In-silico Designing, Synthesis, SAR and Microbiological Evaluation of Novel Amide Derivatives of 2-(3-methylbenzo[b]thiophen-6-yl)-1- (3-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylic Acid

Abstract:

Aim/Background: Due to this increasing problem of antibiotic resistance, the number of different antibiotics available is dwindling and there are only a handful of new antibiotics in the drug development pipeline. Therefore, there is an urgent need for the development of new antimicrobial drugs. In the present study, we have synthesized and investigated antimicrobial activities of novel derivatives with molecular docking studies. Methods: In this article, amide derivatives of 2-(3-methylbenzo[b]thiophen-6-yl)-1-(3-nitrophenyl)-1Hbenzo[ d]imidazole-5-carboxylic acid were synthesized by focusing the aminoacyl-tRNA synthetase (AaRS) and tyrosyl-tRNA synthetase enzymes and inhibition by docking study leads to antimicrobial action. Studies were carried out on a designed amide library of derivatives with the help of Schrodinger’s maestro package and AutoDock Vina 4.2 of molecular docking software against crystal structure of enzymes (PDB ID: 1wny.PDBQT and1jil.PDBQT). Best 23 focused amide derivatives of 2-(3-methylbenzo[b]thiophen-6- yl)-1-(3-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylic acid were selected based upon their dock score for synthesis and further investigated for in vitro antimicrobial. Results: in vitro results revealed that a large number of synthesized compounds were found to possess excellent antimicrobial. Among the library, best compound B-1, B-7 and B-23 possessing excellent dock score by AutoDock Vina/Schrodinger’s maestro against 1wny. PDBQT:1jil.PDBQT is -10.2:-10.1/ -5.26:-5.456, -10.3:-10.0/-5.318:-5.231, -10.0:- 10.5/-5.609:-5.876 and as compared to standard drugs dock score -10.2:-10.6/-5.847:- 5.895, -9.8:-9.9/ -6.323:-6.13. Derivatives B-1, B-7 and B-23 also exhibited good MIC as compared to standard by tube dilution method. Conclusion: In-silico studies played an important role in designing the potent ligands against aminoacyl-tRNA synthetase (AaRS) and tyrosyl-tRNA synthetase enzymes as well as explained the binding pattern of designed and synthesized ligand within active pocket and good antimicrobial compounds can be used for in vivo studies for future.

Key words: Benzimidazole, Molecular Docking, 1wny.PDBQT, 1jil.PDBQT, Antimicrobial Activity.