Isonicotinoyl-butanoic acid hydrazone derivatives as anti-tubercular agents: In-silico studies, synthesis, spectral characterization and biological evaluation

A series of novel 4-(2-isonicotinoylhydrazono)-4-aroylbutanoic acid derivatives (3a-n) were designed, synthesized and characterized by 1H-NMR, 13C-NMR, and mass spectroscopic analyses. The synthesized compounds evaluated for anti-tubercular activity against various M. tb strains showed potent anti-tubercular activity with MIC = 1 µg/ml for 3a, 3b, 3i and 3j against both H37Ra and H37Rv M. tb strains. MBC demonstrated that the synthesized compounds showed good bacteriocidal effect against both H37Ra and H37Rv M. tb strains with equivalent MIC and MBC values. All the compounds were found moderately active against the INH-resistant clinical isolates of M. tb with MIC 64 µg/ml. The most active compounds of the series (3a, 3b and 3i) were evaluated as non-cytotoxic towards normal human cell lines. In-silico docking studies and binding interactions of the synthesized compounds and INH revealed binding affinity towards the active site of the protein target M. tb InhA complexed with NADH (PDB ID: 4DRE). Among the most active compounds, 3a exhibited better binding affinity of -7.798 kcal/mol as compared to standard, INH (−6.925 kcal/mol). Compound 3a displayed hydrogen bonding between nitrogen of the pyridine ring and NH of VAL 65 and aromatic hydrogen bonding with C = O of LYS 63. Both phenyl ring and pyridine ring of the compound 3a exhibited π-π stacking interactions with phenyl ring of PHE 41 and hydrogen bonding between carboxylic oxygen of compound 3a and SER 20. 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.