Design, synthesis, and pharmacological profiling of benzimidazole-based isoniazid analogues: A comprehensive investigation into antitubercular activity, molecular characterization, and computational study

In the present study, a series of novel N'-(2-(2-phenyl-1H-benzo[ d ]imidazole-1-yl)acetyl)isonicotinohydrazide ( 5a-p) and N'-(2-(1H-benzo[ d ]imidazole-1-yl)acetyl)isonicotinohydrazide (5'a-d) compounds were synthesized and evaluated for their pharmacological activities, including antibacterial, antitubercular, MDR-TB, and antioxidant properties. The synthesis involved the condensation of ethyl 2-(1 H -benzo[ d ]imidazole-1-yl)acetate ( 4a-p and 4'a-d ) with nicotinic hydrazide. Comprehensive structural analyses, including 1 H NMR, 13 C NMR, IR, mass spectrometry, and CHN analyses, confirmed the formation of the newly synthesized compounds. The in vitro biological activity assessment revealed that certain compounds exhibited notable activity, as evidenced by their lowest MICs. Additionally, an in-silico computational study was conducted to evaluate the Absorption, Distribution, Metabolism, and Excretion (ADME) pharmacokinetic properties of the compounds. Molecular docking studies against the enoyl-ACP reductase enzyme, utilizing two different Protein Data Bank structures ( PDBs : 4TZK and 4TZT), were performed. Moreover, a molecular dynamics study was undertaken to assess the stability of the ligand (5g) -receptor (4TZK) complex. Our findings suggested that these synthesized derivatives have the potential to serve as promising lead molecules for the development of effective antitubercular agents in the future. • Biologically significant benzimidazole-based isoniazid derivatives were synthesized and tested for their efficacy. • Compounds 5e, 5f, 5g, 5h, 5n, 5'b , and 5'd displayed notable activity against Mycobacterium tuberculosis . • Compounds 5e, 5h, 5n, and 5'd showed superior inhibitory percentages anti-oxident activity. • Molecular docking study revealed that compounds 5g exhibited strong binding affinities.