Development of Isoniazid-Pyrazole Hybrids as Potential Antitubercular Agents

A series of INH-pyrazole molecular hybrids ( 6a - o ) was synthesized and evaluated for in vitro anti-tubercular activity against drug-susceptible, multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains, alongside their corresponding precursors ( 4a - o ), using isoniazid (INH) as the reference drug. Overall, the hybrid compounds exhibited inhibitory activity comparable to or exceeding that of INH against the drug-susceptible strain. Among the series, compounds 6a , 6d - 6f , and 6m demonstrated the highest potency, with a minimum inhibitory concentration (MIC) of 0.9 µM, corresponding to an approximately 4.3-fold enhancement relative to INH. Compounds 6b , c , 6g - i , and 6l , m also showed noticeable activity (MIC = 1.95 µM), representing an approximate twofold improvement over INH and significantly outperforming their respective precursors. Notably, compound 6o exhibited enhanced activity against the XDR strain (MIC = 121 µM), reflecting an approximately 2.8-fold improvement compared to precursor 4o (MIC > 341 µM), thereby highlighting the advantage of molecular hybridization. However, all compounds displayed diminished activity relative to INH against the resistant strains. Against the MDR strain, compounds 4h , 6e , and 6g displayed measurable activity, with MIC values of 76, 125, and 112 µM, respectively. Cytotoxicity assessment using THP-1 human monocytic cells revealed low toxicity, with all tested compounds maintaining acceptable cell viability at 10 µg/mL. In addition, in silico ADME analysis indicated that the hybrid molecules comply with key drug-likeness criteria. Collectively, these findings suggest that INH-pyrazole hybrids represent promising lead scaffolds for the development of next-generation anti-tubercular agents.