TCS-isatin-INH triads as potent and selective anti-mycobacterial with high efficacy against Mycobacterium tuberculosis

A series of novel Triclosan–Isatin–Isoniazid triads were synthesized and evaluated for antitubercular activity. These hybrids showed potent efficacy against Mycobacterium tuberculosis with low minimum inhibitory concentrations (MICs) ranging from 0.78-1.56 μg/mL, along with high selectivity indices, indicating strong activity with minimal cytotoxicity in human macrophages. Time-kill assays revealed bactericidal effects, with some hybrids achieving sustained bacterial growth suppression comparable to INH at equivalent MICs. At higher doses, a 3-log reduction in bacterial viability was achieved within three days, with one triad showing an additional 1-log reduction by day six. Mechanistic evaluation using INH-resistant katG mutant strains revealed reduction in activity, indicating KatG-dependent bioactivation. Cytotoxicity assays confirmed low toxicity (IC 50 >100 μg/mL), underscoring their potential as safe and effective anti-TB agents. • Cu-promoted triclosan-isatin hybrids and triclosan-isatin-isoniazid triads were designed and assayed against mycobacteria. • triclosan-isatin-isoniazid triads ( 13b , 13d , 13e , 13f , 13g and 1 3k ) are promising compounds against M. tuberculosis. • They exhibit low MIC values and low toxicity on mammalian cells. • These compounds have potent bactericidal efficacy in vitro. • The compounds exhibited better binding in the active site of InhA as compared to isoniazid.