Design, synthesis and antitubercular evaluation of 2,5-disubstituted 1,3,4-oxadiazoles bearing a 3,5-dinitrophenyl pharmacophore.

Tuberculosis (TB) continues to demand new chemotypes able to overcome acquired drug-resistance. Here, we designed and synthesized two related series of twenty 3,5-dinitrophenyl-based 1,2-diacylhydrazines and their cyclic analogues, 2,5-disubstituted 1,3,4-oxadiazoles, using 1,2-diacylhydrazine formation followed by cyclodehydration to the oxadiazole core. This approach proved decisive, as the oxadiazoles displayed a broader and markedly stronger antimycobacterial profile than their precursors. The synthesized derivatives inhibited drug-susceptible Mycobacterium tuberculosis H37Rv from 0.125 μM, retained potent activity against drug-resistant TB isolates (0.125-1 μM), and remained active against non-tuberculous mycobacteria (M. kansasii, M. avium), with 2-(3,5-dinitrophenyl)-5-(quinolin-6-yl)-1,3,4-oxadiazole 4t emerging as the most balanced lead across all strains tested. In addition to their anti-TB activity, selected oxadiazoles also displayed complementary antibacterial effects, particularly against Gram-positive bacteria including MRSA and Staphylococcus epidermidis (MIC values from 31.25 μM), whereas antifungal activity was generally limited. Importantly, the most active compounds combined high antimycobacterial potency with low cytotoxicity, and haemolytic activity was also low. Taken together, these data identify 3,5-dinitrophenyl-substituted 1,3,4-oxadiazoles as a synthetically accessible and highly promising platform for further development of selective anti-TB agents.