Rational Design and Antimycobacterial Evaluation of Aryl Sulfonamide-Linked Isoniazid Hydrazones Against Mycobacterium Tuberculosis.

Despite significant advancements in antituberculosis (TB) drug discovery, considerable scope remains for novel therapeutic development. Molecular hybridization represents a promising strategy for generating new anti-TB agents. In this study, in silico molecular docking is employed to design novel isoniazid-sulfonamide hybrids connected via a hydrazone bridge, designated as series 7j-r and 8a-i. Docking analysis reveals that these compounds interact significantly with the active site of InhA, particularly engaging the catalytic triad residues Y158, F149, and K165, as well as the cofactor NAD. Subsequently, both series are synthesized and evaluated against Mycobacterium tuberculosis. Generally, compounds from both series (7 and 8) exhibit enhanced activity compared to their precursors. Notably, compound 8a demonstrated approximately twofold greater potency ( minimum inhibitory concentration (MIC) = 0.156 µg mL^-1) with respect to compound 7j (MIC = 0.313 µg mL^-1). However, these compounds lose efficacy against INH-resistant M. tuberculosis strains harboring katG mutations and remain ineffective against multidrug-resistant and extensively drug-resistant strains of M. tuberculosis. Encouragingly, the tested compounds exhibit little cytotoxicity against the THP-1 human monocytic cell line at a concentration of 20 µg mL^-1. Additionally, the structural stability studies using ¹H NMR confirm the structural integrity of these compounds. Overall, these molecular hybrids are promising for further development as anti-TB agents after relevant structural optimizations.