Design and synthesis of new benzimidazole-hybrids as anti-microbial agents: exploring the mechanistic insights as DNA gyrase inhibitors via in silico and in vitro based studies

Two series of Antibacterial agents, 1,2,3-triazole and aminopyrimidine benzimidazole hybrids, were designed, synthesized, and characterized by IR, NMR, Mass spectroscopy, and X-ray crystallography studies. The biological studies revealed that compounds 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 8d, 8e, 9d, 9e, 9f, 9h, 9j, and 9k exhibited significant Antibacterial activity in vitro compared to the standard drug ciprofloxacin, against Gram-positive and Gram-negative Bacterial strains. The study of hemotoxicity displayed a negligible toxicity profile for all the compounds. Furthermore, the mechanistic insights predicted via molecular docking studies on DNA gyrase revealed (Glide Scores) that compounds 5c and 5f possess better affinity within the active domain of DNA gyrase, which was further corroborated using molecular dynamics followed by direct DNA gyrase-based inhibition assays. Compound 5f was the most potent, while 5c showed an equipotent inhibition compared to a standard drug.

1,2,3-triazole; Benzimidazole; DNA gyrase-based inhibition; molecular docking; molecular dynamic simulation.