Isoniazid-derived vanillin and Salicylaldehyde Hydrazones: Promising Antimycobacterials with KatG-dependent activation.

A series of hydrazones derived from vanillin and salicylaldehyde, incorporating isoniazid (INH) and its analogues (nicotinic hydrazide and pyrazine-2-carbohydrazide), were designed, synthesized, and evaluated for anti-mycobacterial activity. The INH-bearing derivatives demonstrated significant activity against Mycobacterium tuberculosis (Mtb), with MIC values of 0.078-0.625 μg/ml. Salicylaldehyde-based hydrazones exhibited the highest potency (MIC = 0.078 μg/ml), whereas vanillin analogs showed marginally reduced activity, potentially due to linker length effects. All compounds were non-toxic to THP-1 macrophages at concentrations <10 μg/ml, suggesting a favourable safety profile. UV-vis studies showed that the salicylaldehyde-based hydrazone 5d is stable under mildly acidic conditions, suggesting that pH-triggered release of INH is unlikely inside Mtb infected cells. Additionally, their lack of activity against INH-resistant Mtb KatG mutants (MIC >10 μg/ml) implies a KatG-dependent activation mechanism, analogous to INH. These findings highlight the promise of Schiff base dimerization in developing safe and potent anti-tubercular agents, warranting further chemical optimization.