Exploration of Pyridine‐4‐hydrazide Derivatives as Promising Antitubercular Agents: Synthesis, Biological Evaluation, and In Silico Studies

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), remains a major global health concern, exacerbated by the rise of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains. Pyridine‐4‐carbohydrazide (isoniazid), a frontline anti‐TB drug, is limited by high dosage requirements and associated toxicity. To overcome these limitations, a novel series of isoniazid‐based derivatives were synthesized and evaluated for antitubercular activity. Several compounds exhibited potent inhibition against Mtb H 37 Rv, with minimum inhibitory concentrations (MICs) ranging from 0.125 to 2 µg/mL. Among them, compounds 5j, 5k, 5o , and 5p emerged as lead candidates, showing strong activity against MDR clinical isolates. Cytotoxicity evaluation using Vero cells revealed excellent safety profiles, with selectivity indices (SI) ranging from 400 to 800. Time‐kill kinetics confirmed the bactericidal nature of compound 5p . In silico molecular docking and 3D‐QSAR (3D quantitative structure–activity relationship) studies were conducted to identify key structural features responsible for activity and to validate binding interactions with M. tuberculosis target enzymes. The computational studies correlated well with experimental data and supported favorable drug‐like properties. Overall, the synthesized derivatives demonstrate strong potential as next‐generation anti‐TB agents.