Design, Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

Abstract A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity ( P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro , compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC 50 = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC 50 = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.