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 ectonucleotidases 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 mu M 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 mu M. Compound 3d exhibited a significant inhibition of h-NTPDase3 (IC50 = 1.27 +/- 0.08 mu M) whereas, the compound 4c was the most active and selective inhibitor of the isozyme h-NTPDase8 (IC50 = 0.18 +/- 0.01 mu M). Molecular docking studies of the most potent and selective inhibitors validated the in vitro findings, providing insights into their binding interactions.