The therapeutic journey of benzimidazoles: A review

Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 09/2012; 20(21):6208-36. DOI: 10.1016/j.bmc.2012.09.013
Source: PubMed


Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. Varied substitutents around the benzimidazole nucleus have provided a wide spectrum of biological activities. Importance of this nucleus in some activities like, Angiotensin I (AT(1)) receptor antagonism and proton-pump inhibition is reviewed separately in literature. Even some very short reviews on biological importance of this nucleus are also known in literature. However, owing to fast development of new drugs possessing benzimidazole nucleus many research reports are generated in short span of time. So, there is a need to couple the latest information with the earlier information to understand the current status of benzimidazole nucleus in medicinal chemistry research. In the present review, various derivatives of benzimidazole with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole derived compounds for each activity. This discussion will further help in the development of novel benzimidazole compounds.

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    • "CB[7] has drawn much interest from chemists because it binds with various neutral and cationic molecules and can be applied to drug delivery, asymmetric synthesis, molecular switching, and dye tuning [31] [32] [33] [34] [35]. BZ and its derivatives are widely used to develop drugs and have various biological activities, such as antiparasitics, anticonvulsants, analgesics, antihistaminics, antiviral, anticancers, antifungals, and anti-inflammatory activities [36]. BZ is known to form a stable complex with CB[7] and undergo a shift of 4 pK a units during binding [37]. "
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    ABSTRACT: We present a computational scheme to compute the pH-dependence of binding free energy with explicit solvent. [Despite the importance of pH, the effect of pH has been generally neglected in binding free energy calculations because of a lack of accurate methods to model it.] To address this limitation, we use a constant-pH methodology to obtain a true ensemble of multiple protonation states of a titratable system at a given pH and analyze the ensemble using the Bennett acceptance ratio (BAR) method. The constant pH method is based on the combination of enveloping distribution sampling (EDS) with the Hamiltonian replica exchange method (HREM), which yields an accurate semi-grand canonical ensemble of a titratable system. By considering the free energy change of constraining multiple protonation states to a single state or releasing a single protonation state to multiple states, the pH dependent binding free energy profile can be obtained. We perform benchmark simulations of a host-guest system: cucurbit[7]uril (CB[7]) and benzimidazole (BZ). BZ experiences a large pKa shift upon complex formation. The pH-dependent binding free energy profiles of the benchmark system are obtained with three different long-range interaction calculation schemes: a cutoff, the particle mesh Ewald (PME), and the isotropic periodic sum (IPS) method. Our scheme captures the pH-dependent behavior of binding free energy successfully. Absolute binding free energy values obtained with the PME and IPS methods are consistent, while cutoff method results are off by 2 kcal/mol. We also discuss the characteristics of three long-range interaction calculation methods for constant-pH simulations. This article is protected by copyright. All rights reserved. © 2015 The Protein Society.
    Protein Science 07/2015; DOI:10.1002/pro.2755 · 2.85 Impact Factor
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    • "Benzimidazole derivatives have long been therapeutically used for the treatment of various diseases including parasitic diseases and cancer [1] [2] [3] [4]. Presently, this group of compounds has emerged as an important pharmacophore in the development of anticancer agents [4] [5] [6]. "
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    ABSTRACT: Here, we have discovered CXI-benzo-84 as a potential anticancer agent from a library of benzimidazole derivatives using cell based screening strategy. CXI-benzo-84 inhibited cell cycle progression in metaphase stage of mitosis and accumulated spindle assembly checkpoint proteins Mad2 and BubR1 on kinetochores, which subsequently activated apoptotic cell death in cancer cells. CXI-benzo-84 depolymerized both interphase and mitotic microtubules, perturbed EB1 binding to microtubules and inhibited the assembly and GTPase activity of tubulin in vitro. CXI-benzo-84 bound to tubulin at a single binding site with a dissociation constant of 1.2±0.2μM. Competition experiments and molecular docking suggested that CXI-benzo-84 binds to tubulin at the colchicine-site. Further, computational analysis provided a significant insight on the binding site of CXI-benzo-84 on tubulin. In addition to its potential use in cancer chemotherapy, CXI-benzo-84 may also be useful to screen colchicine-site agents and to understand the colchicine binding site on tubulin.
    Biochemical pharmacology 06/2013; 86(3). DOI:10.1016/j.bcp.2013.05.024 · 5.01 Impact Factor
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    • "The major reasons of this cancer are: diet poor in fiber, folate, and calcium or rich in meat and fat, smoking and high alcohol intake (Weitz et al., 2005). Benzimidazole is a heterocyclic moiety possessing a wide spectrum of biological activities; a number of its organic derivatives have shown potential anticancer activity against Leukemia (HL-60), Breast Cancer (MCF- 7), Human colon adenocarcinoma (HT-29), and Cervical cancer (HeLa) (Narasimhan et al., 2012) including a number of other therapeutic activities (Bansal and Silakari, 2012). Due to the aforementioned reasons, a number of benzimidazolium salts (organic salts, IV–VI) were synthesized , unlike organic derivatives of benzimidazole (organic compounds), in order to increase the solubility and efficacy of these heterocycles. "
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    ABSTRACT: The article describes synthesis, characterization (NMR, FT-IR, microanalysis, X-ray crystallography), in vitro anticancer, and antioxidant activity of para-xylyl linked bis-benzimidazolium salts and respective dinuclear Ag–NHC complexes. All the compounds were tested for their cytotoxicity against human colorectal cancer cells (HCT 116) and DPPH antioxidant evaluation. According to cell viability measurements using MTT assay, all the tested compounds showed dose-dependent cytotoxic activity against HCT 116 cells. The tested compounds demon-strated significant activity with IC 50 values range 0.29–3.30 lM for HCT 116 and % age inhibition 6.37–21.00 for DPPH antioxidant study. 5-Fluorouracil was used as standard drug (IC 50 19.2 lM for HCT 116) whereas for DPPH analysis, Gallic acid was used as posi-tive control (% age inhibition 77.68). All the compounds showed potential anticancer activity against human colo-rectal cancer whereas antioxidant activity was not signifi-cant. We found that as the size of N-alkyl substitution on benzimidazolium salt increases its cytotoxicity against cancer decreases whereas a reverse occurs in case of respective complexes.
    Medicinal Chemistry Research 04/2013; 22(10). DOI:10.1007/s00044-012-0461-8 · 1.40 Impact Factor
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