Discovery of HCV NS5B thumb site I inhibitors: Core-refining from benzimidazole to indole scaffold

Zhao, Fabao; Liu, Na; Zhan, Peng; Jiang, Xuemei; Liu, Xinyong

doi:10.1016/j.ejmech.2015.03.012

Cited by 26 publications

(24 citation statements)

References 44 publications

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“…Benzimidazoles and indoles are natural compounds and their aromatic heterocyclic structures are widely used for pharmaceutical synthesis and modification. Many benzimidazole or indole core-based derivatives have good activity against various microbials, such as fungi and bacteria 17,18. Previous studies revealed that tri-substituted benzimidazole derivatives and indole derivatives (Figure 1) can inhibit effectively the growth of bacterial strains such as M. tuberculosis, S. aureus, and B. subtilis via disrupting FtsZ activity 19–22.…”

Section: Introductionmentioning

confidence: 99%

<p>Indole-core-based novel antibacterial agent targeting FtsZ</p>

Yuan¹,

Yu²,

Song³

et al. 2019

IDR

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Background The prevalence of drug-resistant bacterial infections urges the development of new antibacterial agents that possess a mechanism of action different from traditional antibiotics. FtsZ has been recognized as a key functional protein in bacterial cell division and it is currently believed to be a potential target for the development of novel antibacterial agents. Purpose The primary aim of the study is to screen out an inhibitor targeting at FtsZ and followed to investigate its antibacterial activity and mode of action. Methods Cell-based cell division inhibitory screening assay, antimicrobial susceptibility test, minimum bactericidal concentration assay, time-killing curve determination, FtsZ polymerization assay, GTPase activity assay, and molecular modeling were performed in the present study. Results The screening study from a small library consisting of benzimidazole and indole derivatives discovered a compound (CZ74) with an indole-core structure. The compound exhibited strong cell division inhibitory effect. In addition, CZ74 shows high antibacterial potency against a number of tested Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus . The minimum inhibitory concentration values obtained were within the range of 2–4 µg/mL. The results of biological study revealed that CZ74 at 2 µg/mL is able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division. From molecular modeling study, CZ74 is found possibly binding into the interdomain cleft of FtsZ protein and then leads to inhibitory effects. Conclusion This indole-cored molecule CZ74 could be a potential lead compound and could be further developed as a new generation of antibacterial agents targeting FtsZ to combat against multidrug-resistant bacteria.

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Section: Introductionmentioning

confidence: 99%

<p>Indole-core-based novel antibacterial agent targeting FtsZ</p>

Yuan¹,

Yu²,

Song³

et al. 2019

IDR

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“…Several compounds with a benzimidazole moiety were found to possess anti-HCV replication activity [ 22 , 23 , 24 , 25 , 26 ]. Most of them were shown to block exclusively HCV replication through inhibition of viral RNA-dependent RNA polymerase (RDRP), NS5B.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Hepatitis C Virus Genome Replication and Particle Production by a Novel Diacylglycerol Acyltransferases Inhibitor

et al. 2018

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Diacylglycerol acyltransferases (DGATs) play a critical role in the biosynthesis of endogenous triglycerides (TGs) and formation of lipid droplets (LDs) in the liver. In particular, one member of DGATs, DGAT-1 was reported to be an essential host factor for the efficient production of hepatitis C virus (HCV) particles. By utilizing our previously characterized three different groups of twelve DGAT inhibitors, we found that one of the DGAT inhibitors, a 2-((4-adamantylphenoxy) methyl)-N-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxam (10j) is a potent suppressor of both HCV genome replication and particle production. 10j was able to induce inhibition of these two critical viral functions in a mutually separate manner. Abrogation of the viral genome replication by 10j led to a significant reduction in the viral protein expression as well. Interestingly, we found that its antiviral effect did not depend on the reduction of TG biosynthesis by 10j. This suggests that the inhibitory activity of 10j against DGATs may not be directly related with its antiviral action.

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“…Thirty-five (35) imidazole derivatives compounds were selected from the literature (Zhao et al, 2015). The compounds were divided into a training set 80and test set (20) to validate the model.…”

Section: Methodsmentioning

confidence: 99%

Quantitative structure-activity relationship and molecular docking studies of some series of imidazole derivatives as anti-hepatitis C drug

Bello¹,

Uzairu²,

Shallangwa³

et al. 2019

Bayero J. Pure App. Sci.

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Hepatitis C virus (HCV) NS5B RNA enzyme in HCV viral replication and has no functional equivalent in mammalian cells. In silico study was carried out to develop a Quantitative structure activity molecular docking on some selected imidazole derivatives as anti Density functional theory with B3LYP/6 optimization Five QSAR models were generated using Genetic Function Algorithm (GFA) of the material studio software version 8, in which model one (1) was selected as the best model and reported based on the validation parameter with the squared correlation coefficient (R 2) of 0.7114. Adjusted squared correlation coefficient (R 0.6458 and cross-validation coefficient (Q was subjected to external validation and was found to be R obtained from molecular docking studies shows that the compound with the be affinity of-10.7 Kcal/mol formed hydrogen bonding of (GLN hydrophobic interaction with the amino acid residues of the polymerase(NS5B polymerase) propose the direction of designing new imidazole derivatives agent with better activity against the NS5B polymerase target site.

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Discovery of HCV NS5B thumb site I inhibitors: Core-refining from benzimidazole to indole scaffold

Cited by 26 publications

References 44 publications

<p>Indole-core-based novel antibacterial agent targeting FtsZ</p>

<p>Indole-core-based novel antibacterial agent targeting FtsZ</p>

Suppression of Hepatitis C Virus Genome Replication and Particle Production by a Novel Diacylglycerol Acyltransferases Inhibitor

Quantitative structure-activity relationship and molecular docking studies of some series of imidazole derivatives as anti-hepatitis C drug

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