Exploration of novel isoniazid embedded 1,3,4-oxadiazole hybrids as anti-TB, antioxidant, and COX inhibitors: synthesis, spectral analysis, and molecular modeling studies

A series of novel 2-(chloromethyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole (3a-h) derivatives have been synthesized as potential anti-TB, antioxidant, and COX inhibitors. The structure of these derivatives is confirmed by the IR, NMR (¹H and ¹³C), and mass spectral analysis. All the newly synthesized derivatives were evaluated for their physicochemical properties by Swiss ADME. Based on our previous work and structural activity relationship study, foresaid isoniazid derivatives were evaluated for in vitro anti-TB, antioxidant, and COX inhibitory activity. The compound 3f exhibited outstanding anti-TB activity with a MIC value of 0.8 μg/mL. The compounds 3d, 3f, and 3h proved promising antioxidant activity at a concentration of 10 μg/ml with inhibition rates of 66.12%, 67.59%, and 66.28%, respectively. The compounds 3e, 3f, and 3h established excellent COX-I inhibitions with IC₅₀ values of 4.21, 3.24, and 4.89 μM compared to standard drugs. Finally, the molecular docking studies carried out with Mycobacterium tuberculosis enoyl reductase (INHA) complexed with 1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide (PDB ID: 4TZK), cytochrome c peroxidase (PDB ID: 2X08), and cyclooxygenase-2 (PDB ID: 6COX) for all the newly synthesized derivatives.

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