Synthesis of biphenyl oxazole derivatives via Suzuki coupling and biological evaluations as nucleotide pyrophosphatase/phosphodiesterase-1 and -3 inhibitors.

Oxazole derivatives are important medicinal compounds which are inhibitors of various enzymes such as NPP1, NPP2, NPP3, tyrosine kinase, dipeptidyl-peptidase IV, cyclooxygenase-2, and protein tyrosine phosphatase. In this study, an extensive range of new biologically active biphenyl oxazole derivatives was synthesized in high to excellent yields (57-93%) through Suzuki-Miyaura cross-coupling of bromophenyloxazole with different boronic acids. The reaction was carried out in wet toluene under mild conditions. Overexpression of nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and NPP3 has been associated with various health disorders including chondrocalcinosis, cancer, osteoarthritis, and type 2 diabetes. We evaluated the inhibitory potential and selectivity of the synthesized compounds (3a-3q) towards NPP1 and NPP3 at 100 µM concentrations. We found two compounds that were selective and potent inhibitors of these two enzymes on the artificial substrate thymidine 5'-monophosphate para-nitrophenyl ester: compound 3n inhibited NPP1 with an IC50 of 0.15 µM, and compound 3f inhibited NPP3 with an IC50 value of 0.17 µM. The compounds with promising inhibitory potential were docked inside the proteins of NPP1 and NPP3 isozymes to get insight into the plausible binding interactions with active site residues.