Structural and computational supported development of 2,5-disubstituted-1,3,4-oxadiazole analogues as active LOX, urease, and α-glucosidase inhibitors.

A series of N-substituted analogues of 1,3,4-oxadiazole were synthesized and screened for their enzyme inhibitory activity against lipoxygenase, α-glucosidase, and urease enzymes. Spectroscopy studies including IR, 13C-NMR, and 1H-NMR techniques were used to confirm structures of the novel compounds obtained. Compounds 7a, 7f, 7i, 7l, and 7n were found to be the best inhibitor candidates with the highest % of inhibition (89.42 ± 1.33, 78.79 ± 1.29, 84.87 ± 1.53, 75.67 ± 1.62, and 89.54 ± 1.48, respectively) and the least IC50 values (7.15 ± 1.34, 14.26 ± 1.07, 9.12 ± 1.17, 14.31 ± 1.19, and 7.03 ± 1.08 µM, respectively) against α-glucosidase compared to acarbose used as a standard. Compounds 7b, 7h, and 7n were found to be the most potent with % of inhibition 92.2 ± 0.5, 94.5 ± 0.6, and 92.8 ± 0.8, respectively, and with the IC50 values 4 ± 1.05, 1.0 ± 0.3, and 1.5 ± 0.5 µM, respectively, against the lipoxygenase. With the IC50 value of 21.85 ± 1.43 µM and the percentage inhibition of 98.45 ± 1.69%, compound 7l was found to be more active in comparison with the standard drug thiourea. Docking analysis further supported these biological outcomes by demonstrating strong, well-oriented binding poses and favorable interaction profiles for the most active inhibitors.