Design and Synthesis of Schiff Bases and 1,3,4‐Oxadiazole Derivatives as Anti‐Tubercular Agents

ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis , remains a major global health concern, necessitating the need for safer and more effective therapeutics. In this study, Schiff bases (5a–g) and their 1,3,4‐oxadiazole derivatives (6a–g) were synthesized and screened against the M. tuberculosis H37Rv strain using the Microplate Alamar Blue Assay (MABA). Five compounds 5c, 5g, 6d, 6g, and 6f exhibited strong anti‐TB activity with MICs of 3.125–6.25 µg/mL, comparable to ethambutol and pyrazinamide. Cytotoxicity studies on HEK‐293 cells and selectivity index (SI) evaluation revealed compound 5g as the most promising candidate, with the highest SI (736.95) and lowest cytotoxicity (IC 50 = 2303 ± 25.96 µg/mL). Compounds 6g and 6f also showed favorable safety, with IC 50 values of 688 ± 28.31 and 1060 ± 19.43 µg/mL and SI values of 220.16 and 169.6, respectively. In silico ADMET profiling confirmed the drug‐likeness of 5g, while molecular docking suggested strong interactions with key TB targets InhA and arabinosyltransferase. Overall, Schiff base and 1,3,4‐oxadiazole scaffolds demonstrate significant potential as leads for novel anti‐TB agents, warranting further pharmacokinetic and in vivo studies.