L2)2·(H2L3)2+·(5-nsa-)2, 5-nsa- = 5-nitrosalicylate], (5). The five salts have been characterized by XRD technique, IR, and EA, and the melting points of all the salts were also reported. And their structural and supramolecular aspects are fully analyzed. The result reveals that among the five investigated crystals the ring N in the imidazole moieties are protonated when the organic acids are ionized, and the crystal packing is interpreted in terms of the strong Nsbnd H⋯O H-bond from the imidazole and the ionized acids. In addition to the Nsbnd H⋯O H-bond, the Osbnd H⋯O H-bonds were also established at the salts 2-5, compound 1 has the additional Nsbnd H⋯S H-bonds. Further analysis of the crystal packing of the salts displayed that a different family of additional CHsbnd O/CH2sbnd O/CH3sbnd O, CHsbnd S, CHsbnd π, NHsbnd π, and πsbnd π associations contribute to the stabilization and expansion of the total 3D framework structures. For the coexistence of the various weak interactions these structures had homo or hetero supramolecular synthons or both. Some classical supramolecular synthons, such as R12(4), R22(7), and R22(8) usually observed in crystals of organic acids with imidazole, were again shown to be involved in constructing most of these hydrogen bonding networks.

Cytotoxic properties of a new organometallic platinum(II) complex and its gold(I) heterobimetallic derivatives.

PubMed

Serratrice, Maria; Maiore, Laura; Zucca, Antonio; Stoccoro, Sergio; Landini, Ida; Mini, Enrico; Massai, Lara; Ferraro, Giarita; Merlino, Antonello; Messori, Luigi; Cinellu, Maria Agostina

2016-01-14

A novel platinum(ii) organometallic complex, [Pt(pbi)(Me)(DMSO)], bearing the 2-(2'-pyridyl)-benzimidazole (pbiH) ligand, was synthesized and fully characterized. Interestingly, the reaction of this organometallic platinum(ii) complex with two distinct gold(i) phosphane compounds afforded the corresponding heterobimetallic derivatives with the pbi ligand bridging the two metal centers. The antiproliferative properties in vitro of [Pt(pbi)(Me)(DMSO)] and its gold(i) derivatives as well as those of the known coordination platinum(ii) and palladium(ii) complexes with the same ligand, of the general formula [MCl2(pbiH)], were comparatively evaluated against A2780 cancer cells, either sensitive or resistant to cisplatin. A superior biological activity of the organometallic compound clearly emerged compared to the corresponding platinum(ii) complex; the antiproliferative effects are further enhanced upon attaching the gold(i) triphenylphosphine moiety to the organometallic Pt compound. Remarkably, these novel metal species are able to overcome nearly complete resistance to cisplatin. Significant mechanistic insight into the study compounds was gained after investigating their reactions with a few representative biomolecules by electrospray mass spectrometry and X-ray crystallography. The obtained results are comprehensively discussed.

Fidelity Mechanisms of DNA Polymerase Alpha

DTIC Science & Technology

2008-07-23

significantly lowers fidelity. Analogously, adding the equivalent of N-3 to low-fidelity benzimidazole -derived bases (generating 1-deazapurines... benzimidazole or to 1-deazapurines significantly decreases the rate at which pol α polymerizes the resulting bases opposite A, C, and G, while simultaneously

Characterization of some amino acid derivatives of benzoyl isothiocyanate: Crystal structures and theoretical prediction of their reactivity

NASA Astrophysics Data System (ADS)

Odame, Felix; Hosten, Eric C.; Betz, Richard; Lobb, Kevin; Tshentu, Zenixole R.

2015-11-01

The reaction of benzoyl isothiocyanate with L-serine, L-proline, D-methionine and L-alanine gave 2-[(benzoylcarbamothioyl)amino]-3-hydroxypropanoic acid (I), 1-(benzoylcarbamothioyl)pyrrolidine-2-carboxylic acid (II), 2-[(benzoylcarbamothioyl)amino]-4-(methylsulfanyl)butanoic acid (III) and 2-[(benzoylcarbamothioyl)amino]propanoic acid (IV), respectively. The compounds have been characterized by IR, NMR, microanalyses and mass spectrometry. The crystal structures of all the compounds have also been discussed. Compound II showed rotamers in solution. DFT calculations of the frontier orbitals of the compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity of these compounds. The calculations indicated that the carboxylic acid group in these compounds is unreactive hence making the conversion to benzimidazoles via cyclization on the carboxylic acids impractical. This has been further confirmed by the reaction of compounds I-IV, respectively, with o-phenylene diamine which was unsuccessful but gave compound V.

Microwave assisted synthesis and anti-lipase activity of some new fluorine-containing benzimidazoles.

PubMed

Menteşe, E; Yilmaz, F; Ülker, S; Kahveci, B

2015-01-01

In this study, a new series of fluorine containing benzimidazoles (4a-l) and bisbenzimidazoles (6a-c, 8) were synthesized by the reaction of o-phenylenediamines with iminoester hydrochlorides (3a-l, 7) in methanol under microwave irradiation. The structures of these newly synthesized compounds were identified by IR, (1)H-NMR, (13)C-NMR, mass spectroscopy and elemental analysis data. The synthesized compounds were screened for their pancreatic lipase activities. Our results indicate that the compounds 6a, 6b and 6c can serve as an anti-lipase agent. The compounds 6b and 6c inhibited pancreatic lipase activity by 84.03% and 97.49% at a concentration of 3 µg/mL, respectively. © Georg Thieme Verlag KG Stuttgart · New York.

Structural investigation of HIV-1 nonnucleoside reverse transcriptase inhibitors: 2-Aryl-substituted benzimidazoles

NASA Astrophysics Data System (ADS)

Ziółkowska, Natasza E.; Michejda, Christopher J.; Bujacz, Grzegorz D.

2009-11-01

Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) is one of the most destructive epidemics in history. Inhibitors of HIV enzymes are the main targets to develop drugs against that disease. Nonnucleoside reverse transcriptase inhibitors of HIV-1 (NNRTIs) are potentially effective and nontoxic. Structural studies provide information necessary to design more active compounds. The crystal structures of four NNRTI derivatives of 2-aryl-substituted N-benzyl-benzimidazole are presented here. Analysis of the geometrical parameters shows that the structures of the investigated inhibitors are rigid. The important geometrical parameter is the dihedral angle between the planes of the π-electron systems of the benzymidazole and benzyl moieties. The values of these dihedral angles are in a narrow range for all investigated inhibitors. There is no significant difference between the structure of the free inhibitor and the inhibitor in the complex with RT HIV-1. X-ray structures of the investigated inhibitors are a good basis for modeling enzyme-inhibitor interactions in rational drug design.

Synthesis, crystal structure determination and antiproliferative activity of novel 2-amino-4-aryl-4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazoles

NASA Astrophysics Data System (ADS)

Hranjec, Marijana; Pavlović, Gordana; Karminski-Zamola, Grace

2012-01-01

This manuscript describes the synthesis of novel 2-amino-4-aryl-4,10-dihydro-[1,3,5]triazino[1,2- a]benzimidazoles as hydrochloride salts 4a-n and 5b which were prepared in the reaction of cyclocondensation between 2-guanidinobenzimidazole and versatile heteroaromatic aldehydes. Structures of all prepared compounds have been studied by using 1H and 13C NMR, IR and UV/Vis spectroscopy. The crystal and molecular structure of 4f was determined by X-ray diffraction on single crystals. The molecule of 2-amino-4-(4'-methylphenyl)-4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazole hydrochloride 4f (C 16H 16N 5+·Cl -) exists in the solid state in one of the possible tautomeric forms, being protonated at the one of the nitrogen atoms of the 1,4-dihydrotriazine ring. The molecule is highly delocalized within the 4,10-dihydro[1,3,5]triazino[1,2- a]benzimidazole moiety with the highest deviation from the plane for the methine carbon atom and the protonated nitrogen atom of the 1,4-dihydrotriazine ring. The cations are joined via N-H⋯N hydrogen bonds into R22(8) centrosymmetric dimers. Cation dimers are further connected with Cl - ions via N-H⋯Cl and C-H⋯Cl hydrogen bonds into 2D chains spreading along the b axis. The obtained single-crystal X-ray structure determination unequivocally confirms tautomeric form of the compound present in the solid-state and can represent tantative pattern for other prepared compounds. All prepared compounds were tested on their antiproliferative activity in vitro on several human cancer cell lines. Compound 4m was the most active one (IC 50 ≈ 20 μM), while compounds 4d, 4f, 4k, 4l4m showed moderate, but non-selective, antiproliferative activity with IC 50 25-60 μM.

Antioxidative and antiproliferative activities of novel pyrido[1,2-a]benzimidazoles.

PubMed

Tireli, Martina; Starčević, Kristina; Martinović, Tamara; Pavelić, Sandra Kraljević; Karminski-Zamola, Grace; Hranjec, Marijana

2017-02-01

A series of pyrido[1,2-a]benzimidazoles has been designed, and novel examples are synthesized and evaluated for their potential antiproliferative activity against four human tumour cell lines-cervical (HeLa), colorectal (SW620), breast (MCF-7) and hepatocellular carcinoma (HepG2). In addition, their antioxidative potency has been evaluated by in vitro spectrophotometric assays. Preliminary structure-activity relationships among the synthesized compounds are discussed. Evaluation of their antioxidative capacity has shown that two compounds (25 and 26) possess promising reducing characteristics and free radical scavenging activity. Selective antiproliferative effect in the single-digit micromolar range was observed for compound 25 on MCF-7 [Formula: see text] and HeLa [Formula: see text] cell lines, comparable to the standards 5-fluorouracil and cisplatin. The combination of the radical scavenging activity and antiproliferative activity of compound 25 positions this compound as a potential lead candidate for further optimization.

Design, synthesis, molecular docking and biological evaluation of new dithiocarbamates substituted benzimidazole and chalcones as possible chemotherapeutic agents.

PubMed

Bacharaju, Keerthana; Jambula, Swathi Reddy; Sivan, Sreekanth; Jyostnatangeda, Saritha; Manga, Vijjulatha

2012-05-01

A series of novel dithiocarbamates with benzimidazole and chalcone scaffold have been designed synthesised and evaluated for their antimitotic activity. Compounds 4c and 9d display the most promising antimitotic activity with IC(50) of 1.66 μM and 1.52 μM respectively. Copyright © 2012 Elsevier Ltd. All rights reserved.

Quantum-chemical insight into structure-reactivity relationship in 4,5,6,7-tetrahalogeno-1H-benzimidazoles: a combined X-ray, DSC, DFT/QTAIM, Hirshfeld surface-based, and molecular docking approach.

PubMed

Latosińska, Jolanta Natalia; Latosińska, Magdalena; Maurin, Jan Krzysztof; Orzeszko, Andrzej; Kazimierczuk, Zygmunt

2014-03-20

The weak interaction patterns in 4,5,6,7-tetrahalogeno-1H-benzimidazoles, protein kinase CK2 inhibitors, in solid state are studied by the X-ray method and quantum chemistry calculations. The crystal structures of 4,5,6,7-tetrachloro- and 4,5,6,7-tetrabromo-1H-benzimidazole are determined by X-ray diffraction and refined to a final R-factor of 3.07 and 3.03%, respectively, at room temperature. The compound 4,5,6,7-tetrabromo-1H-benzimidazole, which crystallizes in the I41/a space group, is found to be isostructural with previously studied 4,5,6,7-tetraiodo-1H-benzimidazole in contrast to 4,5,6,7-tetrachloro-1H-benzimidazole, which crystallizes as triclinic P1̅ with 4 molecules in elementary unit. For 4,5,6,7-tetrachloro-1H-benzimidazole, differential scanning calorimetry (DSC) revealed a second order glassy phase transition at Tg = 95°/106° (heating/cooling), an indication of frozen disorder. The lack of 3D isostructurality found in all 4,5,6,7-tetrahalogeno-1H-benzimidazoles is elucidated on the basis of the intra- and intermolecular interactions (hydrogen bonding, van der Waals contacts, and C-H···π interactions). The topological Bader's Quantum Theory of Atoms in Molecules (QTAIM) and Spackman's Hirshfeld surface-based approaches reveal equilibration of electrostatic matching and dispersion van der Waals interactions between molecules consistent with the crystal site-symmetry. The weakening of van der Waals forces accompanied by increasing strength of the hydrogen bond (N-H···N) result in a decrease in the crystal site-symmetry and a change in molecular packing in the crystalline state. Crystal packing motifs were investigated with the aid of Hirshfeld surface fingerprint plots. The ordering 4,5,6,7-tetraiodo > 4,5,6,7-tetrabromo > 4,5,6,7-tetrachloro > 4,5,6,7-tetrafluoro reflects not only a decrease in crystal symmetry but also increase in chemical reactivity (electronic activation), which could explain some changes in biological activity of compounds from the 4,5,6,7-tetrahalogeno-1H-benzimidazole series. The ability of formation of a given type of bonds by 4,5,6,7-tetrahalogeno-1H-benzimidazole molecules is the same in the crystal and in CK2. Analysis of the interactions in the crystal permits drawing conclusions on the character (the way) of connections between a given 4,5,6,7-tetrahalogeno-1H-benzimidazole as a ligand with CK2 protein to make a protein-ligand complex.

The synthesis of benzimidazoles and quinoxalines from aromatic diamines and alcohols by iridium-catalyzed acceptorless dehydrogenative alkylation.

PubMed

Hille, Toni; Irrgang, Torsten; Kempe, Rhett

2014-05-05

Benzimidazoles and quinoxalines are important N-heteroaromatics with many applications in pharmaceutical and chemical industry. Here, the synthesis of both classes of compounds starting from aromatic diamines and alcohols (benzimidazoles) or diols (quinoxalines) is reported. The reactions proceed through acceptorless dehydrogenative condensation steps. Water and two equivalents of hydrogen are liberated in the course of the reactions. An Ir complex stabilized by the tridentate P^N^P ligand N(2) ,N(6) -bis(di-isopropylphosphino)pyridine-2,6-diamine revealed the highest catalytic activity for both reactions. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Polybenzimidazoles via aromatic nucleophilic displacement

NASA Technical Reports Server (NTRS)

Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

1995-01-01

Novel molecular weight controlled and endcapped polybenzimidazoles (PBI) are prepared by the aromatic nucleophilic displacement reaction of di(hydroxyphenyl benzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The PBI are endcapped with mono(hydroxyphenyl) benzimidazoles. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. Mono(hydroxyphenyl) benzimidazoles are synthesizedby reacting phenyl-4-hydroxybenzoate with aromatic (o-diamine)s in diphenylsulfone. Molecular weight controlled and endcapped PBI of new chemical structures are prepared that exhibit a favorable combination of physical and mechanical properties.

1-(2-Cyano­ethyl)-2-(2-pyrid­yl)-1H,3H-benzimidazol-3-ium perchlorate

PubMed Central

Li, Yan; Tang, Xiaoliang; Chen, Jiayu; Wu, Daxiang; Liu, Weisheng

2010-01-01

The title compound, C15H13N4 +·ClO4 −, comprises a nonplanar 1-(2-cyano­ethyl)-2-(2-pyrid­yl)-1H,3H-benzimidazol-3-ium cation [dihedral angle between the imidazole and pyridine rings = 22.5 (8)°] and a perchlorate anion. The cation is formed by protonation of the N atom of the benzimidazole ring. A charged N—H⋯O hydrogen bond connects the anion and cation, and inter­molecular C—H⋯O and C—H⋯N inter­actions contribute to the crystal packing. PMID:21579831

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.

Two novel zinc(II) coordination polymers constructed from in situ amidation ligands

NASA Astrophysics Data System (ADS)

Yu, Xiao-Yang; Fu, Yao; Fu, Jian-Tao; Xu, Jia-Ning; Luo, Ya-Nan; Yang, Yan-Yan; Qu, Xiao-Shu; Zhang, Jing; Lu, Shu-Lai

2018-04-01

Two novel coordination compounds, [Zn(Hbimh) (H2O)]·H2O (1) and [Zn(Hbimh)]·(4,4ʹ-bpy)0.5 (2) (H3bimh = benzimidazole-5,6-hydrazide, 4,4ʹ-bpy = 4,4ʹ-bipyridine), have been prepared from the hydrothermal in situ amidation cyclization reactions of H3bimdc (H3bimdc = benzimidazole-5,6-dicarboxylic acid) and hydrazine hydrate (N2H4·H2O). Compound 1 exhibits a one-dimensional (1D) hexagon channel structure. Compound 2 is a three-dimensional (3D) framework structure, with 4,4ʹ-bpy fill the channels. We also obtained the ligand H3bimh. The compounds were characterized by IR, PXRD, TGA and elemental analysis. The fluorescence properties in the solid state at room temperature were also investigated.

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

Medyantseva, E.P.; Budnikov, G.K.; Balakaeva, T.A.

The interest in the analytical chemistry of ruthenium and its compounds has recently been increasing. Ruthenium compounds can be used an antitumor agents and in the treatment of tuberculosis and fungal infections. It has been suggested that there is a specific relationship between the reduction potentials of the compounds and their biological activity. Of greatest interest among the biologically active compounds are the compounds with nitrogen-containing heterocycles. In order to obtain information on the degree of oxidation of the central atom in the complexes and to select the optimum conditions for the determination of the mono- and bi-nuclear complexes ofmore » ruthenium compounds with biologically active ligands such as imidazole (Im), histidine (His), benzimidazole (BIm) and its methyl derivative [1,2(CH{sub 3}){sub 2} - BIm], benzohyroxamic acid (Bha), and 1-phenyl-2-methylamino-1-propanol or ephedrine (Eph) in the present work, the authors studied their electrochemical behavior at dropping mercury (dme) and a platinum electrodes. 6 refs., 1 fig., 2 tabs.« less

Property Predictions for Nitrate Salts with Nitroxy-Functionalized Cations

DTIC Science & Technology

2011-05-01

Imidazole, Indazole, and Benzimidazole . Journal of Chemical Thermodynamics, 1987, 19, 985–992. Jocelyn, P. C. Some Derivatives of 2-2...Enthalpies of Formation of Pyrazole, Imidazole, Indazole, and Benzimidazole . Journal of Chemical Thermodynamics 1987, 19, 985–992. pA B3LYP/6-31+G(d,p

Activity of cationically substituted bis-benzimidazoles against experimental Pneumocystis carinii pneumonia.

PubMed Central

Tidwell, R R; Jones, S K; Naiman, N A; Berger, L C; Brake, W B; Dykstra, C C; Hall, J E

1993-01-01

On the basis of a previously observed correlation between the antimicrobial activity and DNA binding strength of dicationic molecules, a series of 10 dicationically substituted bis-benzimidazoles were tested for activity in the rat model of Pneumocystis carinii pneumonia. One of the compounds, 1,4-bis[5-(2-imidazolinyl)-2-benzimidazolyl]butane, was found to be more potent and less toxic than pentamidine. PMID:8215291

Polybenzimidazole via aromatic nucleophilic displacement

NASA Technical Reports Server (NTRS)

Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G. (Inventor)

1994-01-01

Di(hydroxyphenyl)benzimidazole monomers were prepared from phenyl-4-hydroxybenzoate and aromatic bis(o-diamine)s. These monomers were used in the synthesis of soluble polybenzimidazoles. The reaction involved the aromatic nucleophilic displacement of various di(hydroxyphenyl)benzimidazole monomers with activated aromatic dihalides or activated aromatic dinitro compounds in the presence of an alkali metal base. These polymers exhibited lower glass transition temperatures, improved solubility, and better compression moldability over their commercial counterparts.

Design, synthesis and biological evaluation of novel hydroxy-phenyl-1H-benzimidazoles as radical scavengers and UV-protective agents.

PubMed

Bino, Alessia; Baldisserotto, Anna; Scalambra, Emanuela; Dissette, Valeria; Vedaldi, Daniela Ester; Salvador, Alessia; Durini, Elisa; Manfredini, Stefano; Vertuani, Silvia

2017-12-01

An ever-increasing incidence of skin neoplastic diseases is registered. Therefore, it is important to protect the skin from the UV radiation that reaches the epidermis and dermis but also to block ROS generated by them. Our attention was attracted in developing new compounds provided with both UV filtering and antioxidant capacities. To this end, 2-phenyl-1H-benzimidazole-5-sulfonic acid (PBSA), a known UV filter, was selected as lead compound for its lack of antioxidant activity, high water solubility and good safety profile. PBSA was sequentially modified introducing hydroxyls on the phenyl ring and also substituting the functional group in position 5 of the benzimidazole ring. At the end of the synthetic study, a new, very potent class of antioxidants has been obtained. Surprisingly some of the developed molecules, while devoid of significant UV-filtering activity was endowed with potent UV-filtering booster capability if associated with known commercial UVB and UVA filters.

Imidazole as a parent π-conjugated backbone in charge-transfer chromophores

PubMed Central

Kulhánek, Jiří

2012-01-01

Summary Research activities in the field of imidazole-derived push–pull systems featuring intramolecular charge transfer (ICT) are reviewed. Design, synthetic pathways, linear and nonlinear optical properties, electrochemistry, structure–property relationships, and the prospective application of such D-π-A organic materials are described. This review focuses on Y-shaped imidazoles, bi- and diimidazoles, benzimidazoles, bis(benzimidazoles), imidazole-4,5-dicarbonitriles, and imidazole-derived chromophores chemically bound to a polymer chain. PMID:22423270

Solid-phase microextraction of benzimidazole fungicides in environmental liquid samples and HPLC-fluorescence determination.

PubMed

López Monzón, A; Vega Moreno, D; Torres Padrón, M E; Sosa Ferrera, Z; Santana Rodríguez, J J

2007-03-01

Solid-phase microextraction (SPME) coupled with high-performance liquid chromatography (HPLC) with fluorescence detection was optimized for extraction and determination of four benzimidazole fungicides (benomyl, carbendazim, thiabendazole, and fuberidazole) in water. We studied extraction and desorption conditions, for example fiber type, extraction time, ionic strength, extraction temperature, and desorption time to achieve the maximum efficiency in the extraction. Results indicate that SPME using a Carboxen-polydimethylsiloxane 75 microm (CAR-PDMS) fiber is suitable for extraction of these types of compound. Final analysis of benzimidazole fungicides was performed by HPLC with fluorescence detection. Recoveries ranged from 80.6 to 119.6 with RSDs below 9% and limits of detection between 0.03 and 1.30 ng mL-1 for the different analytes. The optimized procedure was applied successfully to the determination of benzimidazole fungicides mixtures in environmental water samples (sea, sewage, and ground water).

Novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone: a new class of β-glucuronidase inhibitors and in silico studies.

PubMed

Zawawi, Nik Khairunissa Nik Abdullah; Taha, Muhammad; Ahmat, Norizan; Wadood, Abdul; Ismail, Nor Hadiani; Rahim, Fazal; Ali, Muhammad; Abdullah, Norishah; Khan, Khalid Mohammed

2015-07-01

A library of novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone (3a-3r) was synthesized and evaluated for their potential as β-glucuronidase inhibitors. Several compounds such as 3a-3d, 3e-3j, 3l-3o, 3q and 3r showed excellent inhibitory potentials much better than the standard (IC50=48.4±1.25μM: d-saccharic acid 1,4-lactone). All the synthesized compounds were characterized satisfactorily by using different spectroscopic methods. We further evaluated the interaction of the active compounds and the enzyme active site with the help of docking studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Selective and eco-friendly procedures for the synthesis of benzimidazole derivatives. The role of the Er(OTf)3 catalyst in the reaction selectivity

PubMed Central

Herrera Cano, Natividad; Uranga, Jorge G; Nardi, Mónica; Procopio, Antonio; Wunderlin, Daniel A

2016-01-01

An improved and greener protocol for the synthesis of benzimidazole derivatives, starting from o-phenylenediamine, with different aldehydes is reported. Double-condensation products were selectively obtained when Er(OTf)3 was used as the catalyst in the presence of electron-rich aldehydes. Conversely, the formation of mono-condensation products was the preferred path in absence of this catalyst. One of the major advantages of these reactions was the formation of a single product, avoiding extensive isolation and purification of products, which is frequently associated with these reactions. Theoretical calculations helped to understand the different reactivity established for these reactions. Thus, we found that the charge density on the oxygen of the carbonyl group has a significant impact on the reaction pathway. For instance, electron-rich aldehydes better coordinate to the catalyst, which favours the addition of the amine group to the carbonyl group, therefore facilitating the formation of double-condensation products. Reactions with aliphatic or aromatic aldehydes were possible, without using organic solvents and in a one-pot procedure with short reaction time (2–5 min), affording single products in excellent yields (75–99%). This convenient and eco-friendly methodology offers numerous benefits with respect to other protocols reported for similar compounds. PMID:28144309

Selective and eco-friendly procedures for the synthesis of benzimidazole derivatives. The role of the Er(OTf)3 catalyst in the reaction selectivity.

PubMed

Herrera Cano, Natividad; Uranga, Jorge G; Nardi, Mónica; Procopio, Antonio; Wunderlin, Daniel A; Santiago, Ana N

2016-01-01

An improved and greener protocol for the synthesis of benzimidazole derivatives, starting from o -phenylenediamine, with different aldehydes is reported. Double-condensation products were selectively obtained when Er(OTf) 3 was used as the catalyst in the presence of electron-rich aldehydes. Conversely, the formation of mono-condensation products was the preferred path in absence of this catalyst. One of the major advantages of these reactions was the formation of a single product, avoiding extensive isolation and purification of products, which is frequently associated with these reactions. Theoretical calculations helped to understand the different reactivity established for these reactions. Thus, we found that the charge density on the oxygen of the carbonyl group has a significant impact on the reaction pathway. For instance, electron-rich aldehydes better coordinate to the catalyst, which favours the addition of the amine group to the carbonyl group, therefore facilitating the formation of double-condensation products. Reactions with aliphatic or aromatic aldehydes were possible, without using organic solvents and in a one-pot procedure with short reaction time (2-5 min), affording single products in excellent yields (75-99%). This convenient and eco-friendly methodology offers numerous benefits with respect to other protocols reported for similar compounds.

Alternative energy production pathways in Taenia crassiceps cysticerci in vitro exposed to a benzimidazole derivative (RCB20).

PubMed

Fraga, Carolina Miguel; Da Costa, Tatiane Luiza; De Castro, Ana Maria; Reynoso-Ducoing, Olivia; Ambrosio, Javier; Hernández-Campos, Alicia; Castillo, Rafael; Vinaud, Marina Clare

2016-04-01

Biochemical studies of benzimidazole derivatives are important to determine their mode of action and activity against parasites. The lack of antihelminthic alternatives to treat parasitic infections and albendazole resistance cases make the search for new antiparasitary drugs of utmost importance. The 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20) is a benzimidazole derivative with promising effect. This study evaluated the effect of different concentrations of RCB20 in the alternative energetic pathway of in vitro Taenia crassiceps cysticerci. The parasites were in vitro exposed to 6.5 and 13 µM of RCB20 and albendazole sulfoxide (ABZSO). The quantification of acetate, acetoacetate, β-hydroxybutyrate, fumarate and propionate was performed by high-performance liquid chromatography. The quantification of urea, creatinine and total proteins was performed by spectrophotometry. The increase in β-hydroxybutyrate reflects the enhancement of the fatty acid oxidation in the treated groups. Volatile fatty acids secretion, acetate and propionate, was increased in the treated groups. The secretion mechanisms of the treated parasites were impaired due to organic acids increased concentrations in the cysticerci. It is possible to conclude that the metabolic effect on alternative energetic pathways is slightly increased in the parasites treated with RCB20 than the ones treated with ABZSO.

Performance-Enhancing Materials for Future Generation Explosives and Propellants

DTIC Science & Technology

2012-05-25

Benzimidazoles and Oxazolo[4,5-b]pyridines under Solvent-Free Conditions," Cat. Comm., 2007, 8, 1865-1870. Zhang, Z.H., Li, T.S., Li, J.J. "A Highly...Effective Sulfamic Acid/Methanol Catalytic System for the Synthesis of Benzimidazole Derivatives at Room Temperature," Monat, fur Chem., 2007, 138, 89-94

Synthesis, analytical analysis, and medicinal aspect of novel benzimidazoles and their metal complexes.

PubMed

Agrawal, Sangeeta; Bhatnagar, Rishi Raj; Tiwari, Anjani; Srivastava, Rakesh; Sharma, Upasana

2013-11-01

Benzimidazole and their metal analogs that can act as multimodal agent and have non-peptidic CCK-B receptor antagonist were synthesized and characterized on the basis of spectroscopic techniques such as FT-IR, NMR, FAB-MS and also evaluated for biologic efficacy. The ligands showed binding to most of the organs, known to express CCK receptors in biodistribution studies. Cholecystokinin (CCK1 and CCK2) receptor binding affinities of these analogs (IC50) are 0.802 ± 0.007 for compound C and 0.326 ± 0.012 for compound D in rat pancreatic acini. These studies have provided a new template for further development of novel agents for various related diseases.

Conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability.

PubMed

Li, Kun; Ma, Tianyi; Cai, Jingjing; Huang, Min; Guo, Hongye; Zhou, Di; Luan, Shenglin; Yang, Jinyu; Liu, Dan; Jing, Yongkui; Zhao, Linxiang

2017-10-15

Twenty-six conjugates of 18β-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol-2-yl)propanoic acid were designed and synthesized as Pin1 inhibitors. Most of these semi-synthetic compounds showed improved Pin1 inhibitory activity and anti-proliferative effects against prostate cancer cells as compared to 3-(1H-benzo[d]imidazol-2-yl)propanoic acid and GA. Compounds 10a and 12i were the most potent to inhibit growth of prostate cancer PC-3 with GI 50 values of 7.80μM and 3.52μM, respectively. The enzyme inhibition ratio of nine compounds at 10μM was over 90%. Structure-activity relationships indicated that both appropriate structure at ring C of GA and suitable length of linker between GA skeleton and benzimidazole moiety had significant impact on improving activity. Western blot assay revealed that 10a decreased the level of cell cycle regulating protein cyclin D1. Thus, these compounds might represent a novel anti-proliferative agent working through Pin1 inhibition. Copyright © 2017. Published by Elsevier Ltd.

Growth Inhibition of Sporomusa ovata by Incorporation of Benzimidazole Bases into Cobamides

PubMed Central

Mok, Kenny C.

2013-01-01

Phenolyl cobamides are unique members of a class of cobalt-containing cofactors that includes vitamin B12 (cobalamin). Cobamide cofactors facilitate diverse reactions in prokaryotes and eukaryotes. Phenolyl cobamides are structurally and chemically distinct from the more commonly used benzimidazolyl cobamides such as cobalamin, as the lower axial ligand is a phenolic group rather than a benzimidazole. The functional significance of this difference is not well understood. Here we show that in the bacterium Sporomusa ovata, the only organism known to synthesize phenolyl cobamides, several cobamide-dependent acetogenic metabolisms have a requirement or preference for phenolyl cobamides. The addition of benzimidazoles to S. ovata cultures results in a decrease in growth rate when grown on methanol, 3,4-dimethoxybenzoate, H2 plus CO2, or betaine. Suppression of native p-cresolyl cobamide synthesis and production of benzimidazolyl cobamides occur upon the addition of benzimidazoles, indicating that benzimidazolyl cobamides are not functionally equivalent to the phenolyl cobamide cofactors produced by S. ovata. We further show that S. ovata is capable of incorporating other phenolic compounds into cobamides that function in methanol metabolism. These results demonstrate that S. ovata can incorporate a wide range of compounds as cobamide lower ligands, despite its preference for phenolyl cobamides in the metabolism of certain energy substrates. To our knowledge, S. ovata is unique among cobamide-dependent organisms in its preferential utilization of phenolyl cobamides. PMID:23417488

Research on the differences between 2-(2-Chlorophenyl)benzimidazole and 2-(4-Chlorophenyl)benzimidazole based on terahertz time domain spectroscopy

NASA Astrophysics Data System (ADS)

Song, Maojiang; Yang, Fei; Liu, Liping; Shen, Li; Hu, Pengfei; Zhang, Li; Su, Caixia

2018-05-01

Due to wide variety of biological and pharmacological activities of benzimidazole derivatives, the differences between 2-(2-Chlorophenyl)benzimidazole and 2-(4-Chlorophenyl) benzimidazole were researched by employing terahertz time-domain spectroscopy and density functional theory systematically. Although the only difference between their molecular configurations is the arrangement of chlorine atom on chlorophenyl ring, there are distinctive differences in their fingerprint spectra in the range of 0.2-2.5 THz, such as amount, amplitude, and frequency position of absorption peaks. The validity of these results was confirmed by the theoretical results simulated by using density functional theory. The possible reasons of these differences originate from the different van der Waals forces and the different dihedral angles of the molecules within crystal cell. These results indicate the importance of this spectral range as a conformational fingerprint region where even minor changes in the molecular configuration lead to major differences in its THz absorption.

Ball Milling Assisted Solvent and Catalyst Free Synthesis of Benzimidazoles and Their Derivatives.

PubMed

El-Sayed, Taghreed H; Aboelnaga, Asmaa; Hagar, Mohamed

2016-08-24

Benzoic acid and o-phenylenediamine efficiently reacted under the green solvent-free Ball Milling method. Several reaction parameters were investigated such as rotation frequency; milling balls weight and milling time. The optimum reaction condition was milling with 56.6 g weight of balls at 20 Hz frequency for one hour milling time. The study was extended for synthesis of a series of benzimidazol-2-one or benzimidazol-2-thione using different aldehydes; carboxylic acids; urea; thiourea or ammonium thiocyanate with o-phenylenediamine. Moreover; the alkylation of benzimidazolone or benzimidazolthione using ethyl chloroacetate was also studied.

Comparison of experimental and DFT-calculated NMR chemical shifts of 2-amino and 2-hydroxyl substituted phenyl benzimidazoles, benzoxazoles and benzothiazoles in four solvents using the IEF-PCM solvation model.

PubMed

Pierens, Gregory K; Venkatachalam, T K; Reutens, David C

2016-04-01

A comparative study of experimental and calculated NMR chemical shifts of six compounds comprising 2-amino and 2-hydroxy phenyl benzoxazoles/benzothiazoles/benzimidazoles in four solvents is reported. The benzimidazoles showed interesting spectral characteristics, which are discussed. The proton and carbon chemical shifts were similar for all solvents. The largest chemical shift deviations were observed in benzene. The chemical shifts were calculated with density functional theory using a suite of four functionals and basis set combinations. The calculated chemical shifts revealed a good match to the experimentally observed values in most of the solvents. The mean absolute error was used as the primary metric. The use of an additional metric is suggested, which is based on the order of chemical shifts. The DP4 probability measures were also used to compare the experimental and calculated chemical shifts for each compound in the four solvents. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Development and validation of an ultra high performance liquid chromatography tandem mass spectrometry method for simultaneous determination of sulfonamides, quinolones and benzimidazoles in bovine milk.

PubMed

Hou, Xiao-Lin; Chen, Guo; Zhu, Li; Yang, Ting; Zhao, Jian; Wang, Lei; Wu, Yin-Liang

2014-07-01

A simple, sensitive and reliable analytical method was developed for the simultaneous determination of 38 veterinary drugs (18 sulfonamides, 11 quinolones and 9 benzimidazoles) and 8 metabolites of benzimidazoles in bovine milk by ultra high performance liquid chromatography-positive electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Samples were extracted with acidified acetonitrile, cleaned up with Oasis(®) MCX cartridges, and analyzed by LC-MS/MS on an Acquity UPLC(®) BEH C18 column with gradient elution. The method allows such multi-analyte measurements within a 13min runtime while the specificity is ensured through the MRM acquisition mode. The method was validated according to the European Commission Decision 2002/657/EC determining specificity, decision limit (CCα), detection capability (CCβ), recovery, precision, linearity and stability. For compounds which have MRLs in bovine milk, the CCα values fall into a range from 11 to 115μg/kg, and the CCβ values fall within a range of 12-125μg/kg. For compounds which have not MRLs in bovine milk, the CCα values fall into a range from 0.01 to 0.08μg/kg, and the CCβ values fall within a range of 0.02-0.11μg/kg. The mean recoveries of the 46 analytes were between 87 and 119%. The calculated RSD values of repeatability and within-laboratory reproducibility experiments were below 11% and 15% for the 46 compounds, respectively. The method was demonstrated to be suitable for the simultaneous determination of sulfonamides, quinolones and benzimidazoles in bovine milk. Copyright © 2014 Elsevier B.V. All rights reserved.

Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

PubMed Central

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan; Tidwell, Richard R.; Czarny, Agnieszka; Bajic, Miroslav; Bajic, Marina; Kumar, Arvind; Boykin, David; Perfect, John R.

1998-01-01

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential. PMID:9756747

Effects of Substitutions on the Biodegradation Potential of Benzotriazole Derivatives

NASA Astrophysics Data System (ADS)

Abu-Dalo, M. A.; O'Brien, I.; Hernandez, M. T.

2018-02-01

Fourteen benzotriazole derivatives were subjected to microcosm tests to study the influence of substitutions on their biodegradation potential. Methylated, nitrated, carboxylated, and propionated bezotriazoles, a heterocyclic triazole, as well as methylated benzimidazoles, were introduced to activated sludge and soil enrichment cultures as the only carbon source. Some of the enrichment cultures were derived from airport soils that had been previously contaminated with aircraft deicing fluids and subsequently enriched with the commercially significant corrosion inhibitor methylbenzotriazole. The 5-methylbenzotriazole and only the carboxylated derivatives were degraded by soil or activated sludge biomass regardless of acclimation conditions. Radiotracer studies of [U-14C] 5-methylbenzotriazole, and [U-14C] 5-carboxybenzotriazole confirmed that relatively high concentrations (25mg L-1) of these derivatives can be completely mineralized in relatively short time frames by microbial consortia regardless of prior exposure. Observations suggested that the growth yield on these compounds is likely low. Biodegradation patterns suggested that carboxylated benzotriazole derivatives are more readily biodegradable than their more popular methylated counterparts.

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 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.

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model.

PubMed

Singh, Kawaljit; Okombo, John; Brunschwig, Christel; Ndubi, Ferdinand; Barnard, Linley; Wilkinson, Chad; Njogu, Peter M; Njoroge, Mathew; Laing, Lizahn; Machado, Marta; Prudêncio, Miguel; Reader, Janette; Botha, Mariette; Nondaba, Sindisiwe; Birkholtz, Lyn-Marie; Lauterbach, Sonja; Churchyard, Alisje; Coetzer, Theresa L; Burrows, Jeremy N; Yeates, Clive; Denti, Paolo; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Chibale, Kelly

2017-02-23

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Synthesis and potential cytotoxic activity of some new benzoxazoles, imidazoles, benzimidazoles and tetrazoles.

PubMed

Arulmurugan, Subramaniyan; Kavitha, Helen P

2013-06-01

2 The present work deals with the synthesis of some novel heterocyclic compounds such as benzoxazoles , 7, 13 and 19, imidazoles 3, 8, 14 and 20, benzimidazoles 4, 9, 15 and 21, and tetrazoles 10, 16, and 22. The synthesized compounds were characterized by IR, 1H NMR, mass spectrometry and elemental analysis. The compounds were evaluated for cytotoxicity against human cancer cell lines such as MCF-7 (breast cancer) and HT-29 (colon cancer) by the MTT assay method. Among the tested compounds, 4,4'-sulfonylbis(N-(2-(1H-benzo[d]imidazol- -2-yl)ethyl)aniline (9), N-bis(2-(benzo[d]oxazol-2-yl)-ethyl)- 6-phenyl-1,3,5-triazine-2,4-diamine (13), N-bis(2-(1H-benzo[ d]imidazol-2-yl)ethyl)-6-phenyl-1,3,5-triazine-2,4-diamine (15) and N-tris(2-1H-benzo[d]imidazol-2-yl)ethyl)- 1,3,5-triazine-2,4,6-triamine (21) showed potent cytotoxicity.

Synthesis and evaluation of in vitro anti-microbial and anti-tubercular activity of 2-styryl benzimidazoles.

PubMed

Shingalapur, Ramya V; Hosamani, Kallappa M; Keri, Rangappa S

2009-10-01

A new series of novel 5-(nitro/bromo)-styryl-2-benzimidazoles (1-12) has been synthesized by simple, mild and efficient synthetic protocol by attempted condensation of 5-(nitro/bromo)-o-phenylenediamine with trans-cinnamic acids in ethylene glycol. Screening for in vitro anti-tubercular activity against Mycobacterium tuberculosis H(37) Rv, anti-bacterial activity against Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae bacterial strains and anti-fungal activity against Candida albicans and Asperigillus fumigatus fungal strains were carried out. Compounds 5, 7, 8, 9, 11 showed higher anti-tubercular activity and compounds 7, 8, 10, 11, 12 have proved to be effective with MIC (microg/ml) and emerged as lead molecules showing excellent activities against a panel of microorganisms. All synthesized compounds were characterized using IR, (1)H, (13)C NMR, GC-MS and elemental analysis.

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

Conventional and microwave-assisted synthesis of new indole-tethered benzimidazole-based 1,2,3-triazoles and evaluation of their antimycobacterial, antioxidant and antimicrobial activities.

PubMed

Ashok, Dongamanti; Gundu, Srinivas; Aamate, Vikas Kumar; Devulapally, Mohan Gandhi

2018-04-18

A new series of triheterocycles containing indole-benzimidazole-based 1,2,3-triazole hybrids have been synthesized in good yields via a microwave-assisted click reaction. All the compounds were characterized by IR, [Formula: see text] NMR, [Formula: see text] NMR and mass spectroscopy and were evaluated for their in vitro antitubercular activity against the Mycobacterium tuberculosis H37Rv strain. Compounds 4b, 4h and 4i displayed highly potent antitubercular activity with MIC 3.125-6.25 [Formula: see text]. The antioxidant potential was evaluated using 2,2-diphenyl-1-picryl hydrazine and [Formula: see text] radical scavenging activity, and compounds 4e,4f and 4g showed excellent radical scavenging activity with [Formula: see text] values in the range of 08.50-10.05 [Formula: see text]. Furthermore, the compounds were evaluated for antimicrobial activity against numerous bacterial and fungal strains, and compounds 4b, 4c and 4h were found to be the most promising potential antimicrobial molecules with MIC 3.125-6.25 [Formula: see text].

Enantiomeric behaviour of albendazole and fenbendazole sulfoxides in domestic animals: pharmacological implications.

PubMed

Capece, Bettencourt P S; Virkel, Guillermo L; Lanusse, Carlos E

2009-09-01

Albendazole and fenbendazole are methylcarbamate benzimidazole anthelmintics extensively used to control gastrointestinal parasites in domestic animals. These parent compounds are metabolised to albendazole sulfoxide and fenbendazole sulfoxide (oxfendazole), respectively. Both sulfoxide derivatives are anthelmintically active and are manufactured for use in animals. They metabolites have an asymmetric centre on their chemical structures and two enantiomeric forms of each sulfoxide have been identified in plasma, tissues of parasite location and within target helminths. Both the flavin-monooxygenase and cytochrome P450 systems are involved in the enantioselective biotransformation of these anthelmintic compounds in ruminant species. A relevant progress on the understanding of the relationship among enantioselective metabolism and systemic availability of each enantiomeric form has been achieved. This article reviews the current knowledge on the pharmacological implications of the enantiomeric behaviour of albendazole sulfoxide and oxfendazole in domestic animals.

Metabolite profiling of bendamustine in urine of cancer patients after administration of [14C]bendamustine.

PubMed

Dubbelman, Anne-Charlotte; Jansen, Robert S; Rosing, Hilde; Darwish, Mona; Hellriegel, Edward; Robertson, Philmore; Schellens, Jan H M; Beijnen, Jos H

2012-07-01

Bendamustine is an alkylating agent consisting of a mechlorethamine derivative, a benzimidazole group, and a butyric acid substituent. A human mass balance study showed that bendamustine is extensively metabolized and subsequently excreted in urine. However, limited information is available on the metabolite profile of bendamustine in human urine. The objective of this study was to elucidate the metabolic pathways of bendamustine in humans by identification of its metabolites excreted in urine. Human urine samples were collected up to 168 h after an intravenous infusion of 120 mg/m(2) (80-95 μCi) [(14)C]bendamustine. Metabolites of [(14)C]bendamustine were identified using liquid chromatography (high-resolution)-tandem mass spectrometry with off-line radioactivity detection. Bendamustine and a total of 25 bendamustine-related compounds were detected. Observed metabolic conversions at the benzimidazole and butyric acid moiety were N-demethylation and γ-hydroxylation. In addition, various other combinations of these conversions with modifications at the mechlorethamine moiety were observed, including hydrolysis (the primary metabolic pathway), cysteine conjugation, and subsequent biotransformation to mercapturic acid and thiol derivatives, N-dealkylation, oxidation, and conjugation with phosphate, creatinine, and uric acid. Bendamustine-derived products containing phosphate, creatinine, and uric acid conjugates were also detected in control urine incubated with bendamustine. Metabolites that were excreted up to 168 h after the infusion included products of dihydrolysis and cysteine conjugation of bendamustine and γ-hydroxybendamustine. The range of metabolic reactions is generally consistent with those reported for rat urine and bile, suggesting that the overall processes involved in metabolic elimination are qualitatively the same in rats and humans.

Benzimidazole acrylonitriles as multifunctional push-pull chromophores: Spectral characterisation, protonation equilibria and nanoaggregation in aqueous solutions

NASA Astrophysics Data System (ADS)

Horak, Ema; Vianello, Robert; Hranjec, Marijana; Krištafor, Svjetlana; Zamola, Grace Karminski; Steinberg, Ivana Murković

2017-05-01

Heterocyclic donor-π-acceptor molecular systems based on an N,N-dimethylamino phenylacrylonitrile benzimidazole skeleton have been characterised and are proposed for potential use in sensing applications. The benzimidazole moiety introduces a broad spectrum of useful multifunctional properties to the system including electron accepting ability, pH sensitivity and compatibility with biomolecules. The photophysical characterisation of the prototropic forms of these chromophores has been carried out in both solution and on immobilisation in polymer films. The experimental results are further supported by computational determination of pKa values. It is noticed that compound 3 forms nanoaggregates in aqueous solutions with aggregation-induced emission (AIE) at 600 nm. All the systems demonstrate spectral pH sensitivity in acidic media which shifts towards near-neutral values upon immobilisation in polymer films or upon aggregation in an aqueous environment (compound 3). The structure-property relationships of these functional chromophores, involving their spectral characteristics, acid-base equilibria, pKa values and aggregation effects have been determined. Potential applications of the molecules as pH and biomolecular sensors are proposed based on their pH sensitivity and AIE properties.

N-Paranitrophénylhydrazono-α-(2-méthyl­benzimidazol-1-yl)glyoxylate d’éthyle

PubMed Central

Boudina, Aicha; Baouid, Abdesselam; Driss, Mohamed; Soumhi, El Hassane

2011-01-01

There are two independent mol­ecules in the asymmetric unit of the title compound {systematic name: ethyl 2-(2-methyl-1H-benzimidazol-1-yl)-2-[2-(4-nitro­phen­yl)hydrazinyl­idene]ethano­ate}, C18H17N5O4. Each mol­ecule and its inversion-related partner are linked by a pair of inter­molecular N—H⋯N hydrogen bonds, forming inversion dimers in the crystal structure. PMID:21836981

Newly synthesized bis-benzimidazole compound 8 induces apoptosis, autophagy and reactive oxygen species generation in HeLa cells.

PubMed

Chu, Naying; Yao, Guodong; Liu, Yuan; Cheng, Maosheng; Ikejima, Takashi

2016-09-01

Compound 8 (C8) is a newly synthesized bis-benzimidazole derivative and exerts significant anti-tumor activity in vitro. Previous studies demonstrated that C8 induced apoptosis and autophagy in human promyelocytic leukemia HL60 cells. However, cytotoxicity study on human peripheral blood mononuclear cells (hPBMC) showed that C8 exhibited less toxicity in normal cells. In this study, the molecular mechanism of C8 on human cervical carcinoma HeLa cells was investigated. The results showed that C8 inhibited the growth of HeLa cells and triggered both apoptotic and autophagic cell death. Subsequent experiment also indicated that reactive oxygen species (ROS) generation was induced in C8-treated HeLa cells. Since ROS scavenger decreased the ratio of apoptotic and autophagic cells, ROS generation contributed to C8-induced apoptosis and autophagy. Furthermore, inhibitors of apoptosis and autophagy also reduced ROS generation, respectively. Autophagy inhibition increased cell growth compared to C8-treated group and attenuated apoptotic cell death, indicating that C8-induced autophagy promoted apoptosis for cell death. However, the percentage of autophagic cells was enhanced when limiting apoptosis process. Taken together, C8 induced ROS-mediated apoptosis and autophagy in HeLa cells, autophagy promoted apoptosis but the former was antagonized by the latter. The data also gave us a new perspective on the anti-tumor effect of C8. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure-based design of benzimidazole sugar conjugates: synthesis, SAR and in vivo anti-inflammatory and analgesic activities.

PubMed

El-Nezhawy, Ahmed O H; Gaballah, Samir T; Radwan, Mohamed A A; Baiuomy, Ayman R; Abdel-Salam, Omar M E

2009-11-01

A series of 2-methyl-N-substituted-benzimidazoles, bearing hydroxypyrrolidinon-5-yl or hydroxypyrrolidin-2-yl, 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranoside, 2,3,5,6-tetrahydroxy-alpha-D-mannofuranoside, 1:2,5:6-di-O-isopropylidene-alpha-D-gluco-furanose,3-O-benzyl-6,7-dideoxy-1:2-O-isopropylidene-alpha-D-xylo-heptofuranos-5-ulose, 3-O-benzyl-6,7-dideoxy-1,2-dihydroxy-alpha-D-xylo-heptofuranos-5-ulose, 1,2,5,6-tetrahydroxy-alpha-D-glucofuranose sugar moieties, were obtained in good yields from 2-methyl N-(trichloroacetamidomethyl)benzimidazole as a donor and carbohydrate residues as acceptor precursors in the presence of catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as Lewis acid. Compounds 6, 7, 10, 13, 15, and 16 showed significant anti-inflammatory and analgesic activities.

Synthesis of novel synthetic intermediates from the reaction of benzimidazole and triazole carbenes with ketenimines and their application in the construction of spiro-pyrroles.

PubMed

Mo, Jun-Ming; Ma, Yang-Guang; Cheng, Ying

2009-12-07

2-(2-Alkoxycarbonyl-1-arylamino-1-propenyl)benzimidazolium and 5-(2-alkoxycarbonyl-1-arylamino-1-propenyl)triazolium salts were synthesized in good yields from the reaction of benzimidazole and triazole carbenes with ketenimines. Upon treatment with a base, both salts were converted into novel 1,3-dipoles which underwent [3+2] cycloaddition reactions with electron-deficient alkynes and allenes to produce benzimidazole-spiro-pyrroles or triazole-spiro-pyrroles. This work provides novel synthons for the construction of multifunctional spiro-pyrrole derivatives that are not easy accessible by other synthetic methods and are potentially amenable to further transformations.

Synthesis and Biological Evaluation of Analogues of AKT (Protein Kinase B) Inhibitor-IV

PubMed Central

Sun, Qi; Wu, Runzhi; Cai, Sutang; Lin, Yuan; Sellers, Llewlyn; Sakamoto, Kaori; He, Biao; Peterson, Blake R.

2011-01-01

Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl4-catalyzed cyclization of 1,2-arylenediamines with α,β-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells, and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold. PMID:21319800

Benzimidazole-core as an antimycobacterial agent.

PubMed

Keri, Rangappa S; Rajappa, Chethana Kolambae; Patil, Siddappa A; Nagaraja, Bhari Mallanna

2016-12-01

Mycobacterium tuberculosis (Mtb) is considered as one of the precarious bacterial infections around the world. Through a projected 8.7 million new tuberculosis (TB) cases and 1.4 million mortalities per annum, this deadly infection resulted insubstantial amount of human deaths than any other single organism bacterial infections. TB is one of India's most threatening human health problems and it accounts for approximately 33% of the global health issues. Subsequently, for TB there is an imperative need for the improvement of existing drug candidates with newer targets and specified mechanism of action. Within the wide spectra of heterocycles, benzimidazole and its substituted analogues were evidenced promising biological efficacies enabling them to perform as new drug or prodrug candidates. Exceptional structural features of this class of heterocycle and versatile biological applications made it a privileged structural backbone in new drug design and discovery. Majorly, 2,5- and 2,6-disubstituted benzimidazole derivatives shown to induce significant antiTB potential. To seek more insights on this unique feature of benzimidazole candidates, there is an urgency to assemble the recent advances in this promising area. This review presents an overview of the recent advancements and focuses on the structural features responsible for unique antiTB applications and compiled published reports on benzimidazole derivatives emphasizing on different approaches employed for their syntheses in order to help medicinal and clinical chemists in designing next generation, yet effective and safer antiTB candidates. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Trichuris suis and Oesophagostomum dentatum show different sensitivity and accumulation of fenbendazole, albendazole and levamisole in vitro.

PubMed

Hansen, Tina V A; Nejsum, Peter; Friis, Christian; Olsen, Annette; Thamsborg, Stig Milan

2014-04-01

The single-dose benzimidazoles used against Trichuris trichiura infections in humans are not satisfactory. Likewise, the benzimidazole, fenbendazole, has varied efficacy against Trichuris suis whereas Oesophagostomum dentatum is highly sensitive to the drug. The reasons for low treatment efficacy of Trichuris spp. infections are not known. We studied the effect of fenbendazole, albendazole and levamisole on the motility of T. suis and O. dentatum and measured concentrations of the parent drug compounds and metabolites of the benzimidazoles within worms in vitro. The motility and concentrations of drug compounds within worms were compared between species and the maximum specific binding capacity (Bmax) of T. suis and O. dentatum towards the benzimidazoles was estimated. Comparisons of drug uptake in living and killed worms were made for both species. The motility of T. suis was generally less decreased than the motility of O. dentatum when incubated in benzimidazoles, but was more decreased when incubated in levamisole. The Bmax were significantly lower for T. suis (106.6, and 612.7 pmol/mg dry worm tissue) than O. dentatum (395.2, 958.1 pmol/mg dry worm tissue) when incubated for 72 hours in fenbendazole and albendazole respectively. The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole). Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6-17.2%) as compared to O. dentatum (0.8-0.9%). The general lower sensitivity of T. suis towards BZs in vitro seems to be related to a lower drug uptake. Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum.

Trichuris suis and Oesophagostomum dentatum Show Different Sensitivity and Accumulation of Fenbendazole, Albendazole and Levamisole In Vitro

PubMed Central

Hansen, Tina V. A.; Nejsum, Peter; Friis, Christian; Olsen, Annette; Thamsborg, Stig Milan

2014-01-01

Background The single-dose benzimidazoles used against Trichuris trichiura infections in humans are not satisfactory. Likewise, the benzimidazole, fenbendazole, has varied efficacy against Trichuris suis whereas Oesophagostomum dentatum is highly sensitive to the drug. The reasons for low treatment efficacy of Trichuris spp. infections are not known. Methodology We studied the effect of fenbendazole, albendazole and levamisole on the motility of T. suis and O. dentatum and measured concentrations of the parent drug compounds and metabolites of the benzimidazoles within worms in vitro. The motility and concentrations of drug compounds within worms were compared between species and the maximum specific binding capacity (Bmax) of T. suis and O. dentatum towards the benzimidazoles was estimated. Comparisons of drug uptake in living and killed worms were made for both species. Principal findings The motility of T. suis was generally less decreased than the motility of O. dentatum when incubated in benzimidazoles, but was more decreased when incubated in levamisole. The Bmax were significantly lower for T. suis (106.6, and 612.7 pmol/mg dry worm tissue) than O. dentatum (395.2, 958.1 pmol/mg dry worm tissue) when incubated for 72 hours in fenbendazole and albendazole respectively. The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole). Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6–17.2%) as compared to O. dentatum (0.8–0.9%). Conclusion/Significance The general lower sensitivity of T. suis towards BZs in vitro seems to be related to a lower drug uptake. Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum. PMID:24699263

Purine-benzimidazole hybrids: synthesis, single crystal determination and in vitro evaluation of antitumor activities.

PubMed

Sharma, Alka; Luxami, Vijay; Paul, Kamaldeep

2015-03-26

In an effort to identify novel compounds for the treatment of cancer, a diverse array of potential bioactive hybrid, purine-benzimidazole was synthesized in good yields through nucleophilic substitution at C6 position of purine ring with versatile cyclic amines at C2 position. The structures of newly prepared compounds were confirmed by IR, (1)H, (13)C NMR, mass spectroscopy and, in case of 19, by single crystal X-ray diffraction analysis. The newly synthesized compounds were evaluated against 60 human tumour cell lines at one dose concentration level. Compound 6 exhibited significant growth inhibition and was evaluated as 60 cell panel at five dose concentration levels. Compound 6 proved to be 1.25 fold more active than the positive control 5-FU, with GI50 value of 18.12 μM (MG-MID). Interaction of the compounds with Aurora-A enzyme involved in the process of propagation of cancer, has also been investigated. Compound 6 showed selectivity towards Aurora-A kinase inhibition with IC50 value of 0.0l μM. Molecular docking studies in the active binding site provided theoretical support for the experimental biological data acquired. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Discovery of genomic intervals that underlie nematode responses to benzimidazoles.

PubMed

Zamanian, Mostafa; Cook, Daniel E; Zdraljevic, Stefan; Brady, Shannon C; Lee, Daehan; Lee, Junho; Andersen, Erik C

2018-03-01

Parasitic nematodes impose a debilitating health and economic burden across much of the world. Nematode resistance to anthelmintic drugs threatens parasite control efforts in both human and veterinary medicine. Despite this threat, the genetic landscape of potential resistance mechanisms to these critical drugs remains largely unexplored. Here, we exploit natural variation in the model nematodes Caenorhabditis elegans and Caenorhabditis briggsae to discover quantitative trait loci (QTL) that control sensitivity to benzimidazoles widely used in human and animal medicine. High-throughput phenotyping of albendazole, fenbendazole, mebendazole, and thiabendazole responses in panels of recombinant lines led to the discovery of over 15 QTL in C. elegans and four QTL in C. briggsae associated with divergent responses to these anthelmintics. Many of these QTL are conserved across benzimidazole derivatives, but others show drug and dose specificity. We used near-isogenic lines to recapitulate and narrow the C. elegans albendazole QTL of largest effect and identified candidate variants correlated with the resistance phenotype. These QTL do not overlap with known benzimidazole target resistance genes from parasitic nematodes and present specific new leads for the discovery of novel mechanisms of nematode benzimidazole resistance. Analyses of orthologous genes reveal conservation of candidate benzimidazole resistance genes in medically important parasitic nematodes. These data provide a basis for extending these approaches to other anthelmintic drug classes and a pathway towards validating new markers for anthelmintic resistance that can be deployed to improve parasite disease control.

Structure of adducts of isoindolo[2,1-a]benzimidazole derivatives with maleimides

NASA Astrophysics Data System (ADS)

Korolev, Oleksandr; Yegorova, Tatyana; Levkov, Igor; Malytskyy, Volodymyr; Shishkin, Oleg; Zubatyuk, Roman; Palamarchuk, Genadiy; Vedrenne, Marc; Baltas, Michel; Voitenko, Zoia

2015-03-01

The selectivity of formation and some mechanistic insights during the synthesis of substituted isoindolo[2,1-a]benzimidazoles are discussed. Furthermore, the reactions of the obtained products with maleimides were carried out. Two types rearrangement adducts together with intermediate Michael type adducts were isolated. The influence of the reaction conditions and reagents ratio is discussed. Specific spectral criteria for the identification of the Michael type adducts are indicated.

Strategic incorporation of fluorine in the drug discovery of new-generation antitubercular agents targeting bacterial cell division protein FtsZ⋆

PubMed Central

Ojima, Iwao; Awasthi, Divya; Wei, Longfei; Haranahalli, Krupanandan

2016-01-01

This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities. Accordingly, we have performed extensive study on the strategic incorporation of fluorine into lead compounds to improve pharmacological properties. This study has led to the development of highly efficacious fluorine-containing benzimidazoles as potential drug candidates. We have also performed computational docking analysis of these novel FtsZ inhibitors to identify their putative binding site. Based on the structural data and docking analysis, a plausible mode-of-action for this novel class of FtsZ inhibitors is proposed. PMID:28555087

Novel structural hybrids of pyrazolobenzothiazines with benzimidazoles as cholinesterase inhibitors.

PubMed

Aslam, Sana; Zaib, Sumera; Ahmad, Matloob; Gardiner, John M; Ahmad, Aqeel; Hameed, Abdul; Furtmann, Norbert; Gütschow, Michael; Bajorath, Jürgen; Iqbal, Jamshed

2014-05-06

Two series of novel pyrazolobenzothiazine-based hybrid compounds were efficiently synthesized starting from saccharin sodium salt. Pyrazolo[4,3-c][1,2]benzothiazine scaffolds were N-arylated by using p-fluorobenzaldehyde, followed by the incorporation of a benzimidazole or similar ring systems by treatment with arylenediamines. These phenylene-connected hybrid compounds were investigated as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compounds 12d and 12k were the most potent AChE inhibitors with IC50 values of 11 and 13 nM, respectively, while 6j (IC50 = 17 nM) proved to be the most active inhibitor against BuChE with remarkable selectivity for BuChE over AChE. Molecular docking studies were also performed on human AChE and BuChE to suggest possible binding modes in which the inhibitor's extended structure is accommodated along the active site gorge of both enzymes. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

3-(2-aminophenyl)-4-methyl-1,3-thiazole-2(3H)-thione as an ecofriendly sulphur transfer agent to prepare alkanethiols in high yield and high purity.

PubMed

Mehdid, Mohammed Amine; Djafri, Ayada; Roussel, Christian; Andreoli, Federico

2009-11-12

A new process is described for preparing very pure linear alkanethiols and linear alpha,omega-alkanedithiols using a sequential alkylation of the title compound, followed by a ring closure to quantitatively give the corresponding 3-methyl[1,3]thiazolo[3,2-a]-[3,1]benzimidazol-9-ium salt and the alkanethiol derivative under mild conditions. The alkanethiol and the heteroaromatic salt are easily separated by a simple extraction process. The intermediate thiazolium quaternary salts resulting from the first reaction step can be isolated in quantitative yields, affording an odourless protected form of the thiols.

Synthesis, in Vivo Anti-inflammatory, and in Vitro Antimicrobial Activity of New 5-Benzofuranyl Fused Pyrimidines.

PubMed

Nassar, Ekhlass; El-Badry, Yaser Abdel-Moemen; El Kazaz, Hagar

2016-01-01

Chalcone (3) has been synthesized as a new chalcone derivative bearing benzofuran moiety at 1 position. Such chalcone was used as a model dielectrophile applied to react with some nucleophiles such as 5-amino pyrazoles, 5-amino-1,2,4-triazole, 2-aminobenzimidazole, and 6-uraciles under Michael reaction conditions and resulted in a new series of fused pyrimidines such as pyrazolo[1,5-a]pyrimidines 7a-e, [1,2,4]-triazolo[1,5-a]pyrimidine 9, pyrimido[1,2-a]benzimidazole 11, and synthesis of pyrido[2,3-d]pyrimidinones 13a and b. The structures of the synthesized target heterocyclic compounds were confirmed by microanalytical and spectral data such as Fourier transform (FT)-IR, (1)H-NMR, and MS spectra. The newly synthesized compounds were evaluated for their anti-inflammatory and antimicrobial activities; most showed significant activities.

An efficient one-pot two catalyst system in the construction of 2-substituted benzimidazoles: synthesis of benzimidazo[1,2-c]quinazolines.

PubMed

Cimarelli, Cristina; Di Nicola, Matteo; Diomedi, Simone; Giovannini, Riccardo; Hamprecht, Dieter; Properzi, Roberta; Sorana, Federico; Marcantoni, Enrico

2015-12-28

The benzimidazole core is a common moiety in a large number of natural products and pharmacologically active small molecules. The synthesis of novel benzimidazole derivatives remains a main focus in medicinal research. In continuation of the efforts towards Ce(III) catalysts for organic transformations, we observed for the first time the activity of the iodide ion and copper cation in activating CeCl3·7H2O in the selective formation of prototypical 2-substituted benzimidazoles. The one-pot CeCl3·7H2O-CuI catalytic system procedure includes the cyclo-dehydrogenation of aniline Schiff's bases, generated in situ from the condensation of 1,2-phenylenediamine and aldehydes, followed by the oxidation with iodine, which works as a hydrogen sponge. Mild reaction conditions, good to excellent yields, and clean reactions make the procedure a useful contribution to the synthesis of biologically active fused heterocycles containing benzimidazoquinazolines.

Synthesis, characterization and antimicrobial activity of some novel benzimidazole derivatives

PubMed Central

Krishnanjaneyulu, Immadisetty Sri; Saravanan, Govindaraj; Vamsi, Janga; Supriya, Pamidipamula; Bhavana, Jarugula Udaya; Sunil Kumar, Mittineni Venkata

2014-01-01

A series of novel N-((1H-benzoimidazol-1-yl) methyl)-4-(1-phenyl-5-substituted-4, 5-dihydro-1-benzoimidazol-1-yl) methyl)-4-(1-phenyl-5-substituted-4, 5-dihydro-1H-pyrazol-3-yl) benzenamine were synthesized by treating various 1-(4-((1H-benzoimidazol-1-yl) methylamino) phenyl)-3-substitutedprop-2-en-1-one with phenyl hydrazine in the presence of sodium acetate through a simple ring closure reaction. The starting material, 1-(4-((1H-benzoimidazol-1-yl) methylamino) phenyl)-3-substitutedprop-2-en-1-one,-benzoimidazol-1-yl) methylamino) phenyl)-3-substitutedprop-2-en-1-one, was synthesized from o-phenylenediamine by a multistep synthesis. All the synthesized compounds were characterized by spectroscopic means and elemental analyses. The title compounds were investigated for in vitro antibacterial and antifungal properties against some human pathogenic microorganisms by employing the agar streak dilution method using Ciprofloxacin and Ketoconazole as standard drugs. All title compounds showed activity against the entire strains of microorganism. Structural activity relationship studies reveal that compounds possessing an electron-withdrawing group display better activity than the compounds containing electron-donating groups, whereas the unsubstituted derivatives display moderate activity. Based on the results obtained, N-((1H-benzoimidazol-1-yl) methyl)-4-(1-phenyl-5-(4-(trifluoromethyl) phenyl)-4,5-dihydro-1H-pyrazol-3-yl) benzenamine 5i was found to be very active compared with the rest of the compounds and standard drugs that were subjected to antimicrobial assay. PMID:24696814

Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazoles: Tubulin polymerization inhibitors and apoptosis inducing agents.

PubMed

Kamal, Ahmed; Reddy, T Srinivasa; Vishnuvardhan, M V P S; Nimbarte, Vijaykumar D; Subba Rao, A V; Srinivasulu, Vunnam; Shankaraiah, Nagula

2015-08-01

A new series of 2-aryl 1,2,4-oxadiazolo-benzimidazole conjugates have been synthesized and evaluated for their antiproliferative activity in the sixty cancer cell line panel of the National Cancer Institute (NCI). Compounds 5l (NSC: 761109/1) and 5x (NSC: 761814/1) exhibited remarkable cytotoxic activity against most of the cancer cell lines in the one dose assay and were further screened at five dose concentrations (0.01, 0.1, 1, 10 and 100 μM) which showed GI50 values in the range of 0.79-28.2 μM. Flow cytometric data of these compounds showed increased cells in G2/M phase, which is suggestive of G2/M cell cycle arrest. Further, compounds 5l and 5x showed inhibition of tubulin polymerization and disruption of the formation of microtubules. These compounds induce apoptosis by DNA fragmentation and chromatin condensation as well as by mitochondrial membrane depolarization. In addition, structure activity relationship studies within the series are also discussed. Molecular docking studies of compounds 5l and 5x into the colchicine-binding site of the tubulin, revealed the possible mode of interaction by these compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis and structure-activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents.

PubMed

Stolić, Ivana; Čipčić Paljetak, Hana; Perić, Mihaela; Matijašić, Mario; Stepanić, Višnja; Verbanac, Donatella; Bajić, Miroslav

2015-01-27

Current antibacterial chemotherapeutics are facing an alarming increase in bacterial resistance pressuring the search for novel agents that would expand the available therapeutic arsenal against resistant bacterial pathogens. In line with these efforts, a series of 9 amidine derivatives of 3,4-ethylenedioxythiophene were synthesized and, together with 18 previously synthesized analogs, evaluated for their relative DNA binding affinity, in vitro antibacterial activities and preliminary in vitro safety profile. Encouraging antibacterial activity of several subclasses of tested amidine derivatives against Gram-positive (including resistant MRSA, MRSE, VRE strains) and Gram-negative bacterial strains was observed. The bis-phenyl derivatives were the most antibacterially active, while compound 19 from bis-benzimidazole class exhibited the widest spectrum of activity (with MIC of 4, 2, 0.5 and ≤0.25 μg/ml against laboratory strains of Staphyloccocus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, respectively and 4-32 μg/ml against clinical isolates of sensitive and resistant S. aureus, Staphylococcus epidermidis and Enterococcus faecium) and also demonstrated the strongest DNA binding affinity (ΔTm of 15.4 °C). Asymmetrically designed compounds and carboxamide-amidines were, in general, less active. Molecular docking indicated that the shape of the 3,4-ethylenedioxythiophene derivatives and their ability to form multiple electrostatic and hydrogen bonds with DNA, corresponds to the binding modes of other minor-groove binders. Herein reported results encourage further investigation of this class of compounds as novel antibacterial DNA binding agents. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Rhenium(I)-based Double-heterostranded Helicates.

PubMed

Saxena, Priya; Shankar, Bhaskaran; Sathyanarayana, Arruri; Prabusankar, Ganesan; Sathiyendiran, Malaichamy

2015-01-01

Rhenium(I)-based supramolecular coordination complexes were obtained using Re2(CO)10, (2-hydroxyphenyl)benzimidazole-derived bis-chelating N∩O donors and a benzimidazolyl-derived ditopic monodentate N-donor possessing Troger's base spacer in a one-pot approach.

Defining the RNA Internal Loops Preferred by Benzimidazole Derivatives via Two-Dimensional Combinatorial Screening and Computational Analysis

PubMed Central

Velagapudi, Sai Pradeep; Seedhouse, Steven J.; French, Jonathan

2011-01-01

RNA is an important therapeutic target, however, RNA targets are generally underexploited due to a lack of understanding of the small molecules that bind RNA and the RNA motifs that bind small molecules. Herein, we describe the identification of the RNA internal loops derived from a 4096-member 3×3 nucleotide loop library that are the most specific and highest affinity binders to a series of four designer, drug-like benzimidazoles. These studies establish a potentially general protocol to define the highest affinity and most specific RNA motif targets for heterocyclic small molecules. Such information could be used to target functionally important RNAs in genomic sequence. PMID:21604752

Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model

PubMed Central

Knudson, Susan E.; Awasthi, Divya; Kumar, Kunal; Carreau, Alexandra; Goullieux, Laurent; Lagrange, Sophie; Vermet, Hélène; Ojima, Iwao; Slayden, Richard A.

2015-01-01

Objectives The increasing number of clinical strains resistant to one or more of the front-line TB drugs complicates the management of this disease. To develop next-generation benzimidazole-based FtsZ inhibitors with improved efficacy, we employed iterative optimization strategies based on whole bacteria potency, bactericidal activity, plasma and metabolic stability and in vivo efficacy studies. Methods Candidate benzimidazoles were evaluated for potency against Mycobacterium tuberculosis H37Rv and select clinical strains, toxicity against Vero cells and compound stability in plasma and liver microsomes. The efficacy of lead compounds was assessed in the acute murine M. tuberculosis infection model via intraperitoneal and oral routes. Results MICs of SB-P17G-A33, SB-P17G-A38 and SB-P17G-A42 for M. tuberculosis H37Rv and select clinical strains were 0.18–0.39 mg/L. SB-P17G-A38 and SB-P17G-A42 delivered at 50 mg/kg twice daily intraperitoneally or orally demonstrated efficacy in reducing the bacterial load by 5.7–6.3 log10 cfu in the lungs and 3.9–5.0 log10 cfu in the spleen. SB-P17G-A33 delivered at 50 mg/kg twice daily intraperitoneally or orally also reduced the bacterial load by 1.7–2.1 log10 cfu in the lungs and 2.5–3.4 log10 cfu in the spleen. Conclusions Next-generation benzimidazoles with excellent potency and efficacy against M. tuberculosis have been developed. This is the first report on benzimidazole-based FtsZ inhibitors showing an equivalent level of efficacy to isoniazid in an acute murine M. tuberculosis infection model. PMID:26245639

Structure-activity relations of 2-(methylthio)benzimidazole by FTIR, FT-Raman, NMR, DFT and conceptual DFT methods.

PubMed

Arjunan, V; Raj, Arushma; Ravindran, P; Mohan, S

2014-01-24

The vibrational fundamental modes of 2-(methylthio)benzimidazole (2MTBI) have been analysed by combining FTIR, FT-Raman and quantum chemical calculations. The structural parameters of the compound are determined from the optimised geometry by B3LYP with 6-31G(∗∗), 6-311++G(∗∗) and cc-pVTZ basis sets and giving energies, harmonic vibrational frequencies, depolarisation ratios, IR intensities and Raman activities. (1)H and (13)C NMR spectra have been analysed and (1)H and (13)C nuclear magnetic resonance chemical shifts are calculated using the gauge independent atomic orbital (GIAO) method. The structure-activity relationship of the compound is also investigated by conceptual DFT methods. The chemical reactivity and site selectivity of the molecule has been determined with the help of global and local reactivity descriptors. Copyright © 2013 Elsevier B.V. All rights reserved.

Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin.

PubMed

Aleyasin, Hossein; Karuppagounder, Saravanan S; Kumar, Amit; Sleiman, Sama; Basso, Manuela; Ma, Thong; Siddiq, Ambreena; Chinta, Shankar J; Brochier, Camille; Langley, Brett; Haskew-Layton, Renee; Bane, Susan L; Riggins, Gregory J; Gazaryan, Irina; Starkov, Anatoly A; Andersen, Julie K; Ratan, Rajiv R

2015-01-10

Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions, including stroke, Huntington's disease, and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia-inducible factor (HIF)-dependent transcription. Our screen identified more than 40 compounds with the ability to induce hypoxia response element-driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation. Among the chemical entities identified, the antihelminthic benzimidazoles represented one pharmacophore that appeared multiple times in our screen. Secondary assays confirmed that antihelminthics stabilized the transcriptional activator HIF-1α and induced expression of a known HIF target gene, p21(cip1/waf1), in post-mitotic cortical neurons. The on-target effect of these agents in stimulating hypoxic signaling was binding to free tubulin. Moreover, antihelminthic benzimidazoles also abrogated oxidative stress-induced death in vitro, and this on-target effect also involves binding to free tubulin. These studies demonstrate that tubulin-binding drugs can activate a component of the hypoxic adaptive response, specifically the stabilization of HIF-1α and its downstream targets. Tubulin-binding drugs, including antihelminthic benzimidazoles, also abrogate oxidative neuronal death in primary neurons. Given their safety in humans and known ability to penetrate into the central nervous system, antihelminthic benzimidazoles may be considered viable candidates for treating diseases associated with oxidative neuronal death, including stroke.

Polybenzimidazoles Via Aromatic Nucleophilic Displacement

NASA Technical Reports Server (NTRS)

Connell, John W. (Inventor); Hergerrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

1997-01-01

Novel molecular weight controlled and endcapped polybenzimidazoles (PBI) are prepared by the aromatic nucleophilic displacement reaction of di(hydroxyphenylbenzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The PBI are endcapped with mono(hydroxyphenyl)benzimidazoles. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. Mono(hydroxyphenyl)benzimidazoles are synthesized by reacting phenyl-4-hydroxybenzoate with aromatic (o-diamine)s in diphenylsulfone. Molecular weight controlled and endcapped PBI of new chemical structures are prepared that exhibit a favorable combination of physical and mechanical properties.

Synthesis, Biological Activity, and Crystal Structure of Potent Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase That Retain Activity against Mutant Forms of the Enzyme†

PubMed Central

Morningstar, Marshall L.; Roth, Thomas; Farnsworth, David W.; Smith, Marilyn Kroeger; Watson, Karen; Buckheit, Robert W.; Das, Kalyan; Zhang, Wanyi; Arnold, Eddy; Julias, John G.; Hughes, Stephen H.; Michejda, Christopher J.

2010-01-01

In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 μM, EC50 = 0.44 μM, and TC50 ≥ 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants. PMID:17663538

SAR Studies on Trisubstituted Benzimidazoles as Inhibitors of Mtb FtsZ for the Development of Novel Antitubercular Agents

PubMed Central

Awasthi, Divya; Kumar, Kunal; Knudson, Susan E.; Slayden, Richard A.; Ojima, Iwao

2014-01-01

FtsZ, an essential protein for bacterial cell division, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of two lead 2,5,6-trisubstituted benzimidazoles, 1 and 2, targeting Mtb-FtsZ in our previous study, an extensive SAR study for optimization of these lead compounds was performed through systematic modification of the 5 and 6 positions. This study has successfully led to the discovery of a highly potent advanced lead 5f (MIC 0.06 µg/mL) and several other compounds with comparable potencies. These advanced lead compounds possess a dimethylamino group at the 6 position. The functional groups at the 5 position exhibit substantial effects on the antibacterial activity as well. In vitro experiments such as the FtsZ polymerization inhibitory assay and TEM analysis of Mtb-FtsZ treated with 5f and others indicate that Mtb-FtsZ is the molecular target for their antibacterial activity. PMID:24266862

SAR studies on trisubstituted benzimidazoles as inhibitors of Mtb FtsZ for the development of novel antitubercular agents.

PubMed

Awasthi, Divya; Kumar, Kunal; Knudson, Susan E; Slayden, Richard A; Ojima, Iwao

2013-12-12

FtsZ, an essential protein for bacterial cell division, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of two lead 2,5,6-trisubstituted benzimidazoles, 1 and 2, targeting Mtb-FtsZ in our previous study, an extensive SAR study for optimization of these lead compounds was performed through systematic modification of the 5 and 6 positions. This study has successfully led to the discovery of a highly potent advanced lead 5f (MIC = 0.06 μg/mL) and several other compounds with comparable potencies. These advanced lead compounds possess a dimethylamino group at the 6 position. The functional groups at the 5 position exhibit substantial effects on the antibacterial activity as well. In vitro experiments such as the FtsZ polymerization inhibitory assay and TEM analysis of Mtb-FtsZ treated with 5f and others indicate that Mtb-FtsZ is the molecular target for their antibacterial activity.

Unprecedented chemosensing behavior of novel tetra-substituted benzimidazole zinc(II) phthalocynine for selective detection of Bi3 + ion: Synthesis, characterization and ROS generation

NASA Astrophysics Data System (ADS)

Ullah, Azeem; Shah, Faheem; Khan, Imran; Anwar, Muhammad; Shah, Kiramat; Muhammad, Munira Taj; Ahmad, Farid

2018-03-01

In this work, synthesis of novel symmetrical 4-(2-bromo-4-(5-bromo-1H-benzo[d] imidazol-2-yl) phenoxy) tetra substituted zinc phthalocyanine has been reported. The novel benzimidazole zinc phthlocynine compound (3) has been characterized by MALDI-TOF MS, FT-IR, UV-vis, and 1H NMR spectroscopy. This new compound 3 displayed excellent selectivity towards Bi3 + ion in the presence of other competitive ions including Ca2 +, Cd2 +, Co2 + Cu2 +, Fe3 +, Hg2 +, Sn2 +, Mg2 +, Na+, Ni2 + and Pb2 + respectively. Upon addition of Bi3 + into the solution of compound 3 in DMSO, dramatic change was observed in the Q- and the B-bands in UV-visible spectra as a result of donor acceptor interactions. Reactive oxygen species (ROS) were also studied using 2,7-dichlorofluorescin diacetate (DCFH-DA) a fluorescent probe which is converted to highly fluorescent dichlorofluorescein (DCF) in the presence of ROS. This property of non-aggregating zinc phthalocyanine is promising as a photosensitizer in photodynamic therapy of cancer.

Antimalarial pyrido[1,2-a]benzimidazoles.

PubMed

Ndakala, Albert J; Gessner, Richard K; Gitari, Patricia W; October, Natasha; White, Karen L; Hudson, Alan; Fakorede, Foluke; Shackleford, David M; Kaiser, Marcel; Yeates, Clive; Charman, Susan A; Chibale, Kelly

2011-07-14

A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.

Developing novel anthelmintics from plant cysteine proteinases

PubMed Central

Behnke, Jerzy M; Buttle, David J; Stepek, Gillian; Lowe, Ann; Duce, Ian R

2008-01-01

Intestinal helminth infections of livestock and humans are predominantly controlled by treatment with three classes of synthetic drugs, but some livestock nematodes have now developed resistance to all three classes and there are signs that human hookworms are becoming less responsive to the two classes (benzimidazoles and the nicotinic acetylcholine agonists) that are licensed for treatment of humans. New anthelmintics are urgently needed, and whilst development of new synthetic drugs is ongoing, it is slow and there are no signs yet that novel compounds operating through different modes of action, will be available on the market in the current decade. The development of naturally-occurring compounds as medicines for human use and for treatment of animals is fraught with problems. In this paper we review the current status of cysteine proteinases from fruits and protective plant latices as novel anthelmintics, we consider some of the problems inherent in taking laboratory findings and those derived from folk-medicine to the market and we suggest that there is a wealth of new compounds still to be discovered that could be harvested to benefit humans and livestock. PMID:18761736

Impact of zeolite-Y framework on the geometry and reactivity of Ru (III) benzimidazole complexes - A DFT study

NASA Astrophysics Data System (ADS)

Selvaraj, Tamilmani; Rajalingam, Renganathan; Balasubramanian, Viswanathan

2018-03-01

A detailed comparative Density Functional Theory (DFT) study is made to understand the structural changes of the guest complex due to steric and electronic interactions with the host framework. In this study, Ru(III) benzimidazole and 2- ethyl Ru(III) benzimidazole complexes encapsulated in a supercage of zeolite Y. The zeolitic framework integrity is not disturbed by the intrusion of the large guest complex. A blue shift in the d-d transition observed in the UV-Visible spectroscopic studies of the zeolite encapsulated complexes and they shows a higher catalytic efficiency. Encapsulation of zeolite matrix makes the metal center more viable to nucleophilic attack and favors the phenol oxidation reaction. Based on the theoretical calculations, transition states and structures of reaction intermediates involved in the catalytic cycles are derived.

Structure of eight molecular salts assembled from noncovalent bonding between carboxylic acids, imidazole, and benzimidazole

NASA Astrophysics Data System (ADS)

Jin, Shouwen; Zhang, Huan; Liu, Hui; Wen, Xianhong; Li, Minghui; Wang, Daqi

2015-09-01

Eight organic salts of imidazole/benzimidazole have been prepared with carboxylic acids as 2-methyl-2-phenoxypropanoic acid, α-ketoglutaric acid, 5-nitrosalicylic acid, isophthalic acid, 4-nitro-phthalic acid, and 3,5-dinitrosalicylic acid. The eight crystalline forms reported are proton-transfer compounds of which the crystals and compounds were characterized by X-ray diffraction analysis, IR, mp, and elemental analysis. These structures adopted hetero supramolecular synthons, with the most common R22(7) motif observed at salts 2, 3, 5, 6 and 8. Analysis of the crystal packing of 1-8 suggests that there are extensive strong Nsbnd H⋯O, and Osbnd H⋯O hydrogen bonds (charge assisted or neutral) between acid and imidazolyl components in all of the salts. Except the classical hydrogen bonding interactions, the secondary propagating interactions also play important roles in structure extension. This variety, coupled with the varying geometries and number of acidic groups of the acids utilized, has led to the creation of eight supramolecular arrays with 1D-3D structure. The role of weak and strong noncovalent interactions in the crystal packing is analyzed. The results presented herein indicate that the strength and directionality of the Nsbnd H⋯O, and Osbnd H⋯O hydrogen bonds between acids and imidazole/benzimidazole are sufficient to bring about the formation of organic salts.

Effect of acetate and nitrate anions on the molecular structure of 3-(hydroxyimino)-2-butanone-2-(1H-benzimidazol-2-yl)hydrazone

NASA Astrophysics Data System (ADS)

Kamat, Vinayak; Naik, Krishna; Revankar, Vidyanand K.

2017-04-01

A novel Schiff base ligand 3-(hydroxyimino)-2-butanone-2-(1H-benzimidazol-2-yl)hydrazone has been synthesized by the condensation reaction of 2-Hydrazinobenzimidazole with diacetyl monoxime in presence of acetic acid catalyst. The ligand has crystallized as its acetate salt, due to the charge-assisted hydrogen bonding between protonated benzimidazole ring and acetate anion. Efforts to synthesize the zinc(II) complex of the title compound, has resulted in the formation of a nitrate salt of the ligand, instead of coordination complex of zinc(II). Acetate salt has crystallized in monoclinic P 21/n, while the nitrate salt has crystallized in a triclinic crystal system with P -1 space group. Hirshfeld surface analysis is presented for both of the crystal structures. Structures of synthesized molecules are even computationally optimized using DFT. A comparative structural approach between the synthesized molecules and DFT optimized structure of bare ligand without any counterions is analyzed in terms of bond parameters. Hydrogen bonding is explained keeping the anions as the central dogma. Mass fragmentation pattern of the organic molecule and comparative account of IR, 1H and 13C NMR chemical shifts are also presented. Compounds are screened for their antibacterial and antifungal potencies against few pathogenic microorganisms. The organic motif is found be an excellent antifungal agent.

Design and synthesis of N₁-aryl-benzimidazoles 2-substituted as novel HIV-1 non-nucleoside reverse transcriptase inhibitors.

PubMed

Monforte, Anna-Maria; Ferro, Stefania; De Luca, Laura; Lo Surdo, Giuseppa; Morreale, Francesca; Pannecouque, Christophe; Balzarini, Jan; Chimirri, Alba

2014-02-15

A series of novel N1-aryl-2-arylthioacetamido-benzimidazoles were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Some of them proved to be effective in inhibiting HIV-1 replication at submicromolar and nanomolar concentration acting as HIV-1 non-nucleoside RT inhibitors (NNRTIs), with low cytotoxicity. The preliminary structure-activity relationship (SAR) of these new derivatives was discussed and rationalized by docking studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Antihelminthic Benzimidazoles Are Novel HIF Activators That Prevent Oxidative Neuronal Death via Binding to Tubulin

PubMed Central

Aleyasin, Hossein; Karuppagounder, Saravanan S.; Kumar, Amit; Sleiman, Sama; Basso, Manuela; Ma, Thong; Siddiq, Ambreena; Chinta, Shankar J.; Brochier, Camille; Langley, Brett; Haskew-Layton, Renee; Bane, Susan L.; Riggins, Gregory J.; Gazaryan, Irina; Starkov, Anatoly A.; Andersen, Julie K.

2015-01-01

Abstract Aims: Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions, including stroke, Huntington's disease, and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia-inducible factor (HIF)-dependent transcription. Results: Our screen identified more than 40 compounds with the ability to induce hypoxia response element-driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation. Among the chemical entities identified, the antihelminthic benzimidazoles represented one pharmacophore that appeared multiple times in our screen. Secondary assays confirmed that antihelminthics stabilized the transcriptional activator HIF-1α and induced expression of a known HIF target gene, p21cip1/waf1, in post-mitotic cortical neurons. The on-target effect of these agents in stimulating hypoxic signaling was binding to free tubulin. Moreover, antihelminthic benzimidazoles also abrogated oxidative stress-induced death in vitro, and this on-target effect also involves binding to free tubulin. Innovation and Conclusions: These studies demonstrate that tubulin-binding drugs can activate a component of the hypoxic adaptive response, specifically the stabilization of HIF-1α and its downstream targets. Tubulin-binding drugs, including antihelminthic benzimidazoles, also abrogate oxidative neuronal death in primary neurons. Given their safety in humans and known ability to penetrate into the central nervous system, antihelminthic benzimidazoles may be considered viable candidates for treating diseases associated with oxidative neuronal death, including stroke. Antioxid. Redox Signal. 22, 121–134. PMID:24766300

Versatile benzimidazole/triphenylamine hybrids: efficient nondoped deep-blue electroluminescence and good host materials for phosphorescent emitters.

PubMed

Gong, Shaolong; Zhao, Yongbiao; Wang, Meng; Yang, Chuluo; Zhong, Cheng; Qin, Jingui; Ma, Dongge

2010-09-03

Two new bipolar compounds, N,N,N',N'-tetraphenyl-5'-(1-phenyl-1H-benzimidazol-2-yl)-1,1':3',1''-terphenyl-4,4''-diamine (1) and N,N,N',N'-tetraphenyl-5'-(1-phenyl-1H-benzimidazol-2-yl)-1,1':3',1''-terphenyl-3,3''-diamine (2), were synthesized and characterized, and their thermal, photophysical, and electrochemical properties were investigated. Compounds 1 and 2 possess good thermal stability with high glass-transition temperatures of 109-129 degrees C and thermal decomposition temperatures of 501-531 degrees C. The fluorescence quantum yield of 1 (0.52) is higher than that of 2 (0.16), which could be attributed to greater pi conjugation between the donor and acceptor moieties. A nondoped deep-blue fluorescent organic light-emitting diode (OLED) using 1 as the blue emitter displays high performance, with a maximum current efficiency of 2.2 cd A(-1) and a maximum external efficiency of 2.9 % at the CIE coordinates of (0.17, 0.07) that are very close to the National Television System Committee's blue standard (0.15, 0.07). Electrophosphorescent devices using the two compounds as host materials for green and red phosphor emitters show high efficiencies. The best performance of a green phosphorescent device was achieved using 2 as the host, with a maximum current efficiency of 64.3 cd A(-1) and a maximum power efficiency of 68.3 lm W(-1); whereas the best performance of a red phosphorescent device was achieved using 1 as the host, with a maximum current efficiency of 11.5 cd A(-1), and a maximum power efficiency of 9.8 lm W(-1). The relationship between the molecular structures and optoelectronic properties are discussed.

Application of an in vitro drug screening assay based on the release of phosphoglucose isomerase to determine the structure-activity relationship of thiazolides against Echinococcus multilocularis metacestodes.

PubMed

Stadelmann, Britta; Scholl, Sabrina; Müller, Joachim; Hemphill, Andrew

2010-03-01

The disease alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is fatal if treatment is unsuccessful. Current treatment options are, at best, parasitostatic, and involve taking benzimidazoles (albendazole, mebendazole) for the whole of a patient's life. In conjunction with the recent development of optimized procedures for E. multilocularis metacestode cultivation, we aimed to develop a rapid and reliable drug screening test, which enables efficient screening of a large number of compounds in a relatively short time frame. Metacestodes were treated in vitro with albendazole, the nitro-thiazole nitazoxanide and 29 nitazoxanide derivatives. The resulting leakage of phosphoglucose isomerase (PGI) activity into the medium supernatant was measured and provided an indication of compound efficacy. We show that upon in vitro culture of E. multilocularis metacestodes in the presence of active drugs such as albendazole, the nitro-thiazole nitazoxanide and 30 different nitazoxanide derivatives, the activity of PGI in culture supernatants increased. The increase in PGI activity correlated with the progressive degeneration and destruction of metacestode tissue in a time- and concentration-dependent manner, which allowed us to perform a structure-activity relationship analysis on the thiazolide compounds used in this study. The assay presented here is inexpensive, rapid, can be used in 24- and 96-well formats and will serve as an ideal tool for first-round in vitro tests on the efficacy of large numbers of antiparasitic compounds.

Anchoring of Cu(II) onto surface of porous metal-organic framework through post-synthesis modification for the synthesis of benzimidazoles and benzothiazoles

NASA Astrophysics Data System (ADS)

Kardanpour, Reihaneh; Tangestaninejad, Shahram; Mirkhani, Valiollah; Moghadam, Majid; Mohammadpoor-Baltork, Iraj; Zadehahmadi, Farnaz

2016-03-01

Efficient synthesis of various benzimidazoles and benzothiazoles under mild conditions catalyzed by Cu(II) anchored onto UiO-66-NH2 metal organic framework is reported. In this manner, first, the aminated UiO-66 was modified with thiophene-2-carbaldehyde and then the prepared Schiff base was reacted with CuCl2. The prepared catalyst was characterized by FT-IR, UV-vis, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N2 adsorption, inductively coupled plasma atomic emission spectroscopy (ICP-AES) and field emission scanning electron microscopy (FE-SEM). The UiO-66-NH2-TC-Cu was applied as a highly efficient catalyst for synthesis of benzimidazole and benzothiazole derivatives by the reaction of aldehydes with 1,2-diaminobenzene or 2-aminothiophenol. The Cu(II)-containing MOF was reused several times without any appreciable loss of its efficiency.

Iodine-catalyzed Csp3-H functionalization of methylhetarenes: One-pot synthesis and cytotoxic evaluation of heteroarenyl-benzimidazoles and benzothiazole.

PubMed

Baig, Mirza Feroz; Shaik, Siddiq Pasha; Nayak, V Lakshma; Alarifi, Abdullah; Kamal, Ahmed

2017-09-01

An efficient one-pot synthetic procedure has been developed for the preparation of heteroarenyl-benzimidazoles via oxidative C sp3 -H functionalization with o-phenylenediamine using I 2 -DMSO in open air from easily available starting materials. Based on a logical plan a spectrum of multi fundamental reactions like iodination, Kornblum oxidation and amination were brought into one-pot. By using this simple method a library of heteroarenyl-benzimidazoles derivatives (3a-t and 5a-g) and heteroarenyl-benzothiazole (3u) have been synthesized in good to excellent yield and screened for their cytotoxicity against a group of four human cancer cell lines. Among them 3h, 3q and 5b showed significant cytotoxic activities with an IC 50 of 1.69, 1.62 and 2.81µM respectively against lung cancer (A549) cell line. Copyright © 2017 Elsevier Ltd. All rights reserved.

New heterocyclic derivatives of benzimidazole with germicidal activity. IV--In vivo anticandida activity of 5-fluoro-2-(5'-nitro-2'-furyl) benzimidazole (F-O-NO2).

PubMed

Pedini, M; Bistocchi, G A; De Meo, G; Ricci, A; Jacquignon, P; Riccardi, C; Bastianini, L; Sposini, T

1987-07-01

We have studied the possible in vitro and in vivo antibacterial activity of 5-fluoro-2-(5'-nitro-2'-furyl)benzimidazole (F-O-NO2). Our data demonstrate that F-O-NO2 is able to inhibit the in vitro growth of different mycetes and bacteria, including Candida albicans and Cryptococcus neoformans. We also tested the possible in vivo activity against Candida albicans. The results clearly show that treatment with F-O-NO2 is able to significantly augment the survival of all treated animals; in particular, when injected i.p. at the dose of 120 mg/kg, 30' or 1 hr after Candida albicans challenge, it givens a MST (Medium Survival Time) longer than 60 days. These data demonstrate that F-O-NO2 has antibacterial and antimycotic activity.

Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates.

PubMed

Korosh, Travis; Bujans, Emmanuel; Morada, Mary; Karaalioglu, Canan; Vanden Eynde, Jean Jacques; Mayence, Annie; Huang, Tien L; Yarlett, Nigel

2017-10-01

A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH 2 to C 10 H 20 ) containing a meta- (m) or para (p)-benzimidazole linkage to the phenylene ring was tested for ability to inhibit the growth of metronidazole-susceptible (C1) and metronidazole-refractory (085) Trichomonas vaginalis isolates under aerobic and anaerobic conditions. Compound 3m, 2,2'-[α,ω-propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, displayed a 5.5-fold lower minimum inhibitory concentration (MIC) toward T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 μm compared to 145 μm). A dose of 25 mg/kg per day for four days of compound 3m cured a subcutaneous mouse model infection using T. vaginalis isolates 286 (metronidazole susceptible) and 085 (metronidazole refractory). Compound 3m was weakly reduced by pyruvate:ferredoxin oxidoreductase, but unlike metronidazole was not dependent upon added ferredoxin. It is concluded from structure-activity relationships that there was no obvious trend based on the length of the central aliphatic chain, or the steric position of the bisbenzimidazole enabling prediction of biological activity. The compounds generally fulfill Lipinski's rile of five, indicating their potential as drug leads. © 2017 John Wiley & Sons A/S.

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.

In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacteria tuberculosis

PubMed Central

Knudson, Susan E.; Kumar, Kunal; Awasthi, Divya; Ojima, Iwao; Slayden, Richard A.

2014-01-01

Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library based on previous studies for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of M. tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 treatment demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro- in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro–in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis. PMID:24746463

Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines.

PubMed

Xu, Zhigang; Shaw, Arthur Y; Dietrich, Justin; Cappelli, Alexandra P; Nichol, Gary; Hulme, Christopher

2012-02-01

Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines were synthesized via Ugi/de-protection/cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity.

Anchoring of Cu(II) onto surface of porous metal-organic framework through post-synthesis modification for the synthesis of benzimidazoles and benzothiazoles

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

Kardanpour, Reihaneh; Tangestaninejad, Shahram, E-mail: stanges@sci.ui.ac.ir; Mirkhani, Valiollah, E-mail: mirkhani@sci.ui.ac.ir

2016-03-15

Efficient synthesis of various benzimidazoles and benzothiazoles under mild conditions catalyzed by Cu(II) anchored onto UiO-66–NH{sub 2} metal organic framework is reported. In this manner, first, the aminated UiO-66 was modified with thiophene-2-carbaldehyde and then the prepared Schiff base was reacted with CuCl{sub 2}. The prepared catalyst was characterized by FT-IR, UV–vis, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N{sub 2} adsorption, inductively coupled plasma atomic emission spectroscopy (ICP-AES) and field emission scanning electron microscopy (FE-SEM). The UiO-66–NH{sub 2}–TC–Cu was applied as a highly efficient catalyst for synthesis of benzimidazole and benzothiazole derivatives by the reaction of aldehydes with 1,2-diaminobenzenemore » or 2-aminothiophenol. The Cu(II)-containing MOF was reused several times without any appreciable loss of its efficiency. - Graphical abstract: Efficient synthesis of benzimidazoles and benzothiazoles catalyzed by Cu(II) anchored onto UiO-66–NH{sub 2} metal organic framework is reported. - Highlights: • A copper Schiff base was immobilized on UiO-66 via postsynthetic modification. • The modified MOFs were fully characterized by a variety of methods. • The catalyst was used for the preparation of benzimidazoles and benzothiazoles. • In comparison of other catalysts, our catalyst was more efficient and forceful.« less

3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I

PubMed Central

Bansal, Sandhya; Sinha, Devapriya; Singh, Manish; Cheng, Bokun; Tse-Dinh, Yuk-Ching; Tandon, Vibha

2012-01-01

Objectives Antibiotic resistance in bacterial pathogens is a serious clinical problem. Novel targets are needed to combat increasing drug resistance in Escherichia coli. Our objective is to demonstrate that 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-1H-benzimidazole (DMA) inhibits E. coli DNA topoisomerase I more strongly than human topoisomerase I. In addition, DMA is non-toxic to mammalian cells at antibiotic dosage level. Methods In the present study, we have established DMA as an antibacterial compound by determining MICs, post-antibiotic effects (PAEs) and MBCs for different standard as well as clinical strains of E. coli. We have described the differential catalytic inhibitory mechanism of bis-benzimidazole, DMA, for human and E. coli topoisomerase I and topoisomerase II by performing different assays, including relaxation assays, cleavage–religation assays, DNA unwinding assays, ethidium bromide displacement assays, decatenation assays and DNA gyrase supercoiling assays. Results DMA significantly inhibited bacterial growth at a very low concentration, but did not affect human cell viability at higher concentrations. Activity assays showed that it preferentially targeted E. coli topoisomerase I over human topoisomerase I, topoisomerase II and gyrase. Cleavage–religation assays confirmed DMA as a poison inhibitor of E. coli topoisomerase I. This study illuminates new properties of DMA, which may be further modified to develop an efficient topoisomerase inhibitor that is selective towards bacterial topoisomerase I. Conclusions This is the first report of a bis-benzimidazole acting as an E. coli topoisomerase I inhibitor. DMA is a safe, non-cytotoxic molecule to human cells at concentrations that are needed for antibacterial activity. PMID:22945915

Preparation of stir cake sorptive extraction based on polymeric ionic liquid for the enrichment of benzimidazole anthelmintics in water, honey and milk samples.

PubMed

Wang, Yulei; Zhang, Jie; Huang, Xiaojia; Yuan, Dongxing

2014-08-20

In this work, a new stir cake sorptive extraction (SCSE) using polymeric ionic liquid monolith as sorbent was prepared. The sorbent was obtained by in situ copolymerization of an ionic liquid, 1-allyl-3-methylimidazolium bis[(trifluoro methyl)sulfonyl]imide (AMII) and divinylbenzene (DB) in the presence of N,N-dimethylformamide. The influence of the content of ionic liquid and the porogen in the polymerization mixture on extraction performance was studied thoroughly. The physicochemical properties of the polymeric ionic liquid were characterized by infrared spectroscopy, elemental analysis, scanning electron microscopy and mercury intrusion porosimetry. The usefulness of SCSE-AMIIDB was demonstrated by the enrichment of trace benzimidazole anthelmintics. Several parameters affecting the extraction efficiency were investigated, and under the optimized conditions, a simple and effective method for the determination of trace benzimidazoles residues in water, milk and honey samples was established by coupling SCSE-AMIIDB with high performance liquid chromatography/diode array detection (SCSE-AMIIDB-HPLC/DAD). Results indicated that the limits of detection (S/N=3) for target compounds were 0.020-0.072 μg L(-1), 0.035-0.10 μg L(-1) and 0.026-0.076 μg L(-1) in water, milk and honey samples, respectively. In addition, an acceptable reproducibility was achieved by evaluating the repeatability and intermediate precision with relative standard deviations (RSD) of less than 9% and 11%, respectively. Finally, the established AMII-SCSE-HPLC/DAD method was successfully applied for the determination of benzimidazoles residues in milk, honey and environmental water samples. Recoveries obtained for the determination of benzimidazole anthelmintics in spiking samples ranged from 70.2% to 117.6%, with RSD below 12% in all cases. Copyright © 2014 Elsevier B.V. All rights reserved.

Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines

PubMed Central

Xu, Zhigang; Shaw, Arthur Y.; Dietrich, Justin; Cappelli, Alexandra P.; Nichol, Gary; Hulme, Christopher

2012-01-01

Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines were synthesized via Ugi/de-protection/cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity. PMID:22237832

Simultaneous determination of nitroimidazoles, benzimidazoles, and chloramphenicol components in bovine milk by ultra-high performance liquid chromatography-tandem mass spectrometry.

PubMed

Wang, Yuanyuan; Li, Xiaowei; Zhang, Zhiwen; Ding, Shuangyang; Jiang, Haiyang; Li, Jiancheng; Shen, Jianzhong; Xia, Xi

2016-02-01

A sensitive, confirmatory ultra-high performance liquid chromatography-tandem mass spectrometric method was developed and validated to detect 23 veterinary drugs and metabolites (nitroimidazoles, benzimidazoles, and chloramphenicol components) in bovine milk. Compounds of interest were sequentially extracted from milk with acetonitrile and basified acetonitrile using sodium chloride to induce liquid-liquid partition. The extract was purified on a mixed mode solid-phase extraction cartridge. Using rapid polarity switching in electrospray ionization, a single injection was capable of detecting both positively and negatively charged analytes in a 9 min chromatography run time. Recoveries based on matrix-matched calibrations and isotope labeled internal standards for milk ranged from 51.7% to 101.8%. The detection limits and quantitation limits of the analytical method were found to be within the range of 2-20 ng/kg and 5-50 ng/kg, respectively. The recommended method is simple, specific, and reliable for the routine monitoring of nitroimidazoles, benzimidazoles, and chloramphenicol components in bovine milk samples. Copyright © 2015 Elsevier Ltd. All rights reserved.

Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A).

PubMed

Hu, Essa; Kunz, Roxanne K; Chen, Ning; Rumfelt, Shannon; Siegmund, Aaron; Andrews, Kristin; Chmait, Samer; Zhao, Sharon; Davis, Carl; Chen, Hang; Lester-Zeiner, Dianna; Ma, Ji; Biorn, Christopher; Shi, Jianxia; Porter, Amy; Treanor, James; Allen, Jennifer R

2013-11-14

Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.

Benzimidazole--ibuprofen/mesalamine conjugates: potential candidates for multifactorial diseases.

PubMed

Bansal, Yogita; Kaur, Maninder; Silakari, Om

2015-01-07

Ibuprofen (IB) and mesalamine (MES) are commonly used NSAIDs whereas benzimidazole (BZ) and 2-aminobenzimidazole (ABZ) are important pharmacophore for immunomodulatory activities. In the present study, IB and MES were coupled with variedly substituted BZ or ABZ nucleus to synthesize IB-BZ (2a-2e), IB-ABZ (3a-3e), MES-BZ (4a-4e) and MES-ABZ (5a-5e) chimeric conjugates as novel compounds that could elicit both anti-inflammatory and immunomodulatory activities. Each compound retained the anti-inflammatory activity of the parent NSAID. The BZ conjugates (2 and 4) were found immunostimulatory whereas the ABZ conjugates (3 and 5) were immunosuppressive. Each compound also exhibited good antioxidant activity, which is attributed to the electron rich BZ and ABZ nuclei. Compound 2a, 2e, 3a, 3e and 5b exhibited the most significant anti-inflammatory and immunomodulatory activities. Hence, these were evaluated for in vivo acute gastric ulcerogenicity. The compounds were safe to gastric mucosa, probably due to masking of the free -COOH group of IB and MES, and/or to the BZ nucleus itself. A benzoyl group at 5-position of BZ and ABZ incurred maximum immunostimulatory activity. In contrast, a -NO2 group incurred the maximum immunosuppressive action. Docking analysis revealed the compounds to be more selective towards COX-2 enzyme, which support the gastroprotective activity. These results suggest that the compounds can be taken as lead for development of new drugs for the treatment of immune related inflammatory disorders, such as cancer and rheumatoid arthritis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Induction of rat alkaline phosphatase isozymes bearing a glycan-phosphatidylinositol anchor modified by in vivo treatment with a benzimidazole derivative linked to ethylbenzene.

PubMed

Harada, T; Koyama, I; Sato, K; Komoda, T

2000-10-01

Serum alkaline phosphatase (ALP) is detected in soluble-form as a result of translocation from the membrane site by cleavage at the glycosyl-phosphatidylinositol moiety (GPI anchor). It is known that membrane-bound ALP (mALP) can be detected in serum in certain pathological and physiological conditions, and that it can be solubilized in vitro to soluble-ALP (sALP) by phosphatidylinositol-specific phospholipase C (PIPLC), phospholipase D, bile salt, detergent, etc. We observed a marked increase in ALP activity in the serum of rats given a benzimidazole derivative by gavage, and detected it as slow-migrating ALPs (SM-ALPs), which were mALP-like but resistant to PIPLC and n-butanol treatment on disc PAGE. On the other hand, ficin treatment made SM-ALPs shift to the sALP position. The molecular size of the SM-ALPs was smaller than that of sALP on sodium dodecyl sulphide-polyacrylamide slab-gel electrophoresis (SDS-PAGE), and immunoreactivity revealed the intestinal type. SM-ALPs were also detected in the duodenum and jejunum. The main sugar chain structure of SM-ALPs was the biantennary complex-type, which was coincided with intestinal sALP sugar chain. These results suggest that intestinal ALPs induced by the benzimidazole derivative were modified in their C-terminus or GPI anchor region and modification of this region may also participate in translocation into the bloodstream.

Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazoles.

PubMed

Lyons, Dani M; Huttunen, Kristiina M; Browne, Kylie A; Ciccone, Annette; Trapani, Joseph A; Denny, William A; Spicer, Julie A

2011-07-01

A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure-activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

Parallel and automated library synthesis of 2-long alkyl chain benzoazoles and azole[4,5-b]pyridines under microwave irradiation.

PubMed

Martínez-Palou, Rafael; Zepeda, L Gerardo; Höpfl, Herbert; Montoya, Ascensión; Guzmán-Lucero, Diego J; Guzmán, Javier

2005-01-01

A versatile route to 40-membered library of 2-long alkyl chain substituted benzoazoles (1 and 2) and azole[4,5-b]pyridines (3 and 4) via microwave-assisted combinatorial synthesis was developed. The reactions were carried out in both monomode and multimode microwave oven. With the latter, all reactions were performed in high-throughput experimental settings consisting of an 8 x 5 combinatorial library designed to synthesize 40 compounds. Each step, from the addition of reagents to the recovery of final products, was automated. The microwave-assisted N-long chain alkylation reactions of 2-alkyl-1H-benzimidazole (1) and 2-alkyl-1H-benzimidazole[4,5-b] pyridines (3) were also studied.

Structure-activity relationships in cytotoxic Au(I)/Au(III) complexes derived from 2-(2'-pyridyl)benzimidazole.

PubMed

Maiore, Laura; Aragoni, Maria Carla; Deiana, Carlo; Cinellu, Maria Agostina; Isaia, Francesco; Lippolis, Vito; Pintus, Anna; Serratrice, Maria; Arca, Massimiliano

2014-04-21

Gold(I) and gold(III) complexes derived from 2-(2'-pyridyl)benzimidazole (pbiH) were proven to be a promising class of in vitro antitumor agents against A2780 human ovarian cancer cells. In this paper, a comparative electrochemical, UV-vis absorption, and emission spectroscopic investigation is reported on pbiH, the two mononuclear Au(III) complexes [(pbi)AuX2] (X = Cl (1), AcO (2)), the four mononuclear Au(I) derivatives [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)]PF6 ((4(+))(PF6(-))), [(pbi)Au(PPh3)] (5), and [(pbi)Au(TPA)] (6), the three mixed-valence Au(III)/Au(I) complexes [(μ-pbi)Au2Cl3] (7), [(Ph3P)Au(μ-pbi)AuX2]PF6 (X = Cl ((8(+))(PF6(-))), AcO ((9(+))(PF6(-)))), and the binuclear Au(I)-Au(I) compound [(μ-pbi)Au2(PPh3)2]PF6 ((10(+))(PF6(-))). All complexes feature irreversible reduction processes related to the Au(III)/Au(I) or Au(I)/Au(0) processes and peculiar luminescent emission at about 360-370 nm in CH2Cl2, with quantum yields that are remarkably lower ((0.7-14.5) × 10(-2)) in comparison to that determined for the free pbiH ligand (31.5 × 10(-2)) in the same solvent. The spectroscopic and electrochemical properties of all complexes were interpreted on the grounds of time-dependent PBE0/DFT calculations carried out both in the gas phase and in CH2Cl2 implicitly considered within the IEF-PCM SCRF approach. The electronic structure of the complexes, and in particular the energy and composition of the Kohn-Sham LUMOs, can be related to the antiproliferative properties against the A2780 ovarian carcinoma cell line, providing sound quantitative structure-activity relationships and shedding a light on the role played by the global charge and nature of ancillary ligands in the effectiveness of Au-based antitumor drugs.

Identification and hit-to-lead optimization of a novel class of CB1 antagonists.

PubMed

Letourneau, Jeffrey J; Jokiel, Patrick; Olson, John; Riviello, Christopher M; Ho, Koc-Kan; McAleer, Lihong; Yang, Jingchun; Swanson, Robert N; Baker, James; Cowley, Phillip; Edwards, Darren; Ward, Nick; Ohlmeyer, Michael H J; Webb, Maria L

2010-09-15

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Substituent and ring effects on enthalpies of formation: 2-methyl- and 2-ethylbenzimidazoles versus benzene- and imidazole-derivatives

NASA Astrophysics Data System (ADS)

Jiménez, Pilar; Roux, María Victoria; Dávalos, Juan Z.; Temprado, Manuel; Ribeiro da Silva, Manuel A. V.; Ribeiro da Silva, Maria Das Dores M. C.; Amaral, Luísa M. P. F.; Cabildo, Pilar; Claramunt, Rosa M.; Mó, Otilia; Yáñez, Manuel; Elguero, José

The enthalpies of combustion, heat capacities, enthalpies of sublimation and enthalpies of formation of 2-methylbenzimidazole (2MeBIM) and 2-ethylbenzimidazole (2EtBIM) are reported and the results compared with those of benzimidazole itself (BIM). Theoretical estimates of the enthalpies of formation were obtained through the use of atom equivalent schemes. The necessary energies were obtained in single-point calculations at the B3LYP/6-311+G(d,p) on B3LYP/6-31G* optimized geometries. The comparison of experimental and calculated values of benzenes, imidazoles and benzimidazoles bearing H (unsubstituted), methyl and ethyl groups shows remarkable homogeneity. The energetic group contribution transferability is not followed, but either using it or adding an empirical interaction term, it is possible to generate an enormous collection of reasonably accurate data for different substituted heterocycles (pyrazole-derivatives, pyridine-derivatives, etc.) from the large amount of values available for substituted benzenes and those of the parent (pyrazole, pyridine) heterocycles.

Assay of free captopril in human plasma as monobromobimane derivative, using RPLC/(+)ESI/MS/MS: validation aspects and bioequivalence evaluation.

PubMed

Medvedovici, Andrei; Albu, Florin; Sora, Iuliana Daniela; Udrescu, Stefan; Galaon, Toma; David, Victor

2009-10-01

A sensitive method for determination of free captopril as monobromobimane derivative in plasma samples is discussed. The internal standard (IS) was 5-methoxy-1H-benzimidazole-2-thiol. Derivatization with monobromobimane immediately after blood collection and plasma preparation prevents oxidation of captopril to the corresponding disulfide compound and enhances the ionization yield. Consequently, derivatization enhances sample stability and detection sensitivity. Addition of the internal standard was made immediately after plasma preparation. The internal standard was also derivatized by monobromobimane, as it contains a thiol functional group. Preparation of plasma samples containing captopril and IS derivatives was based upon protein precipitation through addition of acetonitrile, in a volumetric ratio 1:2. The reversed-phase liquid chromatographic separation was achieved on a rapid resolution cartridge Zorbax SB-C(18), monitored through positive electrospray ionization and tandem MS detection using the multiple-reaction monitoring mode. Transitions were 408-362 amu for the captopril derivative and 371-260 amu for the internal standard derivative. The kinetics of captopril oxidation to the corresponding disulfide compound in plasma matrix was also studied using the proposed method. A linear log-log calibration was obtained over the concentration interval 2.5-750 ng/mL. A low limit of quantitation in the 2.5 ng/mL range was obtained. The analytical method was fully validated and successfully applied in a three-way, three-period, single-dose (50 mg), block-randomized bioequivalence study for two pharmaceutical formulations (captopril LPH 25 and 50 mg) against the comparator Capoten 50 mg. Copyright (c) 2009 John Wiley & Sons, Ltd.

Copper(II) and zinc(II) as metal-carboxylate coordination complexes based on (1-methyl-1H-benzo[d]imidazol-2-yl) methanol derivative: Synthesis, crystal structure, spectroscopy, DFT calculations and antioxidant activity

NASA Astrophysics Data System (ADS)

Benhassine, Anfel; Boulebd, Houssem; Anak, Barkahem; Bouraiou, Abdelmalek; Bouacida, Sofiane; Bencharif, Mustapha; Belfaitah, Ali

2018-05-01

This work presents a combined experimental and theoretical study of two new metal-carboxylate coordination compounds. These complexes were prepared from (1-methyl-1H-benzimidazol-2-yl)methanol under mild conditions. The structures of the prepared compounds were characterized by single-crystal X-ray analysis, FTIR and UV-Vis spectroscopy. In the Cupper complex, the Cu(II) ion is coordinated by two ligands, which act as bidentate chelator through the non-substituted N and O atoms, and two carboxylicg oxygen atoms, displaying a hexa-coordinated compound in a distorted octahedral geometry, while in the Zinc complex the ligand is ligated to the Zn(II) ion in monodentate fashion through the N atom, and the metal ion is also bonded to carboxylic oxygen atoms. The tetra-coordinated compound displays a distorted tetrahedral shape. The density functional theory calculations are carried out for the determination of the optimized structures. The electronic transitions and fundamental vibrational wave numbers are calculated and are in good agreement with experimental. In addition, the ligand and its Cu(II) and Zn(II) complexes were screened and evaluated for their potential as DPPH radical scavenger.

AzaHx, a novel fluorescent, DNA minor groove and G·C recognition element: Synthesis and DNA binding properties of a p-anisyl-4-aza-benzimidazole-pyrrole-imidazole (azaHx-PI) polyamide.

PubMed

Satam, Vijay; Babu, Balaji; Patil, Pravin; Brien, Kimberly A; Olson, Kevin; Savagian, Mia; Lee, Megan; Mepham, Andrew; Jobe, Laura Beth; Bingham, John P; Pett, Luke; Wang, Shuo; Ferrara, Maddi; Bruce, Chrystal D; Wilson, W David; Lee, Moses; Hartley, John A; Kiakos, Konstantinos

2015-09-01

The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza-benzimidazole-pyrrole-imidazole (5) are described. AzaHx, 2-(p-anisyl)-4-aza-benzimidazole-5-carboxamide, is a novel, fluorescent DNA recognition element, derived from Hoechst 33258 to recognize G·C base pairs. Supported by theoretical data, the results from DNase I footprinting, CD, ΔT(M), and SPR studies provided evidence that an azaHx/IP pairing, formed from antiparallel stacking of two azaHx-PI molecules in a side-by-side manner in the minor groove, selectively recognized a C-G doublet. AzaHx-PI was found to target 5'-ACGCGT-3', the Mlu1 Cell Cycle Box (MCB) promoter sequence with specificity and significant affinity (K(eq) 4.0±0.2×10(7) M(-1)). Copyright © 2015 Elsevier Ltd. All rights reserved.

Proton-transfer lasers based on solid copolymers of modified 2-(2'-hydroxyphenyl)benzimidazoles with methacrylate monomers

NASA Astrophysics Data System (ADS)

Costela, A.; García-Moreno, I.; Mallavia, Ricardo; Amat-Guerri, F.; Barroso, J.; Sastre, R.

1998-06-01

We report on the lasing action of two newly synthesized 2-(2'-hydroxyphenyl) benzimidazole derivatives copolymerized with methyl methacrylate. The laser samples were transversely pumped with a N 2 laser at 337 nm. The influence on the proton-transfer laser performance of the distance between the chromophore group and the polymeric main chain and of the rigidity of the polymeric host matrix, were studied. Significant increases in lasing efficiency and photostability are demonstrated for some of the new materials, as compared to those previously obtained with related proton-transfer dyes also covalently bound to methacrylic monomers.

One-pot green synthesis of zinc oxide nano rice and its application as sonocatalyst for degradation of organic dye and synthesis of 2-benzimidazole derivatives

NASA Astrophysics Data System (ADS)

Paul, Bappi; Vadivel, Sethumathavan; Dhar, Siddhartha Sankar; Debbarma, Shyama; Kumaravel, M.

2017-05-01

In this paper, we report novel and green approach for one-pot biosynthesis of zinc oxide (ZnO) nanoparticles (NPs). Highly stable and hexagonal phase ZnO nanoparticles were synthesized using seeds extract from the tender pods of Parkia roxburghii and characterized by XRD, FT-IR, EDX, TEM, and N2 adsorption-desorption (BET) studies. The present method of synthesis of ZnO NPs is very efficient and cost effective. The powder XRD pattern furnished evidence for the formation of hexagonal close packing structure of ZnO NPs having average crystallite size 25.6 nm. The TEM image reveals rice shapes ZnO NPs are with an average diameter of 40-60 nm. The as-synthesized ZnO NPs has proved to be an excellent sonocatalysts for degradation of organic dye and synthesis of 2-benzimidazole derivatives.

Prevention by thioethers of the hepatotoxicity and covalent binding to macromolecules of N-hydroxy-2-acetylaminofluorene and its sulfate ester in rat liver in vivo and in vitro.

PubMed

van den Goorbergh, J A; de Wit, H; Tijdens, R B; Mulder, G J; Meerman, J H

1987-02-01

In order to find potentially effective compounds that could prevent the covalent binding of the carcinogen N-hydroxy-2-acetylaminofluorene (N-OH-AAF) to rat liver macromolecules in vivo, the prevention of the covalent binding to RNA of the sulfate ester of the carcinogen N-OH-AAF by a series of thioethers was investigated in vitro. The most effective thioethers, which inhibited the covalent binding by 70% or more, were studied for their protection against acute hepatotoxicity of N-OH-AAF in the rat in vivo. Three of these thioethers, thiazolidine, methyl 4-(methylthio)benzoate, and 2-(methylthio)benzimidazole significantly decreased the hepatoxicity of N-OH-AAF, by 45, 71 and 83%, respectively. The effects of these thioethers on the covalent binding of N-OH-AAF to cellular macromolecules in vivo were also studied. Methyl 4-(methylthio)benzoate and 2-(methylthio)benzimidazole decreased the adduct formation of N-OH-AAF to DNA by 54 and 44%, respectively, but had no effect on protein adduct formation. Only 2-(methylthio)benzimidazole caused a slight decrease (23%) in the AAF-- protein adduct formation. 2-Acetylaminofluorene (AAF) and methyl 4-(methyl-sulfinyl)benzoate were the main products in the incubation of methyl 4-(methylthio)benzoate with AAF-N-sulfate in vitro. This suggests that the thioether attacks the nitrenium ion which is formed by spontaneous breakdown of AAF-N-sulfate; the formation of a sulfonium--AAF conjugate is postulated which decomposes into AAF and a sulfinyl compound.

Structure-Activity Relationships of 1,2-Disubstituted Benzimidazoles: Selective Inhibition of Heme Oxygenase-2 Activity.

PubMed

Kong, Xianqi; Vukomanovic, Dragic; Nakatsu, Kanji; Szarek, Walter A

2015-08-01

Devising ways to up- or down-regulate heme oxygenase activity is attracting much interest as a strategy for the treatment of a variety of disorders. With a view of obtaining compounds that exhibit high potency and selectivity as inhibitors of the heme oxygenase-2 (HO-2) isozyme (constitutive) relative to the heme oxygenase-1 (HO-1) isozyme (inducible), several 1,2-disubstituted 1H-benzimidazoles were designed and synthesized. Specifically, analogues were synthesized in which the C2 substituent was the following: (1H-imidazol-1-yl)methyl, (N-morpholinyl)methyl, cyclopentylmethyl, cyclohexylmethyl, or (norborn-2-yl)methyl. Compounds with the cyclic system in the C2 substituent being a carbocyclic ring, especially cyclohexyl or norborn-2-yl, and the N1 substituent being a ring-substituted benzyl group, especially 4-chlorobenzyl or 4-bromobenzyl, best exhibited the target criteria of high potency and selectivity toward inhibition of HO-2. The new candidates should be useful pharmacological tools and may have therapeutic applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer’s disease

PubMed Central

Vangavaragu, Jhansi Rani; Valasani, Koteswara Rao; Gan, Xueqi; Yan, Shirley ShiDu

2014-01-01

Amyloid-β (Aβ), a neurotoxic peptide, is linked to the onset of Alzheimer’s disease (AD). Increased Aβ content within neuronal cell mitochondria is a pathological feature in both human and mouse models with AD. This accumulation of Aβ within the mitochondrial landscape perpetuates increased free radical production and activation of the apoptotic pathway. Human Presequence Protease (hPreP) is responsible for the degradation of mitochondrial amyloid-β peptide in human neuronal cells, and is thus an attractive target to increase the proteolysis of Aβ. Therefore, it offers a potential target for Alzheimer’s drug design, by identifying potential activators of hPreP. We applied structure-based drug design, combined with experimental methodologies to investigate the ability of various compounds to enhance hPreP proteolytic activity. Compounds 3c & 4c enhanced hPreP-mediated proteolysis of Aβ (1–42), pF1β (2–54) and fluorogenic-substrate V. These results suggest that activation of hPreP by small benzimidazole derivatives provide a promising avenue for AD treatment. PMID:24602793

Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells.

PubMed

He, Liu-Jun; Yang, Dong-Lin; Li, Shi-Qiang; Zhang, Ya-Jun; Tang, Yan; Lei, Jie; Frett, Brendan; Lin, Hui-Kuan; Li, Hong-Yu; Chen, Zhong-Zhu; Xu, Zhi-Gang

2018-06-12

Colorectal cancer (CRC) is one of the most frequent, malignant gastrointestinal tumors, and strategies and effectiveness of current therapy are limited. A series of benzimidazole-isoquinolinone derivatives (BIDs) was synthesized and screened to identify novel scaffolds for CRC. Of the compounds evaluated, 7g exhibited the most promising anti-cancer properties. Employing two CRC cell lines, SW620 and HT29, 7g was found to suppress growth and proliferation of the cell lines at a concentration of ∼20 µM. Treatment followed an increase in G 2 /M cell cycle arrest, which was attributed to cyclin B1 and cyclin-dependent kinase 1 (CDK1) signaling deficiencies with simultaneous enhancement in p21 and p53 activity. In addition, mitochondrial-mediated apoptosis was induced in CRC cells. Interestingly, 7g decreased phosphorylated AKT, mTOR and 4E-BP1 levels, while promoting the expression/stability of PTEN. Since PTEN controls input into the PI3K/AKT/mTOR pathway, antiproliferative effects can be attributed to PTEN-mediated tumor suppression. Collectively, these results suggest that BIDs exert antitumor activity in CRC by impairing PI3K/AKT/mTOR signaling. Against a small kinase panel, 7g exhibited low affinity at 5 µM suggesting anticancer properties likely stem through a non-kinase mechanism. Because of the novelty of BIDs, the structure can serve as a lead scaffold to design new CRC therapies. Copyright © 2018. Published by Elsevier Ltd.

Synthesis of novel proxyphylline derivatives with dual Anti-Candida albicans and anticancer activity.

PubMed

Borowiecki, Paweł; Wińska, Patrycja; Bretner, Maria; Gizińska, Małgorzata; Koronkiewicz, Mirosława; Staniszewska, Monika

2018-04-25

Three out of 16 newly synthesized 1,3-dimethylxanthine derivatives (proxyphylline analogues) exhibited consistencies between antifungal and anticancer properties. Proxyphylline possessing 1-(10H-phenothiazin-10-yl)propan-2-yl (6) and polybrominated benzimidazole (41) or benzotriazole moiety (42) remained selectively cidal against Candida albicans (lg R ≥ 3 at conc. of 31, 36 and 20 μM, respectively) however not against normal mammalian Vero cell line in vitro (IC 50  ≥ 280 μM) and Galleria mellonella in vivo. These compounds also displayed moderate antineoplastic activity against human breast adenocarcinoma (MCF-7) cell line (EC 50  = 80 μM) and high against peripheral blood T lymphoblast (CCRF-CEM) (EC 50  = 6.3-6.5 μM). In addition, 6 and 42 exerted: (1) dual activity against fungal adhesion and damage mature biofilm; (2) necrosis of planktonic cells due to loss of membrane function and of structural integrity; (3) biochemical (inhibition of sessile cell respiration) and morphological changes in cell wall polysaccharide contents. Therefore, leading proxyphylline derivatives can be employed to prevent cancer-associated biofilm Candida infections. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Eco-friendly synthesis, in vitro anti-proliferative evaluation, and 3D-QSAR analysis of a novel series of monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates.

PubMed

Racané, Livio; Ptiček, Lucija; Sedić, Mirela; Grbčić, Petra; Kraljević Pavelić, Sandra; Bertoša, Branimir; Sović, Irena; Karminski-Zamola, Grace

2018-04-17

Herein, we describe the synthesis of twenty-one novel water-soluble monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates 3a-3u and present the results of their anti-proliferative assays. Efficient syntheses were achieved by three complementary simple two-step synthetic protocols based on the condensation reaction of aryl/heteroaryl carbaldehydes or carboxylic acid. We developed an eco-friendly synthetic protocol using glycerol as green solvent, particularly appropriate for the condensation of thermally and acid-sensitive heterocycles such as furan, benzofuran, pyrrole, and indole. Screening of anti-proliferative activity was performed on four human tumour cell lines in vitro including pancreatic cancer (CFPAC-1), metastatic colon cancer (SW620), hepatocellular carcinoma (HepG2), and cervical cancer (HeLa), as well as in normal human fibroblast cell lines. All tested compounds showed strong to moderate anti-proliferative activity on tested cell lines depending on the structure containing aryl/heteroaryl moiety coupled to 6-(2-imidazolinyl)benzothiazole moiety. The most potent cytostatic effects on all tested cell lines with [Formula: see text] values ranging from 0.1 to 3.70 [Formula: see text] were observed for benzothiazoles substituted with naphthalene-2-yl 3c, benzofuran-2-yl 3e, indole-3-yl 3j, indole-2-yl 3k, quinoline-2-yl 3s, and quinoline-3-yl 3t and derivatives substituted with phenyl 3a, naphthalene-1-yl 3b, benzothiazole-2-yl 3g, benzothiazole-6-yl 3h, N-methylindole-3-yl 3l, benzimidazole-2-yl 3n, benzimidazole-5(6)-yl 3o, and quinolone-4-yl 3u with [Formula: see text] values ranging from 1.1 to 29.1 [Formula: see text]. Based on obtained anti-proliferative activities, 3D-QSAR models for five cell lines were derived. Molecular volume, molecular surface, the sum of hydrophobic surface areas, molecular mass, and possibility of making dispersion forces were identified by QSAR analyses as molecular properties that are positively correlated with anti-proliferative activity, while compound's capability to accept H-bond was identified as a negatively correlated property. Comparison of molecular properties identified for different cell lines enabled assumptions about similarity of mode of action through which anti-proliferative activities against different cell lines are accomplished. Novel compounds that are predicted to have enhanced activities in comparison with herein presented ones were designed using 3D-QSAR analysis as guideline.

Cancer stem cells CD133 inhibition and cytotoxicity of certain 3-phenylthiazolo[3,2-a]benzimidazoles: design, direct synthesis, crystal study and in vitro biological evaluation.

PubMed

Al-Ansary, Ghada H; Eldehna, Wagdy M; Ghabbour, Hazem A; Al-Rashood, Sara T A; Al-Rashood, Khalid A; Eladwy, Radwa A; Al-Dhfyan, Abdullah; Kabil, Maha M; Abdel-Aziz, Hatem A

2017-12-01

Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC 50  = 9 and 12 μM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of the CSCs. Moreover, compounds 4a and 4c showed moderate activity against HT-29 (IC 50  = 21 and 29 μM, respectively) and MDA-MB-468 (IC 50  = 23 and 24 μM, respectively) cell lines, while they inhibited the CD133 expression by 14% and 48%, respectively. Finally, a single crystal X-ray diffraction was recorded for compound 4d.

2-aryl benzimidazole conjugate induced apoptosis in human breast cancer MCF-7 cells through caspase independent pathway.

PubMed

Nayak, V Lakshma; Nagesh, Narayana; Ravikumar, A; Bagul, Chandrakant; Vishnuvardhan, M V P S; Srinivasulu, Vunnam; Kamal, Ahmed

2017-01-01

Apoptosis is a representative form of programmed cell death, which has been assumed to be critical for cancer prevention. Thus, any agent that can induce apoptosis may be useful for cancer treatment and apoptosis induction is arguably the most potent defense against cancer promotion. In our previous studies, 2-aryl benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity and one of the new molecule (2f) was considered as a potential lead. This lead molecule showed significant antiproliferative activity against human breast cancer cell line, MCF-7. The results of the present study revealed that this compound arrested the cell cycle at G2/M phase. Topoisomerase II inhibition assay and Western blot analysis suggested that this compound effectively inhibits topoisomerase II activity which leads to apoptotic cell death. Apoptosis induction in MCF-7 cells was further confirmed by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome c from mitochondria, an increase in the level of apoptosis inducing factor (AIF), generation of reactive oxygen species (ROS), up regulation of proapoptotic protein Bax and down regulation of anti apoptotic protein Bcl-2. Apoptosis assay using Annexin V-FITC assay also suggested that this compound induced cell death by apoptosis. However, compound 2f induced apoptosis could not be reversed by Z-VAD-FMK (a pan-caspase inhibitor) demonstrated that the 2f induced apoptosis was caspase independent. Further, 2f treatment did not activate caspase-7 and caspase-9 activity, suggesting that this compound induced apoptosis in breast cancer cells via a caspase independent pathway. Most importantly, this compound was less toxic towards non-tumorigenic breast epithelial cells, MCF-10A. Furthermore, docking studies also support the potentiality of this molecule to bind to the DNA topoisomerase II.

Superoxide dismutase from Trichuris ovis--inhibition by benzimidazoles and pyrimidine derivatives.

PubMed

Sanchez-Moreno, M; Garcia-Rejon, L; Salas, I; Osuna, A; Monteoliva, M

1992-01-01

Three superoxide dismutase isoenzymes of different cellular location were detected in an homogenate of Trichuris ovis. Each of these molecular forms was purified by differential centrifugation and precipitation with ammonium sulphate, followed by chromatography on DEAE-cellulose and Sephadex G-75 columns. The activity levels of the two molecular forms detected in the mitochondrial (one cyanide sensitive Cu-Zn-SOD and the other cyanide insensitive Mn-SOD) were higher than that of the superoxide dismutase detected in the cytoplasmic fraction (cyanide sensitive Cu-Zn-SOD). All molecular forms present evident differences to the SODs contained in the host liver. Molecular mass and some of the physical and chemical properties of the enzyme was determined for all three molecular forms. An inhibitory effect on the SOD of the parasite an the host was detected with a series of compounds, some of which markedly inhibited parasite enzyme but not host enzyme.

Crystal structures of eight 3D molecular adducts derived from bis-imidazole, bis(benzimidazole), and organic acids

NASA Astrophysics Data System (ADS)

Ding, Aihua; Jin, Shouwen; Jin, Shide; Hu, KaiKai; Lin, Zhihao; Liu, Hui; Wang, Daqi

2018-01-01

Cocrystallization of the bis(imidazole)/bis(benzimidazole) with a series of organic acids gave a total of eight molecular adducts with the compositions: (3,6-bis(imidazole-1-yl)pyridazine): (trichloroacetic acid)2(1) [(H2L1)2+ · (tca-)2, L1 = 3,6-bis(imidazole-1-yl)pyridazine, tca- = trichloroacetate], (bis(N-imidazolyl)methane): (suberic acid) (2) [(L2) · (H2suba), L2 = bis(N-imidazolyl)methane, H2suba = suberic acid], bis(N-imidazolyl)methane: (3-nitrophthalic acid): 3H2O (3) [(H2L2)2+ · (3-Hnpa-)2 · 3H2O, 3-Hnpa- = 3-nitro hydrogenphthalate], (bis(N-imidazolyl)butane)0.5: (4-nitrophthalic acid): H2O (4) [(H2L3)0.5+ · (4-Hnpa-)- · H2O, L3 = bis(N-imidazolyl)butane, 4-Hnpa- = 4-nitro hydrogenphthalate], (1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole): (3,5-dinitrosalicylic acid) (5) [(HL4) · (3,5-dns-), L4 = 1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole, 3,5-dns- = 3,5-dinitrosalicylate], (1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole): (3-nitrophthalic acid) (6) [(H2L4) · (3-npa2-), L4 = 1-(3-(1H-benzimidazol-1-yl)propyl)-1H-benzimidazole, 3-npa2-=3-nitrogenphthalate], (bis(N-imidazolyl)butane): (pamoic acid) (7) [(H2L3) · (pam), pam = pamoate], and (3,6-bis(imidazole-1-yl)pyridazine): (1,5-naphthalenedisulfonic acid) [(H2L1)2+ · (npda)2- = 1,5-naphthalenedisulfonate] (8). The eight adducts have been characterized by X-ray diffraction technique, infrared spectrum, and elemental analysis, and the melting points of all adducts were also reported. And their structural and supramolecular aspects are fully analyzed. The result reveals that among the eight investigated crystals both the end ring N in the bis(imidazole) moieties are protonated when the organic acids are deprotonated except 2, and 5, and the crystal packing is interpreted in terms of the strong ionic Nsbnd H⋯O H-bond between the imidazolium and the deprotonated acidic groups. Except the Nsbnd H⋯O H-bond, the Osbnd H⋯O H-bonds were also found at the salts 3, 4, 5, and 7, salt 5 has the additional Nsbnd H⋯N H-bond, the Nsbnd H⋯S H-bond was established at 8. Further analysis of the crystal packing of the adducts indicated that a different set of additional CHsbnd O/CH2sbnd O, CHsbnd Cl, CH-π/CH2-π, Clsbnd C, Clsbnd N, Osbnd O, O-π, OH-π, and π-π associations contribute to the stabilization and expansion of the total 3D frameworks. For the coexistence of the various weak interactions these structures had homo or hetero supramolecular synthons or both. Some supramolecular synthons, such as R12(4), R22(7), and R22(8) usually found in crystals of organic acids with imidazole unit, were again shown to be appeared in constructing most of these H-bond networks.

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies.

PubMed

Vázquez-Raygoza, Alejandra; Cano-González, Lucia; Velázquez-Martínez, Israel; Trejo-Soto, Pedro Josué; Castillo, Rafael; Hernández-Campos, Alicia; Hernández-Luis, Francisco; Oria-Hernández, Jesús; Castillo-Villanueva, Adriana; Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Valdez-Solana, Mónica; Téllez-Valencia, Alfredo

2017-11-24

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei . Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1 , 2 and 3 ) with an I 50 value of 84, 82 and 73 µM, respectively. Kinetic analyses indicated that the three molecules were selective when tested against human TIM (HsTIM) activity. Additionally, to study their binding mode in TbTIM, we performed a 100 ns molecular dynamics simulation of TbTIM-inactivator complexes. Simulations showed that the binding of compounds disturbs the structure of the protein, affecting the conformations of important domains such as loop 6 and loop 8. In addition, the physicochemical and drug-like parameters showed by the three compounds suggest a good oral absorption. In conclusion, these molecules will serve as a guide to design more potent inactivators that could be used to obtain new drugs against HAT.

Synthesis of Aminofuran-Linked Benzimidazoles and Cyanopyrrole-Fused Benzimidazoles by Condition-Based Skeletal Divergence.

PubMed

Hsu, Wei-Shun; Tsai, Min-Huan; Barve, Indrajeet J; Yellol, Gorakh S; Sun, Chung-Ming

2017-07-10

A condition-based skeletal divergent synthesis was explored to achieve skeletal diversity in two component condensation reaction. Cyanomethyl benzimidazole was reacted with α-bromoketone under thermal conditions to furnish 2-aminofuranyl-benzimidazoles, while the same reaction afforded 3-cyano-benzopyrrolo-imidazoles under microwave irradiation. Two nonequivalent nucleophilic centers on benzimidazole moiety were manipulated elegantly by different reaction conditions to achieve the skeletal diversity.

2-((Benzimidazol-2-yl)thio)-1-arylethan-1-ones: Synthesis, crystal study and cancer stem cells CD133 targeting potential.

PubMed

Abdel-Aziz, Hatem A; Ghabbour, Hazem A; Eldehna, Wagdy M; Al-Rashood, Sara T A; Al-Rashood, Khalid A; Fun, Hoong-Kun; Al-Tahhan, Mays; Al-Dhfyan, Abdullah

2015-11-02

In order to develop a potent anti-tumor agent that can target both cancer stem cells and the bulk of tumor cells, a series of 2-((benzimidazol-2-yl)thio)-1-arylethan-1-ones 5a-o was synthesized. All compounds were evaluated for their anti-proliferative activity towards colon HT-29 cancer cell line. In addition, their inhibitory effect against cell surface expression of CD133, a potent cancer stem cells (CSCs) marker, in the same cells was evaluated by flow cytometry at 10 μM. Compound 5l emerged as the most active anti-proliferative analog against HT-29 (IC50 = 18.83 ± 1.37 μM), that almost equipotent as 5-fluorouracil (IC50 = 15.83 ± 1.63 μM) with 50.11 ± 4.05% inhibition effect on CD133 expression, suggested dual targeted effect. Also, compounds 5h, 5j, 5k and 5m-o inhibited the expression of CD133 with more than 50%. The SAR study pointed out the significance of substitution of the pendent phenyl group with lipophilic electron-donating groups or replacing it by 2-thienyl or 2-furyl groups. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Synthesis and potent in vitro activity of novel 1H-benzimidazoles as anti-MRSA agents.

PubMed

Karataş, Hacer; Alp, Mehmet; Yildiz, Sulhiye; Göker, Hakan

2012-08-01

A new class of 1H-benzimidazolecarboxamidines was synthesized and evaluated for in vitro antibacterial and antifungal activities, including drug-resistant bacterial strains. The most potent compound (32) has the same ratio of anti-MRSA activity as Vancomycin (minimal inhibitory concentrations value 0.78 μg/mL). The mechanism of action for 1H-benzimidazolecarboxamidine appears to be different from existing antibacterial agents. These compounds have potential for development as a new class of potent anti-MRSA agent. © 2012 John Wiley & Sons A/S.

USE OF THE FUNGICIDE CARBENDAZIM AS A MODEL COMPOUND TO DETERMINE THE IMPACT OF ACUTE CHEMICAL EXPOSURE DURING OOCYTE MATURATION AND FERTILIZATION ON PREGNANCY OUTCOME IN THE HAMSTER

EPA Science Inventory

Here we use a hamster animal model to identify early pregnancy loss due to an acute chemical exposure to the female during the perifertilization interval. The fungicide carbendazim (methyl 1H-benzimidazole-2-carbamate), a microtubule poison with antimitotic activity, was selected...

Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability.

PubMed

Ashraf, Md; Shaik, Thokhir B; Malik, M Shaheer; Syed, Riyaz; Mallipeddi, Prema L; Vardhan, M V P S Vishnu; Kamal, Ahmed

2016-09-15

A series of colchicine site binding tubulin inhibitors were designed and synthesized by the modification of the combretastatin A-4 (CA4) pharmacophore. The ring B was replaced by the pharmacologically relevant benzimidazole or benzothiazole scaffolds, and the cis-configuration of the olefinic bond was restricted by the incorporation of a pyridine ring which is envisaged by the structural resemblance to a tubulin inhibitor like E7010. These compounds were evaluated for their antiproliferative activity on selected cancer cell lines and an insight in the structure activity relationship was developed. The most potent compounds (6c and 6l) demonstrated an antiproliferative effect comparable and superior to that of CA4 (GI50 up to 40nM). Mitotic cell cycle arrest in G2/M phase revealed the disruption of microtubule dynamics that was confirmed by tubulin polymerization assays and immunocytochemistry studies at the cellular level. The molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of combretastatin A-4. Copyright © 2016. Published by Elsevier Ltd.

Regiochemistry in cobalt-mediated intermolecular Pauson-Khand reactions of unsymmetrical internal heteroaromatic alkynes with norbornene.

PubMed

Moulton, Benjamin E; Whitwood, Adrian C; Duhme-Klair, Anne K; Lynam, Jason M; Fairlamb, Ian J S

2011-07-01

The intermolecular Pauson-Khand (PK) reactions of sterically comparable (2-phenylethynyl)heteroaromatic compounds with norbornene, mediated by Co(2)(CO)(8) to give cyclopentenone products, were examined in this study. A synthetic protocol utilizing focused-microwave dielectric heating proved indispensable in the efficient synthesis of the PK cyclopentenone products. "π-Deficient" heteroaromatic substrates, e.g., 2-pyrones, and some "π-excessive" heteroaromatics such as 2- and 3-thiophene and 2-furan favor the β-position in the newly formed cyclopentenone ring. Other π-excessive heteroaromatics such as 2-pyrrole or 2-indole favor the α-position. A π-excessive 3-indole derivative gave a nearly equal mixture of regioisomers. The position of the nitrogen in pyridyl-containing alkyne substrates also affects the regiochemical outcome of the PK reaction. A 2-pyridyl alkyne, possessing a proximal nitrogen, influences the regioselectivity relative to a 4-pyridyl variant quite dramatically, favoring the β-position in the newly formed cyclopentenone ring. A 2-pyrimidylalkyne exhibits similar behavior to the 2-pyridylalkyne. Compounds that do not participate in PK reactions with norbornene include (2-phenylethynyl)imidazoles and the related benzimidazoles, which promote rapid decomposition of the in situ generated (μ(2)-alkyne)Co(2)(CO)(6) complexes. This stands in contrast with other nitrogen-containing heteroaromatics, e.g., pyrrole-, indole-, and pyrimidine-derived compounds, which effectively undergo PK reactions. Overall, the type of heteroaromatic group dramatically influences PK regioselectivity, which can in part be explained by rationalization of the current reaction mechanism, but not fully.

Synthesis of omeprazole analogues and evaluation of these as potential inhibitors of the multidrug efflux pump NorA of Staphylococcus aureus.

PubMed

Vidaillac, Céline; Guillon, Jean; Arpin, Corinne; Forfar-Bares, Isabelle; Ba, Boubakar B; Grellet, Jean; Moreau, Stéphane; Caignard, Daniel-Henri; Jarry, Christian; Quentin, Claudine

2007-03-01

A series of 11 pyrrolo[1,2-a]quinoxaline derivatives, 1a to 1k, sharing structural analogies with omeprazole, a eukaryotic efflux pump inhibitor (EPI) used as an antiulcer agent, was synthesized. Their inhibitory effect was evaluated using Staphylococcus aureus strain SA-1199B overexpressing NorA. By determinations of the MIC of norfloxacin in the presence of these EPIs devoid of intrinsic antibacterial activity and used at 128 microg/ml, and by the checkerboard method, compound 1e (MIC decrease, 16-fold; fractional inhibitory concentration index [SigmaFIC], 0.18) appeared to be more active than compounds 1b to 1d, reserpine, and omeprazole (MIC decrease, eightfold; SigmaFIC, 0.31), followed by compounds 1a and 1f (MIC decrease, fourfold; SigmaFIC, 0.37) and 1g to 1k (MIC decrease, twofold; SigmaFIC, 0.50 to 0.56). By time-kill curves combining norfloxacin (1/4 MIC) and the most efficient EPIs (128 microg/ml), compound 1e persistently restored the bactericidal activity of norfloxacin (inoculum reduction, 3 log(10) CFU/ml at 8 and 24 h), compound 1f led to a delayed but progressive decrease in the number of viable cells, and compounds 1b to 1d and omeprazole acted synergistically (inoculum reduction, 3 log(10) CFU/ml at 8 h but further regrowth), while compound 1a and reserpine slightly enhanced norfloxacin activity. The bacterial uptake of norfloxacin monitored by high-performance liquid chromatography confirmed that compounds 1a to 1f increased antibiotic accumulation, as did reserpine and omeprazole. Since these EPIs did not disturb the Deltapsi and DeltapH, they might directly interact with the pump. A structure-activity relationships study identified the benzimidazole nucleus of omeprazole as the main structural element involved in efflux pump inhibition and highlighted the critical role of the chlorine substituents in the stability and efficiency of compounds 1e to 1f. However, further pharmacomodulation is required to obtain therapeutically applicable derivatives.

2-(2-Hydroxyphenyl)benzimidazole-based four-coordinate boron-containing materials with highly efficient deep-blue photoluminescence and electroluminescence.

PubMed

Zhang, Zhenyu; Zhang, Houyu; Jiao, Chuanjun; Ye, Kaiqi; Zhang, Hongyu; Zhang, Jingying; Wang, Yue

2015-03-16

Two novel four-coordinate boron-containing emitters 1 and 2 with deep-blue emissions were synthesized by refluxing a 2-(2-hydroxyphenyl)benzimidazole ligand with triphenylborane or bromodibenzoborole. The boron chelation produced a new π-conjugated skeleton, which rendered the synthesized boron materials with intense fluorescence, good thermal stability, and high carrier mobility. Both compounds displayed deep-blue emissions in solutions with very high fluorescence quantum yields (over 0.70). More importantly, the samples showed identical fluorescence in the solution and solid states, and the efficiency was maintained at a high level (approximately 0.50) because of the bulky substituents between the boron atom and the benzimidazole unit, which can effectively separate the flat luminescent units. In addition, neat thin films composed of 1 or 2 exhibited high electron and hole mobility in the same order of magnitude 10(-4), as determined by time-of-flight. The fabricated electroluminescent devices that employed 1 or 2 as emitting materials showed high-performance deep-blue emissions with Commission Internationale de L'Eclairage (CIE) coordinates of (X = 0.15, Y = 0.09) and (X = 0.16, Y = 0.08), respectively. Thus, the synthesized boron-containing materials are ideal candidates for fabricating high-performance deep-blue organic light-emitting diodes.

Structural characterization of two solvates of a luminescent copper(II) bis­(pyridine)-substituted benzimidazole complex

PubMed Central

DeStefano, Matthew R.; Lewis, Robert A.

2017-01-01

Copper(II) complexes of benzimidazole are known to exhibit biological activity that makes them of inter­est for chemotherapeutic and other pharmaceutical uses. The complex bis­(acetato-κO){5,6-dimethyl-2-(pyridin-2-yl)-1-[(pyridin-2-yl)meth­yl]-1H-benzimidazole-κ2 N 2,N 3}copper(II), has been prepared. The absorption spectrum has features attributed to intra­ligand and ligand-field transitions and the complex exhibits ligand-centered room-temperature luminescence in solution. The aceto­nitrile monosolvate, [Cu(C2H3O2)2(C20H18N4)]·C2H3N (1), and the ethanol hemisolvate, [Cu(C2H3O2)2(C20H18N4)]·0.5C2H6O (2), have been structurally characterized. Compound 2 has two copper(II) complexes in the asymmetric unit. In both 1 and 2, distorted square-planar N2O2 coordination geometries are observed and the Cu—N(Im) bond distance is slightly shorter than the Cu—N(py) bond distance. Inter­molecular π–π inter­actions are found in 1 and 2. A weak C—H⋯π inter­action is observed in 1. PMID:29152336

Detection of benzimidazole carbamates and amino metabolites in liver by surface plasmon resonance-biosensor

USDA-ARS?s Scientific Manuscript database

Two surface plasmon resonance (SPR) biosensor screening assays were developed and validated to detect 11 benzimidazole carbamate (BZT) and four amino-benzimidazole veterinary drug residues in liver tissue. The assays used polyclonal antibodies, raised in sheep, to detect BZTs and amino-benzimidazole...

Aminopiperidine-Fused Imidazoles as Dipeptidyl Peptidase-IV Inhibitors

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

Edmondson, S.; Mastracchio, A; Cox, J

2009-01-01

A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.

1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells.

PubMed

Okolotowicz, Karl J; Bushway, Paul; Lanier, Marion; Gilley, Cynthia; Mercola, Mark; Cashman, John R

2015-09-01

Cardiomyopathy is the leading cause of death worldwide. Despite progress in medical treatments, heart transplantation is one of the only current options for those with infarcted heart muscle. Stem cell differentiation technology may afford cell-based therapeutics that may lead to the generation of new, healthy heart muscle cells from undifferentiated stem cells. Our approach is to use small molecules to stimulate stem cell differentiation. Herein, we describe a novel class of 1,5-disubstituted benzimidazoles that induce differentiation of stem cells into cardiac cells. We report on the evaluation in vitro for cardiomyocyte differentiation and describe structure-activity relationship results that led to molecules with drug-like properties. The results of this study show the promise of small molecules to direct stem cell lineage commitment, to probe signaling pathways and to develop compounds for the stimulation of stem cells to repair damaged heart tissue. Copyright © 2015 Elsevier Ltd. All rights reserved.

1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells

PubMed Central

Okolotowicz, Karl J.; Bushway, Paul; Lanier, Marion; Gilley, Cynthia; Cynthia, Mark; Cashman, John R.

2016-01-01

Cardiomyopathy is the leading cause of death worldwide. Despite progress in medical treatments, heart transplantation is one of the only current options for those with infarcted heart muscle. Stem cell differentiation technology may afford cell-based therapeutics that may lead to the generation of new, healthy heart muscle cells from undifferentiated stem cells. Our approach is to use small molecules to stimulate stem cell differentiation. Herein, we describe a novel class of 1,5-disubstituted benzimidazoles that induce differentiation of stem cells into cardiac cells. We report on the evaluation in vitro for cardiomyocyte differentiation and describe structure–activity relationship results that led to molecules with drug-like properties. The results of this study show the promise of small molecules to direct stem cell lineage commitment, to probe signaling pathways and to develop compounds for the stimulation of stem cells to repair damaged heart tissue. PMID:26278027

Structure-activity relationships of benzimidazole-based glutaminyl cyclase inhibitors featuring a heteroaryl scaffold.

PubMed

Ramsbeck, Daniel; Buchholz, Mirko; Koch, Birgit; Böhme, Livia; Hoffmann, Torsten; Demuth, Hans-Ulrich; Heiser, Ulrich

2013-09-12

Glutaminyl cyclase (hQC) has emerged as a new potential target for the treatment of Alzheimer's disease (AD). The inhibition of hQC prevents of the formation of the Aβ3(pE)-40,42 species which were shown to be of elevated neurotoxicity and are likely to act as a seeding core, leading to an accelerated formation of Aβ-oligomers and fibrils. This work presents a new class of inhibitors of hQC, resulting from a pharmacophore-based screen. Hit molecules were identified, containing benzimidazole as the metal binding group connected to 1,3,4-oxadiazole as the central scaffold. The subsequent optimization resulted in benzimidazolyl-1,3,4-thiadiazoles and -1,2,3-triazoles with an inhibitory potency in the nanomolar range. Further investigation into the potential binding mode of the new compound classes combined molecular docking and site directed mutagenesis studies.

Evaluating Thermodynamic Integration Performance of the New Amber Molecular Dynamics Package and Assess Potential Halogen Bonds of Enoyl-ACP Reductase (FabI) Benzimidazole Inhibitors

PubMed Central

Su, Pin-Chih; Johnson, Michael E.

2015-01-01

Thermodynamic integration (TI) can provide accurate binding free energy insights in a lead optimization program, but its high computational expense has limited its usage. In the effort of developing an efficient and accurate TI protocol for FabI inhibitors lead optimization program, we carefully compared TI with different Amber molecular dynamics (MD) engines (sander and pmemd), MD simulation lengths, the number of intermediate states and transformation steps, and the Lennard-Jones and Coulomb Softcore potentials parameters in the one-step TI, using eleven benzimidazole inhibitors in complex with Francisella tularensis enoyl acyl reductase (FtFabI). To our knowledge, this is the first study to extensively test the new AMBER MD engine, pmemd, on TI and compare the parameters of the Softcore potentials in the one-step TI in a protein-ligand binding system. The best performing model, the one-step pmemd TI, using 6 intermediate states and 1 ns MD simulations, provides better agreement with experimental results (RMSD = 0.52 kcal/mol) than the best performing implicit solvent method, QM/MM-GBSA from our previous study (RMSD = 3.00 kcal/mol), while maintaining similar efficiency. Briefly, we show the optimized TI protocol to be highly accurate and affordable for the FtFabI system. This approach can be implemented in a larger scale benzimidazole scaffold lead optimization against FtFabI. Lastly, the TI results here also provide structure-activity relationship insights, and suggest the para-halogen in benzimidazole compounds might form a weak halogen bond with FabI, which is a well-known halogen bond favoring enzyme. PMID:26666582

Evaluating thermodynamic integration performance of the new amber molecular dynamics package and assess potential halogen bonds of enoyl-ACP reductase (FabI) benzimidazole inhibitors.

PubMed

Su, Pin-Chih; Johnson, Michael E

2016-04-05

Thermodynamic integration (TI) can provide accurate binding free energy insights in a lead optimization program, but its high computational expense has limited its usage. In the effort of developing an efficient and accurate TI protocol for FabI inhibitors lead optimization program, we carefully compared TI with different Amber molecular dynamics (MD) engines (sander and pmemd), MD simulation lengths, the number of intermediate states and transformation steps, and the Lennard-Jones and Coulomb Softcore potentials parameters in the one-step TI, using eleven benzimidazole inhibitors in complex with Francisella tularensis enoyl acyl reductase (FtFabI). To our knowledge, this is the first study to extensively test the new AMBER MD engine, pmemd, on TI and compare the parameters of the Softcore potentials in the one-step TI in a protein-ligand binding system. The best performing model, the one-step pmemd TI, using 6 intermediate states and 1 ns MD simulations, provides better agreement with experimental results (RMSD = 0.52 kcal/mol) than the best performing implicit solvent method, QM/MM-GBSA from our previous study (RMSD = 3.00 kcal/mol), while maintaining similar efficiency. Briefly, we show the optimized TI protocol to be highly accurate and affordable for the FtFabI system. This approach can be implemented in a larger scale benzimidazole scaffold lead optimization against FtFabI. Lastly, the TI results here also provide structure-activity relationship insights, and suggest the parahalogen in benzimidazole compounds might form a weak halogen bond with FabI, which is a well-known halogen bond favoring enzyme. © 2015 Wiley Periodicals, Inc.

3-(Fur-2-yl)-10-(2-phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a novel adenosine receptor antagonist with A(2A)-mediated neuroprotective effects.

PubMed

Scatena, Alessia; Fornai, Francesco; Trincavelli, Maria Letizia; Taliani, Sabrina; Daniele, Simona; Pugliesi, Isabella; Cosconati, Sandro; Martini, Claudia; Da Settimo, Federico

2011-09-21

In this study, compound FTBI (3-(2-furyl)-10-(2-phenylethyl)[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one) was selected from a small library of triazinobenzimidazole derivatives as a potent A(2A) adenosine receptor (AR) antagonist and tested for its neuroprotective effects against two different kinds of dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) and methamphetamine (METH), in rat PC12 and in human neuroblastoma SH-SY5Y cell lines. FTBI, in a concentration range corresponding to its affinity for A(2A) AR subtype, significantly increased the number of viable PC12 cells after their exposure to METH and, to a similar extent, to MPP+, as demonstrated in both trypan blue exclusion assay and in cytological staining. These neuroprotective effects were also observed with a classical A(2A) AR antagonist, ZM241385, and appeared to be completely counteracted by the AR agonist, NECA, supporting A(2A) ARs are directly involved in FTBI-mediated effects. Similarly, in human SH-SY5Y cells, FTBI was able to prevent cell toxicity induced by MPP+ and METH, showing that this A(2A) AR antagonist has a neuroprotective effect independently by the specific cell model. Altogether these results demonstrate that the A(2A) AR blockade mediates cell protection against neurotoxicity induced by dopaminergic neurotoxins in dopamine containing cells, supporting the potential use of A(2A) AR antagonists in dopaminergic degenerative diseases including Parkinson's disease.

Inhibition of inflammation and oxidative stress by an imidazopyridine derivative X22 prevents heart injury from obesity.

PubMed

Qian, Yuanyuan; Zhang, Yali; Zhong, Peng; Peng, Kesong; Xu, Zheng; Chen, Xuemei; Lu, Kongqin; Chen, Gaozhi; Li, Xiaokun; Liang, Guang

2016-08-01

Inflammation and oxidative stress plays an important role in the development of obesity-related complications and cardiovascular disease. Benzimidazole and imidazopyridine compounds are a class of compounds with a variety of activities, including anti-inflammatory, antioxidant and anti-cancer. X22 is an imidazopyridine derivative we synthesized and evaluated previously for anti-inflammatory activity in lipopolysaccharide-stimulated macrophages. However, its ability to alleviate obesity-induced heart injury via its anti-inflammatory actions was unclear. This study was designed to evaluate the cardioprotective effects of X22 using cell culture studies and a high-fat diet rat model. We observed that palmitic acid treatment in cardiac-derived H9c2 cells induced a significant increase in reactive oxygen species, inflammation, apoptosis, fibrosis and hypertrophy. All of these changes were inhibited by treatment with X22. Furthermore, oral administration of X22 suppressed high-fat diet-induced oxidative stress, inflammation, apoptosis, hypertrophy and fibrosis in rat heart tissues and decreased serum lipid concentration. We also found that the anti-inflammatory and anti-oxidative actions of X22 were associated with Nrf2 activation and nuclear factor-kappaB (NF-κB) inhibition, respectively, both in vitro and in vivo. The results of this study indicate that X22 may be a promising cardioprotective agent and that Nrf2 and NF-κB may be important therapeutic targets for obesity-related complications. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Topological study of diverse hydrogen-bonded patterns found in a system of a nickel(II) complex and the sulfate anion.

PubMed

Harvey, Miguel Angel; Suarez, Sebastián; Zolotarev, Pavel N; Proserpio, Davide M; Baggio, Ricardo

2018-03-01

A nickel(II) coordination complex, bis[2,6-bis(1H-benzimidazol-2-yl-κN 3 )pyridine-κN]nickel(II) sulfate, [Ni(C 19 H 13 N 5 ) 2 ]SO 4 or [Ni(H 2 L) 2 ]SO 4 , having four peripheral tetrahedrally oriented N-H donor units, combines with sulfate bridges to create hydrogen-bonded structures of varied dimensionality. The three crystal structures reported herein in the space groups P2 1 2 1 2 1 , I-4 and Pccn are defined solely by strong charge-assisted N-H...O hydrogen bonds and contain disordered guests (water and dimethylformamide) that vary in size, shape and degree of hydrophilicity. Two of the compounds are channelled solids with three-dimensional structures, while the third is one-dimensional in nature. In spite of their differences, all three present a striking resemblance to the previously reported anhydrous relative [Guo et al. (2011). Chin. J. Inorg. Chem. 27, 1517-1520], which is considered as the reference framework from which all three title compounds are derived. The hydrogen-bonded frameworks are described and compared using crystallographic and topological approaches.

Structural investigation, spectroscopic and energy level studies of Schiff base: 2-[(3‧-N-salicylidenephenyl)benzimidazole] using experimental and DFT methods

NASA Astrophysics Data System (ADS)

Suman, G. R.; Bubbly, S. G.; Gudennavar, S. B.; Muthu, S.; Roopashree, B.; Gayatri, V.; Nanje Gowda, N. M.

2017-07-01

The Schiff base 2-[(3‧-N-salicylidenephenyl)benzimidazole] (Spbzl) was characterized by FT-Raman, 1H NMR, 13C NMR and single crystal X-ray diffraction technique. Crystallographic studies reveal the presence of two water molecules in the asymmetry unit which aid the intermolecular hydrogen bonding with imidazole ring, and the trans-conformation of the azomethine bond. Theoretical computations conducted using density functional theory (DFT) analysis support the experimental facts. Energy levels estimated by DFT studies are in good agreement with the values obtained from cyclic voltammetry technique. Frontier molecular orbital analysis shows that charge transfer has taken place from donor to acceptor moiety, which is also supported by the high hyperpolarizability values in both gaseous and solution phases, indicating high charge transfer capability of the molecule. A comparative theoretical study of Spbzl with derivative 4-((3-(1H-benzimidazol-2-yl)phenylimino)methyl)-3-hydroxybenzoic acid (Pbzlb) having an added anchor group COOH substituted at para position in the acceptor ring has been made. The result shows the feasibility of charge transfer to the semiconductor surface in dye sensitized solar cell (DSSC) applications for Pbzlb.

Functional Chemical Groups that May Likely Become a Source for the Synthesis of Novel Central Nervous System (CNS) Acting Drugs.

PubMed

Saganuwan, Saganuwan A

2017-01-01

Central Nervous System (CNS) disorders are on increase perhaps due to genetic, enviromental, social and dietetic factors. Unfortunately, a large number of CNS drugs have adverse effects such as addiction, tolerance, psychological and physical dependence. In view of this, literature search was carried out with a view to identify functional chemical groups that may serve as lead molecules for synthesis of compounds that may have CNS activity. The search revealed that heterocycles that have heteroatoms such as nitrogen (N), sulphur (S) and oxygen (O) form the largest class of organic compounds. They replace carbon in a benzene ring to form pyridine. Compounds with furan, thiophene, pyrrole, pyridine, azole, imidazole, indole, purine, pyrimidine, esters, carboxylic acid, aldehyde, pyrylium, pyrone, pyrodine, barbituric acid, barbiturate, quinoline, quinolone, isoquinolone, coumarin, alkylpyridine, picoline, piperidine, diazine, carboxamide, flavonoid glycoside, oxindole, aminophenol, benzimidazole, benzoxazole, benzothiazole, and chromone chemical groups among others may have CNS effects ranging from depression passing through euphoria to convulsion. Examples of the compounds with the functional groups include but not limited to coal tar, pyridostigmine, pralidoxime, quinine, mefloquine, pyrilamine, pyronaridine, ciprofloxacin and piroxicam. A number of them can undergo keto-enol tautomerism. Chiral amines may be used for derivation of chiral carboxylic acids which are components of tautomers. Some tautomers may cause parkinsonism and Stevens Johnson syndrome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer

DTIC Science & Technology

2011-05-01

8 4 INTRODUCTION The focus of this project is to evaluate the anti-tumor effects of benzimidazoles as a...potential anti-metastatic prostate cancer therapy. We identified benzimidazoles , a class of anti-parasitic drug, in a drug screening process for...preferential anti-tumor activity on metastatic prostate cancer cells. We have data indicate that benzimidazoles have potent anti-tumor activities

Measuring antiviral activity of benzimidazole molecules that alter IRES RNA structure with an infectious hepatitis C virus chimera expressing Renilla luciferase.

PubMed

Liu, Shuanghu; Nelson, Cassie A; Xiao, Li; Lu, Ling; Seth, Punit P; Davis, Darrell R; Hagedorn, Curt H

2011-01-01

Major progress has been made in developing infectious HCV cell culture systems and these systems have been useful in identifying novel HCV antivirals. However, more rapid and sensitive assays using infectious cell based HCV systems would facilitate the development of additional antivirals, including small molecules directed at unique targets such as the HCV RNA internal ribosomal entry site (IRES). We have found that the V3 region (28 aa) of NS5A of HCV JFH1 can be deleted from the genome with only modest effects on the titer of infectious virus produced in cell culture. Moreover, the V3 region can be replaced with the Renilla reniformis luciferase (Rluc) gene resulting in an infectious virus that stably expresses an NS5A-Rluc fusion protein. Infected cells cultured in 96-well plates provided a robust luciferase signal that accurately reflected the production of infectious virus. This infectious HCV reporter system was used to test the activity of three benzimidazole compounds that bind the HCV RNA IRES. Compounds in this chemical class of small molecules bind and alter the IRES RNA structure at low to sub-micromolar concentrations and interfere with viral replication. The current study shows that these compounds inhibit HCV replication in an infectious HCV cell culture system, defines their IC(50) in this system, and provides a platform for the rapid testing of next generation inhibitors. Copyright © 2010 Elsevier B.V. All rights reserved.

Measuring Antiviral Activity of Benzimidazole Molecules that Alter IRES RNA Structure with an Infectious Hepatitis C Virus Chimera Expressing Renilla Luciferase

PubMed Central

Liu, Shuanghu; Nelson, Cassie A.; Xiao, Li; Lu, Ling; Seth, Punit P.; Davis, Darrell R.; Hagedorn, Curt H.

2010-01-01

Major progress has been made in developing infectious HCV cell culture systems and these systems have been useful in identifying novel HCV antivirals. However, more rapid and sensitive assays using infectious cell based HCV systems would facilitate the development of additional antivirals, including small molecules directed at unique targets such as the HCV RNA internal ribosomal entry site (IRES). We have found that the V3 region (28 aa) of NS5A of HCV JFH1 can be deleted from the genome with only modest effects on the titer of infectious virus produced in cell culture. Moreover, the V3 region can be replaced with the Renilla reniformis luciferase (Rluc) gene resulting in an infectious virus that stably expresses an NS5A-Rluc fusion protein. Infected cells cultured in 96-well plates provided a robust luciferase signal that accurately reflected the production of infectious virus. This infectious HCV reporter system was used to test the activity of three benzimidazole compounds that bind the HCV RNA IRES. Compounds in this chemical class of small molecules bind and alter the IRES RNA structure at low to sub-micromolar concentrations and interfere with viral replication. The current study shows that these compounds inhibit HCV replication in an infectious HCV cell culture system, defines their IC50 in this system, and provides a platform for the rapid testing of next generation inhibitors. PMID:21075143

Benzimidazole ligands in the corrosion inhibition for carbon steel in acid medium: DFT study of its interaction on Fe30 surface

NASA Astrophysics Data System (ADS)

Garcia-Ochoa, E.; Guzmán-Jiménez, S. J.; Hernández, J. Guadalupe; Pandiyan, Thangarasu; Vásquez-Pérez, José M.; Cruz-Borbolla, Julián

2016-09-01

The corrosion inhibition of N,N‧-bis(benzimidazole-2-yl-methyl)amine (L1) and N, N‧-bis(benzimidazole-2-yl-methyl)hydroxyethylamine (L2) was analyzed by electrochemical and theoretical methods. The data show that ligands form an adsorption layer over an iron surface, obeying the Langmuir isotherm (Δ Gads° of -32.96 kJ mol-1); the value are higher than -20 kJ mol-1 but less than -40 kJ mol-1, belonging to a conversion stage of physical adsorption to chemical adsorption or a comprehensive adsorption. This is consistent with fractal dimension of the electrode surface, estimated by an impedance depression angle of a semicircle that the surface is homogeneously covered by the formation of an inhibitor film. Furthermore, the electronic parameters of the ligands were analyzed by DFT, showing that L1 and L2 possesses corrosion inhibition properties that give up its p orbital electron density through its HOMO orbital to the metal LUMO to form an adsorption layer, and this has been proved theoretically by the interaction of ligands with Fe30. In addition, we have collected corrosion inhibition data for around 70 organic compounds reported in the literature, and the inhibition data plotted against different inhibitors, showing that amine ligands are good corrosion inhibitors.

Materials and Manufacturing Challenges of Direct Methanol Fuel Cells

DTIC Science & Technology

2009-04-27

SPSf. Figure 5 shows four basic polymers in which benzimidazole (BIm), amino- benzimidazole (ABIm), nitrobenzimidazole (NBIm), and perimidine (PImd...Membranes Based on Sulfonated Polyetheretherketone and Polysulfone Bearing Benzimidazole Side Groups for Fuel Cells,” Electrochemistry Communications...Bearing Benzimidazole Side Groups for Direct Methanol Fuel Cells,” Electrochemical and Solid State Letters, Vol. 10, 2007, p. B70-B73. [12] Fu, Y.-Z

Trimerization of aromatic nitriles

NASA Technical Reports Server (NTRS)

Hsu, L. C. (Inventor)

1977-01-01

Triazine compounds and cross-linked polymer compositions were made by heating aromatic nitriles to a temperature in the range of about 100 C to about 700 C, in the presence of a catalyst or mixture of catalysts. Aromatic nitrile-modified (terminated and/or appended) imide, benzimidazole, imidazopyrrolone, quinoxaline, and other condensation type prepolymers or their precopolymers were made which were trimerized with or without a filler by the aforementioned catalytic trimerization process.

Blocking of valinomycin-mediated bilayer membrane conductance by substituted benzimidazoles.

PubMed Central

Kuo, K H; Fukuto, T R; Miller, T A; Bruner, L J

1976-01-01

Valinomycin selectively transports alkali cations, e.g. potassium ions, across lipid bilayer membranes. The blocking of this carrier-mediated transport by four substituted benzimidazoles has been investigated. The compounds are 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidazole, (TTFB); 4,5,6,7,-tetrachloro-2-methylbenzimidazole, (TMB); 2-trifluoromethylbenzimidazole, (TFB); and 2-methylbenzimidazole, (MBM). Because of its low acidic dissociation constant (pKa = 5.04), the blocking efficiency of TTFB in both neutral and anionic forms in the aqueous phase could be studied. The compounds exhibit the blocking efficiency sequence, TTFB- greater than TTFB0 greater than TMB0 greater than TFB0 greater than MBM0. The corresponding scale of decreasing lipophilicity, as determined by octanol/water partitioning, is TTFB0 greater than TMB0 greater than TTFB- greater than TFB0 greater than MBM0. Comparison of neutral species establishes a positive correlation of blocking efficiency with lipophilicity, with the latter being conferred primarily by chlorination of the benzenoid nucleus. Anionic TTFB, on the other hand, is the most effective blocking agent studied in spite of the fact that its dissociation in the aqueous phase markedly impedes its entry (presumably as a neutral species) into a bulk hydrocarbon phase. This observation suggests that the blocking of valinomycin-mediated bilayer membrane conductance takes place at the membrane/solution interface. PMID:1247644

Oxidized derivatives of Octopus vulgaris and Carcinus aestuarii hemocyanins at pH 7.5 and related models by x-ray absorption spectroscopy.

PubMed Central

Borghi, Elena; Solari, Pier Lorenzo; Beltramini, Mariano; Bubacco, Luigi; Di Muro, Paolo; Salvato, Benedetto

2002-01-01

The binuclear copper sites of the met and met-azido derivatives of Octopus vulgaris and Carcinus aestuarii hemocyanins at pH 7.5 were characterized by high-resolution x-ray absorption spectroscopy in the low energy region (XANES) and in the higher region (EXAFS). The accuracy of the analysis of the data was tested with two mononuclear and six binuclear copper(II) complexes of the poly(benzimidazole) ligand systems 2-BB, L-5,5 and L-6,6 (Casella et al., 1993, Inorg. Chem. 32:2056-2067; 1996, Inorg. Chem. 35:1101-1113). Their structural and reactivity properties are related to those of the protein's derivatives. The results obtained for those models with resolved x-ray structure (the 2-BB-aquo and azido mononuclear complexes, and the binuclear L-5,5 Cu(II)-bis(hydroxo) (Casella et al., unpublished)), extends the validity of our approach to the other poly(benzimidazole)-containing complexes and to the hemocyanin derivatives. Comparison between the protein's and the complexes' data, support a description of the met-derivatives as a five-coordinated O-bridged binuclear copper(II) center and favors, for both species, a bis(hydroxo) structure with a 3-A Cu-Cu distance. For O. vulgaris met-azido derivative a mu-1,3 bridging mode for the ligand appears the most likely. The structural situation of C. aestuarii met-azido-derivative is less clear: a mu-1,1 mode is favored, but a terminal mode cannot be excluded. PMID:12023249

Metal-free annulation of arenes with 2-aminopyridine derivatives: the methyl group as a traceless non-chelating directing group.

PubMed

Manna, Srimanta; Matcha, Kiran; Antonchick, Andrey P

2014-07-28

A novel annulation reaction between 2-aminopyridine derivatives and arenes under metal-free conditions is described. The presented intermolecular transformation provided straightforward access to the important pyrido[1,2-a]benzimidazole scaffold under mild reaction conditions. The unprecedented application of the methyl group of methylbenzenes as a traceless, non-chelating, and highly regioselective directing group is reported. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Use of a benzimidazole derivative BF-188 in fluorescence multispectral imaging for selective visualization of tau protein fibrils in the Alzheimer's disease brain.

PubMed

Harada, Ryuichi; Okamura, Nobuyuki; Furumoto, Shozo; Yoshikawa, Takeo; Arai, Hiroyuki; Yanai, Kazuhiko; Kudo, Yukitsuka

2014-02-01

Selective visualization of amyloid-β and tau protein deposits will help to understand the pathophysiology of Alzheimer's disease (AD). Here, we introduce a novel fluorescent probe that can distinguish between these two deposits by multispectral fluorescence imaging technique. Fluorescence spectral analysis was performed using AD brain sections stained with novel fluorescence compounds. Competitive binding assay using [(3)H]-PiB was performed to evaluate the binding affinity of BF-188 for synthetic amyloid-β (Aβ) and tau fibrils. In AD brain sections, BF-188 clearly stained Aβ and tau protein deposits with different fluorescence spectra. In vitro binding assays indicated that BF-188 bound to both amyloid-β and tau fibrils with high affinity (K i  < 10 nM). In addition, BF-188 showed an excellent blood-brain barrier permeability in mice. Multispectral imaging with BF-188 could potentially be used for selective in vivo imaging of tau deposits as well as amyloid-β in the brain.

Multifunctional Poly(2,5-benzimidazole)/Carbon Nanotube Composite Films

DTIC Science & Technology

2010-01-01

Multifunctional Poly(2,5- benzimidazole )/Carbon Nanotube Composite Films JI-YE KANG,1 SOO-MI EO,1 IN-YUP JEON,1 YEONG SUK CHOI,2 LOON-SENG TAN,3 JONG...molecular-weight poly(2,5- benzimidazole ) (ABPBI). ABPBI/carbon nanotube (CNT) compo- sites were prepared via in situ polymerization of the AB-monomer in the...polymerization; multiwalled carbon nanotube (MWCNT); nano- composites; poly(2,5- benzimidazole ); (ABPBI); polycondensa- tion; poly(phosphoric acid); single-walled

Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium tuberculosis Appear to Target QcrB

PubMed Central

2017-01-01

The phenoxy alkyl benzimidazoles (PABs) have good antitubercular activity. We expanded our structure–activity relationship studies to determine the core components of PABs required for activity. The most potent compounds had minimum inhibitory concentrations against Mycobacterium tuberculosis in the low nanomolar range with very little cytotoxicity against eukaryotic cells as well as activity against intracellular bacteria. We isolated resistant mutants against PAB compounds, which had mutations in either Rv1339, of unknown function, or qcrB, a component of the cytochrome bc1 oxidase of the electron transport chain. QcrB mutant strains were resistant to all PAB compounds, whereas Rv1339 mutant strains were only resistant to a subset, suggesting that QcrB is the target. The discovery of the target for PAB compounds will allow for the improved design of novel compounds to target intracellular M. tuberculosis. PMID:29035551

Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)

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

Mehboob, Shahila; Song, Jinhua; Hevener, Kirk E.

Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. In the bacterial FASII pathway we found it a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here, we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. Furthermore, these compounds display an improved low nanomolar enzymatic activity as well as promisingmore » low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). Finally, the improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.« less

Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)

DOE PAGES

Mehboob, Shahila; Song, Jinhua; Hevener, Kirk E.; ...

2015-01-29

Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. In the bacterial FASII pathway we found it a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here, we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. Furthermore, these compounds display an improved low nanomolar enzymatic activity as well as promisingmore » low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). Finally, the improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.« less

Enantioseparation of angiotensin II receptor type 1 blockers: evaluation of 6-substituted carbamoyl benzimidazoles on immobilized polysaccharide-based chiral stationary phases. Unusual temperature behavior.

PubMed

Su, Ran; Hou, Zhun; Sang, Lihong; Zhou, Zhi-Ming; Fang, Hao; Yang, Xinying

2017-09-15

Enantioseparation of thirteen 6-substituted carbamoyl benzimidazoles by high-performance liquid chromatography (HPLC) was investigated using two immobilized polysaccharide-based chiral stationary phases (CSPs), Chiralpak IC and Chiralpak IA, in normal-phase mode. Most of the examined compounds were completely resolved. The effects of a polar alcohol modifier, analyte structure, and column temperature on the chiral recognition were investigated. Furthermore, the structure-retention relationship was evaluated, and thermodynamic parameters were calculated from plots of ln k' or ln α versus 1/T. The thermodynamic parameters indicated that the separations were enthalpy-driven. Moreover, nonlinear van't Hoff plots were obtained on Chiralpak IA. However, two unusual phenomena were observed: (1) an unusual increase in retention with increasing temperature with linear van't Hoff plots on Chiralpak IC and (2) an extremely high T iso value (i.e., several thousand degrees centigrade). Copyright © 2017 Elsevier B.V. All rights reserved.

Reversible mechanical protection: building a 3D “suit” around a T-shaped benzimidazole axle† †Electronic supplementary information (ESI) available: Synthetic details and full characterisation of all new compounds. CCDC 1533271 and 1533272. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc00790f Click here for additional data file. Click here for additional data file.

PubMed Central

Baggi, Giorgio; Vukotic, V. Nicholas

2017-01-01

The T-shaped benzimidazolium/crown ether recognition motif was used to prepare suit[1]anes. These novel mechanically interlocked molecules (MIMs) were fully characterized by 1H and 13C NMR spectroscopy, single-crystal X-ray diffraction, UV-vis absorption and fluorescence spectroscopy. By conversion to a suit[1]ane, a simple benzimidazole was shown to be protected from deprotonation by strong base. Moreover, it was demonstrated that this unique three-dimensional encapsulation can be made reversible, thus introducing the concept of “reversible mechanical protection”; a protecting methodology that may have potential applications in synthetic organic chemistry and the design of molecular machinery. PMID:28626559

Novel Reagents for Multi-Component Reactions

NASA Astrophysics Data System (ADS)

Wang, Yanguang; Basso, Andrea; Nenajdenko, Valentine G.; Gulevich, Anton V.; Krasavin, Mikhail; Bushkova, Ekaterina; Parchinsky, Vladislav; Banfi, Luca; Basso, Andrea; Cerulli, Valentina; Guanti, Giuseppe; Riva, Renata; Rozentsveig, Igor B.; Rozentsveig, Gulnur N.; Popov, Aleksandr V.; Serykh, Valeriy J.; Levkovskaya, Galina G.; Cao, Song; Shen, Li; Liu, Nianjin; Wu, Jingjing; Li, Lina; Qian, Xuhong; Chen, Xiaopeng; Wang, Hongbo; Feng, Jinwu; Wang, Yanguang; Lu, Ping; Heravi, Majid M.; Sadjadi, Samaheh; Kazemizadeh, Ali Reza; Ramazani, Ali; Kudyakova, Yulia S.; Goryaeva, Marina V.; Burgart, Yanina V.; Saloutin, Victor I.; Mossetti, Riccardo; Pirali, Tracey; Tron, Gian Cesare; Rozhkova, Yulia S.; Mayorova, Olga A.; Shklyaev, Yuriy V.; Zhdanko, Alexander G.; Nenajdenko, Valentine G.; Stryapunina, Olga G.; Plekhanova, Irina V.; Glushkov, Vladimir A.; Shklyaev, Yurii V.

Ketenimines are a class of versatile and highly reactive intermediates that can participate in a variety of organic reactions, such as nucleophilic additions, radical additions, [2 + 2] and [2 + 4] cycloadditions, and sigmatropic rearrangements. In this presentation, we report on a series of multi-component reactions that involve a ketenimine intermediate. These reactions could furnish diverse heterocyclic compounds, including functionalized iminocoumarin, iminodihydroqunolines, iminothiochromens, pyrrolines, isoquinolines, pyridines, β-lactams, imino-1,2-dihydrocoumarins, and benzimidazoles.

Prostate Cancer and Pesticide Exposure in Diverse Populations in California’s Central Valley

DTIC Science & Technology

2008-12-01

2.38 23.21 153 Control 15 years prior to DX 0.62 1.58 10.78 143 Benzimidazole Benomyl DX Year 0.28 1.57 15.82 163 1974 - 1999 0.60 1.77...prostate cancer with exposure to Benzimidazole Benomyl in California’s Central Valley 2005 - 2006 Benzimidazole Benomyl Frequency...associated with exposure to methyl bromide, captan, simazine, organochlorine group, paraquat dichloride and benzimidazole benomyl, after adjusting for

Determination of benzimidazole anthelmintics in animal-derived biological matrices.

PubMed

Neri, Bruno; Bidolli, Gentilina; Felli, Marialinda; Cozzani, Roberto

2002-04-01

This paper describes an easy multiresidue procedure for the determination of 8 benzimidazole anthelmintics (Albendazole, Albendazole sulphone, Albendazole sulphoxide, Ox-bendazole, Ossibendazole, p-OH-Fenbendazole, Fenbendazole, Flubendazole) in foodstuffs of animal origin for human consumption. According to the proposed procedure, 10 g of homogenised sample were extracted with acetonitrile in ultrasonic bath, the organic layer was evaporated to dryness and the residue dissolved in HCl 0.005 M. After an initial washing with hexane to remove fats, the aqueous layer was purified on SPE C2 column and the analytes were eluted with methanol, evaporated to dryness and reconstituted with phosphate buffer/acetonitrile (50/50). The solution obtained was analysed by HPLC with diode array detector (DAD); this detector provides useful information about the peaks present in routine samples, because it gains not only retention times of analytes, as well as their UV-spectra. Benzthiazuron was used as internal standard and the method was validated in the range 10-100 ppb, as requested by the imposed limits. The mean recoveries in spiked samples ranged between 70% and 95%, for 10 and 100 ppb respectively. The developed method resulted sensitive, simple and fast. It is particularly suitable for laboratories that execute screening analysis on a great number of samples, observing the EC regulations that establish the benzimidazole Maximum Residue Limits (MRLs) in food.

Synthesis of benzimidazoles via iridium-catalyzed acceptorless dehydrogenative coupling.

PubMed

Sun, Xiang; Lv, Xiao-Hui; Ye, Lin-Miao; Hu, Yu; Chen, Yan-Yan; Zhang, Xue-Jing; Yan, Ming

2015-07-21

Iridium-catalyzed acceptorless dehydrogenative coupling of tertiary amines and arylamines has been developed. A number of benzimidazoles were prepared in good yields. An iridium-mediated C-H activation mechanism is suggested. This finding represents a novel strategy for the synthesis of benzimidazoles.

Special Issue on Powering the Future Force: New Power & Energy Technologies for the Warfighter (AMMTIAC Quarterly, Volume 4, Number 1 / WSTIAC Quarterly, Volume 9, Number 1)

DTIC Science & Technology

2009-04-27

an aromatic acidic polymer such as SPEEK or SPSf. Figure 5 shows four basic polymers in which benzimidazole (BIm), amino- benzimidazole (ABIm...Z., A. Manthiram, and M. D. Guiver, “Blend Membranes Based on Sulfonated Polyetheretherketone and Polysulfone Bearing Benzimidazole Side Groups for...Sulfonated Poly(ether ether ketone) and Polysulfone Bearing Benzimidazole Side Groups for Direct Methanol Fuel Cells,” Electrochemical and Solid State Letters

Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

PubMed Central

Rice, Christopher A.; Colon, Beatrice L.; Alp, Mehmet; Göker, Hakan; Boykin, David W.

2015-01-01

Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. PMID:25605363

A bioinspired catalytic aerobic oxidative C-H functionalization of primary aliphatic amines: synthesis of 1,2-disubstituted benzimidazoles.

PubMed

Nguyen, Khac Minh Huy; Largeron, Martine

2015-09-01

Aerobic oxidative CH functionalization of primary aliphatic amines has been accomplished with a biomimetic cooperative catalytic system to furnish 1,2-disubstituted benzimidazoles that play an important role as drug discovery targets. This one-pot atom-economical multistep process, which proceeds under mild conditions, with ambient air and equimolar amounts of each coupling partner, constitutes a convenient environmentally friendly strategy to functionalize non-activated aliphatic amines that remain challenging substrates for non-enzymatic catalytic aerobic systems. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of Creative Commons Attribution NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Nanostructured poly(benzimidazole): from mesoporous networks to nanofibers.

PubMed

Weber, Jens

2010-02-22

Poly(benzimidazole)s (PBIs) are a class of high-performance polymers which have been receiving increasing interest during the last years due to their high potential as constituents of membrane materials in proton-exchange membrane fuel cells (PEMFCs). In addition to the importance of PBI in fuel-cell technology, there are a number of other applications (e.g., catalysis) that make use of the special properties of this material. The scope of this Minireview is to first give a short overview about the use of nanostructured, mesoporous PBI as a proton conductor. Secondly, the use of spirobifluorene derivatives as new monomers, which allow the synthesis of hierarchically structured PBI, is presented. Limitations of traditional synthetic methods will be discussed, and an ionothermal scheme towards PBI will be presented as a versatile tool for the synthesis of plain and spirobifluorene-based PBIs. Finally, the use of electrospinning as a powerful processing technique for PBI will be presented briefly.

Evaluation of the membrane permeability (PAMPA and skin) of benzimidazoles with potential cannabinoid activity and their relation with the Biopharmaceutics Classification System (BCS).

PubMed

Alvarez-Figueroa, M Javiera; Pessoa-Mahana, C David; Palavecino-González, M Elisa; Mella-Raipán, Jaime; Espinosa-Bustos, Cristián; Lagos-Muñoz, Manuel E

2011-06-01

The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P(oct) value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).

3D chiral and 2D achiral cobalt(ii) compounds constructed from a 4-(benzimidazole-1-yl)benzoic ligand exhibiting field-induced single-ion-magnet-type slow magnetic relaxation.

PubMed

Wang, Yu-Ling; Chen, Lin; Liu, Cai-Ming; Du, Zi-Yi; Chen, Li-Li; Liu, Qing-Yan

2016-05-04

Organizing magnetically isolated 3d transition metal ions, which behave as single-ion magnet (SIM) units, in a coordination network is a promising approach to design novel single-molecule magnets (SMMs). Herein 3D chiral and 2D achiral cobalt(ii) coordination compounds based on single metal nodes with a 4-(benzimidazole-1-yl)benzoic acid (Hbmzbc) ligand, namely, [Co(bmzbc)2(1,2-etdio)]n () (1,2-etdio = 1,2-ethanediol) and [Co(bmzbc)2(Hbmzbc)]n (), have been synthesized and structurally characterized. The 3D chiral structure with 2-fold interpenetrating qtz topological nets consisting of totally achiral components was obtained via spontaneous resolution, while the achiral structure is a 2D (4,4) net. In both structures, individual cobalt(ii) ions are spatially well separated by the long organic ligands in the well-defined networks. Magnetic measurements on and showed field-induced slow magnetic relaxation resulting from single-ion anisotropy of the individual Co(ii) ions. Analysis of the dynamic ac susceptibilities with the Arrhenius law afforded an anisotropy energy barrier of 16.8(3) and 31.3(2) K under a 2 kOe static magnetic field for and , respectively. The distinct coordination environments of the Co(ii) ions in and lead to the different anisotropic energy barriers.

Recyclization reactions leading to benzimidazoles

NASA Astrophysics Data System (ADS)

Mamedov, Vakhid A.; Murtazina, Anna M.

2011-05-01

The published data on the recyclization reactions that afford benzimidazoles are generalized and systematized. Both classical and new methods of benzimidazole synthesis are considered. Attention is focused on the publications over the recent 10-15 years; of the earlier publications, only those unknown to the wide circle of chemists are analyzed.

Microwave promoted simple, efficient and regioselective synthesis of trisubstituted imidazo[1,2-a]benzimidazoles on soluble support.

PubMed

Chen, Li-Hsun; Hsiao, Ya-Shan; Yellol, Gorakh S; Sun, Chung-Ming

2011-03-14

An efficient microwave-assisted and soluble polymer-supported synthesis of medicinally important imidazole-fused benzimidazoles has been developed. The protocol involves the rapid condensation of polymer-bound amino benzimidazoles with various α-bromoketones and subsequent in situ intramolecular cyclization under microwave irradiation resulting in a one pot synthesis of imidazole interlacing benzimidazole polymer conjugates. The condensed product was obtained with excellent regioselectivity. The biologically interesting imidazo[1,2-a]benzimidazoles was released from polymer support at ambient temperature. Diversity in the triheterocyclic nucleus was achieved by the different substitutions at its 2, 3, and 9 positions. The new protocol has the advantages of short reaction time, easy workup process, excellent yields, reduced environmental impact, wide substrate scope and convenient procedure.

Computational Study Exploring the Interaction Mechanism of Benzimidazole Derivatives as Potent Cattle Bovine Viral Diarrhea Virus Inhibitors.

PubMed

Wang, Jinghui; Yang, Yinfeng; Li, Yan; Wang, Yonghua

2016-07-27

Bovine viral diarrhea virus (BVDV) infections are prevailing in cattle populations on a worldwide scale. The BVDV RNA-dependent RNA polymerase (RdRp), as a promising target for new anti-BVDV drug development, has attracted increasing attention. To explore the interaction mechanism of 65 benzimidazole scaffold-based derivatives as BVDV inhibitors, presently, a computational study was performed based on a combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations. The resultant optimum CoMFA and CoMSIA models present proper reliabilities and strong predictive abilities (with Q(2) = 0. 64, R(2)ncv = 0.93, R(2)pred = 0.80 and Q(2) = 0. 65, R(2)ncv = 0.98, R(2)pred = 0.86, respectively). In addition, there was good concordance between these models, molecular docking, and MD results. Moreover, the MM-PBSA energy analysis reveals that the major driving force for ligand binding is the polar solvation contribution term. Hopefully, these models and the obtained findings could offer better understanding of the interaction mechanism of BVDV inhibitors as well as benefit the new discovery of more potent BVDV inhibitors.

Proton-conducting membranes based on benzimidazole polymers for high-temperature PEM fuel cells. A chemical quest.

PubMed

Asensio, Juan Antonio; Sánchez, Eduardo M; Gómez-Romero, Pedro

2010-08-01

The development of high-temperature PEM fuel cells (working at 150-200 degrees C) is pursued worldwide in order to solve some of the problems of current cells based on Nafion (CO tolerance, improved kinetics, water management, etc.). Polybenzimidazole membranes nanoimpregnated with phosphoric acid have been studied as electrolytes in PEMFCs for more than a decade. Commercially available polybenzimidazole (PBI) has been the most extensively studied and used for this application in membranes doped with all sorts of strong inorganic acids. In addition to this well-known polymer we also review here studies on ABPBI and other polybenzimidazole type membranes. More recently, several copolymers and related derivatives have attracted many researchers' attention, adding variety to the field. Furthermore, besides phosphoric acid, many other strong inorganic acids, as well as alkaline electrolytes have been used to impregnate benzimidazole membranes and are analyzed here. Finally, we also review different hybrid materials based on polybenzimidazoles and several inorganic proton conductors such as heteropoly acids, as well as sulfonated derivatives of the polymers, all of which contribute to a quickly-developing field with many blooming results and useful potential which are the subject of this critical review (317 references).

Intermolecular interactions between imidazole derivatives intercalated in layered solids. Substituent group effect

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

González, M.; Lemus-Santana, A.A.; Rodríguez-Hernández, J.

2013-08-15

This study sheds light on the intermolecular interactions between imidazole derive molecules (2-methyl-imidazole, 2-ethyl-imidazole and benzimidazole) intercalated in T[Ni(CN){sub 4}] layers to form a solid of formula unit T(ImD){sub 2}[Ni(CN){sub 4}]. These hybrid inorganic–organic solids were prepared by soft chemical routes and their crystal structures solved and refined from X-ray powder diffraction data. The involved imidazole derivative molecules were found coordinated through the pyridinic N atom to the axial positions for the metal T in the T[Ni(CN){sub 4}] layer. In the interlayers region ligand molecules from neighboring layers remain stacked in a face-to-face configuration through dipole–dipole and quadrupole–quadrupole interactions. Thesemore » intermolecular interactions show a pronounced dependence on the substituent group and are responsible for an ImD-pillaring concatenation of adjacent layers. This is supported by the structural information and the recorded magnetic data in the 2–300 K temperature range. The samples containing Co and Ni are characterized by presence of spin–orbit coupling and pronounced temperature dependence for the effective magnetic moment except for 2-ethyl-imidazole related to the local distortion for the metal coordination environment. For this last one ligand a weak ferromagnetic ordering ascribed to a super-exchange interaction between T metals from neighboring layers through the ligands π–π interaction was detected. - Graphical abstract: In the interlayers region imidazole derivative molecules are oriented according to their dipolar and quadrupolar interactions and minimizing the steric impediment. Highlights: • Imidazole derivatives intercalation compounds. • Intermolecular interaction between intercalated imidazole derivatives. • Hybrid inorganic–organic solids. • Pi–pi interactions and ferromagnetic coupling. • Dipolar and quadrupolar interactions between intercalated imidazole derivatives.« less

Advances in analytical methods and occurrence of organic UV-filters in the environment--A review.

PubMed

Ramos, Sara; Homem, Vera; Alves, Arminda; Santos, Lúcia

2015-09-01

UV-filters are a group of compounds designed mainly to protect skin against UVA and UVB radiation, but they are also included in plastics, furniture, etc., to protect products from light damage. Their massive use in sunscreens for skin protection has been increasing due to the awareness of the chronic and acute effects of UV radiation. Some organic UV-filters have raised significant concerns in the past few years for their continuous usage, persistent input and potential threat to ecological environment and human health. UV-filters end up in wastewater and because wastewater treatment plants are not efficient in removing them, lipophilic compounds tend to sorb onto sludge and hydrophilics end up in river water, contaminating the existing biota. To better understand the risk associated with UV-filters in the environment a thorough review regarding their physicochemical properties, toxicity and environmental degradation, analytical methods and their occurrence was conducted. Higher UV-filter concentrations were found in rivers, reaching 0.3mg/L for the most studied family, the benzophenone derivatives. Concentrations in the ng to μg/L range were also detected for the p-aminobenzoic acid, cinnamate, crylene and benzoyl methane derivatives in lake and sea water. Although at lower levels (few ng/L), UV-filters were also found in tap and groundwater. Swimming pool water is also a sink for UV-filters and its chlorine by-products, at the μg/L range, highlighting the benzophenone and benzimidazole derivatives. Soils and sediments are not frequently studied, but concentrations in the μg/L range have already been found especially for the benzophenone and crylene derivatives. Aquatic biota is frequently studied and UV-filters are found in the ng/g-dw range with higher values for fish and mussels. It has been concluded that more information regarding UV-filter degradation studies both in water and sediments is necessary and environmental occurrences should be monitored more frequently and deeply. Copyright © 2015 Elsevier B.V. All rights reserved.

Specific detection of benzimidazole resistance in Colletotrichum gloeosporioides from fruit crops by PCR-RFLP.

PubMed

Chung, Wen-Hsin; Chung, Wen-Chuan; Peng, Mun-Tsu; Yang, Hong-Ren; Huang, Jenn-Wen

2010-02-28

Anthracnose diseases, caused by Colletotrichum gloeosporioides, are a worldwide problem and are especially important in Taiwan owing to the severe economic damage they cause to tropical fruits that are grown for local consumption and export. Benzimidazoles are systemic fungicides widely used for controlling these diseases in Taiwan. Thirty-one isolates of C. gloeosporioides from mango and strawberry grown in Taiwan were examined for their sensitivity to benzimidazole fungicides. The responses of the isolates grown on benzimidazole-amended culture media were characterized as sensitive, moderately resistant, resistant or highly resistant. Analysis of point mutations in the beta-tubulin gene by DNA sequencing of PCR-amplified fragments revealed a substitution of GCG for GAG at codon 198 in resistant and highly resistant isolates and a substitution of TAC for TTC at codon 200 in moderately resistant isolates. A set of specific primers, TubGF1 and TubGR, was designed to amplify a portion of the beta-tubulin gene for the detection of benzimidazole-resistant C. gloeosporioides. Bsh1236I restriction maps of the amplified beta-tubulin gene showed that the resistant isolate sequence, but not the sensitive isolate sequence, was cut. The PCR restriction fragment length polymorphism (PCR-RFLP) was validated to detect benzimidazole-resistant and benzimidazole-sensitive C. gloeosporioides isolates recovered from avocado, banana, carambola, dragon fruit, grape, guava, jujube, lychee, papaya, passion fruit and wax apple. This method has the potential to become a valuable tool for monitoring the occurrence of benzimidazole-resistant C. gloeosporioides and for assessment of the need for alternative management practices. Copyright 2009 Elsevier B.V. All rights reserved.

Boron-dipyrromethene based reversible and reusable selective chemosensor for fluoride detection.

PubMed

Madhu, Sheri; Ravikanth, Mangalampalli

2014-02-03

We synthesized benzimidazole substituted boron-dipyrromethene 1 (BODIPY 1) by treating 3,5-diformyl BODIPY 2 with o-phenylenediamine under mild acid catalyzed conditions and characterized by using various spectroscopic techniques. The X-ray structure analysis revealed that the benzimidazole NH group is involved in intramolecular hydrogen bonding with fluoride atoms which resulted in a coplanar geometry between BODIPY and benzimidazole moiety. The presence of benzimidazole moiety at 3-position of BODIPY siginificantly altered the electronic properties, which is clearly evident in bathochromic shifts of absorption and fluorescence bands, improved quantum yields, increased lifetimes compared to BODIPY 2. The anion binding studies indicated that BODIPY 1 showed remarkable selectivity and specificity toward F(-) ion over other anions. Addition of F(-) ion to BODIPY 1 resulted in quenching of fluorescence accompanied by a visual detectable color change from fluorescent pink to nonfluorescent blue. The recognition mechanism is attributed to a fluoride-triggered disruption of the hydrogen bonding between BODIPY and benzimidazole moieties leading to (i) noncoplanar geometry between BODIPY and benzimidazole units and (ii) operation of photoinduced electron transfer (PET) from benzimidazole moiety to BODIPY unit causing quenching of fluorescence. Interestingly, when we titrated the nonfluorescent blue 1-F(-) solution with TFA resulted in a significant enhancement of fluorescence intensity (15-fold) because the PET quenching is prevented due to protonation of benzimidazole group. Furthermore, the reversibility and reusability of sensor 1 for the detection of F(-) ion was tested for six cycles indicating the sensor 1 is stable and can be used in reversible manner.

Benzimidazole Carbamate Residues in Milk: Detection by SPR Biosensor; using a Modified QuEChERS Method for Extraction

USDA-ARS?s Scientific Manuscript database

A surface plasmon resonance (SPR) biosensor screening assay was developed and validated to detect 11 benzimidazole carbamate (BZT) veterinary drug residues in milk. The polyclonal antibody used was raised in sheep against a methyl 5 (6)-[(carboxypentyl)-thio]-2-benzimidazole carbamate protein conjug...

Evaluation of chromatographic columns packed with semi- and fully porous particles for benzimidazoles separation.

PubMed

Gonzalo-Lumbreras, Raquel; Sanz-Landaluze, Jon; Cámara, Carmen

2015-07-01

The behavior of 15 benzimidazoles, including their main metabolites, using several C18 columns with standard or narrow-bore diameters and different particle size and type were evaluated. These commercial columns were selected because their differences could affect separation of benzimidazoles, and so they can be used as alternative columns. A simple screening method for the analysis of benzimidazole residues and their main metabolites was developed. First, the separation of benzimidazoles was optimized using a Kinetex C18 column; later, analytical performances of other columns using the above optimized conditions were compared and then individually re-optimized. Critical pairs resolution, analysis run time, column type and characteristics, and selectivity were considered for chromatographic columns comparison. Kinetex XB was selected because it provides the shortest analysis time and the best resolution of critical pairs. Using this column, the separation conditions were re-optimized using a factorial design. Separations obtained with the different columns tested can be applied to the analysis of specific benzimidazoles residues or other applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

π-stacking and C-X...D (X = H, NO2; D = O, π) interactions in the crystal network of both C-H...N and π-stacked dimers of 1,2-bis(4-bromophenyl)-1H-benzimidazole and 2-(4-bromophenyl)-1-(4-nitrophenyl)-1H-benzimidazole.

PubMed

González-Padilla, Jazmin E; Rosales-Hernández, Martha C; Padilla-Martínez, Itzia I; García-Báez, Efren V; Rojas-Lima, Susana; Salazar-Pereda, Veronica

2014-01-01

Molecules of 1,2-bis(4-bromophenyl)-1H-benzimidazole, C19H12Br2N2, (I), and 2-(4-bromophenyl)-1-(4-nitrophenyl)-1H-benzimidazole, C19H12BrN3O2, (II), are arranged in dimeric units through C-H...N and parallel-displaced π-stacking interactions favoured by the appropriate disposition of N- and C-bonded phenyl rings with respect to the mean benzimidazole plane. The molecular packing of the dimers of (I) and (II) arises by the concurrence of a diverse set of weak intermolecular C-X...D (X = H, NO2; D = O, π) interactions.

In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles

PubMed Central

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan K.; Tidwell, Richard R.; Kumar, Arvind; Boykin, David W.; Perfect, John R.

1998-01-01

Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents. PMID:9756748

Structure of substituted 2-(phenoxy)benzimidazoles

NASA Astrophysics Data System (ADS)

Pavlova, I. S.; Pervova, I. G.; Lipunova, G. N.; Novikova, R. K.; Slepukhin, P. A.; Lipunov, I. N.

2013-03-01

The synthesis and X-ray diffraction study of 1-benzyl-2-[2-(5-ethyltetrazole-2-yl)-phenoxy]-1H-benzimidazole and 1-benzyl-2-[2-(5-ethyltetrazole-2-yl)-4-nitrophenoxy]-1H-benzimidazole single crystals have been performed. The oxidative splitting of an azo-hydrazone group of 1-(2-hydroxy-(5-nitro)phenyl)-3-ethyl-5-(benzylbenzimidazolyl)formazans, a break in the C2-N1 bond, the interaction of o-hydroxyl group of aryl fragment with oxygen, and the formation of new 2-(phenoxy)benzimidazoles are found to occur in the presence of perchlorate iron(III).

Development of Enabling Chemical Technologies for Power from Green Sources

DTIC Science & Technology

2013-11-18

structurally analogous polymers based on N-heterocycles (triazole, imidazole and pyrazole) and benz-N-heterocycles (benzotriazole, benzimidazole ...found that triazole (benzotriazole) and imidazole ( benzimidazole ) containing polymers exhibit similar proton conductivities, about 4 orders of...magnitude higher than those with pyrazole (benzopyrazole) (Figure 6b). The similar behavior of triazole and imidazole (benzotriazole and benzimidazole

Mating type idiomorphs distribution and their correlation to benzimidazole-resistance in Cercospora beticola from the Central High Plains Region, USA

USDA-ARS?s Scientific Manuscript database

Cercospora leaf spot (CLS) of sugarbeet is caused by Cercospora beticola Sacc., and is one of the most destructive foliar diseases worldwide. Fungicides used for disease suppression include benzimidazoles. Resistance to benzimidazoles can develop quickly, and was first reported in C. beticola in 197...

Benzimidazole resistance in equine cyathostomins in India.

PubMed

Kumar, Sunil; Garg, Rajat; Kumar, Saroj; Banerjee, P S; Ram, Hira; Prasad, A

2016-03-15

Benzimidazole resistance is a major hindrance to the control of equine cyathostominosis throughout the world. There is a paucity of knowledge on the level of benzimidazole resistance in small strongyles of horses in India. In the present study, allele-specific PCR (AS-PCR) that detects F200Y mutation of the isotype 1 β-tubulin gene and faecal egg count reduction test (FECRT) were used for detecting benzimidazole resistance in equine cyathostomin populations in different agro-climatic zones of Uttar Pradesh, India. Results of the FECRT revealed prevalence of benzimidazole resistance in cyathostomins in an intensively managed equine farm in the mid-western plain (FECR=27.5%, LCI=0) and in working horses (extensively managed) at three locations in central plains of Uttar Pradesh (FECR=75.7-83.6%, LCI=29-57%). Post-treatment larval cultures revealed the presence of exclusively cyathostomin larvae. Genotyping of cyathostomin larvae by AS-PCR revealed that the frequency of homozygous resistant (rr) individuals and the resistant allele frequency was significantly higher (p<0.001) in the intensively managed farm in the mid-western plain and in working horses at two locations in central plains of the state. The resistant allele (r) frequency in cyathostomins was significantly higher (p<0.05) in Vindhyan and Tarai and Bhabar zones of Uttar Pradesh. The prevalence of benzimidazole resistant allele (r) was significantly higher (p<0.05) in cyathostomins of intensively managed horses (allelic frequency-0.35) as compared to extensively managed horses (allelic frequency-0.22). The widespread prevalence of benzimidazole resistant alleles in equine cyathostomins in Uttar Pradesh, India, necessitates immediate replacement of the drugs of benzimidazole group with other unrelated effective anthelmintics for management and control of equine cyathostomins. Copyright © 2016 Elsevier B.V. All rights reserved.

Seven benzimidazole pesticides combined at sub-threshold levels induce micronuclei in vitro

PubMed Central

Ermler, Sibylle; Scholze, Martin; Kortenkamp, Andreas

2013-01-01

Benzimidazoles act by disrupting microtubule polymerisation and are capable of inducing the formation of micronuclei. Considering the similarities in their mechanisms of action (inhibition of microtubule assembly by binding to the colchicine-binding site on tubulin monomers), combination effects according to the principles of concentration addition might occur. If so, it is to be expected that several benzimidazoles contribute to micronucleus formation even when each single one is present at or below threshold levels. This would have profound implications for risk assessment, but the idea has never been tested rigorously. To fill this gap, we analysed micronucleus frequencies for seven benzimidazoles, including the fungicide benomyl, its metabolite carbendazim, the anthelmintics albendazole, albendazole oxide, flubendazole, mebendazole and oxibendazole. Thiabendazole was also tested but was inactive. We used the cytochalasin-blocked micronucleus assay with CHO-K1 cells according to OECD guidelines, and employed an automated micronucleus scoring system based on image analysis to establish quantitative concentration–response relationships for the seven active benzimidazoles. Based on this information, we predicted additive combination effects for a mixture of the seven benzimidazoles by using the concepts of concentration addition and independent action. The observed effects of the mixture agreed very well with those predicted by concentration addition. Independent action underestimated the observed combined effects by a large margin. With a mixture that combined all benzimidazoles at their estimated threshold concentrations for micronucleus induction, micronucleus frequencies of ~15.5% were observed, correctly anticipated by concentration addition. On the basis of independent action, this mixture was expected to produce no effects. Our data provide convincing evidence that concentration addition is applicable to combinations of benzimidazoles that form micronuclei by disrupting microtubule polymerisation. They present a rationale for grouping these chemicals together for the purpose of cumulative risk assessment. PMID:23547264

The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design

PubMed Central

Kalusa, Andrew; Cano, Celine; Travers, Jon; Boxall, Kathy; Chow, Chiau Ling; Burns, Sam; Schmitt, Jessica; Pickard, Lisa; Barillari, Caterina; McAndrew, P. Craig; Clarke, Paul A.; Linardopoulos, Spiros; Griffin, Roger J.; Aherne, G. Wynne; Raynaud, Florence I.; Workman, Paul; Jones, Keith; van Montfort, Rob L.M.

2013-01-01

The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases. PMID:24072592

Spectroscopic Analysis of a Biomimetic Model of Tyr(Z) Function in PSII.

PubMed

Ravensbergen, Janneke; Antoniuk-Pablant, Antaeres; Sherman, Benjamin D; Kodis, Gerdenis; Megiatto, Jackson D; Méndez-Hernández, Dalvin D; Frese, Raoul N; van Grondelle, Rienk; Moore, Thomas A; Moore, Ana L; Gust, Devens; Kennis, John T M

2015-09-17

Using natural photosynthesis as a model, bio-inspired constructs for fuel generation from sunlight are being developed. Here we report the synthesis and time-resolved spectroscopic analysis of a molecular triad in which a porphyrin electron donor is covalently linked to both a cyanoporphyrin electron acceptor and a benzimidazole-phenol model for the TyrZ-D1His190 pair of PSII. A dual-laser setup enabled us to record the ultrafast kinetics and long-living species in a single experiment. From this data, the photophysical relaxation pathways were elucidated for the triad and reference compounds. For the triad, quenching of the cyanoporphyrin singlet excited state lifetime was interpreted as photoinduced electron transfer from the porphyrin to the excited cyanoporphyrin. In contrast to a previous study of a related molecule, we were unable to observe subsequent formation of a long-lived charge separated state involving the benzimidazole-phenol moiety. The lack of detection of a long-lived charge separated state is attributed to a change in energetic landscape for charge separation/recombination due to small differences in structure and solvation of the new triad.

Theoretical study of β- and γ-cyclodextrin complexes with ferrocene-containing azoles

NASA Astrophysics Data System (ADS)

Kiselev, S. S.; Snegur, L. V.; Simenel, A. A.; Davankov, V. A.; Il'in, M. M.; Borisov, Yu. A.

2017-12-01

The interaction between cyclodextrins (β- and γ-CD) and ferrocenyl azoles (i.e., pyrazole ferrocenes (I, III-V) and benzimidazole ferrocenes (VI, VII)), along with 1-ferrocenylethanol (II), each in the form of (R)- and (S)-enantiomers, in forming inclusion complexes is studied for the first time using detailed quantum chemical calculations. Compounds are calculated in terms of the density functional theory (DFT), using the Becke-Lee-Yang-Parr (B3LYP) approach in the 6-31G* basis sets. For the considered CD complexes with enantiomers of I-VII, structures in which a guest partially enters a host cavity from the side of the heterocyclic substituent (pyrazole or benzimidazole) are found to be energetically advantageous. It is shown that for successful resolution of (R,S)-enantiomers on chiral phases containing cyclodextrins, we must consider the interaction between outer hydroxyl groups on the CD cone's surface, in addition to the correspondence of geometric dimensions. The calculated data correlate well with the data from the chromatographic separation of guest enantiomers on cyclodextrin sorbents.

Effect of the physicochemical parameters of benzimidazole molecules on their retention by a nonpolar sorbent from an aqueous acetonitrile solution

NASA Astrophysics Data System (ADS)

Shafigulin, R. V.; Safonova, I. A.; Bulanova, A. V.

2015-09-01

The effect of the structure of benzimidazoles on their chromatographic retention on octadecyl silica gel from an aqueous acetonitrile eluent was studied. One- and many-parameter correlation equations were obtained by linear regression analysis, and their prognostic potential in determining the retention factors of benzimidazoles under study was analyzed.

Regio- and Enantioselective N-Allylations of Imidazole, Benzimidazole, and Purine Heterocycles Catalyzed by Single-Component Metallacyclic Iridium Complexes

PubMed Central

Stanley, Levi M.

2010-01-01

Highly regio- and enantioselective iridium-catalyzed N-allylations of benzimidazoles, imidazoles, and purines have been developed. N-Allylated benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9:N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustrate the effect of nucleophile pKa on the rate of iridium-catalyzed N-allylation reactions. Kinetic studies on the allylation of benzimidazole catalyzed by metallacyclic iridium-phosphoramidite complexes, in combination with studies on the deactivation of these catalysts in the presence of heterocyclic nucleophiles, provide insight into the effects of the structure of the phosphoramidite ligands on the stability of the metallacyclic catalysts. The data obtained from these studies has led to the development of N-allylations of benzimidazoles and imidazoles in the absence of an exogenous base. PMID:19480431

Bis-benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens.

PubMed

Rice, Christopher A; Colon, Beatrice L; Alp, Mehmet; Göker, Hakan; Boykin, David W; Kyle, Dennis E

2015-04-01

Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A benzimidazole derivative (RCB15) in vitro induces the alternative energetic metabolism and glycolysis in Taenia crassiceps cysticerci.

PubMed

de Andrade Picanço, Guaraciara; de Lima, Nayana Ferreira; Fraga, Carolina Miguel; da Costa, Tatiane Luiza; Isac, Eliana; Ambrosio, Javier; Castillo, Rafael; Vinaud, Marina Clare

2017-12-01

The emergence of resistance to albendazole has encouraged the search for effective alternatives for cysticercosis and other parasitosis treatment. RCB15 is a benzimidazole derivative that may be used against such diseases. The aim of this study was to determine the in vitro effect of RCB15 on the alternative energetic pathways of Taenia crassiceps cysticerci. The cysticerci were in vitro exposed to albendazole sulphoxide (ABZSO) or RCB15 at different concentrations during 24h. The cysticerci extract and the culture medium were analyzed through spectrophotometry and high performance liquid chromatography as to detect glucose, urea, creatinine and organic acids of the energetic metabolism. The drugs did not influence the protein catabolism. Fatty acids oxidation was enhanced through significantly higher acetate concentrations in the groups treated with RCB15 and ABZSO. Beta-hydroxybutyrate concentrations were decreased which indicates the use of fatty acids towards acetyl-CoA synthesis. There was a decrease in glucose uptake and pyruvate concentrations. The absence of lactate indicates the use of pyruvate in gluconeogenesis. Therefore it is possible to conclude that RCB15 enhanced the alternative energetic pathways of cysticerci in vitro exposed to different concentration, with emphasis on the fatty acids catabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

A turn-on supramolecular fluorescent probe for sensing benzimidazole fungicides and its application in living cell imaging

NASA Astrophysics Data System (ADS)

Tang, Qing; Zhang, Jing; Sun, Tao; Wang, Cheng-Hui; Huang, Ying; Zhou, Qingdi; Wei, Gang

2018-02-01

A cucurbit[8]uril-based turn-on supramolecular fluorescent probe between cucurbit[8]uril (Q[8]) and pyronine Y (PyY) (designated 2PyY@Q[8]) in acidic aqueous solution showed a remarkable fluorescence 'turn-on' response to benzimidazole fungicides such as thiabendazole, fuberidazole and carbendazim. The 2PyY@Q[8] fluorescent probe can be used to detect benzimidazole fungicides with high sensitivity and selectivity with a detection limit of 10- 8 mol/L. A good linear relationship of emission intensity at 580 nm for benzimidazole fungicides at concentrations of 0.4-5.0 μmol/L was observed. The proposed sensing mechanism was investigated using 1H NMR spectroscopy combined with density functional theory calculations at the B3LYP/6-31G(d) level. The cell imaging study showed that the 2PyY@Q[8] complex could be used to image benzimidazole fungicide in prostate cancer (PC3) cells, which may help to elucidate relevant biological processes at the molecular level.

Spectro- and electrochemical studies of some ruthenium and osmium complexes of 2-(2'-pyridyl)benzimidazole; complexes with intra-molecular charge transfer.

PubMed

Khalil, M M; Ali, S A; Ramadan, R M

2001-04-01

Reaction of Ru3(CO)12, with 2-(2'-pyridyl)benzimidazole (HPBI) resulted in the formation of Ru(CO)3(HPBI) (I) complex. In presence of pyridine or dipyridine, the two derivatives [Ru(CO)3(HPBI)].Py (II) and [Ru(CO)3(HPBI)].dpy (III) were isolated. The corresponding reactions of Os3(CO)12 yielded only one single product; Os(CO)2(HPBI)2 (IV). Spectroscopic studies of these complexes revealed intramolecular metal to ligand CT interactions. Reactions of RuCl3 with HPBI gave three distinct products; [Ru(HPBI)2Cl2]Cl (V), [Ru(HPBI)(dipy)Cl2]C1 (VI) and [Ru(PBI)2(py)2]Cl (VII). The UV-vis studies indicated the presence of intramolecular ligand to metal CT interactions. Electrochemical investigation of the complexes showed some irreversible, reversible and quasi-reversible redox reactions due to tautomeric interconversions through electron transfer.

Synthesis, electronic structure and spectral fluorescent properties of vinylogous merocyanines derived from 1,3-dialkyl-benzimidazole and malononitrile

NASA Astrophysics Data System (ADS)

Kulinich, Andrii V.; Mikitenko, Elena K.; Ishchenko, Alexander A.

2017-01-01

A vinylogous series of merocyanines were synthesized with 1,3-dibutyl-benzimidazole and malononitrile residues as the donor and acceptor terminal groups. These dyes do not comprise carbonyl groups, which are prone to the strong specific solvation by polar solvents up to hydrogen bond formation, and nevertheless they possess distinct reversed solvatochromism, i.e. their molecules have very high dipolarity. At that, they are soluble in a wide range of solvents from n-hexane to ethanol and do not aggregate readily. They were studied thoroughly by UV/Vis, fluorescence, IR, and NMR spectroscopy methods. Their structure and spectral properties in the ground and excited fluorescent states were modelled at the DFT level both in vacuum and in solvents of various polarities by using the PCM solvent field simulation. The calculations were performed using several hybrid functionals (B3LYP, CAM-B3LYP, and wB97XD) and the split-valence 6-31G (d,p) basis set.

Hypersensitivity reaction to mizolastine: study of cross reactions.

PubMed

Gonzalo-Garijo, M A; Jiménez-Ferrera, G; Bobadilla-González, P; Cordobés-Durán, C

2006-01-01

A 26-year-old male suffering from acute rhinitis took the first dose of Zolistan (mizolastine, 10 mg), orally, and 15 minutes later he developed intense generalized pruritus, cutaneous rash, oropharyngeal pruritus, edema on his face, difficulty in swallowing, and mild dyspnea. He was treated with methylprednisolone and epinephrine and improved within 30 minutes. The patient had not taken mizolastine before and he has avoided it since the reaction. Cutaneous tests with Zolistan and its excipients proved negative. Simple-blind oral challenge tests with the excipients and then with Zolistan were positive only with Zolistan. In order to confirm the absence of cross-reactivity between mizolastine and other benzimidazoles, we tested omeprazole, domperidone and mebendazole, all of which yielded negative results. To our knowledge, this is the second case of immediate hypersensitivity to mizolastine documented to date. In our case, the clinical history, physical examination and provocation tests allow us to establish the diagnosis of hypersensitivity to mizolastine and exclude the cross reactivity with other benzimidazole derivatives.

Benzimidazole derivative vs. different phases of TiO2-physico-chemical approach.

PubMed

Karunakaran, C; Jayabharathi, J; Jayamoorthy, K

2013-10-01

1-Benzyl-2-phenyl-1H-benzo[d]imidazole (BPBI) has been synthesized by simple steps and characterized by spectral studies. Absorption and fluorescence spectral studies have been employed to investigate the interaction of BPBI with the anatase, hombikat, P25 and rutile phases of TiO2. The emission of the BPBI is efficiently quenched by anatase, hombikat and P25 TiO2 nanoparticles owing to charge injection from the excited singlet state of BPBI to the conduction band of the TiO2 nanoparticles. Surprisingly, rutile phase enhances the fluorescence which is likely due to lowering of LUMO and HOMO levels of the ligand on ducking of the benzimidazole moiety of the BPBI molecule into the void space of rutile TiO2. Electron injection from photoexcited BPBI to the TiO2 conduction band (S*→S(+)+e(-)(CB)) is likely to enhance the fluorescence. Copyright © 2013 Elsevier B.V. All rights reserved.

Benzimidazoles as benzamide replacements within cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists.

PubMed

Cherney, Robert J; Mo, Ruowei; Meyer, Dayton T; Pechulis, Anthony D; Guaciaro, Michael A; Lo, Yvonne C; Yang, Gengjie; Miller, Persymphonie B; Scherle, Peggy A; Zhao, Qihong; Cvijic, Mary Ellen; Barrish, Joel C; Decicco, Carl P; Carter, Percy H

2012-10-01

We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide. Copyright © 2012 Elsevier Ltd. All rights reserved.

MAO enzymes inhibitory activity of new benzimidazole derivatives including hydrazone and propargyl side chains.

PubMed

Can, Özgür Devrim; Osmaniye, Derya; Demir Özkay, Ümide; Sağlık, Begüm Nurpelin; Levent, Serkan; Ilgın, Sinem; Baysal, Merve; Özkay, Yusuf; Kaplancıklı, Zafer Asım

2017-05-05

In the present work, 15 new N'-(arylidene)-4-(1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-yl)benzohydrazide (4a-4o) were designed and synthesized. The structures of the synthesized compounds were elucidated using FT-IR, 1 H-NMR, 13 C-NMR, and HRMS spectral data. The inhibitory activity of the compounds 4a-4o against hMAO-A and hMAO-B enzymes was evaluated by using in vitro Amlex Red ® reagent based fluorometric method. Due to lots of high-cost kits including this assay, we determined the ingredients of the kits from the data sheets of several suppliers, and adjusted a protocol by working with various concentrations and volumes of these ingredients. As a result, a fast and sensitive assay was applied as in the commercially available MAO kits with lower costs and clearer ingredients than those of the kits. The enzyme inhibition assay revealed that synthesized compounds have selective inhibition potency against hMAO-B. The compound 4e and 4f displayed IC 50 values of 0.075 μM and 0.136 μM against hMAO-B, respectively. The reference drugs selegiline (IC 50  = 0.040 μM) and rasagiline (IC 50  = 0.066 μM) also displayed a significant inhibition against hMAO-B. The enzyme kinetic study was performed in order to observe the effect of the most active compound 4e on substrate-enzyme relationship and non-competitive inhibition of hMAO-B was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 4e was found as non-cytotoxic and non-genotixic. Theoretical calculation of ADME properties suggested that compound 4e may have a good pharmacokinetic profile. The docking study of compound 4e revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Oligomerization of mononucleotides on montmorillonite: A potential approach to the prebiotic synthesis of RNA. [Abstract only

NASA Technical Reports Server (NTRS)

Ferris, James P.; Ertem, Goezen; Ding, Zi Ping; Prabahar, Joseph

1994-01-01

The condensation of the 5'-phosphorimidazolide of adenosine (ImpA) on montmorillonite in a pH 8 aqueous solution yields oligomers containing up to 10 monomer units. The regiospecificity of 3',5'-phosphodiester bond formation is enhanced by addition of 10% diadenosine pyrophosphate (AppA) to the reaction mixture. A series of activated derivatives of 5'-AMP was prepared to investigate the effect of the leaving group on oligomer formation. The benzimidazole and p-dimethylamino-pyridine derivatives gave the best yields of oligomers. Factors important for oligomer formation is discussed.

Structure-based drug design for envelope protein E2 uncovers a new class of bovine viral diarrhea inhibitors that block virus entry.

PubMed

Pascual, María José; Merwaiss, Fernando; Leal, Emilse; Quintana, María Eugenia; Capozzo, Alejandra V; Cavasotto, Claudio N; Bollini, Mariela; Alvarez, Diego E

2018-01-01

Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. Here, we took a computer-guided approach with the aim of identifying new antivirals against the envelope protein E2 of bovine viral diarrhea virus (BVDV). BVDV is an enveloped virus with an RNA genome responsible for major economic losses of the cattle industry worldwide. Based on the crystal structure of the envelope protein E2, we defined a binding site at the interface of the two most distal domains from the virus membrane and pursued a hierarchical docking-based virtual screening search to identify small-molecule ligands of E2. Phenyl thiophene carboxamide derivative 12 (PTC12) emerged as a specific inhibitor of BVDV replication from in vitro antiviral activity screening of candidate molecules, displaying an IC 50 of 0.30 μM against the reference NADL strain of the virus. Using reverse genetics we constructed a recombinant BVDV expressing GFP that served as a sensitive reporter for the study of the mechanism of action of antiviral compounds. Time of drug addition assays showed that PTC12 inhibited an early step of infection. The mechanism of action was further dissected to find that the compound specifically acted at the internalization step of virus entry. Interestingly, we demonstrated that similar to PTC12, the benzimidazole derivative 03 (BI03) selected in the virtual screen also inhibited internalization of BVDV. Furthermore, docking analysis of PTC12 and BI03 into the binding site revealed common interactions with amino acid residues in E2 suggesting that both compounds could share the same molecular target. In conclusion, starting from a targeted design strategy of antivirals against E2 we identified PTC12 as a potent inhibitor of BVDV entry. The compound can be valuable in the design of antiviral strategies in combination with already well-characterized polymerase inhibitors of BVDV. Copyright © 2017 Elsevier B.V. All rights reserved.

2-Methoxyestradiol as a Chemotherapeutic for Prostate Cancer

DTIC Science & Technology

2007-04-01

294002, 5,6-dichloro-1-h-D-ribofurano- syl- benzimidazole , alsterpaullone, epoxomicin, and parthe- nolide were purchased from Calbiochem (San Diego, CA... benzimidazole (75 Amol/L; required for transcription elongation; ref. 40) for 24 hours followed by vehicle control or 5,6-dichloro-1-h-D-ribofuranosyl-benz...inhibitor 5,6-dichloro-1-h-D-ribofuranosyl- benzimidazole (75 Amol/L) did not result in increased apoptosis (data not shown), indicating that the ability of

High Performance Organic Semiconductors

DTIC Science & Technology

2012-07-31

O D D N O CD3 CD3 >>99% D--aattoomm iinnccoorrpoorraattiioonn Reeaaccttiioonn 1 Reeaaccttiioonn 2 Reeaaccttiioonn 3 1H- benzimidazoles and...solution processed 1H- benzimidazole doped PC61BM thin-films is dependent upon the mixing time before spin coating. The precipitation of a dopant/PC61BM...the application of 1H- benzimidazole dopants may be limited to materials that are capable of accepting a hydride or that have very low LUMO energies

Toward a Modular Ionic Liquid Platform for the Custom Design of Energetic Materials: Understanding How the Dual Nature of Ionic Liquids Relates Key Physical Properties to Target Structures

DTIC Science & Technology

2009-11-30

cations were obtained and isolated with a diverse group of azolate anions including nitro- substituted benzotriazolate, benzimidazolate , 1,2,4-triazolate... benzimidazolate , or benzotrizolate) have received much less attention than those containing azolium cations, although more results are now starting to...phosphonium cations combined with energetically-substituted tetrazolate, triazolate, imidazolate, benzimidazolate , and benzotriazolate anions (Figure

Thermodynamics of the Sorption of Benzimidazoles on Octadecyl Silica Gel from Water-Methanol Eluents

NASA Astrophysics Data System (ADS)

Shafigulin, R. V.; Bulanova, A. V.

2018-02-01

The standard enthalpy and entropy component of transferring benzimidazoles from water-methanol solutions to surfaces of octadecyl silica gel are determined using reversed-phase high-performance liquid chromatography (RP HPLC). The dependences between the enthalpy and polarizability of the molecules of the studied benzimidazoles, the enthalpy and the entropy factor are studied, and the influence of the quantitative composition of the water-methanol solution on the enthalpy are studied.

Rationale for the Coadministration of Albendazole and Ivermectin to Humans for Malaria Parasite Transmission Control

DTIC Science & Technology

2014-07-28

programs and supported by global public health funding agencies. Albendazole belongs to the class of benzimidazole anthel- mintics that are active against...blood-stage P. falciparum in vitro83,84 and P. berghei in vivo85,86 but not at human-relevant concentrations. The benzimidazoles are microtubule...cycles at which benzimidazoles may inhibit microtubule assem- bly, including micro- and macrogametocytogenisis, microga- mete exflaggelation, and the

Pubertal Development and Thyroid Function in Intact Juvenile Rats Exposed to 3-Nitro-1,2,4-Trazol-5-One (NTO), February-June 2012

DTIC Science & Technology

2014-02-01

direct testicular toxicants (Noriega et al. 2009). Benzimidazole fungicides induce characteristic vacuolization of Sertoli cells and stage-specific...apoptosis of spermatocytes (Okamura et al. 2004; Hess and Nakai 2000). Benzimidazoles bind to tubulin and inhibit the polymerization of microtubules (Lacey...1990), disrupting spermatocytic meiosis and spermatogonial mitosis, leading to apoptosis (Okamura et al. 2004). The benzimidazole carbendazim induces

Very High Performance Organic Photonic Devices

DTIC Science & Technology

2008-01-15

example, in photovoltaic cells based on copper phthalocyanine (CuPc) as the donor and 3.4.9,10-perylenetetracarboxylic bis- benzimidazole b (PTCBI) as...perylenetetracarboxylic bis- benzimidazole (PTCBI), the as- mixed D-A layer shows very poor Received: April 25, 2t(X4 grown, homogeneously Final version: September 13, 2(X04...perylenetetracarboxylic bis- benzimidazole thin-film photovoltaic cell with a patterned stripe of sputter- (PTCBI). Purified organic source materialss were loaded into

Growth and properties of benzil doped benzimidazole (BMZ) single crystals

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

Babu, R. Ramesh, E-mail: rampap2k@yahoo.co.in; Crystal Growth and Crystallography Section, National Physical Laboratory, Krishnan Marg, New Delhi 110 012; Sukumar, M.

2010-09-15

In the present work, we have made an attempt to study the effect of benzil doping on the properties of benzimidazole single crystals. For this purpose we have grown pure and benzil doped benzimidazole single crystals by vertical Bridgman technique. The grown crystals were characterized by various characterization techniques. The presence of dopants confirmed by powder X-ray diffraction (XRD). Crystalline perfection of the grown crystals has been analysed by high-resolution X-ray diffraction (HRXRD). The transmittance, electrical property and mechanical strength have been analysed using UV-vis-NIR spectroscopic, dielectric and Vicker's hardness studies. The relative second harmonic generation efficiency of pure andmore » doped benzimidazole crystals measured using Kurtz powder test.« less

Benzimidazoles: veterinary uses.

PubMed

Campbell, W C

1990-04-01

Benzimidazoles are valued for use against helminth infections in domestic animals. Here, Bill Campbell discusses efficacy, dosages, methods of administration and the species of parasite against which they are applied.

Oxidative polycondensation of benzimidazole using NaOCl: Synthesis, characterization, optical, thermal and electrical properties of polybenzimidazoles

NASA Astrophysics Data System (ADS)

Anand, Siddeswaran; Muthusamy, Athianna; Dineshkumar, Sengottuvelu; Chandrasekaran, J.

2017-11-01

A series of polybenzimidazole polymers, poly-2-(1H-benzo[d] imidazole-2-yl) phenol (PBIP2), poly-3-(1H-benzo[d] imidazole-2-yl) phenol (PBIP3) and poly-4-(1H-benzo[d] imidazole-2-yl) phenol (PBIP4) were synthesized by oxidative polycondensation of benzimidazole monomers 2-(1H-benzo [d] imidazole-2-yl) phenol (BIP2), 3-(1H-benzo [d] imidazole-2-yl) phenol (BIP3) and 4-(1H-benzo [d] imidazole-2-yl) phenol (BIP4). The structure of benzimidazoles monomers and polybenzimidazoles (PBI) were confirmed by various spectroscopic techniques. The quantum theoretical calculations of band gap energy values of monomers were done with DFT and are compared with its optical band gap energy values. Fluorescence spectra of these compounds showed maximum emission in blue region. The electrical conductivity of PBIs was measured by four-point probe technique and showed good electrical response on iodine doping and conductivity increases with increase iodine doping time. The differences in conductivities among the three PBIs are in accordance with the charge density on imidazole nitrogens calculated by Huckel method. The high carbines residue (∼40%) at 500 °C in thermo gravimetric analysis shows that the PBIs are having reasonably good thermal stability. Polymers have recorded high dielectric constant at low applied frequency of 50 Hz at 393 K. The I-V characteristics of polybenzimidazoles p-n diodes showed rectifying nature with a typical forward to reverse current in the range -4 to 4 V. The high n values are caused by non homogeneities and effect of series resistance.

A one-dimensional zinc(II) coordination polymer with a three-dimensional supramolecular architecture incorporating 1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole and adipate.

PubMed

Liu, Chun Li; Huang, Qiu Ying; Meng, Xiang Ru

2016-12-01

The synthesis of coordination polymers or metal-organic frameworks (MOFs) has attracted considerable interest owing to the interesting structures and potential applications of these compounds. It is still a challenge to predict the exact structures and compositions of the final products. A new one-dimensional coordination polymer, catena-poly[[[bis{1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole-κN 3 }zinc(II)]-μ-hexane-1,6-dicarboxylato-κ 4 O 1 ,O 1' :O 6 ,O 6' ] monohydrate], {[Zn(C 6 H 8 O 4 )(C 9 H 8 N 6 ) 2 ]·H 2 O} n , has been synthesized by the reaction of Zn(Ac) 2 (Ac is acetate) with 1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole (bimt) and adipic acid (H 2 adi) at room temperature. In the polymer, each Zn II ion exhibits an irregular octahedral ZnN 2 O 4 coordination geometry and is coordinated by two N atoms from two symmetry-related bimt ligands and four O atoms from two symmetry-related dianionic adipate ligands. Zn II ions are connected by adipate ligands into a one-dimensional chain which runs parallel to the c axis. The bimt ligands coordinate to the Zn II ions in a monodentate mode on both sides of the main chain. In the crystal, the one-dimensional chains are further connected through N-H...O hydrogen bonds, leading to a three-dimensional supramolecular architecture. In addition, the title polymer exhibits fluorescence, with emissions at 334 and 350 nm in the solid state at room temperature.

Biomolecular Specificity Regulated Synthesis of Nanocatalysts and Heterointegration of Photosynthesis Nanodevices

DTIC Science & Technology

2016-01-01

TiO2-Au/Pd nanocomposite composed of P25 TiO2 nanoparticles and Au/Pd nanowheels is applied in benzimidazole synthesis as plasmon-enhanced...activity and selectivity. In this work, TiO2-Au/Pd nanocomposite composed of P25 TiO2 nanoparticles and Au/Pd nanowheels is applied in benzimidazole ...Pd Nanocomposite Photocatalyst for Tandem Synthesis of Benzimidazole 2.1 Approaches: Wet-chemical synthetic routes are explored to create

Fragment-based design of symmetrical bis-benzimidazoles as selective inhibitors of the trimethoprim-resistant, type II R67 dihydrofolate reductase.

PubMed

Bastien, Dominic; Ebert, Maximilian C C J C; Forge, Delphine; Toulouse, Jacynthe; Kadnikova, Natalia; Perron, Florent; Mayence, Annie; Huang, Tien L; Vanden Eynde, Jean Jacques; Pelletier, Joelle N

2012-04-12

The continuously increasing use of trimethoprim as a common antibiotic for medical use and for prophylactic application in terrestrial and aquatic animal farming has increased its prevalence in the environment. This has been accompanied by increased drug resistance, generally in the form of alterations in the drug target, dihydrofolate reductase (DHFR). The most highly resistant variants of DHFR are known as type II DHFR, among which R67 DHFR is the most broadly studied variant. We report the first attempt at designing specific inhibitors to this emerging drug target by fragment-based design. The detection of inhibition in R67 DHFR was accompanied by parallel monitoring of the human DHFR, as an assessment of compound selectivity. By those means, small aromatic molecules of 150-250 g/mol (fragments) inhibiting R67 DHFR selectively in the low millimolar range were identified. More complex, symmetrical bis-benzimidazoles and a bis-carboxyphenyl were then assayed as fragment-based leads, which procured selective inhibition of the target in the low micromolar range (K(i) = 2-4 μM). The putative mode of inhibition is discussed according to molecular modeling supported by in vitro tests. © 2012 American Chemical Society

Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

DTIC Science & Technology

2010-05-01

hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro- 2H- benzimidazol -2-one (J-113397). J Med Chem 42: 5061–5063. Ko MC, Butelman ER, Traynor JR, Woods JH (1998a...ethyl-1,3-dihydro-2H- benzimidazol -2-one) was used to compare their antagonist effects against both morphine (100 nmol)- and UFP-112 (10 nmol)-induced...3S,4S)-1- (Cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl- 1,3-dihydro-2H- benzimidazol -2-one) (Tocris Bioscience, Ellisville, MO), and

The development of anthelmintic resistance with best practice control of nematodes on commercial sheep farms in the UK.

PubMed

Learmount, Jane; Stephens, Nathalie; Boughtflower, Valerie; Barrecheguren, Alba; Rickell, Kayleigh

2016-10-15

Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections. The widespread development of anthelmintic resistance is a major global issue affecting the effective control of parasite diseases in grazing livestock production. Sustainable control strategies that reduce dependence on antimicrobials have the potential to slow the further development of resistance but there is little data on the effect of control strategies on resistance development in the field. This report documents a study undertaken to measure the temporal effect of the UK sustainable control of parasites in sheep (SCOPS) guidelines on the development of anthelmintic resistance. Farms carrying out SCOPS or traditional worm control (TRADITIONAL) were tested for resistance to the benzimidazole and imidazothiazole anthelmintics in vitro using a discriminating dose (dd) larval development test (LDT) in year 1 and then 7 years later. In years 5 and 7, resistance was also measured using a dose-response LDT assay. There was a significant increase in Teladorsagia survivors at the benzimidazole dd assay between year 1 and year 7 for both treatment groups, but the increase in survivors was greater for the farms carrying out their traditional worm control compared to the SCOPS farms. There was also a significant difference between benzimidazole dd results generated across years for Trichostrongylus, but the year and treatment interaction was not significant. Only one of the farm Teladorsagia populations had survivors in the imidazothiazole dd assay in years 1 and 7 and none of the Trichostrongylus populations survived in year 1 compared to isolates from three of the farms in year 7. Dose-response data showed a significant effect for time for both the benzimidazole and imidazothiazole anthelmintics and the increase was again significantly higher for the Teladorsagia populations in the TRADITIONAL group compared to the SCOPS group. This data suggests an increased sensitivity both to detect and to measure changes in response to anthelmintics with the dose-response assay compared to the dd and this is important particularly when allele frequencies are low as might be the case when novel compounds are released to the market. Anthelmintic use across years 5-7 was significantly lower for the farms in the SCOPS group compared to the TRADITIONAL group and farmers in the SCOPS group had selected products from the benzimidazole group less often than farmers in the TRADITIONAL group. Both groups had made minimal use of the imidazothiazole anthelmintic classes and the majority of ewe treatments were selected from the macrocyclic lactone class. Further research is required to determine the effect of these anthelmintic choices on the development of resistance to the macrocyclic lactones. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Bangalore India Bio 2010.

PubMed

Thammanabhatla, Pratibha; Pailla, Mamatha

2010-08-01

The Bangalore India Bio 2010 conference, held in Bangalore, India, included topics covering new developments in the biopharma industry. This conference report highlights selected presentations on novel therapeutics for the treatment of cancer, including identification of novel benzimidazole, N-subsituted isatin and azetidine derivatives, and an Wnt antagonist. In addition, presentations from several biopharma companies and universities are highlighted, including Proteomics International Pty Ltd, Oxford BioMedica plc, AnaptysBio Inc, SIOGEN Biotech, RV College of Engineering and Indian Institute of Science.

Discovery, SAR, and Radiolabeling of Halogenated Benzimidazole Carboxamide Antagonists as Useful Tools for (alpha)4(beta)1 Integrin Expressed on T- and B-cell Lymphomas

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

Carpenter, R D; Natarajan, A; Lau, E Y

2010-02-08

The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin is an attractive yet poorly understood target for selective diagnosis and treatment of T- and B-cell lymphomas. This report focuses on the rapid microwave preparation of medicinally pertinent benzimidazole heterocycles, structure-activity relationships (SAR) of novel halobenzimidazole carboxamide antagonists 3-6, and preliminary biological evaluation of radioiodinated agents 7, 8, and 18. The I-125 derivative 18 had good tumor uptake (12 {+-} 1% ID/g at 24 h; 4.5 {+-} 1% ID/g at 48 h) and tumor:kidney ratio ({approx}4:1 at 24 h; 2.5:1 at 48 h) in xenograft murine models of B-cell lymphoma. Molecular homologymore » models of {alpha}{sub 4}{beta}{sub 1} integrin have predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. These high affinity ({approx} pM binding) halogenated ligands are attractive tools for medicinal and biological use; the fluoro and iodo derivatives are potential radiodiagnostic ({sup 18}F) or radiotherapeutic ({sup 131}I) agents, whereas the chloro and bromo analogues could provide structural insight into integrin-ligand interactions through photoaffinity cross-linking/mass spectroscopy experiments, as well as co-crystallization X-ray studies.« less

Synthesis and antibacterial evaluation of new, unsymmetrical triaryl bisamidine compounds

PubMed Central

Nguyen, Son T.; Williams, John D.; Butler, Michelle M.; Ding, Xiaoyuan; Mills, Debra M.; Tashjian, Tommy F.; Panchal, Rekha G.; Weir, Susan K.; Moon, Chaeho; Kim, Hwa-Ok; Marsden, Jeremiah; Peet, Norton P.; Bowlin, Terry L.

2014-01-01

Herein we describe the synthesis and antibacterial evaluation of a new, unsymmetrical triaryl bisamidine compound series, [Am]-[indole]-[linker]-[HetAr/Ar]-[Am], in which [Am] is an amidine or amino group, [linker] is a benzene, thiophene or pyridine ring, and [HetAr/Ar] is a benzimidazole, imidazopyridine, benzofuran, benzothiophene, pyrimidine or benzene ring. When the [HetAr/Ar] unit is a 5,6-bicyclic heterocycle, it is oriented such that the 5-membered ring portion is connected to the [linker] unit and the 6-membered ring portion is connected to the [Am] unit. Among the 34 compounds in this series, compounds with benzofuran as the [HetAr/Ar] unit showed the highest potencies. Introduction of a fluorine atom or a methyl group to the triaryl core led to the more potent analogs. Bisamidines are more active toward bacteria while the monoamidines are more active toward mammalian cells (as indicated by low CC50 values). Importantly, we identified compound P12a (MBX 1887) with a relatively narrow spectrum against bacteria and a very high CC50 value. Compound P12a has been scaled up and is currently undergoing further evaluations for therapeutic applications. PMID:24969013

Polarized two-photon fluorescence excitation spectra of indole and benzimidazole

NASA Astrophysics Data System (ADS)

Anderson, Bruce E.; Jones, Richard D.; Rehms, Aden A.; Ilich, Predrag; Callis, Patrik R.

1986-03-01

Polarized two-photon fluorescence excitation spectra of indole in hexane, benzimidazole in isopropanol, and benzimidazole cation in methanol-H 2SO 4, all at 0.2 M and 25°C are reported for the excitation range 470-600 nm, the region of their L b, and L a bands. Relative two-photon absorptivities are deduced by correcting for different fluorescence response and are compared to toluene's L b band. The indole integrated absorptivity is about 10 times greater than that of toluene. The L a band of indole appears less dominant than in one-photon but still outweighs the L b band by a factor of 4. The two-photon polarization spectrum for indole indicates that the L a origin lies ≈500-1000 cm -1 above the L b origin in hexane. The benzimidazoles absorb only about twice as strongly as toluene and show strong vibronic peaks; the L a, bands are only faintly seen. Two-photon properties calculated from INDO/S CI wavefunctions with doubly excited configurations are in good agreement with those of indole, but predict the benzimidazole TPA to be several times stronger than observed. For the cation, the predicted results are nearly two orders of magnitude too high.

Synthesis of benzimidazoles by PIDA-promoted direct C(sp2)-H imidation of N-arylamidines.

PubMed

Huang, Jinbo; He, Yimiao; Wang, Yong; Zhu, Qiang

2012-10-29

A metal-free synthesis of diversified benzimidazoles from N-arylamidines through a phenyliodine(III) diacetate (PIDA) promoted intramolecular direct C(sp(2))-H imidation has been developed. The reaction proceeds smoothly at 0 °C or ambient temperature to provide the desired products in good to excellent yields. The synthesis of 2-alkyl- or 2-alkyl-fused benzimidazoles, which are generally inaccessible by similar Pd- or Cu-catalyzed approaches, can also be achieved. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A concise synthesis of benzimidazoles via the microwave-assisted one-pot batch reaction of amino acids up to a 10-g scale.

PubMed

Peng, Pai; Xiong, Jin-Feng; Mo, Guang-Zhen; Zheng, Jia-Li; Chen, Ren-Hong; Chen, Xiao-Yun; Wang, Zhao-Yang

2014-10-01

An efficient method for the synthesis of aminomethyl benzimidazoles is developed by using a one-pot batch reaction between amino acids and o-phenylenediamines. This reaction proceeds smoothly in an unmodified household microwave oven, even though scale-up is to 10 g. A desirable method for the quick synthesis of benzimidazoles, which are used as a kind of important intermediates in drug synthesis, is provided by the scale-up utilization of amino acid resource.

An Efficient Synthesis of 2-Substituted Benzimidazoles via Photocatalytic Condensation of o-Phenylenediamines and Aldehydes.

PubMed

Kovvuri, Jeshma; Nagaraju, Burri; Kamal, Ahmed; Srivastava, Ajay K

2016-10-10

A photocatalytic method has been developed for the efficient synthesis of functionalized benzimidazoles. This protocol involves photocatalytic condensation of o-phenylenediamines with various aldehydes using the Rose Bengal as photocatalyst. The method was found to be general and was successfully employed for accessing pharmaceutically important benzimidazoles by the condensation of aromatic, heteroaromatic and aliphatic aldehydes with o-phenylenediamines, in good-to-excellent yields. Notably, the method was found to be effective for the condensation of less reactive heterocyclic aldehydes with o-phenylenediamines.

Optical, thermal and electrical properties of polybenzimidazoles derived from substituted benzimidazoles

NASA Astrophysics Data System (ADS)

Anand, Siddeswaran; Muthusamy, Athianna

2017-11-01

Three benzimidazole monomers synthesized by condensing various substituted phenolic aldehydes with 4-methylphenylenediamine were converted in to polymers by oxidative polycondensation. The structure of the monomers and polymers were confirmed by various spectroscopic techniques. Electronic distribution of molecular frontier orbitals and optimized geometries of monomers were calculated by Gaussian 09 package. The spectral results showed that the repeating units are connected through both Csbnd C and Csbnd Osbnd C linkages. Both polymers and monomers are showing good fluorescence emission in blue region. The electrical conductivity of I2 doped PBIs was measured using two point probe technique. The conductivities of PBIs were compared on the basis of the charge densities obtained from Huckel method on imidazole nitrogen which is involved in iodine coordination. The conductivity of polymers increases with increase in iodine vapour contact time. The dielectric properties of the synthesized polymers have been investigated at different temperature and frequency. Among the PBIs, PBIOP is having greater thermal stability and is shown by high carbines residues of around 50% at 500 °C in thermogravimetric analysis.

Complexation of imidazopyridine-based cations with a 24-crown-8 ether host: [2]pseudorotaxane and partially threaded structures.

PubMed

Moreno-Olivares, Surisadai I; Cervantes, Ruy; Tiburcio, Jorge

2013-11-01

A new series of linear molecules derived from 1,2-bis(imidazopyridin-2-yl)ethane can fully or partially penetrate the cavity of the dibenzo-24-crown-8 macrocycle to produce a new family of host-guest complexes. Protonation or alkylation of the nitrogen atoms on the pyridine rings led to an increase in the guest total positive charge up to 4+ and simultaneously generated two new recognition sites (pyridinium motifs) that are in competition with the 1,2-bis(benzimidazole)ethane motif for the crown ether. The relative position of the pyridine ring and the chemical nature of the N-substituent determined the preferred motif and the host-guest complex geometry: (i) for linear guests with relatively bulky groups (i.e., a benzyl substituent), the 1,2-bis(benzimidazole)ethane motif is favored, leading to a fully threaded complex with a [2]pseudorotaxane geometry; (ii) for small substituents, such as -H and -CH3 groups, regardless of the guest shape, the pyridinium motifs are preferred, leading to external partially threaded complexes in a 2:1 host to guest stoichiometry.

Syntheses, structures and characterization of isomorphous CoII and NiII coordination polymers based on 2-[(1H-imidazol-1-yl)methyl]-6-methyl-1H-benzimidazole and benzene-1,4-dicarboxylate.

PubMed

Huang, Qiu Ying; Zhao, Yang; Meng, Xiang Ru

2017-08-01

Careful choice of the organic ligands is one of the most important parameters in the rational design and synthesis of coordination polymers. Aromatic polycarboxylates have been widely used in the preparation of metal-organic polymers since they can utilize various coordination modes to form diverse structures and can act as hydrogen-bond acceptors and donors in the assembly of supramolecular structures. Nitrogen-heterocyclic organic compounds have also been used extensively as ligands for the construction of polymers with interesting structures. In the polymers catena-poly[[[diaquabis{2-[(1H-imidazol-1-yl)methyl]-6-methyl-1H-benzimidazole-κN 3 }cobalt(II)]-μ 2 -benzene-1,4-dicarboxylato-κ 2 O 1 :O 4 ] dihydrate], {[Co(C 8 H 4 O 4 )(C 12 H 11 N 4 ) 2 (H 2 O) 2 ]·2H 2 O} n , (I), and catena-poly[[[diaquabis{2-[(1H-imidazol-1-yl)methyl]-6-methyl-1H-benzimidazole-κN 3 }nickel(II)]-μ 2 -benzene-1,4-dicarboxylato-κ 2 O 1 :O 4 ] dihydrate], {[Ni(C 8 H 4 O 4 )(C 12 H 11 N 4 ) 2 (H 2 O) 2 ]·2H 2 O} n , (II), the Co II or Ni II ion lies on an inversion centre and exhibits a slightly distorted octahedral coordination geometry, coordinated by two N atoms from two imidazole rings and four O atoms from two monodentate carboxylate groups and two water molecules. The dicarboxylate ligands bridge metal ions forming a polymeric chain. The 2-[(1H-imidazol-1-yl)methyl]-6-methyl-1H-benzimidazole ligands coordinate to the Co II or Ni II centres in monodentate modes through an imidazole N atom and are pendant on opposite sides of the main chain. The two structures are isomorphous. In the crystal, the one-dimensional chains are further connected through O-H...O, O-H...N and N-H...O hydrogen bonds, leading to a three-dimensional supramolecular architecture. In addition, the IR spectroscopic properties, PXRD patterns, thermogravimetric behaviours and fluorescence properties of both polymers have been investigated.

Benzimidazoles: an ideal privileged drug scaffold for the design of multitargeted anti-inflammatory ligands.

PubMed

Kaur, Gaganpreet; Kaur, Maninder; Silakari, Om

2014-01-01

The recent research area endeavors to discover ultimate multi-target ligands, an increasingly feasible and attractive alternative to existing mono-targeted drugs for treatment of complex, multi-factorial inflammation process which underlays plethora of debilitated health conditions. In order to improvise this option, exploration of relevant chemical core scaffold will be an utmost need. Privileged benzimidazole scaffold being historically versatile structural motif could offer a viable starting point in the search for novel multi-target ligands against multi-factorial inflammation process since, when appropriately substituted, it can selectively modulate diverse receptors, pathways and enzymes associated with the pathogenesis of inflammation. Despite this remarkable capability, the multi-target capacity of the benzimidazole scaffold remains largely unexploited. With this in focus, the present review article attempts to provide synopsis of published research to exemplify the valuable use of benzimidazole nucleus and focus on their suitability as starting scaffold to develop multi-targeted anti-inflammatory ligands.

Effect of substituents on polarizability and hyperpolarizability values of benzimidazole metal complexes

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

Praveen, P. A.; Babu, R. Ramesh, E-mail: rampap2k@yahoo.co.in

2016-05-23

In this report, the polarizability and first and second order hyperpolarizability values of bis benzimidazole Zn(II)-2R and bis benzimidazole Cd(II)-2R complexes, with different electron donating moieties R (R= Cl, Br, I, Acetate) were calculated using time dependent Hartree-Fock (TDHF) formalism embedded in MOPAC2012 package. Further the role of substituents on polarizability and hyperpolarizability values is investigated for the first time by analyzing the frontier molecular orbitals of the complexes with respect to the electronegativity of the substituents. It is found that the increase in electronegativity of the substituents correspondingly increases the energy gap of the molecules, which in turn reducesmore » the polarizability values of both Zn and Cd benzimidazole complexes. Similarly, increase in electronegativity reduces the electric quadrupole moments of both the metal complexes, which in turn reduces the hyperpolarizability values.« less

Benzimidazoles and benzoxazoles via the nucleophilic addition of anilines to nitroalkanes.

PubMed

Aksenov, Alexander V; Smirnov, Alexander N; Aksenov, Nicolai A; Bijieva, Asiyat S; Aksenova, Inna V; Rubin, Michael

2015-04-14

PPA-induced umpolung triggers efficient nucleophilic addition of unactivated anilines to nitroalkanes to produce N-hydroxyimidamides. The latter undergo sequential acid-promoted cyclocondensation with ortho-OH or ortho-NHR moieties to afford benzoxazoles and benzimidazoles, respectively.

L-shaped benzimidazole fluorophores: synthesis, characterization and optical response to bases, acids and anions.

PubMed

Lirag, Rio Carlo; Le, Ha T M; Miljanić, Ognjen Š

2013-05-14

Nine L-shaped benzimidazole fluorophores have been synthesized, computationally evaluated and spectroscopically characterized. These "half-cruciform" fluorophores respond to bases, acids and anions through changes in fluorescence that vary from moderate to dramatic.

Development and Synthesis of DNA-Encoded Benzimidazole Library.

PubMed

Ding, Yun; Chai, Jing; Centrella, Paolo A; Gondo, Chenaimwoyo; DeLorey, Jennifer L; Clark, Matthew A

2018-04-25

Encoded library technology (ELT) is an effective approach to the discovery of novel small-molecule ligands for biological targets. A key factor for the success of the technology is the chemical diversity of the libraries. Here we report the development of DNA-conjugated benzimidazoles. Using 4-fluoro-3-nitrobenzoic acid as a key synthon, we synthesized a 320 million-member DNA-encoded benzimidazole library using Fmoc-protected amino acids, amines and aldehydes as diversity elements. Affinity selection of the library led to the discovery of a novel, potent and specific antagonist of the NK3 receptor.

Benzimidazole resistance in helminths: From problem to diagnosis.

PubMed

Furtado, Luis Fernando Viana; de Paiva Bello, Ana Cristina Passos; Rabelo, Élida Mara Leite

2016-10-01

Helminth parasites cause significant morbidity and mortality in endemic countries. Given the severity of symptoms that helminths may elicit in the host, intervention with prophylactic and therapeutic measures is imperative. Treatment with benzimidazoles is the most widely used means of combatting these parasites. However, widespread use of these drugs can select for drug-resistant parasite strains. In this review, we approach the problem of benzimidazole resistance in helminths in both humans and animals, focusing on the properties of the drug, the molecular mechanisms of drug resistance and how resistance is diagnosed. Copyright © 2016 Elsevier B.V. All rights reserved.

Determination of benzimidazole anthelmintics in milk and honey by monolithic fiber-based solid-phase microextraction combined with high-performance liquid chromatography-diode array detection.

PubMed

Zhang, Yong; Huang, Xiaojia; Yuan, Dongxing

2015-01-01

A porous poly(methacrylic acid-co-ethylene dimethacrylate) monolithic fiber (MEMF) for solid-phase microextraction (SPME) of five benzimidazole anthelmintics was prepared by in-situ polymerization. The effect of polymerization conditions on SPME of the target analytes was studied thoroughly. The physicochemical properties of the monolith were characterized by infrared spectroscopy, elemental analysis, scanning electron microscopy, and mercury intrusion porosimetry. Several conditions affecting the extraction efficiency were investigated and, under the optimized conditions, a simple and sensitive method for the determination of trace benzimidazoles residues in milk and honey was established by coupling MEMF-SPME with high-performance liquid chromatography-diode array detection (MEMF-SPME-HPLC-DAD). Under the optimum experimental conditions, the limits of detection (S/N = 3) of the method were 0.11-0.30 μg L(-1) for milk and 0.086-0.28 μg L(-1) for honey. Evaluation of intra-day and inter-day precision showed reproducibility was satisfactory-relative standard deviations (RSD) for both were <10 %. Finally, the method was successfully used for determination of benzimidazole residues in milk and honey. Recoveries obtained for determination of benzimidazole anthelmintics in spiked samples ranged from 72.3 to 121 %, with RSD always <11 %.

New Polybenzimidazole Architectures by Diels Alder Polymerization

DTIC Science & Technology

2012-02-14

stable organic polymers known.9 This class of polymers is aromatic with the heterocyclic benzimidazole group, a five membered imidazole ring...will allow benzimidazole ring systems to be prepared from the cycloaddition with an imidazole diene. The goals of the project included synthesis

Synthesis of deleobuvir, a potent hepatitis C virus polymerase inhibitor, and its major metabolites labeled with carbon-13 and carbon-14.

PubMed

Latli, Bachir; Hrapchak, Matt; Chevliakov, Maxim; Li, Guisheng; Campbell, Scot; Busacca, Carl A; Senanayake, Chris H

2015-05-30

Deleobuvir, (2E)-3-(2-{1-[2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido]cyclobutyl}-1-methyl-1H-benzimidazol-6-yl)prop-2-enoic acid (1), is a non-nucleoside, potent, and selective inhibitor of hepatitis C virus NS5B polymerase. Herein, we describe the detailed synthesis of this compound labeled with carbon-13 and carbon-14. The synthesis of its three major metabolites, namely, the reduced double bond metabolite (2) and the acyl glucuronide derivatives of (1) and (2), is also reported. Aniline-(13) C6 was the starting material to prepare butyl (E)-3-(3-methylamino-4-nitrophenyl-(13) C6 )acrylate [(13) C6 ]-(11) in six steps. This intermediate was then used to obtain [(13) C6 ]-(1) and [(13) C6 ]-(2) in five and four more steps, respectively. For the radioactive synthesis, potassium cyanide-(14) C was used to prepare 1-cylobutylaminoacid [(14) C]-(23) via Buchrer-Bergs reaction. The carbonyl chloride of this acid was then used to access both [(14) C]-(1) and [(14) C]-(2) in four steps. The acyl glucuronide derivatives [(13) C6 ]-(3), [(13) C6 ]-(4) and [(14) C]-(3) were synthesized in three steps from the acids [(13) C6 ]-(1), [(13) C6 ]-(2) and [(14) C]-(1) using known procedures. Copyright © 2015 John Wiley & Sons, Ltd.

Efficiency of a genetic test to detect benzimidazole resistant Haemonchus contortus nematodes in sheep farms in Quebec, Canada.

PubMed

Barrère, Virginie; Keller, Kathy; von Samson-Himmelstjerna, Georg; Prichard, Roger K

2013-10-01

Haemonchus contortus is a hemophilic nematode which infects sheep and causes anemia and death to lambs. Benzimidazole drugs are used to remove these parasites, but the phenomenon of resistance has arisen worldwide. A sensitive test to detect resistance before treatment would be a useful tool to enable farmers to anticipate the efficiency of the drug before drenching the flock. In this study, we compared a test for benzimidazole resistance based on detection of genetic markers in H. contortus before treatment with the common method of fecal egg count reduction test (FECRT). We recruited 11 farms from different regions of Quebec for this study. Fecal samples from animals were collected per rectum before and after treatment in control and treated groups (10 animals per group). The 10 sheep were treated with fenbendazole at the recommended dose rate. Among the 11 farms participating in the study, we found H. contortus in 8 of them and it was the most predominant nematode species detected by egg count. Using the genetic test, we found benzimidazole resistance in each of these 8 farms. In 5 of these 8 farms there were sufficient sheep with an egg count for H. contortus above 150 eggs per gram to allow the FECRT test to be conducted. Benzimidazole resistance was observed in each of these 5 farms by the FECRT. When we compared the results from the genetic test for samples off pasture and from individual sheep, with the results from the FECRT, we concluded that the genetic test can be applied to samples collected off pasture to estimate benzimidazole resistance levels before treatment for H. contortus infections. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

2-(4-Hy-droxy-phen-yl)-1H-benzimidazol-3-ium chloride monohydrate.

PubMed

González-Padilla, Jazmin E; Rosales-Hernández, Martha Cecila; Padilla-Martínez, Itzia I; García-Báez, Efren V; Rojas-Lima, Susana

2013-01-01

The title mol-ecular salt, C13H11N2O(+)·Cl(-)·H2O, crystallizes as a monohydrate. In the cation, the phenol and benzimidazole rings are almost coplanar, making a dihedral angle of 3.18 (4)°. The chloride anion and benzimidazole cation are linked by two N(+)-H⋯Cl(-) hydrogen bonds, forming chains propagating along [010]. These chains are linked through O-H⋯Cl hydrogen bonds involving the water mol-ecule and the chloride anion, which form a diamond core, giving rise to the formation of two-dimensional networks lying parallel to (10-2). Two π-π inter-actions involving the imidazolium ring with the benzene and phenol rings [centroid-centroid distances = 3.859 (3) and 3.602 (3) Å, respectively], contribute to this second dimension. A strong O-H⋯O hydrogen bond involving the water mol-ecule and the phenol substituent on the benzimidazole unit links the networks, forming a three-dimensional structure.

Highly efficient water-mediated approach to access benzazoles: metal catalyst and base-free synthesis of 2-substituted benzimidazoles, benzoxazoles, and benzothiazoles.

PubMed

Bala, Manju; Verma, Praveen Kumar; Sharma, Deepika; Kumar, Neeraj; Singh, Bikram

2015-05-01

An efficient water-catalyzed method has been developed for the synthesis of 2-substituted benzimidazoles, benzoxazoles, and benzothiazoles in one step. The present method excludes the usage of toxic metal catalysts and bases to produce benzazoles in good to excellent yields. An efficient and versatile water-mediated method has been established for the synthesis of various 2-arylbenzazoles. The present protocol excludes the usage of any catalyst and additive provided excellent selectivities and yields with high functional group tolerance for the synthesis of 2-arylated benzimidazoles, benzoxazoles, and benzothiazoles. Benzazolones were also synthesized using similar reaction protocol.

C2-Selective Branched Alkylation of Benzimidazoles by Rhodium(I)-Catalyzed C-H Activation.

PubMed

Tran, Gaël; Confair, Danielle; Hesp, Kevin D; Mascitti, Vincent; Ellman, Jonathan A

2017-09-01

Herein, we report a Rh(I)/bisphosphine/K 3 PO 4 catalytic system allowing for the first time the selective branched C-H alkylation of benzimidazoles with Michael acceptors. Branched alkylation with N,N-dimethyl acrylamide was successfully applied to the alkylation of a broad range of benzimidazoles incorporating a variety of N-substituents and with both electron-rich and -poor functionality displayed at different sites of the arene. Moreover, the introduction of a quaternary carbon was achieved by alkylation with ethyl methacrylate. The method was also shown to be applicable to the C2-selective branched alkylation of azabenzimidazoles.

Deciphering the Adaptive Immune Response to Ovarian Cancer

DTIC Science & Technology

2013-10-01

Additionally, anti-cancer drugs such as 2-phenyl benzimidazole (2- PB) disrupt the Golgi apparatus, which leads to reduced cell proliferation and tumour...of Golgi processing by 2-phenyl benzimidazole analogs blocks cell proliferation and slows tumor growth. Cancer Chemother Pharmacol 2008; 61: 1045–1058

Synthesis and In Vitro Activity of Polyhalogenated 2-phenylbenzimidazoles as a New Class of anti-MRSA and Anti-VRE Agents.

PubMed

Göker, Hakan; Karaaslan, Cigdem; Püsküllü, Mustafa Orhan; Yildiz, Sulhiye; Duydu, Yalcin; Üstündağ, Aylin; Yalcin, Can Özgür

2016-01-01

A series of novel polyhalogenated 2-phenylbenzimidazoles have been synthesized and evaluated for in vitro antistaphylococcal activity against drug-resistant bacterial strains (methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. Certain compounds inhibit bacterial growth perfectly. 11 was active than vancomycin (0.78 μg/mL) with the lowest MIC values with 0.19 μg/mL against methicillin-resistant Staphylococcus aureus, 8 and 35 exhibited best inhibitory activity against vancomycin-resistant Enterococcus faecium (1.56 μg/mL). The mechanism of action for this class of compounds appears to be different than clinically used antibiotics. These polyhalogenated benzimidazoles have potential for further investigation as a new class of potent anti-methicillin-resistant Staphylococcus aureus and anti-vancomycin-resistant Enterococcus faecium agents. © 2015 John Wiley & Sons A/S.

Toxicity of anthelmintic drugs (fenbendazole and flubendazole) to aquatic organisms.

PubMed

Wagil, Marta; Białk-Bielińska, Anna; Puckowski, Alan; Wychodnik, Katarzyna; Maszkowska, Joanna; Mulkiewicz, Ewa; Kumirska, Jolanta; Stepnowski, Piotr; Stolte, Stefan

2015-02-01

Flubendazole (FLU) and fenbendazole (FEN) belong to benzimidazoles-pharmaceuticals widely used in veterinary and human medicine for the treatment of intestinal parasites as well as for the treatment of systemic worm infections. In recent years, usage of these drugs increased, which resulted in a larger contamination of the environment and possible negative effects on biota. Hence, in our research, we investigated an aquatic ecotoxicity of these pharmaceuticals towards: marine bacteria (Vibrio fischeri), green algae (Scenedesmus vacuolatus), duckweed (Lemna minor) and crustacean (Daphnia magna). Ecotoxicity tests were combined with chemical analysis in order to investigate the actual exposure concentration of the compounds used in the experiment as well as to stability and adsorption studies. As a result, study evaluating sensitivity of different aquatic organisms to these compounds and new ecotoxicological data is presented. The strongest negative impact of FLU and FEN was observed to D. magna.

Microsporidiosis

DTIC Science & Technology

2011-06-01

Microsporidia and basis for benzimidazole sensitivity: an update. J Eukaryot Microbiol. 1996;43:109S. 76. Edlind TD, Li J, Visvesvara GS, Vodkin MH... benzimidazole resistance. Antimicrob Agents Chemother. 2008;52:790- 793. 168. Didier ES. Effects of albendazole, fumagillin, and TNP-470 on microsporidial replication in vitro. Antimicrob Agents Chemother. 1997;41:1541-1546.

Grafting of Conductive Polymers onto the Functionalized Carbon Nanotubes

DTIC Science & Technology

2010-08-23

2,5- benzimidazole )/carbon nanotube composite film” Journal of Polymer Science, Part A: Polymer Chemistry 2010, 48, 1067. 3. Han, S.-W.; Oh, S.-J...34Synthesis and Characterization of poly(2,5- benzimidazole ) (ABPBI) Grafted CArbon Nanotubes." MRS. 2009 fall meeting, Prepr. Boston, MA, November 30

Fixation of carbon dioxide into dimethyl carbonate over titanium-based zeolitic thiophene-benzimidazolate framework

EPA Science Inventory

A titanium-based zeolitic thiophene-benzimidazolate framework has been designed for the direct synthesis of dimethyl carbonate (DMC) from methanol and carbon dioxide. The developed catalyst activates carbon dioxide and delivers over 16% yield of DMC without the use of any dehydra...

Theoretical understanding of ruthenium(II) based fluoride sensor derived from 4,5-bis(benzimidazol-2-yl)imidazole (H3ImBzim) and bipyridine: electronic structure and binding nature.

PubMed

Wang, Jian; Bai, Fu-Quan; Xia, Bao-Hui; Sun, Lei; Zhang, Hong-Xing

2011-03-17

Using density functional theory (DFT) approach, we assessed the newly developed fluoride sensor: [(bpy)(2)Ru(H(3)ImBzim)](2+) (denoted as 1, where H(3)ImBzim = 4,5-bis(benzimidazol-2-yl)imidazole and byp = 2,2'-bipyridine). On the basis of our benchmark test, a PBE0 functional with a LanL2DZ basis set was chosen to explore the electronic structure of 1 in both ground and singlet excited states in acetonitrile solution. Both absorption bands at 426 and 352 nm are assigned as metal-to-ligand charge-transfer transition characters. By analyzing the difference of absorption spectrum between the binding adducts and the experimental measurement, the fluoride detection process was found to be driven by the proton transfer model, which makes 1 not only capable of detecting fluoride, but also for other Bønster base anions. And the result is in general accordance with the experimental observations. We hope the current exploration can give some knowledge about the detection mechanism of the F(-) anion sensor and provide some inspiration for the design of functional molecular detectors for F(-) anion.

[Primary hydatid cyst of the thyroid, an unusual localisation of hydatidosis].

PubMed

Lada, P; Lermite, E; Hennekinne-Mucci, S; Etienne, S; Pessaux, P; Arnaud, J-P

2005-04-23

Echinococcus granulosus, responsible for hydatidosis, most often lodges in the liver and lungs, but is found in other organs of the body in 10% of cases. A painless, left cervical tumefaction suddenly developed in a 28-year-old Portuguese man. After thyroid lobectomy with isthmusectomy, the pathology findings led to the diagnosis of hydatidosis. The thyroid is a rare location for a hydatid cyst. Diagnosis can be difficult and fine-needle aspiration cytology is not usually helpful. Treatment requires surgical excision, and administration of benzimidazole derivatives to prevent recurrence.

In Vitro Activities of Rabeprazole, a Novel Proton Pump Inhibitor, and Its Thioether Derivative Alone and in Combination with Other Antimicrobials against Recent Clinical Isolates of Helicobacter pylori

PubMed Central

Kawakami, Yoshiyuki; Akahane, Takayuki; Yamaguchi, Masaru; Oana, Kozue; Takahashi, Yuko; Okimura, Yukie; Okabe, Tadashi; Gotoh, Akira; Katsuyama, Tsutomu

2000-01-01

The MICs of rabeprazole sodium (RPZ), a newly developed benzimidazole proton pump inhibitor (PPI), against 133 clinical Helicobacter pylori strains revealed a higher degree of activity than the another two PPIs, lansoprazole and omeprazole. Time-kill curve assays of RPZ, when combined with amoxicillin, clarithromycin, or metronidazole, disclosed that synergistic effects were demonstrated in combination with each antibiotic examined. Moreover, no apparent antagonistic effect appeared among all of the strains tested. PMID:10639386

Targeted Approaches to Overcoming Endocrine Resistance in Breast Cancer

DTIC Science & Technology

2011-08-01

NM_001012271 BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog AF053305 CDC20 Cell division cycle 20 homolog BG256659 CDC25B Cell division cycle...by benzimidazoles 1 homolog), BIRC5/ Survivin, CDCA8 (cell division cycle-associated protein 8), AURKB (aurora kinase B), CDC25B (cell division cycle

Targeted Approaches to Overcoming Endocrine Resistance in Breast Cancer

DTIC Science & Technology

2012-08-01

kinase B CD049340 BIRC5 Effector cell peptidase receptor 1 NM_001012271 BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog AF053305 CDC20 Cell...P ≤ 0.0001). Among these were BUB1 (bud- ding uninhibited by benzimidazoles 1 homolog), BIRC5/ Survivin, CDCA8 (cell division cycle-associated

The Aged Microenvironment Influences Prostate Carcinogenesis

DTIC Science & Technology

2009-12-01

Pcdhb4 protocadherin beta 4 NM_053129 -2.3 BC068157 cDNA sequence BC068157 NM_207203 -2.3 Bub1 budding uninhibited by benzimidazoles 1 NM_009772...protein phosphatase 2, regulatory subunit B NM_028392 -2.1 Bub3 budding uninhibited by benzimidazoles 3 AK083742 -2.1 Kif4 kinesin family member 4

Control of live oak decline in Texas with Lignasan and Arbotech

Treesearch

R. Lewis

1978-01-01

Two systemic fungicides, Arbotect 20-S (2-(4-thiazolyl) benzimidazole) and Lignasan (methyl-2-benzimidazole carbamate phosphate), were tested as possible controls for live oak decline in Texas. Both fungicides killed Ceratocystis fagacearum in vitro at 1 μg/ml. Live oaks with incipient and advanced wilt were pressure injected with the...

Metal-free TEMPO-promoted C(sp³)-H amination to afford multisubstituted benzimidazoles.

PubMed

Xue, Ding; Long, Ya-Qiu

2014-05-16

An efficient TEMPO-air/cat. TEMPO-O2 oxidative protocol was developed to synthesize multisubstituted or fused tetracyclic benzimidazoles via a metal-free oxidative C-N coupling between the sp(3) C-H and free N-H of readily available N(1)-benzyl/alkyl-1,2-phenylenediamines.

2-(4-Hy­droxy­phen­yl)-1H-benzimidazol-3-ium chloride monohydrate

PubMed Central

González-Padilla, Jazmin E.; Rosales-Hernández, Martha Cecila; Padilla-Martínez, Itzia I.; García-Báez, Efren V.; Rojas-Lima, Susana

2013-01-01

The title mol­ecular salt, C13H11N2O+·Cl−·H2O, crystallizes as a monohydrate. In the cation, the phenol and benzimidazole rings are almost coplanar, making a dihedral angle of 3.18 (4)°. The chloride anion and benzimidazole cation are linked by two N+—H⋯Cl− hydrogen bonds, forming chains propagating along [010]. These chains are linked through O—H⋯Cl hydrogen bonds involving the water mol­ecule and the chloride anion, which form a diamond core, giving rise to the formation of two-dimensional networks lying parallel to (10-2). Two π–π inter­actions involving the imidazolium ring with the benzene and phenol rings [centroid–centroid distances = 3.859 (3) and 3.602 (3) Å, respectively], contribute to this second dimension. A strong O—H⋯O hydrogen bond involving the water mol­ecule and the phenol substituent on the benzimidazole unit links the networks, forming a three-dimensional structure. PMID:24427105

Hydrogen-bond-driven electrophilic activation for selectivity control: scope and limitations of fluorous alcohol-promoted selective formation of 1,2-disubstituted benzimidazoles and mechanistic insight for rationale of selectivity.

PubMed

Chebolu, Rajesh; Kommi, Damodara N; Kumar, Dinesh; Bollineni, Narendra; Chakraborti, Asit K

2012-11-16

Hydrogen-bond-driven electrophilic activation for selectivity control during competitive formation of 1,2-disubstituted and 2-substituted benzimidazoles from o-phenylenediamine and aldehydes is reported. The fluorous alcohols trifluoroethanol and hexafluoro-2-propanol efficiently promote the cyclocondensation of o-phenylenediamine with aldehydes to afford selectively the 1,2-disubstituted benzimidazoles at rt in short times. A mechanistic insight is invoked by NMR, mass spectrometry, and chemical studies to rationalize the selectivity. The ability of the fluorous alcohols in promoting the reaction and controlling the selectivity can be envisaged from their better hydrogen bond donor (HBD) abilities compared to that of the other organic solvents as well as of water. Due to the better HBD values, the fluorous alcohols efficiently promote the initial bisimine formation by electrophilic activation of the aldehyde carbonyl. Subsequently the hydrogen-bond-mediated activation of the in situ-formed bisimine triggers the rearrangement via 1,3-hydride shift to form the 1,2-disubstituted benzimidazoles.

Electrochemical oxidation of nitrogen-heterocyclic compounds at boron-doped diamond electrode.

PubMed

Xing, Xuan; Zhu, Xiuping; Li, Hongna; Jiang, Yi; Ni, Jinren

2012-01-01

Nitrogen-heterocyclic compounds (NHCs) are toxic and bio-refractory contaminants widely spread in environment. This study investigated electrochemical degradation of NHCs at boron-doped diamond (BDD) anode with particular attention to the effect of different number and position of nitrogen atoms in molecular structure. Five classical NHCs with similar structures including indole (ID), quinoline (QL), isoquinoline (IQL), benzotriazole (BT) and benzimidazole (BM) were selected as the target compounds. Results of bulk electrolysis showed that degradation of all NHCs was fit to a pseudo first-order equation. The five compounds were degraded with the following sequence: ID>QL>IQL>BT>BM in terms of their rates of oxidation. Quantum chemical calculation was combined with experimental results to describe the degradation character of NHCs at BDD anode. A linear relationship between degradation rate and delocalization energy was observed, which demonstrated that electronic charge was redistributed through the conjugation system and accumulated at the active sites under the attack of hydroxyl radicals produced at BDD anode. Moreover, atom charge was calculated by semi empirical PM3 method and active sites of NHCs were identified respectively. Analysis of intermediates by GC-MS showed agreement with calculation results. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis, characterization, crystal structure and theoretical study of a compound with benzodiazole ring: antimicrobial activity and DNA binding.

PubMed

Latha, P; Kodisundaram, P; Sundararajan, M L; Jeyakumar, T

2014-08-14

2-(Thiophen-2-yl)-1-((thiophen-2-yl)methyl)-1H-1,3-benzodiazole (HL) is synthesized and characterized by elemental analysis, UV-Vis, FT-IR, (1)H, (13)C NMR, mass spectra, scanning electron microscope (SEM) and single crystal X-ray diffraction. The crystal structure is stabilized by intermolecular CH⋯N and CH⋯π interactions. The molecular structure is also optimized at the B3LYP/6-31G level using density functional theory (DFT). The structural parameters from the theory are nearer to those of crystal, the calculated total energy of coordination is -1522.814a.u. The energy of HOMO-LUMO and the energy gap are -0.20718, -0.04314, 0.16404a.u, respectively. All data obtained from the spectral studies support the structural properties of the compound HL. The benzimidazole ring is essentially planar. The in vitro biological screening effects of the synthesized compound is tested against four bacterial and four fungal strains by well diffusion method. Antioxidant property and DNA binding behaviour of the compound has been investigated using spectrophotometric method. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of lysine at C-terminus of the Dmt-Tic opioid pharmacophore.

PubMed

Balboni, Gianfranco; Onnis, Valentina; Congiu, Cenzo; Zotti, Margherita; Sasaki, Yusuke; Ambo, Akihiro; Bryant, Sharon D; Jinsmaa, Yunden; Lazarus, Lawrence H; Trapella, Claudio; Salvadori, Severo

2006-09-07

Substitution of Gly with side-chain-protected or unprotected Lys in lead compounds containing the opioid pharmacophore Dmt-Tic [H-Dmt-Tic-Gly-NH-CH(2)-Ph, mu agonist/delta antagonist; H-Dmt-Tic-Gly-NH-Ph, mu agonist/delta agonist; and H-Dmt-Tic-NH-CH(2)-Bid, delta agonist (Bid = 1H-benzimidazole-2-yl)] yielded a new series of compounds endowed with distinct pharmacological activities. Compounds (1-10) included high delta- (Ki(delta) = 0.068-0.64 nM) and mu-opioid affinities (Ki(mu) = 0.13-5.50 nM), with a bioactivity that ranged from mu-opioid agonism {10, H-Dmt-Tic-NH-CH[(CH2)4-NH2]-Bid (IC50 GPI = 39.7 nM)} to a selective mu-opioid antagonist [3, H-Dmt-Tic-Lys-NH-CH2-Ph (pA2(mu) = 7.96)] and a selective delta-opioid antagonist [5, H-Dmt-Tic-Lys(Ac)-NH-Ph (pA2(delta) = 12.0)]. The presence of a Lys linker provides new lead compounds in the formation of opioid peptidomimetics containing the Dmt-Tic pharmacophore with distinct agonist and/or antagonist properties.

Halide/pseudohalide complexes of cadmium(II) with benzimidazole: Synthesis, crystal structures and fluorescence properties

NASA Astrophysics Data System (ADS)

Zhao, Hai-Yan; Yang, Fu-Li; Li, Na; Wang, Xiao-Jing

2017-11-01

Two new dinuclear Cd(II) complexes, [CdL1Cl2]2·H2O (1) and [CdL1(N3)2]2·CH3OH (2) and one dicyanamide bridged one-dimensional polynuclear network [CdL1(μ1,5-dca)dca]n (3) of the potentially tridentate NNN-donor Schiff base 2-((1H-benzimidazol-2-yl-ethylimino)-methyl)pyridine (L1) and another dinucler Cd(II) complex [CdL2Cl(dca)]2 (4) of a similar NNN-donor Schiff base ligand 2-((1H-benzimidazol-2-yl-propylimino)-methyl)pyridine (L2), have been synthesized and characterized by elemental analyses, IR and single crystal X-ray crystallography. The ligands L1 and L2 are [1 + 1] condensation products of pyridine-2-carbaldehyde with 2-aminoethyl-1H-benzimidazole and 2-aminopropyl-1H-benzimidazole, respectively. In the complexes 1 and 4 the two Cd(II) centers are held together by the bridged chloride ligands, while in 2 the two Cd(II) centers are bridged by μ1,1-azide ions. Complex 3 has a one-dimensional infinite chain structure in which Cd(II) ions are bridged by single dicyanamide groups in end-to-end fashion. All the metal centers have a distorted octahedral geometry and H-bonding or π⋯π interactions are operative to bind the complex units in the solid state. Furthermore, these complexes have been investigated by thermogravimetric analyses and fluorescence spectra.

Activities of fenbendazole in comparison with albendazole against Echinococcus multilocularis metacestodes in vitro and in a murine infection model.

PubMed

Küster, Tatiana; Stadelmann, Britta; Aeschbacher, Denise; Hemphill, Andrew

2014-04-01

The current chemotherapeutic treatment of alveolar echinococcosis (AE) in humans is based on albendazole and/or mebendazole. However, the costs of treatment, life-long consumption of drugs, parasitostatic rather than parasiticidal activity of chemotherapy, and high recurrence rates after treatment interruption warrant more efficient treatment options. Experimental treatment of mice infected with Echinococcus multilocularis metacestodes with fenbendazole revealed similar efficacy to albendazole. Inspection of parasite tissue from infected and benzimidazole-treated mice by transmission electron microscopy (TEM) demonstrated drug-induced alterations within the germinal layer of the parasites, and most notably an almost complete absence of microtriches. On the other hand, upon in vitro exposure of metacestodes to benzimidazoles, no phosphoglucose isomerase activity could be detected in medium supernatants during treatment with any of these drugs, indicating that in vitro treatment did not severely affect the viability of metacestode tissue. Corresponding TEM analysis also revealed a dramatic shortening/retraction of microtriches as a hallmark of benzimidazole action, and as a consequence separation of the acellular laminated layer from the cellular germinal layer. Since TEM did not reveal any microtubule-based structures within Echinococcus microtriches, this effect cannot be explained by the previously described mechanism of action of benzimidazoles targeting β-tubulin, thus benzimidazoles must interact with additional targets that have not been yet identified. In addition, these results indicate the potential usefulness of fenbendazole for the chemotherapy of AE. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells

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

Payton-Stewart, Florastina; Tilghman, Syreeta L.; Williams, LaKeisha G.

Highlights: • The methyl-substituted benzimidazole was more effective at inhibiting growth in MDA-MB 231 cells. • The naphthyl-substituted benzimidazole was more effective at inhibiting growth in MCF-7 cells than ICI. • The benzimidazole molecules demonstrated a dose-dependent reduction in ERE transcriptional activity. • The benzimidazole molecules had binding mode in ERα and ERβ comparable to that of the co-crystallized ligand. - Abstract: Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets formore » developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulfonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel, while the naphthyl analog did not significantly alter gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules upregulate ERβ activity while down regulating that of ERα.« less

In-situ complex with by-product HCl and release chloride ions to dissolve aramid.

PubMed

Dai, Yu; Cheng, Zheng; Yuan, Yihao; Meng, Chenbo; Qin, Jiaqiang; Liu, Xiangyang

2018-06-20

Because of the strong hydrogen-bond interaction among macromolecular chains, addition of chloride salts is generally needed to offer Cl- ions for dissolution of aromatic polyamides. In this paper, poly-(benzimidazole-terephthalamide) which complexed with by-product HCl during polymerization (PABI-HCl) was prepared and imidazole compound as cosolvent was added into dimethylacetamide (DMAc) to dissolve PABI-HCl. Due to stronger affinity to protons, imidazole compound could in-situ complex with HCl of PABI-HCl and form imidazolium hydrochloride. Then imidazolium hydrochloride would ionize and produce much free Cl- ions which acted as stronger hydrogen-bond acceptor to disrupt interaction among macromolecular chains. As a result, solubility of PABI-HCl in DMAc was improved significantly in existence of small amount of imidazole compound. Moreover, DMAc-imidazole mixture was utlized for synthesis of different kinds of aramids and no precipitation was observed with progress of the reaction. So the mixture was suitable to be utlized as solvent for polymerization of aramid. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure-based design of Aurora A & B inhibitors

NASA Astrophysics Data System (ADS)

Poulsen, Anders; William, Anthony; Lee, Angeline; Blanchard, Stéphanie; Teo, Eeling; Deng, Weiping; Tu, Noah; Tan, Evelyn; Sun, Eric; Goh, Kay Lin; Ong, Wai Chung; Ng, Chee Pang; Goh, Kee Chuan; Bonday, Zahid

2008-12-01

The Aurora family of serine/threonine kinases are mitotic regulators involved in centrosome duplication, formation of the bipolar mitotic spindle and the alignment of the chromosomes along the spindle. These proteins are frequently overexpressed in tumor cells as compared to normal cells and are therefore potential therapeutic oncology targets. An Aurora A high throughput screen revealed a promising sub-micromolar indazole-benzimidazole lead. Modification of the benzimidazole portion of the lead to a C2 linker with a phenyl ring was proposed to achieve novelty. Docking revealed that a conjugated linker was optimal and the resulting compounds were equipotent with the lead. Further structure-guided optimization of substituents on the 5 & 6 position of the indazole led to single digit nanomolar potency. The homology between the Aurora A & Aurora B kinase domains is 71% but their binding sites only differ at residues 212 & 217 (Aurora A numbering). However interactions with only the latter residue may be used for obtaining selectivity. An analysis of published Aurora A and Aurora B X-ray structures reveals subtle differences in the shape of the binding sites. This was exploited by introduction of appropriately sized substituents in the 4 & 6 position of the indazole leading to Aurora B selective inhibitors. Finally we calculate the conformational energy penalty of the putative bioactive conformation of our inhibitors and show that this property correlates well with the Aurora A binding affinity.

Metal-containing Complexes of Lactams, Imidazoles, and Benzimidazoles and Their Biological Activity

NASA Astrophysics Data System (ADS)

Kukalenko, S. S.; Bovykin, B. A.; Shestakova, S. I.; Omel'chenko, A. M.

1985-07-01

The results of the latest investigations of the problem of the synthesis of metal-containing complexes of lactams, imidazoles, and benzimidazoles, their structure, and their stability in solutions are surveyed. Some data on their biological activity (pesticide and pharmacological) and the mechanism of their physiological action are presented. The bibliography includes 190 references.

Transition-metal-free synthesis of imidazo[2,1-b]thiazoles and thiazolo[3,2-a]benzimidazoles via an S-propargylation/5-exo-dig cyclization/isomerization sequence using propargyl tosylates as substrates.

PubMed

Omar, Mohamed A; Frey, Wolfgang; Conrad, Jürgen; Beifuss, Uwe

2014-11-07

A transition-metal-free route for the synthesis of several N-fused heterocycles, including thiazolo[3,2-a]benzimidazoles and imidazo[2,1-b]thiazoles, is reported. The reaction between propargyl tosylates and 2-mercaptobenzimidazoles under basic conditions results in 3-substituted thiazolo[3,2-a]benzimidazoles, in yields up to 92% in a single synthesis step. With 2-mercaptoimidazoles as the substrate, the corresponding imidazo[2,1-b]thiazoles were exclusively obtained. The transformation is considered to proceed as an intermolecular S-propargylation that is followed by 5-exo-dig ring closure and double-bond isomerization.

[The specific enzyme inhibitors for potential therapeutic use].

PubMed

Bretner, Maria

2015-01-01

Therapy for hepatitis C virus (HCV) initially consisted on administering ribavirin - having a broad spectrum of action - and pegylated interferon, and was only effective in 40-50% of patients. Appropriate was to find effective inhibitors of viral replication e.g. by inhibition of a viral enzyme, NTPase/helicase required in the process of translation and RNA replication of the HCV. We developed methods of synthesis of many compounds belonging to different groups - derivatives of nucleosides, benzotriazole, benzimidazole, tropolone and epirubicine. Some of the derivatives inhibit HCV helicase activity at low concentrations and reduces replication of the viral RNA in subgenomic replicon system. In the process of HCV replication casein kinase CK2 plays an important role. It regulates the level of phosphorylation of HCV protein NS5A, which affects the production of infectious virions of HCV. Effective and selective inhibitors of kinase CK2 could be of use in the treatment of HCV in combination with other drugs. CK2 kinase phosphorylates approximately 300 proteins that affect the growth, differentiation, proliferation or apoptosis. Elevated CK2 kinase activity has been observed in several types of cancer and other diseases, therefore, inhibitors of this enzyme are potential therapeutic importance, particularly for anti-cancer treatment. Research carried out in collaboration with prof. Shugar led to the synthesis of one of the most selective inhibitors of this enzyme which is 4,5,6,7-tetrabromo-1H-benzotriazole, used for the study of the role of kinase CK2 in a number of metabolic processes in tumor cells.

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.

PubMed

O'Dowd, Hardwin; Shannon, Dean E; Chandupatla, Kishan R; Dixit, Vaishali; Engtrakul, Juntyma J; Ye, Zhengqi; Jones, Steven M; O'Brien, Colleen F; Nicolau, David P; Tessier, Pamela R; Crandon, Jared L; Song, Bin; Macikenas, Dainius; Hanzelka, Brian L; Le Tiran, Arnaud; Bennani, Youssef L; Charifson, Paul S; Grillot, Anne-Laure

2015-07-09

Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.

Sorption of benzimidazole anthelmintics to dissolved organic matter surrogates and sewage sludge.

PubMed

Kim, Hyo-Jung; Lee, Dong Soo; Kwon, Jung-Hwan

2010-06-01

The sorption coefficients of four rarely studied zwitterionic pharmaceuticals (benzimidazoles: fenbendazole, albendazole, thiabendazole and flubendazole) and four metabolites of fenbendazole to various dissolved organic matter surrogates (humic acid, sodium dodecyl sulfate micelle, hydroxypropyl-beta-cyclodextrin and liposomes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and sewage sludge) were measured to extend the available sorption coefficients and eventually to evaluate their environmental fate in soil and water environment. For the entire range of dissolved organic matters, the more hydrophobic fenbendazole and albendazole had higher sorption coefficients than thiabendazole and flubendazole, indicating that the traditional hypothesis of hydrophobic interaction holds for zwitterionic benzimidazole anthelmintics. However, the sorption coefficients of a given benzimidazole to selected dissolved organic matters (DOMs) varied within an order of magnitude. The measured K(oc) values decreased in the order of fenbendazole, albendazole, thiabendazole and flubendazole for sewage sludge and hydroxypropyl-beta-cyclodextrin whereas the orders were different for the other DOM surrogates, implying the hydrophilic nature of sewage sludge. This was also supported by the (N+O)/C elemental ratio of the sewage sludge sample used in this study. The correlations between log K(oc) and log K(ow) were weak (r(2)=0.28-0.64) and the magnitude of the sorption coefficients to the hydrophilic organic matters (hydroxypropyl-beta-cyclodextrin and sewage sludge) were similar to or slightly smaller than those for the hydrophobic organic matters (humic acids and liposome). This suggests that specific hydrophilic interactions also play a significant role in the sorption of moderately hydrophobic benzimidazoles to organic matters. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Synthesis of amino ester-embedded benzimidazoles: a one-pot sequential protocol under metal-free neutral conditions.

PubMed

Roy, Priyabrata; Bodhak, Chandan; Pramanik, Animesh

2017-02-01

A one-pot three-component protocol has been developed for the synthesis of amino ester-embedded benzimidazoles under metal-free neutral conditions. Sequentially, the methodology involves coupling of an amino ester with 1-fluoro-2-nitrobenzene, reduction of the coupled nitroarene by sodium dithionite, and cyclization of the corresponding diamine with an aldehyde.

Pressure injection of methyl 2-benzimidazole carbamate hydrochloride solution as a control for Dutch elm disease

Treesearch

Garold F. Gregory; Thomas W. Jones

1973-01-01

A preliminary evaluation of the effectiveness of injecting methyl 2-benzimidazole carbamate hydrochloride solution into elms for prevention or cure of Dutch elm disease is reported. Symptom development was diminished or prevented in elms injected with fungicide before inoculation. Symptom development was arrested in all crown-inoculated diseased trees injected with the...

A thiazepino[4,5-a]benzimidazole derivative hampers the RNA replication of Eurasian serotypes of foot-and-mouth disease virus.

PubMed

Lefebvre, David J; De Vleeschauwer, Annebel R; Goris, Nesya; Van Borm, Steven; Chimirri, Alba; Monforte, Anna Maria; Valdazo-Gonzalez, Begona; King, Donald P; Neyts, Johan; De Clercq, Kris

2014-12-12

The stamping-out policy for the control of foot-and-mouth disease virus (FMDV) in countries that are free from FMD without vaccination has a dramatic socio-economic impact, huge animal welfare issues and may result in the loss of farm animal genetic resources. As an alternative to pre-emptive culling or emergency vaccination we further explore the possibility to use antiviral drugs in the event of an FMD outbreak. In the present study, we tested the in vitro cytotoxicity and anti-FMDV activity of 1,2,4,5-tetrahydro-[1,4]thiazepino[4,5-a]benzimidazole. The molecule was shown to inhibit the replication of reference strains of the Eurasian FMDV serotypes O, A, C and Asia but not the FMDV serotypes from the South African Territories (SAT) neither a related picornavirus, i.e. swine vesicular disease virus. The molecule can be added until 2h post inoculation in a 'single replication cycle experiment' without losing its antiviral activity. The genetic characterization of progressively selected resistant FMD viruses shows that the molecule presumably interacts with the non-structural 2C protein of FMDV. Further studies are required on the use of this molecule in vivo. Copyright © 2014 Elsevier Inc. All rights reserved.

Experimental chemotherapy in horses infected with benzimidazole-resistant small strongyles.

PubMed

Britt, D P; Clarkson, M J

1988-08-27

The presence of benzimidazole-resistant strains of equine small strongyles was confirmed in horses at two properties in north west England by a series of faecal egg counts and larval cultures after treatment with mebendazole. A trail formulation of mebendazole in combination with piperazine citrate gave greater reductions in faecal egg counts than mebendazole alone but was much less effective than pyrantel embonate or dichlorvos.

Sequence-based design of bioactive small molecules that target precursor microRNAs.

PubMed

Velagapudi, Sai Pradeep; Gallo, Steven M; Disney, Matthew D

2014-04-01

Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate). Among 27 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide.

Sequence-based design of bioactive small molecules that target precursor microRNAs

PubMed Central

Velagapudi, Sai Pradeep; Gallo, Steven M.; Disney, Matthew D.

2014-01-01

Oligonucleotides are designed to target RNA using base pairing rules, however, they are hampered by poor cellular delivery and non-specific stimulation of the immune system. Small molecules are preferred as lead drugs or probes, but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA precursors and identified bioactive small molecules that inhibit biogenesis by binding to nuclease processing sites (41% hit rate). Amongst 29 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Importantly, microRNA profiling shows that 1 only significantly effects microRNA-96 biogenesis and is more selective than an oligonucleotide. PMID:24509821

[Novel hybrid inhibitors of the phage T7 RNA polymerase: synthesis, docking and screening in vitro].

PubMed

Kostina, V H; Pal'chykovs'ka, L H; Platonov, M O; Vasyl'chenko, O V; Lysenko, N A; Alekseeva, I V

2012-01-01

A number of new hybrid heteroaromatic compounds, consisting of tricyclic fragments (acridone, thioxanthone and phenazine) and bicyclic fragments (benzimidazole, benzothiazole and benzoxazole) were synthesized using the method, developed by the authors. As a result of screening against the transcription model system of the phage T7 DNA-dependent RNA polymerase three effective inhibitors of the RNA syntheses with the IC50 value of 8.9, 5.7 and 19.8 microM were detected. To cast light on the mode of interaction between the synthesized compounds and the target, the molecular docking was applied to the model pocket of the phage T7 RNA polymerase transcription complex. It was established that these ligands form networks of H-bonds with residues of the pocket conservative amino acids and pi-interaction with the Mg2+ ion. A planar geometry of the hybrid molecules, realized due to the intramolecular H-bonds, proved to be an important structural feature, which correlates with an efficacious inhibitory activity.

Outcome after Discontinuing Long-Term Benzimidazole Treatment in 11 Patients with Non-resectable Alveolar Echinococcosis with Negative FDG-PET/CT and Anti-EmII/3-10 Serology

PubMed Central

Stumpe, Katrin D. M.; Grimm, Felix; Deplazes, Peter; Huber, Sabine; Bertogg, Kaja; Fischer, Dorothee R.; Müllhaupt, Beat

2015-01-01

Background/Aims Benzimidazoles are efficacious for treating non-resectable alveolar echinococcosis (AE), but their long-term parasitocidal (curative) effect is disputed. In this study, we prospectively analyzed the potential parasitocidal effect of benzimidazoles and whether normalization of FDG-PET/CT scans and anti-Emll/3-10-antibody levels could act as reliable "in vivo" parameters of AE-inactivation permitting to abrogate chemotherapy with a low risk for AE-recurrence. Method This prospective study included 34 patients with non-resectable AE subdivided into group A (n = 11), followed-up after diagnosis and begin of chemotherapy at months 6, 12 and 24, and group B (n = 23) with a medium duration of chemotherapy of 10 (range 2–25) years. All patients were assessed by FDG-PET/CT examinations and anti-EmII/3-10 serology. Chemotherapy was abrogated in patients with normalization of FDG-PET/CT and serum anti-EmII/3-10 levels. These patients were closely followed-up for AE recurrence. Endpoint (parasitocidal efficacy) was defined by the absence of AE-recurrence >24 months after stopping treatment. Results Normalization of FDG-PET/CT scan and anti-EmII/3-10 levels occurred in 11 of 34 patients (32%). After abrogation of chemotherapy in these 11 patients, there was no evidence of AE-recurrence within a median of 70.5 (range 16–82) months. However, the patients’ immunocompetence appears pivotal for the described long-term parasitocidal effect of benzimidazoles. Conclusions The combination of negative FDG-PET/CT-scans and anti-EmII/3-10 antibody levels seem to be reliable parameters for assessing in vivo AE-larval inactivity after long-term benzimidazole chemotherapy. Trial Registration clinicaltrials.gov: NCT00658294 PMID:26389799

In Situ Synthesis of a Magnetic Graphene Platform for the Extraction of Benzimidazoles from Food Samples and Analysis by High-Performance Liquid Chromatography

PubMed Central

Liu, Yulan; Wang, Xingyi; Li, Huimin; Chen, Junyu

2017-01-01

A novel method was proposed for the determination of five benzimidazoles (oxfendazole, mebendazole, flubendazole, albendazole, and fenbendazole) using magnetic graphene (G-Fe3O4). G-Fe3O4 was synthesized via in situ chemical coprecipitation. The properties of G-Fe3O4 were characterized by various instrumental methods. G-Fe3O4 exhibited a great adsorption ability and good stability towards analytes. Various experimental parameters that might affect the extraction efficiency such as the amount of G-Fe3O4, extraction solvent, extraction time, and desorption conditions were evaluated. Under the optimized conditions, a method based on G-Fe3O4 magnetic solid-phase extraction coupled with high-performance liquid chromatography was developed. A good linear response was observed in the concentration range of 0.100–100 μg/L for the five benzimidazoles, with correlation coefficients ranging from 0.9966 to 0.9998. The limits of detection (S/N = 3) of the method were between 17.2 and 32.3 ng/L. Trace benzimidazoles in chicken, chicken blood, and chicken liver samples were determined and the concentrations of oxfendazole, mebendazole, flubendazole, and fenbendazole in these samples were 13.0–20.2, 1.62–4.64, 1.94–6.42, and 0.292–1.04 ng/g, respectively. The recovery ranged from 83.0% to 115%, and the relative standard deviations were less than 7.9%. The proposed method was sensitive, reliable, and convenient for the analysis of trace benzimidazoles in food samples. PMID:28546882

Convenient synthesis of benzothiazoles and benzimidazoles through Brønsted acid catalyzed cyclization of 2-amino thiophenols/anilines with β-diketones.

PubMed

Mayo, Muhammad Shareef; Yu, Xiaoqiang; Zhou, Xiaoyu; Feng, Xiujuan; Yamamoto, Yoshinori; Bao, Ming

2014-02-07

Brønsted acid catalyzed cyclization reactions of 2-amino thiophenols/anilines with β-diketones under oxidant-, metal-, and radiation-free conditions are described. Various 2-substituted benzothiazoles/benzimidazoles are obtained in satisfactory to excellent yields. Different groups such as methyl, chloro, nitro, and methoxy linked on benzene rings were tolerated under the optimized reaction conditions.

Luminescence and electroluminescence of bis (2-(benzimidazol-2-yl) quinolinato) zinc. Exciplex formation and energy transfer in mixed film of bis (2-(benzimidazol-2-yl) quinolinato) zinc and N,N‧-bis-(1-naphthyl)-N,N‧-diphenyl-1,1‧-biphenyl-4,4‧-diamine

NASA Astrophysics Data System (ADS)

Chen, Tsun-Ren

2005-02-01

The absorption and emission properties of benzimidazol-2-yl-quinoline (BIQ) and bis (2-(benzimidazol-2-yl) quinolinato) zinc (ZnBIQ) a new emitter used for organic light emitting device (OLED) were reported. Exciplexes are observed for ZnBIQ with N, N'-bis-(1-naphthyl)- N, N'-diphenyl-1,1'-biphenyl-4,4'-diamine (NPB) system, in both electro- and photoluminescent processes. The identification of exciplex emission in co-evaporated and multi-layer ZnBIQ thin film was reported for the first time. The optical formation of the exciplex involves the excitation of a single molecule, followed by the relaxation of that exciton into a lower energy exciplex state. Both BIQ and ZnBIQ possess very high thermal stabilities and can be purified by subliming under the high vacuum condition. Devices consisting of ZnBIQ as the emitting layer have been fabricated, and the emission spectra of ZnBIQ-base devices gave a voltage-dependent spectrum, with the red emission observed (3-7 V), switching over to strong white emission as the bias was raised.

Poly(N-arylenbenzimidazoles) via aromatic nucleophilic displacement

NASA Technical Reports Server (NTRS)

Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Joseph G., Jr. (Inventor)

1995-01-01

Novel poly(N-arylenebenzimidazole)s (PNABIs) are prepared by the aromatic nucleophilic displacement reaction of novel di(hydroxyphenyl-N-arylene benzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. The di(hydroxyphenyl N-arylenebenzimidazole) monomers are synthesized by reacting phenyl 4-hydroxybenzoate with bis(2-aminoanilino) arylenes in diphenylsulfone. Moderate molecular weight PNABIs of new chemical structures were prepared that exhibit a favorable combination of physical and mechanical properties. The use of the novel di(hydroxyphenyl N-arylenebenzimidazole)s permits a more economical and easier way to prepare PNABIs than previous routes.

Poly(N-arylenebenzimidazole)s via aromatic nucleophilic displacement

NASA Technical Reports Server (NTRS)

Connell, John W. (Inventor); Hergenrother, Paul M. (Inventor); Smith, Jr., Joseph G. (Inventor)

1996-01-01

Novel poly(N-arylenebenzimidazole)s (PNABls) are prepared by the aromatic nucleophilic displacement reaction of novel di(hydroxyphenyl-N-arylene benzimidazole) monomers with activated aromatic dihalides or activated aromatic dinitro compounds. The polymerizations are carried out in polar aprotic solvents such as N-methyl-2-pyrrolidinone or N,N-dimethylacetamide using alkali metal bases such as potassium carbonate at elevated temperatures under nitrogen. The di(hydroxyphenyl-N-arylenebenzimidazole) monomers are synthesized by reacting phenyl-4-hydroxybenzoate with bis(2-aminoanilino)arylenes in diphenylsulfone. Moderate molecular weight PNABIs of new chemical structures were prepared that exhibit a favorable combination of physical and mechanical properties. The use of the novel di(hydroxyphenyI-N-arylenebenzimidazole)s permits a more economical and easier way to prepare PNABIs than previous routes.

Electronic properties and free radical production by nitrofuran compounds.

PubMed

Paulino-Blumenfeld, M; Hansz, M; Hikichi, N; Stoppani, A O

1992-01-01

Substitution of nifurtimox tetrahydrothiazine moiety by triazol-4-yl, benzimidazol-l-yl, pyrazol-l-yl or related aromatic nitrogen heterocycles determines changes in the quantum chemistry descriptors of the molecule, namely, (a) greater negative LUMO energy; (b) lesser electron density on specific atoms, especially on the nitro group atoms, and (c) modification of individual net atomic charges at relevant atoms. These variations correlate with the greater capability of nifurtimox analogues for redox-cycling and oxygen radical production, after one-electron reduction by ascorbate or reduced flavoenzymes. Variation of the nitrofurans electronic structure can also explain the greater activity of nifurtimox analogues as inhibitors of glutathione reductase and Trypanosoma cruzi growth, although other factors, such as molecular hydrophobicity and connectivity may contribute to the latter inhibition.

New 2',6'-dimethyl-L-tyrosine (Dmt) opioid peptidomimetics based on the Aba-Gly scaffold. Development of unique mu-opioid receptor ligands.

PubMed

Ballet, Steven; Salvadori, Severo; Trapella, Claudio; Bryant, Sharon D; Jinsmaa, Yunden; Lazarus, Lawrence H; Negri, Lucia; Giannini, Elisa; Lattanzi, Roberta; Tourwé, Dirk; Balboni, Gianfranco

2006-06-29

The Aba-Gly scaffold, incorporated into Dmt-Tic ligands (H-Dmt-Tic-Gly-NH-CH2-Ph, H-Dmt-Tic-Gly-NH-Ph, H-Dmt-Tic-NH-CH2-Bid), exhibited mixed micro/delta or delta opioid receptor activities with micro agonism. Substitution of Tic by Aba-Gly coupled to -NH-CH2-Ph (1), -NH-Ph (2), or -Bid (Bid=1H-benzimidazole-2-yl) (3) shifted affinity (Ki(micro)=0.46, 1.48, and 19.9 nM, respectively), selectivity, and bioactivity to micro-opioid receptors. These compounds represent templates for a new class of lead opioid agonists that are easily synthesized and suitable for therapeutic pain relief.

Reactivity of tris(acetylacetonato) iron(III) with tridentate [ONO] donor Schiff base as an access to newer mixed-ligand iron(III) complexes

NASA Astrophysics Data System (ADS)

Bhattacharjee, Chira R.; Goswami, Pankaj; Pramanik, Harun A. R.; Paul, Pradip C.; Mondal, Paritosh

2011-05-01

Two new mixed-ligand iron(III) complexes, [Fe(L n)(acac)(C 2H 5OH)] incorporating coordinated ethanol from the reaction solvent were accessed from the reaction of [Fe(acac) 3] with [ONO] donor dibasic tridentate unsymmetrical Schiff base ligands derived from condensation of 2-hydroxy-1-napthaldehyde with 2-aminophenol (H 2L 1) or 2-aminobenzoic acid (H 2L 2). The thermal study (TGA-DTA) provided evidence for weakly bound ethanol which is readily substituted by neutral N-donor molecule imidazole, benzimidazole or pyridine to produce an array of newer complexes, [Fe(L n)(acac)X] ( n = 1, 2; X = Im, Bim, Py). The compounds were characterized by elemental analyses, FT-IR, UV-vis, solution electrical conductivity, FAB mass, 1H and 13C NMR spectroscopy. Room temperature magnetic susceptibility measurements ( μeff ˜ 5.8 B.M.) are consistent with spin-free octahedral iron(III) complexes. Cyclic voltammetry of ethanol complexes revealed a quasi-reversible one electron redox response (Δ Ep > 100 mV) for the Fe(III)/Fe(II) couple. Low half wave redox potential ( E1/2) values suggested easy redox susceptibility. The ground state geometries of the ethanol and imidazole complexes have been ascertained to be distorted octahedral by density functional theory using DMol3 program at BLYP/DNP level.

One-pot, two-step synthesis of imidazo[1,2-a]benzimidazoles via a multicomponent [4 + 1] cycloaddition reaction.

PubMed

Hsiao, Ya-Shan; Narhe, Bharat D; Chang, Ying-Sheng; Sun, Chung-Ming

2013-10-14

A one-pot, two-step synthesis of imidazo[1,2-a]benzimidazoles has been achieved by a three-component reaction of 2-aminobenzimidazoles with an aromatic aldehyde and an isocyanide. The reaction involving condensation of 2-aminobenzimidazole with an aldehyde is run under microwave activation to generate an imine intermediate under basic conditions which then undergoes [4 + 1] cycloaddition with an isocyanide.

Rhodium(III)-catalyzed vinylic sp2 C-H bond functionalization: efficient synthesis of pyrido[1,2-α]benzimidazoles and imidazo[1,2-α]pyridines.

PubMed

Dong, Lin; Huang, Ji-Rong; Qu, Chuan-Hua; Zhang, Qian-Ru; Zhang, Wei; Han, Bo; Peng, Cheng

2013-09-28

A simple approach for synthesis of novel aza-fused scaffolds such as pyrido[1,2-α]benzimidazoles and imidazo[1,2-α]pyridines was developed by Rh(III)-catalyzed direct oxidative coupling between alkenes and unactivated alkynes without an extra directing group. The method would allow a broad substrate scope, providing fused heterocycles with potential biological properties.

Synthesis and Characterization of Poly (Arylene Ether Benzimidazole) Oligomers

NASA Technical Reports Server (NTRS)

Leonard, Michael J.

1995-01-01

Several poly(arylene ether benzimidazole) oligomers were prepared by the nucleophilic aromatic substitution reaction of a bisphenol benzimidazole and various alkyl-substituted aromatic bisphenols with an activated aromatic dihalide in N, N-dimethylacetarnide. Moderate to high molecular weight terpolymers were obtained in all cases, as shown by their inherent viscosities, which ranged from 0.50 to 0.87 dL g(sup -1). Glass transition temperatures (T(sub g)s) of polymer powders ranged from 267-280 C. Air-dried unoriented thin film T(sub g)s were markedly lower than those of the powders, whereas T(sub g)s of films dried in a nitrogen atmosphere were identical to those of the corresponding powders. In addition, air-dried films were dark amber and brittle, whereas nitrogen-dried films were yellow and creasable. Nitrogen-dried films showed slightly higher thin-film tensile properties than the air-dried films, as well.

(2-{[2-(1H-Benzimidazol-2-yl-κN 3)phen­yl]imino­methyl-κN}-5-methyl­phenolato-κO)chloridozinc(II)

PubMed Central

Eltayeb, Naser Eltaher; Teoh, Siang Guan; Chantrapromma, Suchada; Fun, Hoong-Kun

2011-01-01

In the title mononuclear complex, [Zn(C21H16N3O)Cl], the ZnII ion is coordinated in a distorted tetra­hedral geometry by two benzimidazole N atoms and one phenolate O atom from the tridentate Schiff base ligand and a chloride ligand. The benzimidazole ring system forms dihedral angles of 26.68 (9) and 56.16 (9)° with the adjacent benzene ring and the methyl­phenolate group benzene ring, respectively. In the crystal, mol­ecules are linked by N—H⋯Cl hydrogen bonds into chains along [100]. Furthermore, weak C—H⋯O and C—H⋯π inter­actions, in addition to π–π inter­actions with centroid–centroid distances in the range 3.5826 (13)–3.9681 (13) Å, are also observed. PMID:22065469

Crystal structure, quantum mechanical investigation, IR and NMR spectroscopy of two new organic perchlorates: (C6H18N3)·(ClO4)3H2O (I) and (C9H11N2)·ClO4(II)

NASA Astrophysics Data System (ADS)

Bayar, I.; Khedhiri, L.; Soudani, S.; Lefebvre, F.; Ferretti, V.; Ben Nasr, C.

2018-06-01

The reaction of perchloric acid with 1-(2-aminoethyl)piperazine or 5,6-dimethyl-benzimidazole results in the formation of 1-(2-amonioethyl)piperazine-1,4-dium triperchlorate hydrate (C6H18N3)·(ClO4)3·H2O (I) or 5,6-dimethyl-benzylimidazolium perchlorate (C9H11N2)·ClO4(II). Both compounds were fully structurally characterized including single crystal X-ray diffraction analysis. Compound (I) crystallizes in the centrosymmetric triclinic space group P 1 bar with the lattice parameters a = 7.455 (2), b = 10.462 (2), c = 10.824 (2) Å, α = 80.832 (2), β = 88.243 (2), γ = 88.160 (2) °, Z = 2 and V = 832.77 (3) Å3. Compound (II) has been found to belong to the P21/c space group of the monoclinic system, with a = 7.590 (3), b = 9.266 (3), c = 16.503 (6) Å, β = 107.38 (2) °, V = 1107.69 (7) Å3 and Z = 4. The structures of (I) and (II) consist of slightly distorted [ClO4]- tetrahedra anions and 1-(2-amonioethyl)piperazine-1,4-dium trication (I) or 5,6-dimethyl-benzylimidazolium cations (II) and additionally a lattice water in (I). The crystal structures of (I) and (II) exhibit complex three-dimensional networks of H-bonds connecting all their components. In the atomic arrangement of (I), the ClO4- anions form corrugated chains, while in (II) the atomic arrangement exhibits wide pseudo-hexagonal channels of ClO4 tetrahedra including the organic entities. The lattice water serves as a link between pairs of cations and pairs of anions via several Osbnd H⋯O and N-H⋯O interactions in compound (I). The vibrational absorption bands were identified by infrared spectroscopy. These compounds were also investigated by solid-state 13C, 35Cl and 15N NMR spectroscopy. DFT calculations allowed the attribution of the IR and NMR bands. Intermolecular interactions were investigated by Hirshfeld surfaces. Electronic properties such as HOMO and LUMO energies were derived.

Comparison of mibefradil and derivative NNC 55-0396 effects on behavior, cytochrome P450 activity, and tremor in mouse models of essential tremor

PubMed Central

Quesada, Arnulfo; Bui, Peter H.; Homanics, Gregg E.; Hankinson, Oliver; Handforth, Adrian

2014-01-01

NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2, 3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride], is a mibefradil derivative that retains potent in vitro T-type calcium channel antagonist efficacy. We compared the two compounds for behavioral toxicity, effects on cytochrome P450 activity, and efficacy against tremor in the γ-aminobutyric acid type A (GABAA) receptor subunit α1-null mouse, and the harmaline tremor model of essential tremor in wild-type mice. NNC 55-0396 was better tolerated than mibefradil in the horizontal wire test of sedation/motor function, with 3/6 failing at 300 and 30 mg/kg respectively. To assess for a potential interaction with harmaline, mice were given the drugs, followed by harmaline or vehicle, and tested 30 min later in the inverted wire grid test. Mibefradil exacerbated, whereas NNC 55-0396 ameliorated harmaline-induced test deficits. In mouse liver microsomes, NNC 55-0396 was a less potent inhibitor of harmaline O-demethylation than mibefradil (Ki: 0.95 and 0.29 µM respectively), and also less potent at inhibiting testosterone 6-β-hydroxylation (Ki: 0.71 and 0.12 µM respectively). In the GABAA α1-null model, NNC 55-0396 but not mibefradil, (each at 20 mg/kg), suppressed tremor while NNC 55-0396 at 12.5 mg/kg suppressed harmaline-induced tremor by half by 20–100 min, whereas mibefradil at the same dose did not significantly affect tremor. In contrast to mibefradil, NNC 55-0396 is well tolerated and suppresses tremor, and exerts less cytochrome P450 inhibition. These results suggest potential clinical utility for NNC 55-0396 or similar derivatives as a T-type calcium antagonist. PMID:21256842

Benzimidazole resistance in Nematodirus spathiger and N. filicollis in New Zealand.

PubMed

Oliver, Amb; Pomroy, W E; Leathwick, D M

2016-07-01

To determine the prevalence of benzimidazole resistance in Nematodirus spathiger and N. filicollis from a sample of New Zealand farms. The efficacy of albendazole (ABZ) against Nematodirus spp. was assessed by faecal nematode egg count reduction (FECR) tests undertaken in lambs aged 3-8 months old on 27 sheep farms throughout New Zealand. On each farm, groups of 10-16 lambs were either treated with ABZ (4.75 mg/kg) or remained as untreated controls. Faecal samples were collected from all animals at the time of treatment and 7-10 days later. Faecal nematode egg counts (FEC) were performed using a modified McMaster technique. Larvae were cultured from pooled faecal samples, collected 7-10 days after treatment from each group, by incubation at 20°C for 6 weeks, 4°C for 26 weeks then 13°C for 2 weeks. The resulting third stage larvae were identified to species using a multiplex PCR assay, that identified species-specific sequences in the second internal transcribed spacer region of ribosomal DNA. The efficacy of ABZ for N. spathiger and N. filicollis was calculated from the proportion of the two species in culture and the group mean FEC before and after treatment. Only farms with a mean of 10 epg for each species in untreated samples were included for analysis. Resistance was defined as an efficacy <95%. On farms that met the threshold of 10 epg in faecal samples, benzimidazole resistance was found on 20/21 (95%) farms for N. spathiger compared with 4/10 (40%) farms for N. filicollis (p<0.05). In samples collected following treatment, a mean of 83 (min 46, max 100)% of Nematodirus spp. larvae recovered from the untreated groups were N. spathiger, compared with 94 (min 45, max 100)% in the ABZ treated groups (p=0.03). This change in percentage was not influenced by the overall efficacy of treatment based on the FECR test (p=0.324). The results confirm the high level of resistance in N. spathiger in New Zealand and that benzimidazole resistance was more common in N. spathiger than N. filicollis. While resistance to benzimidazole anthelmintics has been reported previously in New Zealand, this is the first report of N. filicollis being resistant to benzimidazole anthelmintics.

New Organocatalyst Scaffolds with High Activity in Promoting Hydrazone and Oxime Formation at Neutral pH

PubMed Central

2015-01-01

The discovery of two new classes of catalysts for hydrazone and oxime formation in water at neutral pH, namely 2-aminophenols and 2-(aminomethyl)benzimidazoles, is reported. Kinetics studies in aqueous solutions at pH 7.4 revealed rate enhancements up to 7-fold greater than with classic aniline catalysis. 2-(Aminomethyl)benzimidazoles were found to be effective catalysts with otherwise challenging aryl ketone substrates. PMID:25545888

Targeting G-quadruplex DNA structures in the telomere and oncogene promoter regions by benzimidazole‒carbazole ligands.

PubMed

Kaulage, Mangesh H; Maji, Basudeb; Pasadi, Sanjeev; Ali, Asfa; Bhattacharya, Santanu; Muniyappa, K

2018-03-25

Recent studies support the idea that G-quadruplex structures in the promoter regions of oncogenes and telomere DNA can serve as potential therapeutic targets in the treatment of cancer. Accordingly, several different types of organic small molecules that stabilize G-quadruplex structures and inhibit telomerase activity have been discerned. Here, we describe the binding of benzimidazole-carbazole ligands to G-quadruplex structures formed in G-rich DNA sequences containing the promoter regions of human c-MYC, c-KIT1, c-KIT2, VEGF and BCL2 proto-oncogenes. The fluorescence spectroscopic data indicate that benzimidazole-carbazole ligands bind and stabilize the G-quadruplexes in the promoter region of oncogenes. The molecular docking studies provide insights into the mode and extent of binding of this class of ligands to the G-quadruplexes formed in oncogene promoters. The high stability of these G-quadruplex structures was validated by thermal denaturation and telomerase-catalyzed extension of the 3' end. Notably, benzimidazole-carbazole ligands suppress the expression of oncogenes in cancer cells in a dose-dependent manner. We anticipate that benzimidazole-carbazole ligands, by virtue of their ability to stabilize G-quadruplex structures in the promoter regions of oncogenes, might reduce the risk of cancer through the loss of function in the proteins encoded by these genes. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Laser assisted anticancer activity of benzimidazole based metal organic nanoparticles.

PubMed

Praveen, P A; Ramesh Babu, R; Balaji, P; Murugadas, A; Akbarsha, M A

2018-03-01

Recent studies showed that the photothermal therapy can be effectively used for the targeted cancerous cells destruction. Hence, in the present study, benzimidazole based metal organic complex nanoparticles, dichloro cobalt(II) bis-benzimidazole (Co-BMZ) and dichloro copper(II) bis-benzimidazole (Cu-BMZ), were synthesized by reprecipitation method and their anti-cancer activity by means of photothermal effect has been studied. Transmission electron microscopy analysis shows that the particle size of Cu-BMZ is ∼100 nm and Co-BMZ is in the range between 100 and 400 nm. Zeta potential analysis ensures the stability of the synthesized nanoparticles. It is found that the nonlinear absorption of the nanoparticles increases with increase in laser power intensity. Phototoxicity of human lung cancer (A549) and the normal mouse embryonic fibroblast (NIH-3T3) cells was studied using a 650 nm laser. Even though both the cell lines were affected by laser irradiation, A549 cells show higher cell destruction and lower IC 50 values than the normal cells. Docking studies were used to analyse the interaction site and the results showed that the Cu-BMZ molecules have higher dock score than the Co-BMZ molecules. The obtained results indicate that Cu-BMZ samples have lesser particle size, higher nonlinear absorption and higher interaction energy than the Co-BMZ samples. Copyright © 2018 Elsevier B.V. All rights reserved.

Analytical method for fast screening and confirmation of multi-class veterinary drug residues in fish and shrimp by LC-MS/MS.

PubMed

Kim, Junghyun; Suh, Joon Hyuk; Cho, Hyun-Deok; Kang, Wonjae; Choi, Yong Seok; Han, Sang Beom

2016-01-01

A multi-class, multi-residue analytical method based on LC-MS/MS detection was developed for the screening and confirmation of 28 veterinary drug and metabolite residues in flatfish, shrimp and eel. The chosen veterinary drugs are prohibited or unauthorised compounds in Korea, which were categorised into various chemical classes including nitroimidazoles, benzimidazoles, sulfones, quinolones, macrolides, phenothiazines, pyrethroids and others. To achieve fast and simultaneous extraction of various analytes, a simple and generic liquid extraction procedure using EDTA-ammonium acetate buffer and acetonitrile, without further clean-up steps, was applied to sample preparation. The final extracts were analysed by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The method was validated for each compound in each matrix at three different concentrations (5, 10 and 20 ng g(-1)) in accordance with Codex guidelines (CAC/GL 71-2009). For most compounds, the recoveries were in the range of 60-110%, and precision, expressed as the relative standard deviation (RSD), was in the range of 5-15%. The detection capabilities (CCβs) were below or equal to 5 ng g(-1), which indicates that the developed method is sufficient to detect illegal fishery products containing the target compounds above the residue limit (10 ng g(-1)) of the new regulatory system (Positive List System - PLS).

Photoactive layer based on T-shaped benzimidazole dyes used for solar cell: from photoelectric properties to molecular design

NASA Astrophysics Data System (ADS)

Xu, Beibei; Li, Yuanzuo; Song, Peng; Ma, Fengcai; Sun, Mengtao

2017-03-01

Three benzimidazole-based organic dyes, possessing the same triphenylamine donors and cyanoacrylic acid acceptors with the bithiophene π-bridges combined in different nuclear positions of benzimidazole, were investigated in the utility of dye-sensitizer solar cells. The structure, molecular orbital and energy, absorption spectra and some important parameters (such as light harvesting efficiency (LHE), electron injection driving force, the electron injection time, chemical reactivity parameters, vertical dipole moment as well as interaction models of dye-I2) were obtained according to Newns-Anderson model and DFT calculation. The process and strength of charge transfer and separation were visualized with charge different density and index of spatial extent (S, D and Δq). Current work paid attention to the new T-shaped dyes to reveal the relation between the structure and photoelectric performance. Furthermore, nine dyes (substitution of alkyl chains and π-bridges) have been designed and characterized to screen promising sensitizer candidates with excellent photo-electronic properties.

Chemical and biological evaluation of moxifloxacin-benzimidazole mixed ligands complexes: Anti-cancer and anti-oxidant activities

NASA Astrophysics Data System (ADS)

Refaat, Heba M.; Noor El-Din, Doaa A.

2018-07-01

Novel complexes of the formula [M(MOX)(Ben)Cl(H2O)m].nH2O and [Ag(MOX)(Ben)] 3.5H2O; M = Co, Ni, and Zn, n = 1.5, 2 and 1, m = 0 or 2, MOX; Moxifloxacin and Ben; benzimidazole, were synthesized. Their effect on different cancer cells together with bacterial and fungal activity was determined. Formulation of the complexes was based on elemental analyses, different spectrophotometric methods (FT-IR, UV/Vis, NMR), and magnetic studies. FT-IR data indicated that the bonding of the Co(II), Ni(II) and Zn(II) ions with MOX to be achieved through the quinolone and carboxylate oxygen atoms. On the other hand Ag(I) bonded to the MOX through hydro-pyrrolopyridine nitrogen atom. TGA and DTA studies for the metal complexes showed them to possess considerable stability. Thermodynamic parameters ΔE*, ΔS* and ΔH* were evaluated and the appearance of fractional orders suggested that the reactions proceed via complicated mechanisms. The novel mixed ligands complexes were evaluated for their biological activity against the bacterial species (S. aureus) and (E. coli) and the fungal species Aspergillus flavus and Candida albicans. The complexes were found to possess better antibacterial and antifungal activities compared to the Moxifloxacin ligand. The compounds' effects were also screened for their anti-oxidant activity by DPPH method and were tested for their cytotoxicity activity against Breast cancer cell lines (MCF-7), Colon carcinoma cells (HCT) and Hepatocellular carcinoma cells (HepG2) by viability assay method.

Direct inhibition of the DNA-binding activity of POU transcription factors Pit-1 and Brn-3 by selective binding of a phenyl-furan-benzimidazole dication.

PubMed

Peixoto, Paul; Liu, Yang; Depauw, Sabine; Hildebrand, Marie-Paule; Boykin, David W; Bailly, Christian; Wilson, W David; David-Cordonnier, Marie-Hélène

2008-06-01

The development of small molecules to control gene expression could be the spearhead of future-targeted therapeutic approaches in multiple pathologies. Among heterocyclic dications developed with this aim, a phenyl-furan-benzimidazole dication DB293 binds AT-rich sites as a monomer and 5'-ATGA sequence as a stacked dimer, both in the minor groove. Here, we used a protein/DNA array approach to evaluate the ability of DB293 to specifically inhibit transcription factors DNA-binding in a single-step, competitive mode. DB293 inhibits two POU-domain transcription factors Pit-1 and Brn-3 but not IRF-1, despite the presence of an ATGA and AT-rich sites within all three consensus sequences. EMSA, DNase I footprinting and surface-plasmon-resonance experiments determined the precise binding site, affinity and stoichiometry of DB293 interaction to the consensus targets. Binding of DB293 occurred as a cooperative dimer on the ATGA part of Brn-3 site but as two monomers on AT-rich sites of IRF-1 sequence. For Pit-1 site, ATGA or AT-rich mutated sequences identified the contribution of both sites for DB293 recognition. In conclusion, DB293 is a strong inhibitor of two POU-domain transcription factors through a cooperative binding to ATGA. These findings are the first to show that heterocyclic dications can inhibit major groove transcription factors and they open the door to the control of transcription factors activity by those compounds.

N-H···S Interaction Continues To Be an Enigma: Experimental and Computational Investigations of Hydrogen-Bonded Complexes of Benzimidazole with Thioethers.

PubMed

Wategaonkar, Sanjay; Bhattacherjee, Aditi

2018-05-03

The N-H···S hydrogen bond, even though classified as an unconventional hydrogen bond, is found to bear important structural implications on protein structure and folding. In this article, we report a gas-phase study of the N-H···S hydrogen bond between the model compounds of histidine (benzimidazole, denoted BIM) and methionine (dimethyl sulfide, diethyl sulfide, and tetrahydrothiophene, denoted Me 2 S, Et 2 S, and THT, respectively). A combination of laser spectroscopic methods such as laser-induced fluorescence (LIF), two-color resonant two-photon ionization (2cR2PI), and fluorescence depletion by infrared spectroscopy (FDIR) is used in conjunction with DFT and ab initio calculations to characterize the nature of this prevalent H-bonding interaction in simple bimolecular complexes. A single conformer was found to exist for the BIM-Me 2 S complex, whereas the BIM-Et 2 S and BIM-THT complexes showed the presence of three and two conformers, respectively. These conformers were characterized on the basis of IR spectroscopic results and electronic structure calculations. Quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO), and energy decomposition (NEDA) analyses were performed to investigate the nature of the N-H···S H-bond. Comparison of the results with the N-H···O type of interactions in BIM and indole revealed that the strength of the N-H···S H-bond is similar to N-H···O in these binary gas-phase complexes.

A new serotonin 5-HT6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding

NASA Astrophysics Data System (ADS)

González-Vera, Juan A.; Medina, Rocío A.; Martín-Fontecha, Mar; Gonzalez, Angel; de La Fuente, Tania; Vázquez-Villa, Henar; García-Cárceles, Javier; Botta, Joaquín; McCormick, Peter J.; Benhamú, Bellinda; Pardo, Leonardo; López-Rodríguez, María L.

2017-01-01

Serotonin 5-HT6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer’s disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT6 receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2B subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1 mg/kg, ip) in the novel object recognition task as a model of memory deficit.

Using spectral information in forensic imaging.

PubMed

Miskelly, Gordon M; Wagner, John H

2005-12-20

Improved detection of forensic evidence by combining narrow band photographic images taken at a range of wavelengths is dependent on the substance of interest having a significantly different spectrum from the underlying substrate. While some natural substances such as blood have distinctive spectral features which are readily distinguished from common colorants, this is not true for visualization agents commonly used in forensic science. We now show that it is possible to select reagents with narrow spectral features that lead to increased visibility using digital cameras and computer image enhancement programs even if their coloration is much less intense to the unaided eye than traditional reagents. The concept is illustrated by visualising latent fingermarks on paper with the zinc complex of Ruhemann's Purple, cyanoacrylate-fumed fingerprints with Eu(tta)(3)(phen), and soil prints with 2,6-bis(benzimidazol-2-yl)-4-[4'-(dimethylamino)phenyl]pyridine [BBIDMAPP]. In each case background correction is performed at one or two wavelengths bracketing the narrow absorption or emission band of these compounds. However, compounds with sharp spectral features would also lead to improved detection using more advanced algorithms such as principal component analysis.

Stepwise Construction of Polynuclear Complexes of Rhodium and Iridium Assisted by Benzimidazole-2-thiol. NMR and X-ray Diffraction Studies.

PubMed

Tejel, Cristina; Villarroya, B. Eva; Ciriano, Miguel A.; Oro, Luis A.; Lanfranchi, Maurizio; Tiripicchio, Antonio; Tiripicchio-Camellini, Marisa

1996-07-17

Reactions of [M(2)(&mgr;-Cl)(2)(cod)(2)] (cod = 1,5-cyclooctadiene, M = Rh, Ir) with benzimidazole-2-thiol (H(2)Bzimt) afford the mononuclear complexes [MCl(H(2)Bzimt)(cod)] (M = Rh (1), Ir (2)) for which a S-coordination of the ligand is proposed based on their spectroscopic data. The dinuclear complexes [M(2)(&mgr;-HBzimt)(2)(cod)(2)] (M = Rh (3), Ir (4)) are isolated from the reaction of [M(acac)(cod)] and benzimidazole-2-thiol. They contain the monodeprotonated ligand (HBzimt(-)) bridging the two metals in a &mgr;(2)-(1kappaN,2kappaS) coordination mode and in a relative cis,cis-HT arrangement. Complexes 3 and 4 react with the appropriate species [M(cod)(Me(2)CO)(2)](+) to afford the trinuclear cationic aggregates [M(3)(&mgr;-HBzimt)(2)(cod)(3)](+) (M = Rh (5), Ir (6)) and with the [M'(2)(&mgr;-OMe)(2)(cod)(2)] compounds to give the homo- and heterotetranuclear complexes [MM'(&mgr;-Bzimt)(cod)(2)](2) (M = M' = Rh (7), Ir (8); M = Ir, M' = Rh (9)) containing the dideprotonated ligand (Bzimt(2)(-)). The trinuclear neutral complexes [M(3)(&mgr;-Bzimt)(&mgr;-HBzimt)(cod)(3)] are intermediates detected in the synthesis of the tetranuclear complexes. Protonation of 9 with HBF(4) gives the unsymmetrical complex [Ir(2)Rh(&mgr;-HBzimt)(2)(cod)(3)]BF(4) (10). This reaction involves the protonation of the bridging ligands followed by the removal of one "Rh(cod)" moiety to give a single isomer. The molecular structure of [Rh(2)(&mgr;-Bzimt)(cod)(2)](2) (7) has been determined by X-ray diffraction methods. Crystals are monoclinic, space group P2(1)/n, a = 20.173(5) Å, b = 42.076(8) Å, c = 10.983(3) Å, beta = 93.32(2) degrees, Z = 8, 7145 reflections, R = 0.0622, and R(w) = 0.0779. The complete assignment of the resonances of the (1)H NMR spectra of the complexes 3, 4, and 7-9 was carried out by selective decoupling, NOE, and H,H-COSY experiments. The differences in the chemical shifts of the olefinic protons are discussed on the basis of steric and magnetic anisotropy effects.

Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum.

PubMed

Mohapatra, Subash Chandra; Tiwari, Hemandra Kumar; Singla, Manisha; Rathi, Brijesh; Sharma, Arun; Mahiya, Kuldeep; Kumar, Mukesh; Sinha, Saket; Chauhan, Shyam Singh

2010-03-01

A new class of copper(II) nanohybrid solids, LCu(CH(3)COO)(2) and LCuCl(2), have been synthesized and characterized by transmission electron microscopy, dynamic light scattering, and IR spectroscopy, and have been found to be capped by a bis(benzimidazole) diamide ligand (L). The particle sizes of these nanohybrid solids were found to be in the ranges 5-10 and 60-70 nm, respectively. These nanohybrid solids were evaluated for their in vitro antimalarial activity against a chloroquine-sensitive isolate of Plasmodium falciparum (MRC 2). The interactions between these nanohybrid solids and plasmepsin II (an aspartic protease and a plausible novel target for antimalarial drug development), which is believed to be essential for hemoglobin degradation by the parasite, have been assayed by UV-vis spectroscopy and inhibition kinetics using Lineweaver-Burk plots. Our results suggest that these two compounds have antimalarial activities, and the IC(50) values (0.025-0.032 microg/ml) are similar to the IC(50) value of the standard drug chloroquine used in the bioassay. Lineweaver-Burk plots for inhibition of plasmepsin II by LCu(CH(3)COO)(2) and LCuCl(2) show that the inhibition is competitive with respect to the substrate. The inhibition constants of LCu(CH(3)COO)(2) and LCuCl(2) were found to be 10 and 13 microM, respectively. The IC(50) values for inhibition of plasmepsin II by LCu(CH(3)COO)(2) and LCuCl(2) were found to be 14 and 17 microM, respectively. Copper(II) metal capped by a benzimidazole group, which resembles the histidine group of copper proteins (galactose oxidase, beta-hydroxylase), could provide a suitable anchoring site on the nanosurface and thus could be useful for inhibition of target enzymes via binding to the S1/S3 pocket of the enzyme hydrophobically. Both copper(II) nanohybrid solids were found to be nontoxic against human hepatocellular carcinoma cells and were highly selective for plasmepsin II versus human cathepsin D. The pivotal mechanism of antimalarial activity of these compounds via plasmepsin II inhibition in the P. falciparum malaria parasite is demonstrated.

Gold nanoparticles supported on titanium dioxide: an efficient catalyst for highly selective synthesis of benzoxazoles and benzimidazoles.

PubMed

Tang, Lin; Guo, Xuefeng; Yang, Yu; Zha, Zhenggen; Wang, Zhiyong

2014-06-11

A highly efficient and selective reaction for the synthesis of 2-substituted benzoxazoles and benzimidazoles catalyzed by Au/TiO2 has been developed via two hydrogen-transfer processes. This reaction has a good tolerance to air and water, a wide substrate scope, and represents a new avenue for practical C-N and C-O bond formation. More importantly, no additional additives, oxidants and reductants are required for the reaction and the catalyst can be recovered and reused readily.

Solvent/oxidant-switchable synthesis of multisubstituted quinazolines and benzimidazoles via metal-free selective oxidative annulation of arylamidines.

PubMed

Lin, Jian-Ping; Zhang, Feng-Hua; Long, Ya-Qiu

2014-06-06

A fast and simple divergent synthesis of multisubstituted quinazolines and benzimidazoles was developed from readily available amidines, via iodine(III)-promoted oxidative C(sp(3))-C(sp(2)) and C(sp(2))-N bond formation in nonpolar and polar solvents, respectively. Further selective synthesis of quinazolines in polar solvent was realized by TEMPO-catalyzed sp(3)C-H/sp(2)C-H direct coupling of the amidine with K2S2O8 as the oxidant. No metal, base, or other additives were needed.

A Bioinspired Catalytic Aerobic Oxidative C–H Functionalization of Primary Aliphatic Amines: Synthesis of 1,2-Disubstituted Benzimidazoles

PubMed Central

Nguyen, Khac Minh Huy; Largeron, Martine

2015-01-01

Aerobic oxidative C–H functionalization of primary aliphatic amines has been accomplished with a biomimetic cooperative catalytic system to furnish 1,2-disubstituted benzimidazoles that play an important role as drug discovery targets. This one-pot atom-economical multistep process, which proceeds under mild conditions, with ambient air and equimolar amounts of each coupling partner, constitutes a convenient environmentally friendly strategy to functionalize non-activated aliphatic amines that remain challenging substrates for non-enzymatic catalytic aerobic systems. PMID:26206475

Tris(5,6-dimethyl-1H-benzimidazole-κN(3))(pyridine-2,6-dicarboxyl-ato-κ(3)O(2),N,O(6))nickel(II).

PubMed

Li, Yue-Hua; Li, Feng-Feng; Liu, Xin-Hua; Zhao, Ling-Yan

2012-06-01

The title mononuclear complex, [Ni(C(7)H(3)NO(4))(C(9)H(10)N(2))(3)], shows a central Ni(II) atom which is coordinated by two carboxyl-ate O atoms and the N atom from a pyridine-2,6-dicarboxyl-ate ligand and by three N atoms from different 5,6-dimethyl-1H--benzimidazole ligands in a distorted octa-hedral geometry. The crystal structure shows intermolecular N-H⋯O hydrogen bonds.

[Qualitative and quantitative determination of amino-2 benzimidazole in aqueous medium by polarography (author's transl)].

PubMed

Roche, Y; Cantin, D; Vigier, J; Boucherle, A

1978-03-01

Amino-2 Benzimidazole, a residue of the decomposition of some fungicides (Benomyl, Carbendazine, Thiophanate, Methylthiophanate), is measured by polarography in aqueous medium, with a platinium rotating electrode, for the exploration in potentials from +0.5 v to 1.4 v. The best conditions for the quantitative determination are investigated, the study according to pH is performed and the standard curve is given for concentrations from 10(-5) to 10(-3) M/l. The interaction of elementts found in tap water and in aquarium water is also investigated.

Reactivity of tris(acetylacetonato) iron(III) with tridentate [ONO] donor Schiff base as an access to newer mixed-ligand iron(III) complexes.

PubMed

Bhattacharjee, Chira R; Goswami, Pankaj; Pramanik, Harun A R; Paul, Pradip C; Mondal, Paritosh

2011-05-01

Two new mixed-ligand iron(III) complexes, [Fe(L(n))(acac)(C(2)H(5)OH)] incorporating coordinated ethanol from the reaction solvent were accessed from the reaction of [Fe(acac)(3)] with [ONO] donor dibasic tridentate unsymmetrical Schiff base ligands derived from condensation of 2-hydroxy-1-napthaldehyde with 2-aminophenol (H(2)L(1)) or 2-aminobenzoic acid (H(2)L(2)). The thermal study (TGA-DTA) provided evidence for weakly bound ethanol which is readily substituted by neutral N-donor molecule imidazole, benzimidazole or pyridine to produce an array of newer complexes, [Fe(L(n))(acac)X] (n=1, 2; X=Im, Bim, Py). The compounds were characterized by elemental analyses, FT-IR, UV-vis, solution electrical conductivity, FAB mass, (1)H and (13)C NMR spectroscopy. Room temperature magnetic susceptibility measurements (μ(eff)∼5.8 B.M.) are consistent with spin-free octahedral iron(III) complexes. Cyclic voltammetry of ethanol complexes revealed a quasi-reversible one electron redox response (ΔE(p)>100 mV) for the Fe(III)/Fe(II) couple. Low half wave redox potential (E(1/2)) values suggested easy redox susceptibility. The ground state geometries of the ethanol and imidazole complexes have been ascertained to be distorted octahedral by density functional theory using DMol3 program at BLYP/DNP level. Copyright © 2011 Elsevier B.V. All rights reserved.

A concise synthesis of a highly substituted 6-(1H-benzimidazol-1-yl)-5-nitrosopyrimidin-2-amine: synthetic sequence and the molecular and supramolecular structures of one product and two intermediates.

PubMed

Cobo, Justo; Vicentes, Daniel E; Rodríguez, Ricaurte; Marchal, Antonio; Glidewell, Christopher

2018-06-01

A concise and efficient synthesis of 6-benzimidazolyl-5-nitrosopyrimidines has been developed using Schiff base-type intermediates derived from N 4 -(2-aminophenyl)-6-methoxy-5-nitrosopyrimidine-2,4-diamine. 6-Methoxy-N 4 -{2-[(4-methylbenzylidene)amino]phenyl}-5-nitrosopyrimidine-2,4-diamine, (I), and N 4 -{2-[(ethoxymethylidene)amino]phenyl}-6-methoxy-5-nitrosopyrimidine-2,4-diamine, (III), both crystallize from dimethyl sulfoxide solution as the 1:1 solvates C 19 H 18 N 6 O 2 ·C 2 H 6 OS, (Ia), and C 14 H 16 N 6 O 3 ·C 2 H 6 OS, (IIIa), respectively. The interatomic distances in these intermediates indicate significant electronic polarization within the substituted pyrimidine system. In each of (Ia) and (IIIa), intermolecular N-H...O hydrogen bonds generate centrosymmetric four-molecule aggregates. Oxidative ring closure of intermediate (I), effected using ammonium hexanitratocerate(IV), produced 4-methoxy-6-[2-(4-methylphenyl-1H-benzimidazol-1-yl]-5-nitrosopyrimidin-2-amine, C 19 H 16 N 6 O 2 , (II) [Cobo et al. (2018). Private communication (CCDC 1830889). CCDC, Cambridge, England], where the extent of electronic polarization is much less than in (Ia) and (IIIa). A combination of N-H...N and C-H...O hydrogen bonds links the molecules of (II) into complex sheets.

Design, Synthesis, and Biological Evaluation of Benzimidazole-Derived Biocompatible Copper(II) and Zinc(II) Complexes as Anticancer Chemotherapeutics

PubMed Central

AlAjmi, Mohamed F.; Hussain, Afzal; Khan, Azmat Ali; Shaikh, Perwez Alam; Khan, Rais Ahmad

2018-01-01

Herein, we have synthesized and characterized a new benzimidazole-derived “BnI” ligand and its copper(II) complex, [Cu(BnI)2], 1, and zinc(II) complex, [Zn(BnI)2], 2, using elemental analysis and various spectroscopic techniques. Interaction of complexes 1 and 2 with the biomolecules viz. HSA (human serum albumin) and DNA were studied using absorption titration, fluorescence techniques, and in silico molecular docking studies. The results exhibited the significant binding propensity of both complexes 1 and 2, but complex 1 showed more avid binding to HSA and DNA. Also, the nuclease activity of 1 and 2 was analyzed for pBR322 DNA, and the results obtained confirmed the potential of the complexes to cleave DNA. Moreover, the mechanistic pathway was studied in the presence of various radical scavengers, which revealed that ROS (reactive oxygen species) are responsible for the nuclease activity in complex 1, whereas in complex 2, the possibility of hydrolytic cleavage also exists. Furthermore, the cytotoxicity of the ligand and complexes 1 and 2 were studied on a panel of five different human cancer cells, namely: HepG2, SK-MEL-1, HT018, HeLa, and MDA-MB 231, and compared with the standard drug, cisplatin. The results are quite promising against MDA-MB 231 (breast cancer cell line of 1), with an IC50 value that is nearly the same as the standard drug. Apoptosis was induced by complex 1 on MDA-MB 231 cells predominantly as studied by flow cytometry (FACS). The adhesion and migration of cancer cells were also examined upon treatment of complexes 1 and 2. Furthermore, the in vivo chronic toxicity profile of complexes 1 and 2 was also studied on all of the major organs of the mice, and found them to be less toxic. Thus, the results warrant further investigations of complex 1. PMID:29772746

Design, Synthesis, and Biological Evaluation of Benzimidazole-Derived Biocompatible Copper(II) and Zinc(II) Complexes as Anticancer Chemotherapeutics.

PubMed

AlAjmi, Mohamed F; Hussain, Afzal; Rehman, Md Tabish; Khan, Azmat Ali; Shaikh, Perwez Alam; Khan, Rais Ahmad

2018-05-16

Herein, we have synthesized and characterized a new benzimidazole-derived "BnI" ligand and its copper(II) complex, [Cu(BnI)₂], 1 , and zinc(II) complex, [Zn(BnI)₂], 2 , using elemental analysis and various spectroscopic techniques. Interaction of complexes 1 and 2 with the biomolecules viz. HSA (human serum albumin) and DNA were studied using absorption titration, fluorescence techniques, and in silico molecular docking studies. The results exhibited the significant binding propensity of both complexes 1 and 2 , but complex 1 showed more avid binding to HSA and DNA. Also, the nuclease activity of 1 and 2 was analyzed for pBR322 DNA, and the results obtained confirmed the potential of the complexes to cleave DNA. Moreover, the mechanistic pathway was studied in the presence of various radical scavengers, which revealed that ROS (reactive oxygen species) are responsible for the nuclease activity in complex 1 , whereas in complex 2 , the possibility of hydrolytic cleavage also exists. Furthermore, the cytotoxicity of the ligand and complexes 1 and 2 were studied on a panel of five different human cancer cells, namely: HepG2, SK-MEL-1, HT018, HeLa, and MDA-MB 231, and compared with the standard drug, cisplatin. The results are quite promising against MDA-MB 231 (breast cancer cell line of 1 ), with an IC 50 value that is nearly the same as the standard drug. Apoptosis was induced by complex 1 on MDA-MB 231 cells predominantly as studied by flow cytometry (FACS). The adhesion and migration of cancer cells were also examined upon treatment of complexes 1 and 2 . Furthermore, the in vivo chronic toxicity profile of complexes 1 and 2 was also studied on all of the major organs of the mice, and found them to be less toxic. Thus, the results warrant further investigations of complex 1 .

Aromatic carboxylate effect on dimensionality of three bis(benzimidazole)-based cobalt(II) coordination polymers: Syntheses, structures and properties

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

Zhang, Ju-Wen; Gong, Chun-Hua; Hou, Li-Li

2013-09-15

Three new metal-organic coordination polymers [Co(4-bbc){sub 2}(bbbm)] (1), [Co(3,5-pdc)(bbbm)]·2H{sub 2}O (2) and [Co(1,4-ndc)(bbbm)] (3) (4-Hbbc=4-bromobenzoic acid, 3,5-H{sub 2}pdc=3,5-pyridinedicarboxylic acid, 1,4-H{sub 2}ndc=1,4-naphthalenedicarboxylic acid and bbbm=1,1-(1,4-butanediyl)bis-1H-benzimidazole) were hydrothermally synthesized and structurally characterized. Polymer 1 is a 1D chain formed by the bbbm ligands and Co{sup II} ions. Polymer 2 exhibits a 2D network with a (3·4·5)(3{sup 2}·4·5·6{sup 2}·7{sup 4}) topology. Polymer 3 possesses a 3D three-fold interpenetrating framework. The versatile structures of title polymers indicate that the aromatic carboxylates have an important influence on the dimensionality of 1–3. Moreover, the thermal stability, electrochemical and luminescent properties of 1–3 were investigated. - graphicalmore » abstract: Three bis(benzimidazole)-based cobalt(II) coordination polymers tuned by aromatic carboxylates were hydrothermally synthesized and structurally characterized. The aromatic carboxylates play a key role in the dimensionality of three polymers. The electrochemical and luminescent properties of three polymers were investigated. Display Omitted - Highlights: • Three bis(benzimidazole)-based cobalt(II) coordination polymers tuned by aromatic carboxylates were obtained. • The aromatic carboxylates have an important influence on the dimensionality of three polymers. • The electrochemical and luminescent properties of three polymers were investigated.« less

AN INDIRECT METHOD TO ASSAY FOR MITOTIC CENTERS IN SAND DOLLAR (DENDRASTER EXCENTRICUS) EGGS

PubMed Central

Went, Hans A.

1966-01-01

It is possible consistently to induce sea urchin and sand dollar eggs to cleave directly from one cell into four cells. This is done by exposing the fertilized eggs to benzimidazole for 20 to 30 min beginning about early metaphase. The mitotic apparatus regresses, the cells do not cleave, and shortly after they are returned to normal sea water an early-prophase-appearing nucleus is present in each cell. Each cell then organizes a tetrapolar tetrahedral mitotic apparatus de novo, instead of transforming a bipolar mitotic apparatus into a tetrapolar figure, and cleaves one-to-four. In another type of experiment, it appears that sand dollar eggs exposed to mercaptoethanol during the first period of mitotic center duplication have only half as many centers by first cleavage metaphase as the normal controls. This is consistent with an earlier report by Mazia et al (1960). Using this same experimental technique, it was demonstrated that benzimidazole, on the contrary, does not interfere with mitotic center duplication in sand dollar eggs. A labeling experiment demonstrated that benzimidazole does not interfere markedly with the normal pattern of incorporation of C14-thymidine into the DNA of sea urchin eggs. The data reported here suggest that judicious treatment of sand dollar eggs (and probably sea urchin eggs, too) with benzimidazole can induce the eggs to cleave into as many cells as there were mitotic centers sometime earlier, for example at early metaphase of the first cleavage division. This provides a very useful tool for studies on the process of mitotic center duplication. PMID:6008198

An indirect method to assay for mitotic centers in sand dollar (Dendraster excentricus) eggs.

PubMed

Went, H A

1966-09-01

It is possible consistently to induce sea urchin and sand dollar eggs to cleave directly from one cell into four cells. This is done by exposing the fertilized eggs to benzimidazole for 20 to 30 min beginning about early metaphase. The mitotic apparatus regresses, the cells do not cleave, and shortly after they are returned to normal sea water an early-prophase-appearing nucleus is present in each cell. Each cell then organizes a tetrapolar tetrahedral mitotic apparatus de novo, instead of transforming a bipolar mitotic apparatus into a tetrapolar figure, and cleaves one-to-four. In another type of experiment, it appears that sand dollar eggs exposed to mercaptoethanol during the first period of mitotic center duplication have only half as many centers by first cleavage metaphase as the normal controls. This is consistent with an earlier report by Mazia et al (1960). Using this same experimental technique, it was demonstrated that benzimidazole, on the contrary, does not interfere with mitotic center duplication in sand dollar eggs. A labeling experiment demonstrated that benzimidazole does not interfere markedly with the normal pattern of incorporation of C(14)-thymidine into the DNA of sea urchin eggs. The data reported here suggest that judicious treatment of sand dollar eggs (and probably sea urchin eggs, too) with benzimidazole can induce the eggs to cleave into as many cells as there were mitotic centers sometime earlier, for example at early metaphase of the first cleavage division. This provides a very useful tool for studies on the process of mitotic center duplication.

Degradation and mineralization of organic UV absorber compound 2-phenylbenzimidazole-5-sulfonic acid (PBSA) using UV-254nm/H2O2.

PubMed

Abdelraheem, Wael H M; He, Xuexiang; Duan, Xiaodi; Dionysiou, Dionysios D

2015-01-23

Various studies have revealed the non-biodegradable and endocrine disrupting properties of sulfonated organic UV absorbers, directing people's attention toward their risks on ecological and human health and hence their removal from water. In this study, UV-254nm/H2O2 advanced oxidation process (AOP) was investigated for degrading a model UV absorber compound 2-phenylbenzimidazole-5-sulfonic acid (PBSA) and a structurally similar compound 1H-benzimidazole-2-sulfonic acid (BSA), with a specific focus on their mineralization. At 4.0mM [H2O2]0, a complete removal of 40.0μM parent PBSA and 25% decrease in TOC were achieved with 190min of UV irradiation; SO4(2-) was formed and reached its maximum level while the release of nitrogen as NH4(+) was much lower (around 50%) at 190min. Sulfate removal was strongly enhanced by increasing [H2O2]0 in the range of 0-4.0mM, with slight inhibition in 4.0-12.0mM. Faster and earlier ammonia formation was observed at higher [H2O2]0. The presence of Br(-) slowed down the degradation and mineralization of both compounds while a negligible effect on the degradation was observed in the presence of Cl(-). Our study provides important technical and fundamental results on the HO based degradation and mineralization of SO3H and N-containing UV absorber compounds. Copyright © 2014 Elsevier B.V. All rights reserved.

The mechanism of transition-metal (Cu or Pd)-catalyzed synthesis of benzimidazoles from amidines: theoretical investigation.

PubMed

Li, Juan; Gu, Honghong; Wu, Caihong; Du, Lijuan

2014-11-28

In this study, the Cu(OAc)2- and [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines were theoretically investigated using density functional theory calculations. For the Cu-catalyzed system, our calculations supported a four-step-pathway involving C-H activation of an arene with Cu(II) via concerted metalation-deprotonation (CMD), followed by oxidation of the Cu(II) intermediate and deprotonation of the imino group by Cu(III), and finally reductive elimination from Cu(III). In our calculations, the barriers for the CMD step and the oxidation step are the same. The results are different from the ones reported by Fu et al. in which the whole reaction mechanism includes three steps and the CMD step is rate determining. On the basis of the calculation results for the [PdCl2(PhCN)2]-catalyzed system, C-H bond breaking by CMD occurs first, followed by the rate-determining C-N bond formation and N-H deprotonation. Pd(III) species is not involved in the [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines.

Development of a two-step high-resolution melting (HRM) analysis for screening sequence variants associated with resistance to the QoIs, benzimidazoles and dicarboximides in airborne inoculum of Botrytis cinerea.

PubMed

Chatzidimopoulos, Michael; Ganopoulos, Ioannis; Vellios, Evangelos; Madesis, Panagiotis; Tsaftaris, Athanasios; Pappas, Athanassios C

2014-11-01

A rapid, high-resolution melting (HRM) analysis protocol was developed to detect sequence variations associated with resistance to the QoIs, benzimidazoles and dicarboximides in Botrytis cinerea airborne inoculum. HRM analysis was applied directly in fungal DNA collected from air samplers with selective medium. Three and five different genotypes were detected and classified according to their melting profiles in BenA and bos1 genes associated with resistance to benzimidazoles and dicarboximides, respectively. The sensitivity of the methodology was evident in the case of the QoIs, where genotypes varying either by a single nucleotide polymorphism or an additional 1205-bp intron were separated accurately with a single pair of primers. The developed two-step protocol was completed in 82 min and showed reduced variation in the melting curves' formation. HRM analysis rapidly detected the major mutations found in greenhouse strains providing accurate data for successfully controlling grey mould. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Optoelectronic performance comparison of new thiophene linked benzimidazole conjugates with diverse substitution patterns

NASA Astrophysics Data System (ADS)

Saltan, Gözde Murat; Dinçalp, Haluk; Kırmacı, Eser; Kıran, Merve; Zafer, Ceylan

2018-01-01

In an approach to develop efficient organic optoelectronic devices to be used in light-driven systems, a series of three thiophene linked benzimidazole conjugates were synthesized and characterized. The combination of two thiophene rings to a benzimidazole core decorated with different functional groups (such as sbnd OCH3, sbnd N(CH3)2, sbnd CF3) resulted in donor-acceptor type molecular scaffold. The effect of the electronic behavior of the substituents on the optical, electrochemical, morphological and electron/hole transporting properties of the dyes were systematically investigated. DTBI2 dye exhibited distinct absorption properties among the other studied dyes because N,N-dimethylamino group initiated intramolecular charge transfer (ICT) process in the studied solvents. In solid state, the dyes exhibit peaks extending up to 600 nm. Depending on the solvent polarities, dyes show significant wavelength changes on their fluorescence emission spectra in the excited states. Morphological parameters of the thin films spin-coated from CHCl3 solution were investigated by using AFM instrument; furthermore photovoltaic responses are reported, even though photovoltaic performances of the fabricated solar cells with different configurations are quite low.

Identification and Characterization of Benzimidazole Resistance in Monilinia fructicola from Stone Fruit Orchards in California

PubMed Central

Ma, Zhonghua; Yoshimura, Michael A.; Michailides, Themis J.

2003-01-01

Low and high levels of resistance to the benzimidazole fungicides benomyl and thiophanate-methyl were observed in field isolates of Monilinia fructicola, which is the causative agent of brown rot of stone fruit. Isolates that had low levels of resistance (hereafter referred to as LR isolates) and high levels of resistance (hereafter referred to as HR isolates) were also cold and heat sensitive, respectively. Results from microsatellite DNA fingerprints showed that genetic identities among the populations of sensitive (S), LR, and HR isolates were very high (>0.96). Analysis of DNA sequences of the β-tubulin gene showed that the LR isolates had a point mutation at codon 6, causing a replacement of the amino acid histidine by tyrosine. Codon 198, which encodes a glutamic acid in S and LR isolates, was converted to a codon for alanine in HR isolates. Based on these point mutations in the β-tubulin gene, allele-specific PCR assays were developed for rapid detection of benzimidazole-resistant isolates of M. fructicola from stone fruit. PMID:14660360

Co(II), Ni(II) and Cu(II) complexes of methyl-5-(Phenylthio) benzimidazole-2-carbamate: Molecular structures, spectral and DFT calculations

NASA Astrophysics Data System (ADS)

Mansour, Ahmed M.; El Bakry, Eslam M.; Abdel-Ghani, Nour T.

2016-05-01

[Co(FBZ)2(H2O)]·2NO3·0.5H2O (1), [Ni(FBZ)2X2]·zH2O (X = Cl​-, z = 0.5 (2) and X = CH3COO-, z = 1 (3)) and [Cu(FBZ)2(H2O) (NO3)]·NO3·1.5H2O (4) (FBZ = methyl-5-(Phenylthio) benzimidazole-2-carbamate; Fenbendazole) complexes were synthesized and characterized by elemental analysis, thermal, IR, EPR, UV-Vis, magnetic and conductance measurements. Geometry optimization, molecular electrostatic potential maps and natural bond orbital analysis were carried out at DFT/B3LYP/6-31G∗ level of theory. FBZ behaves as a neutral bidentate ligand via the pyridine-type nitrogen of the benzimidazole moiety and the carbamate group. Three-step ionization with pKa values of 3.38, 4.06 and 10.07 were reported for FBZ. The coordination of FBZ to the metal ions led to an increase in the antibacterial activity against the tested Staphylococcus aureus and Escherichia coli bacteria.

Design, Synthesis and Qualitative Structure Activity Relationship Evaluations of Quinoline-Based Bisarylimidazoles as Antibacterial Motifs.

PubMed

Al-Qawasmeh, Raed A; Huthail, Basil B; Sinnokrot, Mutasem O; Semreen, Mohammad H; Odeh, Raed A; Abu-Zarga, Musa H; Tarazi, Hamadeh; Yousef, Imad A; Al-Tel, Taleb H

2016-01-01

The emergence of drug-resistant bacteria in clinical practice has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We previously described a set of imidazopyridine antibacterial leads that contain a core composed of benzimidazole and a central phthalic acid linker. These compounds showed potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. In this respect, we conducted a systematic exploration of new disubstituted imidazole functionalities on quinoline 4-position as the central linker, to determine the factors that direct the potent antibacterial activity. We found that some of the newly synthesized compounds possessed more potent activity compared to currently available medications. The newly synthesized compounds were screened against several clinical isolates and Staphylococcus aureus, including the methicillinresistant (MRSA) and the methicillin-sensitive (MSAA). The goal of this work is to undertake rigorous testing of new hybrid scaffolds of quinoline flanked by diaryl imidazoles and their structure-activity against a range of bacterial strains. Described herein is the account of the modification of the central linker region, the imidazole functionality, and substituents at the 4-position of the quinoline, and their effect on the antibacterial potency of the resulting derivatives. Our efforts here have been driven by previous reports on the applications of Pfitzinger cyclization protocol. This complexity-generating reaction transforms a relatively simple substrate, into a more complex products with the potential for diversification via functionalization of the resultant acid. We identified compounds that possess potent and broad-spectrum antibacterial activities against clinical isolates and drug resistant strains. Structure-Activity relationships of these compounds were further explored to determine the crucial structural features needed to enhance their antibacterial activity. In this respect, it was found that, hydrophobic and electron-withdrawing moieties, such as halogens, were required on each end of the isoquinoline-based bisaryl imidazole hybrid motifs to produce broad-spectrum activity against the tested strains. Thus, molecules containing halophenyl or pyridyl arms were found more potent than molecules containing thiophene and/or electron-releasing groups on the phenyl arms, which showed much less antibacterial activity against the tested strains. In summary, 4-(4,5-diphenyl-1H-imidazol-2-yl)-2-phenylquinoline systems can be assembled efficiently through the Pfitzinger ring expansion- condensation strategy. This approach appears to hold considerable synthetic utility. The particular value of such a synthetic route resides on the conciseness and efficiency through which imidazo-quinoline construction can be synthesized from structurally simple and accessible acetophenone precursors.

Design, fabrication and evaluation of intelligent sulfone-selective polybenzimidazole nanofibers.

PubMed

Ogunlaja, Adeniyi S; du Sautoy, Carol; Torto, Nelson; Tshentu, Zenixole R

2014-08-01

Molecularly imprinted polybenzimidazole nanofibers fabricated for the adsorption of oxidized organosulfur compounds are presented. The imprinted polymers exhibited better selectivity for their target model sulfone-containing compounds with adsorption capacities of 28.5±0.4mg g(-1), 29.8±2.2mg g(-1) and 20.1±1.4mg g(-1) observed for benzothiophene sulfone (BTO2), dibenzothiophene sulfone (DBTO2) and 4,6-dimethyldibenzothiophene sulfone (4,6-DMDBTO2) respectively. Molecular modeling based upon the density functional theory (DFT) indicated that hydrogen bond interactions may take place between sulfone oxygen groups with NH groups of the PBI. Further DFT also confirmed the feasibility of π-π interactions between the benzimidazole rings and the aromatic sulfone compounds. The adsorption mode followed the Freundlich (multi-layered) adsorption isotherm which indicated possible sulfone-sulfone interactions. A home-made pressurized hot water extraction (PHWE) system was employed for the extraction/desorption of sulfone compounds within imprinted nanofibers at 1mL min(-1), 150°C and 30 bar. PHWE used a green solvent (water) and achieved better extraction yields compared to the Soxhlet extraction process. The application of molecularly imprinted polybenzimidazole (PBI) nanofibers displayed excellent sulfur removal, with sulfur in fuel after adsorption falling below the determined limit of detection (LOD), which is 2.4mg L(-1)S, and with a sulfur adsorption capacity of 5.3±0.4mg g(-1) observed for application in the fuel matrix. Copyright © 2014 Elsevier B.V. All rights reserved.

A convergent approach to the total synthesis of telmisartan via a Suzuki cross-coupling reaction between two functionalized benzimidazoles.

PubMed

Martin, Alex D; Siamaki, Ali R; Belecki, Katherine; Gupton, B Frank

2015-02-06

A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1-methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes.

A novel sodium iodide and ammonium molybdate co-catalytic system for the efficient synthesis of 2-benzimidazoles using hydrogen peroxide under ultrasound irradiation.

PubMed

Bai, Guo-Yi; Lan, Xing-Wang; Chen, Guo-Feng; Liu, Xiao-Fang; Li, Tian-Yu; Shi, Ling-Juan

2014-03-01

The reaction of aldehydes and o-phenylenediamine for the preparation of 2-benzimidazoles has been studied using hydrogen peroxide as an oxidant under ultrasound irradiation at room temperature in this paper. The combination of substoichiometric sodium iodide and ammonium molybdate as co-catalysts, together with using small amounts of hydrogen peroxide, makes this transformation very efficient and attractive under ultrasound. Thus, a mild, green and efficient method is established to carry out this reaction in high yield. Copyright © 2013 Elsevier B.V. All rights reserved.

BF3·Et2O-promoted cleavage of the Csp-Csp2 bond of 2-propynolphenols/anilines: route to C2-alkenylated benzoxazoles and benzimidazoles.

PubMed

Song, Xian-Rong; Qiu, Yi-Feng; Song, Bo; Hao, Xin-Hua; Han, Ya-Ping; Gao, Pin; Liu, Xue-Yuan; Liang, Yong-Min

2015-02-20

A novel BF3·Et2O-promoted tandem reaction of easily prepared 2-propynolphenols/anilines and trimethylsilyl azide is developed to give C2-alkenylated benzoxazoles and benzimidazoles in moderate to good yields. Most reactions could be accomplished in 30 min at room temperature. This tandem process involves a Csp-Csp2 bond cleavage and a C-N bond formation. Moreover, both tertiary and secondary propargylic alcohols with diverse functional groups were tolerated under the mild conditions.

The Curious Case of 2-Propyl-1H-benzimidazole in the Solid State: An Experimental and Theoretical Study.

PubMed

Quesada-Moreno, María Mar; Cruz-Cabeza, Aurora J; Avilés-Moreno, Juan Ramón; Cabildo, Pilar; Claramunt, Rosa M; Alkorta, Ibon; Elguero, José; Zúñiga, Francisco J; López-González, Juan Jesús

2017-08-03

2-Propyl-1H-benzimidazole (2PrBzIm) is a small molecule, commercially available, which displays a curious behavior in the solid state. 2PrBzIm, although devoid of chirality by fast rotation about a single bond of the propyl group in solution, crystallizes as a conglomerate showing chiroptical properties. An exhaustive analysis of its crystal structure and a wide range of experiments monitored by vibrational circular dichroism spectroscopy eliminated all possibilities of an artifact. What remains is a new example of the unexplained phenomenon of persistent supramolecular chirality.

Tris(5,6-dimethyl-1H-benzimidazole-κN 3)(pyridine-2,6-dicarboxyl­ato-κ3 O 2,N,O 6)nickel(II)

PubMed Central

Li, Yue-Hua; Li, Feng-Feng; Liu, Xin-Hua; Zhao, Ling-Yan

2012-01-01

The title mononuclear complex, [Ni(C7H3NO4)(C9H10N2)3], shows a central NiII atom which is coordinated by two carboxyl­ate O atoms and the N atom from a pyridine-2,6-dicarboxyl­ate ligand and by three N atoms from different 5,6-dimethyl-1H-­benzimidazole ligands in a distorted octa­hedral geometry. The crystal structure shows intermolecular N—H⋯O hydrogen bonds. PMID:22719301

Anthelmintic resistance in equine nematodes

PubMed Central

Matthews, Jacqueline B.

2014-01-01

Anthelmintics have been applied indiscriminately to control horse nematodes for over 40 years. Three broad-spectrum anthelmintic classes are currently registered for nematode control in horses: benzimidazoles (fenbendazole, oxibendazole), tetrahydropyrimidines (pyrantel) and macrocyclic lactones (ivermectin, moxidectin). Generally, control strategies have focused on nematode egg suppression regimens that involve the frequent application of anthelmintics to all horses at intervals based on strongyle egg reappearance periods after treatment. The widespread use of such programmes has substantially reduced clinical disease, especially that associated with large strongyle species; however, high treatment frequency has led to considerable selection pressure for anthelmintic resistance, particularly in cyathostomin species. Field studies published over the last decade indicate that benzimidazole resistance is widespread globally in cyathostomins and there are also many reports of resistance to pyrantel in these worms. Cyathostomin resistance to macrocyclic lactone compounds is emerging, principally measured as a reduction in strongyle egg reappearance time observed after treatment. Ivermectin resistance is a further concern in the small intestinal nematode, Parascaris equorum, an important pathogen of foals. These issues indicate that horse nematodes must now be controlled using methods less dependent on anthelmintic use and more reliant on management practices designed to reduce the force of infection in the environment. Such strategies include improved grazing management integrated with targeted anthelmintic administration involving faecal egg count (FEC)-directed treatments. The latter require that the supporting diagnostic tests available are robust and practically applicable. Recent research has focused on maximising the value of FEC analysis in horses and on optimizing protocols for anthelmintic efficacy testing. Other studies have sought to develop diagnostics that will help define levels of pre-patent infection. This review describes recent advances in each of these areas of research. PMID:25516842

Chiral 2-Aminobenzimidazole as Bifunctional Catalyst in the Asymmetric Electrophilic Amination of Unprotected 3-Substituted Oxindoles.

PubMed

Benavent, Llorenç; Baeza, Alejandro; Freckleton, Megan

2018-06-06

The use of readily available chiral trans -cyclohexanediamine-benzimidazole derivatives as bifunctional organocatalysts in the asymmetric electrophilic amination of unprotected 3-substituted oxindoles is presented. Different organocatalysts were evaluated; the most successful one contained a dimethylamino moiety ( 5 ). With this catalyst under optimized conditions, different oxindoles containing a wide variety of substituents at the 3-position were aminated in good yields and with good to excellent enantioselectivities using di- tert -butylazodicarboxylate as the aminating agent. The procedure proved to be also efficient for the amination of 3-substituted benzofuranones, although with moderate results. A bifunctional role of the catalyst, acting as Brønsted base and hydrogen bond donor, is proposed according to the experimental results observed.

Effect of leaving group on the oligomerization of 5'-AMP on montmorillonite. [Abstract only

NASA Technical Reports Server (NTRS)

Prabahar, K. Joseph; Ferris, James P.

1994-01-01

The oligomerization of imidazole derivative of 5'-AMP (ImpA) in the presence of montmorillonite clay yields oligomers containing up to 10 monomer units. In these reactions, the heterocyclic base, imidazole is the leaving group. In our present study, we synthesized a series of activated nucleotides of 5'AMP using other leaving groups such as pyrazole, 1,2,4-triazole, piperidine, morpholine, 4-aminopyridine, 4-methylaminopyridine, 4-dimethylaminopyridine, 2-aminobenzimidazole etc. to determine the effect of amine leaving group on the products of the oligomerization reaction. Earlier results from our laboratory showed that the presence AppA in the clay reaction of ImpA enhances the oligomerization reaction to yield higher oligomers. We also studied the effect of AppA in the clay mediated oligomerization reaction of the activated nucleotides. Oligomerization of 2-amino-benzimidazole derivative of 5'-AMP gave higher oligomers containing up to nine monomer units in the presence of AppA.

Salting-out assisted liquid-liquid extraction with the aid of experimental design for determination of benzimidazole fungicides in high salinity samples by high-performance liquid chromatography.

PubMed

Wen, Yingying; Li, Jinhua; Yang, Fangfang; Zhang, Weiwei; Li, Weiran; Liao, Chunyang; Chen, Lingxin

2013-03-15

A novel method for the simultaneous separation and determination of four benzimidazole fungicides (i.e., carbendazim, fuberidazole, thiophanate-methyl and thiophanate) in high salinity samples was developed by using salting-out assisted liquid-liquid extraction (SALLE) via water-miscible acetonitrile as the extractant coupled with high-performance liquid chromatography. Box-Behnken design and response surface were employed to assist the optimization of SALLE conditions, including volume of salting-out solvent, the pH of sample solution and salting-out solvent as variable factors. The optimal salting-out parameters were obtained as follows: 2 mL of acetonitrile was added to 2 mL of sample solution with pH=4 and then 2 mL salting-out solvent containing 5 mol L(-1) sodium chloride at a pH of 7 was added to the solution for extraction. This procedure afforded a convenient and cost-saving operation with good cleanup ability for the benzimidazole fungicides, such as good linear relationships (R>0.996) between peak area and concentration from 2.5 ng mL(-1) to 500 ng mL(-1), low limits of detection between 0.14 ng mL(-1) and 0.38 ng mL(-1) and the intra-day precisions of retention time below 1.0%. The method recoveries obtained at fortified three concentrations for three seawater samples ranged from 60.4% to 99.1%. The simple, rapid and eco-benign SALLE based method proved potentially applicable for trace benzimidazole fungicides analysis in high salinity samples. Copyright © 2012 Elsevier B.V. All rights reserved.

Determination of benzimidazoles in meat samples by capillary zone electrophoresis tandem mass spectrometry following dispersive liquid-liquid microextraction.

PubMed

Tejada-Casado, Carmen; Moreno-González, David; Lara, Francisco J; García-Campaña, Ana M; Del Olmo-Iruela, Monsalud

2017-03-24

A novel method based on capillary zone electrophoresis-tandem mass spectrometry has been proposed and validated for the identification and simultaneous quantification of twelve benzimidazoles in meat samples. Electrophoretic separation was carried out using 500mM formic acid (pH 2.2) as background electrolyte and applying a voltage of 25kV at 25°C. In order to improve the sensitivity, stacking mode injection was applied, using as injection solvent a mixture of 30:70 acetonitrile/water at 50mbar for 75s. Sensitivity enhancement factors from 74 to 317 were obtained under these conditions. Detection using an ion trap as analyzer, operating in multiple reactions monitoring mode was employed. The main MS/MS parameters as well as the composition of the sheath liquid and other electrospray variables were optimized in order to obtain the highest sensitivity and precision in conjunction with an unequivocal identification. The method was applied to poultry and pork muscle samples. The deproteinization of samples and extraction of benzimidazoles was carried out with acetonitrile. MgSO 4 and NaCl were added as salting-out agents. Subsequently, dispersive liquid-liquid microextraction was applied as clean up procedure. The organic layer (acetonitrile, used as dispersant) containing the benzimidazoles was mixed with the extractant (chloroform) and both were injected in water, producing a cloudy solution. Recoveries for fortified samples were higher than 70%, with relative standard deviations lower than 16% were obtained in all cases. The limits of detection were below 3μgkg -1 , demonstrating the applicability of this fast, simple, and environmentally friendly method. Copyright © 2017 Elsevier B.V. All rights reserved.

Why do proton conducting polybenzimidazole phosphoric acid membranes perform well in high-temperature PEM fuel cells?

PubMed

Melchior, Jan-Patrick; Majer, Günter; Kreuer, Klaus-Dieter

2016-12-21

Transport properties and hydration behavior of phosphoric acid/(benz)imidazole mixtures are investigated by diverse NMR techniques, thermogravimetric analysis (TGA) and conductivity measurements. The monomeric systems can serve as models for phosphoric acid/poly-benzimidazole membranes which are known for their exceptional performance in high temperature PEM fuel cells. 1 H- and 31 P-NMR data show benzimidazole acting as a strong Brønsted base with respect to neat phosphoric acid. Since benzimidazole's nitrogens are fully protonated with a low rate for proton exchange with phosphate species, proton diffusion and conduction processes must take place within the hydrogen bond network of phosphoric acid only. The proton exchange dynamics between phosphate and benzimidazole species pass through the intermediate exchange regime (with respect to NMR line separations) with exchange times being close to typical diffusion times chosen in PFG-NMR diffusion measurements (ms regime). The resulting effects, as described by the Kärger equation, are included into the evaluation of PFG-NMR data for obtaining precise proton diffusion coefficients. The highly reduced proton diffusion coefficient within the phosphoric acid part of the model systems compared to neat phosphoric acid is suggested to be the immediate consequence of proton subtraction from phosphoric acid. This reduces hydrogen bond network frustration (imbalance of the number of proton donors and acceptors) and therefore also the rate of structural proton diffusion, phosphoric acid's acidity and hygroscopicity. Reduced water uptake, shown by TGA, goes along with reduced electroosmotic water drag which is suggested to be the reason for PBI-phosphoric acid membranes performing better in fuel cells than other phosphoric-acid-containing electrolytes with higher protonic conductivity.

Polymeric and Solid Lipid Nanoparticles for Sustained Release of Carbendazim and Tebuconazole in Agricultural Applications

NASA Astrophysics Data System (ADS)

Campos, Estefânia Vangelie Ramos; Oliveira, Jhones Luiz De; da Silva, Camila Morais Gonçalves; Pascoli, Mônica; Pasquoto, Tatiane; Lima, Renata; Abhilash, P. C.; Fernandes Fraceto, Leonardo

2015-09-01

Carbendazim (MBC) (methyl-2-benzimidazole carbamate) and tebuconazole (TBZ) ((RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol) are widely used in agriculture for the prevention and control of fungal diseases. Solid lipid nanoparticles and polymeric nanocapsules are carrier systems that offer advantages including changes in the release profiles of bioactive compounds and their transfer to the site of action, reduced losses due to leaching or degradation, and decreased toxicity in the environment and humans. The objective of this study was to prepare these two types of nanoparticle as carrier systems for a combination of TBZ and MBC, and then investigate the release profiles of the fungicides as well as the stabilities and cytotoxicities of the formulations. Both nanoparticle systems presented high association efficiency (>99%), indicating good interaction between the fungicides and the nanoparticles. The release profiles of MBC and TBZ were modified when the compounds were loaded in the nanoparticles, and cytotoxicity assays showed that encapsulation of the fungicides decreased their toxicity. These fungicide systems offer new options for the treatment and prevention of fungal diseases in plants.

Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB₂R selective benzimidazoles reveal unexpected intrinsic properties.

PubMed

Nimczick, Martin; Pemp, Daniela; Darras, Fouad H; Chen, Xinyu; Heilmann, Jörg; Decker, Michael

2014-08-01

The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB₂R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity

PubMed Central

2012-01-01

A novel series of benzimidazole designed multiple ligands (DMLs) with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the μ-opioid receptor was developed. Targeting of the structurally dissimilar heme-containing enzyme and the μ-opioid GPCR was predicated on the modulatory role of nitric oxide on μ-opioid receptor function. Structure–activity relationship studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC50 = 0.44 μM), selectivity over both endothelial nitric oxide synthase (10-fold) and inducible nitric oxide synthase (125-fold), and potent μ-opioid binding affinity, Ki = 5.4 nM. The functional activity as measured in the cyclic adenosine monosphospate secondary messenger assay resulted in full agonist activity (EC50 = 0.34 μM). This work represents a novel approach in the development of new analgesics for the treatment of pain. PMID:24900459

NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity.

PubMed

Renton, Paul; Green, Brenda; Maddaford, Shawn; Rakhit, Suman; Andrews, John S

2012-03-08

A novel series of benzimidazole designed multiple ligands (DMLs) with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the μ-opioid receptor was developed. Targeting of the structurally dissimilar heme-containing enzyme and the μ-opioid GPCR was predicated on the modulatory role of nitric oxide on μ-opioid receptor function. Structure-activity relationship studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC50 = 0.44 μM), selectivity over both endothelial nitric oxide synthase (10-fold) and inducible nitric oxide synthase (125-fold), and potent μ-opioid binding affinity, K i = 5.4 nM. The functional activity as measured in the cyclic adenosine monosphospate secondary messenger assay resulted in full agonist activity (EC50 = 0.34 μM). This work represents a novel approach in the development of new analgesics for the treatment of pain.

3-[1-(3-Hy­droxy­benz­yl)-1H-benzimid­azol-2-yl]phenol dimethyl sulfoxide monosolvate

PubMed Central

Quezada-Miriel, Magdalena; Avila-Sorrosa, Alcives; German-Acacio, Juan Manuel; Reyes-Martínez, Reyna; Morales-Morales, David

2012-01-01

Crystals of the title compound were obtained as a 1:1 dimethyl sulfoxide solvate, C20H16N2O2·C2H6O. The mol­ecular conformation of the organic mol­ecule is similar to that in the previously reported unsolvated structure [Eltayeb et al. (2009 ▶). Acta Cryst. E65, o1374–o1375]. Thus, the dihedral angles formed by the benzimidazole moiety with the two benzene rings are 57.54 (4) and 76.22 (5)°, and the dihedral angle between the benzene rings is 89.23 (5)°. In the crystal, a three-dimensional network features O—H⋯O, O—H⋯N and O—H⋯S hydrogen bonds, as well as C—H⋯O and C—H⋯π inter­actions. PMID:23125815

Single-step synthesis of a new series of meso di-Mannich bases from the cyclic aminal (2S,7R,11S,16R)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,7011,16]icosane and p-substituted phenols

PubMed Central

2013-01-01

Background The results presented herein show that the cyclic aminal (2S,7R,11S,16R)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,7011,16]icosane (6), derived from cis-(meso)-1,2-diaminocyclohexane and formaldehyde, is a suitable substrate for the preption of a series of cis-meso Mannich bases such as 8a-l by reaction with p-substituted phenols 7a-l in basic media. These compounds are valuable synthetic products and may find application in asymmetric catalysis. Results The products were characterized principally by NMR and IR spectroscopy. Both the benzylic and aminalic protons of the perhydrobenzimidazolidine moiety were diastereotopic due to the presence of stereogenic nitrogen centers. The occurrence of intramolecular hydrogen bonding interactions was confirmed by the broad OH stretching vibration band in the IR spectra. Vibrational spectra were calculated using B3LYP at 6-31G(d,p) level, and the calculated frequencies for the νOH vibrations were compared to those of the experimental spectra. Hydrogen bonding interactions in the solid state were observed through the X-ray crystallography of 8j. Additionally, Mulliken charges and Fukui indices for 6 were calculated as theoretical descriptors of electrophilicity. Conclusion A new series of meso Mannich bases called 4,4′-disubstituted-2,2′-{[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diyl]bis(methylene)} diphenols (8a-l) which are derived from cis-(meso)-1,2-diaminocyclohexane, were obtained from cyclic aminal 6. These results confirmed the behavior of 6 as an electrophilic preformed reagent in Mannich reactions in basic media. PMID:23758899

Copper-Catalyzed Domino Three-Component Approach for the Assembly of 2-Aminated Benzimidazoles and Quinazolines.

PubMed

Tran, Lam Quang; Li, Jihui; Neuville, Luc

2015-06-19

A copper-promoted three-component synthesis of 2-aminobenzimidazoles (1) or of 2-aminoquinazolines (2) involving cyanamides, arylboronic acids, and amines has been developed. The operationally simple oxidative process, performed in the presence of K2CO3, a catalytic amount of CuCl2·2H2O, 2,2'-bipyridine, and an O2 atmosphere (1 atm), allows the rapid assembly of either benzimidazoles or quinazolines starting from aryl- or benzyl-substituted cyanamides, respectively. In this process, the copper promotes the formation of three bonds, two C-N bonds, and an additional bond resulting from C-H functionalization event.

A novel magnetic core-shell nanocomposite Fe3O4@chitosan@ZnO for the green synthesis of 2-benzimidazoles

NASA Astrophysics Data System (ADS)

Tian, Fei; Niu, Libo; Chen, Bo; Gao, Xuejia; Lan, Xingwang; Huo, Li; Bai, Guoyi

2017-10-01

A novel magnetic core-shell nanocomposite Fe3O4@Chitosan@ZnO was successfully prepared by in situ chemical precipitation method. It has a clear core-shell structure with magnetic Fe3O4 (about 160 nm in diameter) as core, chitosan as the inner shell, and ZnO as the outer shell, as demonstrated by the transmission electron microscopy and the related elemental mapping. Moreover, this nanocomposite has high magnetization (43.6 emu g-1) so that it can be easily separated from the reaction mixture within 4 s by an external magnetic field. The introduction of the natural chitosan shell, instead of the conventional SiO2 shell, and its combination with the active ZnO ensures this novel nanocomposite green character and good catalytic performance in the synthesis of 2-benzimidazoles with moderate to excellent isolated yields at room temperature. Notably, it can be recycled seven times without appreciable loss of its initial catalytic activity, demonstrating its good stability and making it an attractive candidate for the green synthesis of 2-benzimidazoles. [Figure not available: see fulltext.

Efficacy of osthole for Echinococcus granulosus in vitro and Echinococcus multilocularis in vivo.

PubMed

Yuan, Miaomiao; Luo, Yanping; Xin, Qi; Gao, Haijun; Zhang, Guochao; Jing, Tao

2016-08-15

Echinococcosis is a zoonotic infection caused by cestode species of the genus Echinococcus; in addition, this zoonosis has long been neglected as a parasitic disease and has limited treatment options. Clinical drugs such as benzimidazole derivatives have limited treatment efficacy. The current study evaluated a novel drug, osthole, with low toxicity and high activity against Echinococcus in vitro and in vivo. The results in vitro indicated that the viability of Echinococcus granulosus protoscoleces in the group treated with osthole (120μM) decreased by 100% within 3days. In vivo experiments were conducted using parasite-infected mice. For this purpose, three groups of infected mice were treated daily for 6 weeks with albendazole (ABZ, 100mg/kg, positive control group), osthole (100mg/kg, experimental group), or honey/PBS (100mg/kg, negative control group), respectively. The osthole- and ABZ-treated groups presented a significant reduction in wet weight of metacestodes, increase in the level of interleukin (IL)-4 and the percentage of eosinophils compared with the control group. Osthole exhibited a high activity against echinococcosis in vivo. In addition, the toxicity of osthole was evaluated via an in vitro 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, as well as via morphological observation and calculation of liver and kidney function indexes in vivo. No obvious toxic effects of osthole were observed in our study. Therefore, this novel drug may be a promising alternative to benzimidazole in anti-echinococcosis chemotherapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Comprehensive screening and quantification of veterinary drugs in milk using UPLC–ToF-MS

PubMed Central

Rutgers, P.; Oosterink, E.; Lasaroms, J. J. P.; Peters, R. J. B.; van Rhijn, J. A.; Nielen, M. W. F.

2008-01-01

Ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC–ToF-MS) has been used for screening and quantification of more than 100 veterinary drugs in milk. The veterinary drugs represent different classes including benzimidazoles, macrolides, penicillins, quinolones, sulphonamides, pyrimidines, tetracylines, nitroimidazoles, tranquillizers, ionophores, amphenicols and non-steroidal anti-inflammatory agents (NSAIDs). After protein precipitation, centrifugation and solid-phase extraction (SPE), the extracts were analysed by UPLC–ToF-MS. From the acquired full scan data the drug-specific ions were extracted for construction of the chromatograms and evaluation of the results. The analytical method was validated according to the EU guidelines (2002/657/EC) for a quantitative screening method. At the concentration level of interest (MRL level) the results for repeatability (%RSD < 20% for 86% of the compounds), reproducibility (%RSD < 40% for 96% of the compounds) and the accuracy (80–120% for 88% of the compounds) were satisfactory. Evaluation of the CCβ values and the linearity results demonstrates that the developed method shows adequate sensitivity and linearity to provide quantitative results. Furthermore, the method is accurate enough to differentiate between suspected and negative samples or drug concentrations below or above the MRL. A set of 100 samples of raw milk were screened for residues. No suspected (positive) results were obtained except for the included blind reference sample containing sulphamethazine (88 μg/l) that tested positive for this compound. UPLC–ToF-MS combines high resolution for both LC and MS with high mass accuracy which is very powerful for the multi-compound analysis of veterinary drugs. The technique seems to be powerful enough for the analysis of not only veterinary drugs but also organic contaminants like pesticides, mycotoxins and plant toxins in one single method. PMID:18491081

Metronidazole within phosphatidylcholine lipid membranes: new insights to improve the design of imidazole derivatives.

PubMed

Lopes-de-Campos, Daniela; Nunes, Cláudia; Sarmento, Bruno; Jakobtorweihen, Sven; Reis, Salette

2018-05-30

Metronidazole is a benzimidazole derivative with antibacterial and antiprotozoal activity. Despite its therapeutic efficacy, several studies have been developing new imidazole derivatives with lower toxicity. Considering that drug-membrane interactions are key factors for drugs pharmacokinetic and pharmacodynamic properties, the aim of this work is to provide new insights into the structure-toxicity relationships of metronidazole within phosphatidylcholine membranes. For that purpose, lipid membrane models (liposomes and monolayers) composed of dipalmitoylphosphatidylcholine were used. Experimental techniques (determination of partition coefficients and Langmuir isotherm measurements) were combined with molecular dynamics simulations. Different pHs and lipid phases were evaluated to enable a better extrapolation for in vivo conditions. The partition of metronidazole depends on the pH and on the biphasic system (octanol/water or DPPC/water system). At pH 1.2, metronidazole is hydrophilic. At pH 7.4, metronidazole disturbs the order and the packing of phospholipids. For this toxic effect, the hydroxyl group of the side chain of metronidazole is a key by interacting with the water embedded in the membrane and with the phosphate group and the apolar chains of phospholipids. Copyright © 2018. Published by Elsevier B.V.

Preparation, characterization and catalytic application of CoFe2O4 nanoparticles in the synthesis of benzimidazoles

NASA Astrophysics Data System (ADS)

Borade, Ravikumar M.; Shinde, Pavan R.; Kale, Swati B.; Pawar, Rajendra P.

2018-05-01

A highly efficient magnetically recoverable cobalt ferrite nano-catalyst was prepared by sol-gel autocombustion method using glycine as green fuel. The prepared material has been characterized by X-ray powder diffraction and scanning. An investigation of its catalytic activity showed it to be a heterogeneous Lewis acid catalyst for the synthesis of substituted benzimidazoles. The aqueous ethanol used as green solvent for the reaction. The nm size range of these particles facilitates the catalysis process, as an increased surface area available for the reaction. The easy separation of the catalyst by an external magnet and their recovery and reuse in next cycle reaction are additional benefits.

Efficient FeCl3/SiO2 as heterogeneous nanocatalysis for the synthesis of benzimidazoles under mild conditions

NASA Astrophysics Data System (ADS)

Taher, Mohammad Ali; Karami, Changiz; Arabi, Mehdi Sheikh; Ahmadian, Hossein; Karami, Yasaman

2016-11-01

Iron(III) supported on nano silica as a new catalyst has been synthesized. Structural properties of this complex have been studied by TEM, SEM and EDX. The average crystalline size of Iron(III) supported on nano silica is 30-50 nm. Catalytic activity of this catalyst has been investigated by synthesis of benzimidazoles from 1, 2-diaminobenzene and aromatic aldehydes, and also the other variables investigated such as the amount of catalyst, reaction temperature and the effect of various solvents are also studied. The present procedure offers several advantages such as short reaction time, simple workup, recovery and reusability of the catalyst.

Reduction of benzimidazole resistance in established Haemonchus contortus populations in goats using a single infection with a benzimidazole-susceptible isolate.

PubMed

Chan-Pérez, J I; Torres-Acosta, J F J; Rodríguez-Vivas, R I; Villegas-Pérez, S L

2015-09-01

An in vivo study in goats evaluated the effect of superimposing a single artificial infection with a benzimidazole (BZ)-susceptible Haemonchus contortus isolate upon established H. contortus populations of known BZ resistance by measuring the phenotypic BZ resistance of eggs collected from faeces before and after re-infection. Two H. contortus isolates, one benzimidazole resistant (BZR) and the other susceptible (BZS), were used to infect worm-free goats. Eight goats were initially infected with 2000 third-stage larvae (L3). In each case the inoculum contained a pre-determined proportion of the two isolates: 100% BZS (one goat), 75% BZS/25% BZR (two goats), 50% BZS/50% BZR (two goats), 25%BZS/75% BZR (two goats) and, finally, 100% BZR (one goat). The phenotypic BZ susceptibility of the H. contortus population formed in each goat after the first infection was determined on days 30 and 36 post-infection using an egg-hatch assay (EHA) that estimated the concentration of thiabendazole (TBZ) required for 95% inhibition of larval hatching (EC(95)) with a 95% confidence interval (95% CI). On day 49 post-infection, goats were re-infected with 2000 L3 of the BZS isolate alone. A second set of EHA bioassays was performed 28 days and 34 days after re-infection. The first infection protocol produced three populations classified as BZS (EC(95) 0.055-0.065 μg TBZ/ml) while four were categorized as BZR (EC(95) 0.122-0.344 μg TBZ/ml). The status of one other population could not be determined. After re-infection with BZS L3, the number of susceptible populations increased to six (EC(95) 0.043-0.074 μg TBZ/ml) while the remaining two were deemed resistant (EC(95) 0.114-119 μg TBZ/ml). Re-infection with BZS L3 thereby reduced the resistance status of most H. contortus populations.

Watch and Wait Management of Inactive Cystic Echinococcosis - Does the Path to Inactivity Matter - Analysis of a Prospective Patient Cohort.

PubMed

Stojkovic, Marija; Rosenberger, Kerstin Daniela; Steudle, Franziska; Junghanss, Thomas

2016-12-01

Overdiagnosis and overtreatment are rarely discussed in the context of NTDs despite their relevance for patients under the care of health services with limited resources where the risks of therapy induced complications are often disproportionate to the benefit. The advantages of cyst staging-based management of patients with cystic echinococcosis (CE) are not yet fully explored. Questions are: Do inactive cysts (CE 4 and CE 5) need treatment and is there a difference between cysts which reach CE4 and CE5 naturally or by benzimidazole therapy? Analysis of long-term follow-up data from a prospective CE patient cohort of 223 patients of a national clinical center for echinococcosis. The event of interest "relapse" was defined as the reversal of a cyst from an inactive stage (CE4, CE5) back to an active stage. The watch &wait (ww) group included 30 patients with 46 inactive cysts who never received medical treatment. The benzimidazole-treated (med) group included 15 patients with 17 cysts. There was no relapse in the ww-group whereas 8/17 cysts showed relapse within 18 months after treatment in the med-group. Loss to follow-up was 15.5%. Data from the watch & wait group impressively show how stable naturally inactivated cysts are in contrast to cysts which reach inactivity through treatment with benzimidazoles. A substantial proportion of patients can be spared from treatment through cyst staging. Cysts which inactivated through a natural course do not relapse with very high likelihood. We recommend follow up of 5 years to confirm the stability of the inactive stage. Cysts driven into inactivity through benzimidazole therapy instead need careful monitoring to identify those which reactivate (around 50% within 18 months). 5 years follow-up appears safe to make a final decision on the need for further monitoring.

Vibrational spectroscopic analysis, molecular dynamics simulations and molecular docking study of 5-nitro-2-phenoxymethyl benzimidazole

NASA Astrophysics Data System (ADS)

Menon, Vidya V.; Foto, Egemen; Mary, Y. Sheena; Karatas, Esin; Panicker, C. Yohannan; Yalcin, Gözde; Armaković, Stevan; Armaković, Sanja J.; Van Alsenoy, C.; Yildiz, Ilkay

2017-02-01

FT-IR and FT-Raman spectra of 5-nitro-2-phenoxymethylbenzimidazole were recorded and analyzed theoretically and experimentally. The splitting of Nsbnd H stretching mode in the IR spectrum with a red shift from the calculated value indicates the weakening of the NH bond. The theoretical calculations give the phenyl ring breathing modes at 999 cm-1 for mono substituted benzene ring and at 1040 cm-1 for tri-substituted benzene ring. The theoretical NMR chemical shifts are in agreement with the experimental chemical shifts. The most reactive sites for electrophilic and nucleophilic attack are predicted from the MEP analysis. HOMO of π nature is delocalized over the entire molecule whereas the LUMO is located over the complete molecule except mono-substituted phenyl ring and oxygen atom. Reactive sites of the title molecule have been located with the help of ALIE surfaces and Fukui functions. In order to determine locations prone to autoxidation and locations interesting for starting of degradation, bond dissociation energies have been calculated for all single acyclic bonds. For the determination of atoms with pronounced interactions with water we have calculated radial distribution functions obtained after molecular dynamics simulations. The calculated first hyperpolarizability of the title compound is 58.03 times that of standard nonlinear optical material urea. The substrate binding site interactions of the title compound with Topo II enzyme is reported by using molecular docking study. Biological activity studies show that the title compound can be leaded for developing new anticancer agents.

In vitro effects of benzimidazole/thioether-copper complexes with antitumor activity on human erythrocytes.

PubMed

Suwalsky, Mario; Castillo, Ivan; Sánchez-Eguía, Brenda N; Gallardo, María José; Dukes, Nathan; Santiago-Osorio, Edelmiro; Aguiñiga, Itzen; Rivera-Martínez, Ana R

2018-01-01

Two cytotoxic copper(II) complexes with N-H and N-methylated benzimidazole-derived ligands (Cu-L 1 and Cu-L 1Me ; L 1 =bis(2-methylbenzimidazolyl)(2-methylthioethyl)amine, L 1Me =bis(1-methyl-2-methylbenzimidazolyl)(2-methylthioethyl)amine) were synthesized and exposed to human erythrocytes and molecular models of its membrane. The latter were bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), classes of lipids present in the external and internal moieties of the human red cell membrane, respectively. Scanning electron microscopy (SEM) of erythrocytes incubated with solutions of both Cu(II) complexes showed that they induced morphological changes to the normal cells to echinocytes, and hemolysis at higher concentrations. Real-time observation of the dose-dependent effects of the complexes on live erythrocytes by defocusing microscopy (DM) confirmed SEM results. The formation of echinocytes implied that complex molecules inserted into the outer moiety of the red cell membrane. X-ray diffraction studies on DMPC and DMPE showed that none of these complexes interacted with DMPE and only Cu-L 1 interacted with DMPC. This difference was explained by the fact that Cu-L 1Me complex is more voluminous than Cu-L 1 because it has two additional methyl groups; on the other hand, DMPC molecule has three methyl groups in its bulky terminal amino end. Thus, by steric hindrance Cu-L 1Me molecules cannot intercalate into DMPC bilayer, which besides is present in the gel phase. These results, together with the increased antiproliferative capacity of the N-methylated complex Cu-L 1Me over that of Cu-L 1 are rationalized mainly based on its higher lipophilicity. Copyright © 2017 Elsevier Inc. All rights reserved.

[Increasing the resolution of chromosome analysis using pyrido[1,2alpha]benzimidazoles].

PubMed

Rachinskaia, O A; Popov, K V; Ryzvanovich, G A; Bol'sheva, N L; Begunov, R S; Iurkevich, O Iu; Zelenin, A V; Muravlenko, O V

2012-10-01

We studied the influence of three derivatives of pyrido[1,2alpha]benzimidazoles (PBIs), which have DNA-intercalating properties, on plant mitotic chromosome condensation, in order to increase the resolution of chromosome analysis. The efficiency of the influence of these agents was assessed using the median chromosome length on chromosome slides, as well as by the number and size of chromosome DAPI bands. We used the third chromosome of Linum grandiflorum Desf. in these experiments. The chromosome was identified on the slides using its DAPI band pattern and a molecular marker, viz., the 5S rDNA site, which is located in the proximal region of the long arm of the chromosome. The influence of the well-known 9-aminoacridine (9-AMA) DNA intercalator, which is widely used in karyotype studies of short-chromosome organisms, was used as a control in all of the experiments. It was found that the influence of each of the three PBIs in the study on the root meristem of L. grandiflorum resulted in an increase in the median length of the third chromosome, the linear centromeric DAPI band size, and the number ofintercalary DAPI bands. All three PBIs acted more efficiently than 9-AMA. The median chromosome length was increased by 15-40% and the number of intercalary bands increased by 1.5-3 times after PBI treatment, as compared to 9-AMA treatment. At the same time, 7-CF3-PBI, in a similar manner to 9-AMA, did not change the relative size of the centromeric DAPI band, while 7-NH2-PBI and 7-CF3-9-NH2-PBI gradually increased this parameter. It is concluded that these substances can be used as intercalating agents in cytogenetic studies in order to increase the resolution of chromosome analysis.

Impairment of the Ubiquitin-Proteasome Pathway by Methyl N-(6-Phenylsulfanyl-1H-benzimidazol-2-yl)carbamate Leads to a Potent Cytotoxic Effect in Tumor Cells

PubMed Central

Dogra, Nilambra; Mukhopadhyay, Tapas

2012-01-01

In recent years, there has been a great deal of interest in proteasome inhibitors as a novel class of anticancer drugs. We report that fenbendazole (FZ) (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl)carbamate) exhibits a potent growth-inhibitory activity against cancer cell lines but not normal cells. We show here, using fluorogenic substrates, that FZ treatment leads to the inhibition of proteasomal activity in the cells. Succinyl-Leu-Leu-Val-Tyr-methylcoumarinamide (MCA), benzyloxycarbonyl-Leu-Leu-Glu-7-amido-4-MCA, and t-butoxycarbonyl-Gln-Ala-Arg-7-amido-4-MCA fluorescent derivatives were used to assess chymotrypsin-like, post-glutamyl peptidyl-hydrolyzing, and trypsin-like protease activities, respectively. Non-small cell lung cancer cells transiently transfected with an expression plasmid encoding pd1EGFP and treated with FZ showed an accumulation of the green fluorescent protein in the cells due to an increase in its half-life. A number of apoptosis regulatory proteins that are normally degraded by the ubiquitin-proteasome pathway like cyclins, p53, and IκBα were found to be accumulated in FZ-treated cells. In addition, FZ induced distinct ER stress-associated genes like GRP78, GADD153, ATF3, IRE1α, and NOXA in these cells. Thus, treatment of human NSCLC cells with fenbendazole induced endoplasmic reticulum stress, reactive oxygen species production, decreased mitochondrial membrane potential, and cytochrome c release that eventually led to cancer cell death. This is the first report to demonstrate the inhibition of proteasome function and induction of endoplasmic reticulum stress/reactive oxygen species-dependent apoptosis in human lung cancer cell lines by fenbendazole, which may represent a new class of anticancer agents showing selective toxicity against cancer cells. PMID:22745125

Development of a pharmacophore for cruzain using oxadiazoles as virtual molecular probes: quantitative structure-activity relationship studies

NASA Astrophysics Data System (ADS)

de Souza, Anacleto S.; de Oliveira, Marcelo T.; Andricopulo, Adriano D.

2017-09-01

Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR (r_{{{pred}}}2 = 0.81) and a 3D-QSAR-based pharmacophore (r_{{{pred}}}2 = 0.82) from a series of non-covalent cruzain inhibitors represented mostly by oxadiazoles (lead compound, IC50 = 200 nM). Both models allowed us to map key intermolecular interactions in S1', S2 and S3 cruzain sub-sites (including halogen bond and C‒H/π). To probe the predictive capacity of obtained models, inhibitors available in the literature from different classes displaying a range of scaffolds were evaluate achieving mean absolute deviation of 0.33 and 0.51 for 2D and 3D models, respectively. CoMFA revealed an unexplored region where addition of bulky substituents to produce new compounds in the series could be beneficial to improve biological activity.

2-({4-[4-(1H-Benzimidazol-2-yl)phen­yl]-1H-1,2,3-triazol-1-yl}meth­oxy)ethanol

PubMed Central

Ouahrouch, Abdelaaziz; Taourirte, Moha; Lazrek, Hassan B.; Bats, Jan W.; Engels, Joachim W.

2012-01-01

In the title molecule, C18H17N5O2, the dihedral angle between the benzene plane and the benzimidazole plane is 19.8 (1)° and the angle between the benzene plane and the triazole plane is 16.7 (1)°. In the crystal, mol­ecules are connected by O—H⋯N hydrogen bonds, forming zigzag chains along the c-axis direction. The chains are connected by bifurcated N—H⋯(N,N) hydrogen bonds into layers parallel to (100). These layers are connected along the a-axis direction by weak C—H⋯O contacts, forming a three-dimensional network. PMID:22719663

DNA-Compatible Nitro Reduction and Synthesis of Benzimidazoles.

PubMed

Du, Huang-Chi; Huang, Hongbing

2017-10-18

DNA-encoded chemical libraries have emerged as a cost-effective alternative to high-throughput screening (HTS) for hit identification in drug discovery. A key factor for productive DNA-encoded libraries is the chemical diversity of the small molecule moiety attached to an encoding DNA oligomer. The library structure diversity is often limited to DNA-compatible chemical reactions in aqueous media. Herein, we describe a facile process for reducing aryl nitro groups to aryl amines. The new protocol offers simple operation and circumvents the pyrophoric potential of the conventional method (Raney nickel). The reaction is performed in aqueous solution and does not compromise DNA structural integrity. The utility of this method is demonstrated by the versatile synthesis of benzimidazoles on DNA.

The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Brazil.

PubMed

Echevarria, F; Borba, M F; Pinheiro, A C; Waller, P J; Hansen, J W

1996-04-01

This survey was conducted in the southern Brazilian state of Rio Grande do Sul and involved 182 farms located in 26 counties. In addition to the three major broad-spectrum anthelmintic groups (viz. benzimidazole, levamisole and ivermectin) the combination benzimidazole and levamisole and the H. contortus specific anthelmintic, closantel, were tested by the faecal egg count reduction method for the prevalence of anthelmintic resistance. Resistance was found to be 90%, 84%, 13%, 73% and 20%, respectively. This is a crisis situation. Immediate, drastic action needs to be implemented, otherwise the sheep industry in this region (approx. 10 million head) will soon face a lack of any effective anthelmintics with the inevitable consequences of major restructuring or abandonment.

Green and simple analytical method to determine benzimidazoles in milk samples by using salting-out assisted liquid-liquid extraction and capillary liquid chromatography.

PubMed

Tejada-Casado, Carmen; Del Olmo-Iruela, Monsalud; García-Campaña, Ana M; Lara, Francisco J

2018-08-01

A green and simple multiresidue method using capillary liquid chromatography (CLC) with UV-diode array detection (DAD) has been developed for the determination of sixteen benzimidazoles (BZs) and its metabolites in milk samples. The separation was achieved in <32 min, using a Zorbax XDB-C18 column (150 mm × 0.5 mm I.D, 5 μm), with a mobile phase consisting of 50 mM ammonium acetate (solvent A) and a mixture of acetonitrile/methanol (1:1 v/v) (solvent B), at a flow rate of 9 μL min -1 . The temperature of the column was 20 °C and 6 μL of sample were injected. In spite of the complexity of milk samples, an effective, simple and fast sample preparation method called salting out-assisted liquid-liquid extraction (SALLE) was developed for the analysis of these compounds in cow milk samples. To obtain satisfactory extraction efficiencies for the studied analytes, several parameters affecting the SALLE procedure were optimized including the amount of sample, type and volume of the extraction solvent, and the nature and amount of the salt. Good linearity was obtained (R 2  > 0.9985 for all BZs) with limits of detection (LOD) between 1.0 and 2.8 μg kg -1 . Relative standard deviations of repeatability and intermediate precision were below 1.6 and 14.2%, respectively. Satisfactory recoveries between 79.1 and 99.6% were also obtained for three types of milk samples (cow, sheep and goat). The advantages of a miniaturized technique such as CLC in terms of better efficiencies and reduced solvent consumption, combined with the simplicity of the SALLE procedure, make this method a useful alternative for the monitoring of these residues at trace level. Copyright © 2018 Elsevier B.V. All rights reserved.

BT-benzo-29 inhibits bacterial cell proliferation by perturbing FtsZ assembly.

PubMed

Ray, Shashikant; Jindal, Bhavya; Kunal, Kishore; Surolia, Avadhesha; Panda, Dulal

2015-10-01

We have identified a potent antibacterial agent N-(4-sec-butylphenyl)-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4-carboxamide (BT-benzo-29) from a library of benzimidazole derivatives that stalled bacterial division by inhibiting FtsZ assembly. A short (5 min) exposure of BT-benzo-29 disassembled the cytokinetic Z-ring in Bacillus subtilis cells without affecting the cell length and nucleoids. BT-benzo-29 also perturbed the localization of early and late division proteins such as FtsA, ZapA and SepF at the mid-cell. Further, BT-benzo-29 bound to FtsZ with a dissociation constant of 24 ± 3 μm and inhibited the assembly and GTPase activity of purified FtsZ. A docking analysis suggested that BT-benzo-29 may bind to FtsZ at the C-terminal domain near the T7 loop. BT-benzo-29 displayed significantly weaker inhibitory effects on the assembly and GTPase activity of two mutants (L272A and V275A) of FtsZ supporting the prediction of the docking analysis. Further, BT-benzo-29 did not appear to inhibit DNA duplication and nucleoid segregation and it did not perturb the membrane potential of B. subtilis cells. The results suggested that BT-benzo-29 exerts its potent antibacterial activity by inhibiting FtsZ assembly. Interestingly, BT-benzo-29 did not affect the membrane integrity of mammalian red blood cells. BT-benzo-29 bound to tubulin with a much weaker affinity than FtsZ and exerted significantly weaker effects on mammalian cells than on the bacterial cells indicating that the compound may have a strong antibacterial potential. © 2015 FEBS.

Role of annealing on the structural and optical properties of nanostructured diaceto bis-benzimidazole Mn(II) complex thin films

NASA Astrophysics Data System (ADS)

Praveen, P. A.; Babu, R. Ramesh; Ramamurthi, K.

2017-02-01

A coordination complex, manganese incorporated benzimidazole, thin films were prepared by chemical bath deposition method. Structural characterization of the deposited films, carried out by Fourier transform infrared spectroscopy, Raman and electron paramagnetic resonance spectral analyses, reveals the distorted tetrahedral environment of the metal ion with bis-benzimidazole ligand. Further the molecular composition of the deposited metal complex was estimated by energy-dispersive X-ray spectroscopy. The prepared thin films were thermally treated to study the effect of annealing temperature on the surface morphology and the results showed that the surface homogeneity of the films increased for thermally treated films up to 150 °C. But distortion and voids were observed for the films annealed at 200 °C. The Raman analysis reveals the molecular hydrogen bond distortion which leads to the evaporation of the metal complex from the thin film surface with respect to annealing temperature. The linear and nonlinear optical properties of the as prepared and annealed films were studied using ultraviolet-visible transmittance spectroscopy, second harmonic generation and Z-scan analyses. Films annealed at 150 °C show a better linear transmittance in the visible region and larger SHG efficiency and third order nonlinear susceptibility when compared with the other samples. Further, the film annealed at 150 °C was subjected to optical switching analysis and demonstrated to have an inverted switching behavior.

A study of vibrational spectra and investigations of charge transfer and chemical bonding features of 2-chloro benzimidazole based on DFT computations

NASA Astrophysics Data System (ADS)

Muthunatesan, S.; Ragavendran, V.

2015-01-01

Benzimidazoles are bicyclic heteroatomic molecules. Polycyclic heteroatomic molecules have extensive coupling of different modes leading to strong coupling of force constants associated with the various chemical bonds of the molecules. To carry out a detailed vibrational spectroscopic analysis of such a bicyclic heteroatomic molecule, FT-IR and FT-Raman spectra of 2-chloro benzimidazole (CBZ) have been recorded in the condensed phase. Density Functional Theory calculations in the B3LYP/6-31G* level have been carried out to determine the optimized geometry and vibrational frequencies. In order to obtain a close agreement between theoretical and observed frequencies and hence to perform a reliable assignment, the theoretical DFT force field was transformed from Cartesian to local symmetry co-ordinates and then scaled empirically using SQM methodology. The SQM treatment resulted in a RMS deviation of 9.4 cm-1. For visual comparison, the observed and calculated spectra are presented on a common wavenumber scale. From the NBO analysis, the electron density (ED) charge transfers in the σ* and π* antibonding orbitals and second order delocalization energies E(2) confirms the occurrence of intramolecular charge transfer (ICT) within the molecule. The calculated Homo and Lumo energies show that charge transfer occurs within the molecule. The results obtained from the vibrational, NBO and HOMO-LUMO analyses have been properly tabulated.