Isonicotinoylhydrazonobutanoic acidderivatives as anti-tubercular agents: In-silico studies, synthesis, spectral characterization and biological evaluation.

Abstract

Abstract A series of novel 4-(2-isonicotinoylhydrazono) butanoic acid derivatives (3a-n) were designed, synthesized and evaluated for anti-tubercular activity. The synthesized compounds were characterized by 1H-NMR, 13C-NMR, FT-IR, and Mass Spectroscopic analyses. The synthesized compounds were evaluated for anti-mycobacterial activity against avirulent (H37Ra), virulent (H37Rv) as well as INH-Resistant strains that showed good to moderate activity. The MIC and MBC values observed were found identical for both H37Ra and H37Rv. 3a, 3c, 3e and 3i were found as the most potent in the series with a MIC and MBC = 1µg/ml. The compounds showed moderate activity against the INH-resistant clinical isolates as well. The potent compounds 3a, 3c and 3i showed least cytotoxicity towards normal human cell lines (HEK-293, AML12 and RAW-264). Molecular docking studies of the synthesized compounds performed with the protein target M. tuberculosis InhA in complex with NADH (PDB ID: 4DRE) revealed that compound 3c showed the best dock score of -7.798. The compound 3c forms two hydrogen bonds with Valine (VAL 65) and Serine (SER 20) whereas INH forms two hydrogen bonds with Valine (VAL 65) and Glycine (GLY 96). Both the benzene ring and pyridine ring of the compound 3c displayed the π-π interactions with Phenylalanine (PHE 41). Physicochemical properties and pharmacokinetic profiling assessed for the synthesized compounds were found to follow Lipinski’s rule using Swiss ADME online prediction tools. These findings make them promising candidates for the future development of new anti-tubercular agents.