Design, Synthesis and Molecular Docking of New Benzimidazole Derivatives of Potential Antimicrobial Activity as DNA Gyrase and Topoisomerase IV Inhibitors

Document Type : Original Article


1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt

2 Department of Therapeutic Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt

3 Chemistry of Natural and Microbial Products Department, National Research Centre, Dokki, Cairo, 12622, Egypt

4 Chemistry Department, Faculty of Pharmacy October 6 University El-Giza, Egypt


A new series of benzimidazole derivatives 3a-3d, 4a-4c, 8a-8d, 9a,9b, 10a-10d and 11 was synthesized and evaluated as antimicrobial agents against various gram-positive, gram-negative bacteria and fungi using vibramycin and fluconazole as positive controls for the antibacterial and antifungal activities, respectively. The examined microbial strains showed variable sensitivities against the target compounds.The examined microbial strains showed variable sensitivities against the target compounds. The minimum inhibitory concentration (MIC) was determined for the compounds showed zone of inhibition ≥ 16 mm (4a, 4c, 8a, 10a). The latter derivatives were also examined as S. aureus DNA gyrase/topoisomerase IV inhibitors. The compounds 4a, and 8a represented the most promising activity for both enzymes in ATPase assay (IC50 4a 0.39, 0.52 and 8a 0.66, 0.28 µM respectively) as well as the safest profile against the human normal WI38 cells upon comparing with Ciprofloxacin and Novobiocin. Compounds 8a showed dual inhibitory effect against both targets DNA gyrase and topoisomerase IV in supercoiling and decatenation assay (IC50 0.443 and 1.15 µM respectively). Both compounds 4a and 8a can be considered as lead compounds for further structural modifications to obtain more potent DNA gyrase and topoisomerase inhibitors as antibacterial agents. Molecular docking study was performed for the most promising compounds to explore the pharmacophoric moieties that governed their binding with amino acid residues of DNA gyrase and topoisomerase IV using MOE software. The results revealed a binding mode and docking scores comparable to those of a reference ligand and consistent with their DNA gyrase and topoisomerase IV inhibition activity.


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