Synthesis of 1,3,4-oxadiazole derivatives via transition metal catalyzed cross-coupling and their biological evaluation as selective inhibitors of Ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)-2, -3 and -8 inhibitors

Oxadiazole-based drugs, such as raltegravir, zibotentan, furamizole, and nesapidil exhibit the potential to act as neuraminidase inhibitors, ecto-nucleoside triphosphate diphosphohydrolase inhibitors, urease inhibitors, liver X receptor agonists, M4 receptor agonists, orexin type-2 receptor agonists, SSTR5 antagonists, and S1P1 receptor modulators. In the present study, Suzuki, Heck, Sonogashira, and Goldberg cross-coupling were employed to synthesize 1,3,4-oxadiazole derivatives from iodophenyloxadiazole and various coupling partners. The ecto-nucleotidases have been associated with various health disorders such as cancer, chronic renal failure, diabetes, hypertension, and hypercholesterolemia. The ability of the synthesized oxadiazole-based compounds to minimize the enzyme activity was examined against h-NTPDase2, hNTPDase3, and h-NTPDase8 at 100 μM concentrations. As a result, compound 3f was identified as the most potent inhibitor of h-NTPDase2, which presented the IC₅₀ of 0.25 ± 0.21 µM. Compound 3d exhibited a significant inhibition of h-NTPDase3 (IC50 = 1.27 ± 0.08 µM) whereas, the compound 4c was the most active and selective inhibitor of the isozyme h-NTPDase8 (IC50 = 0.18 ± 0.01 µM). Molecular docking studies of the most potent and selective inhibitors validated the in vitro findings, providing insights into their binding interactions.[Figure