Design, synthesis, and biological evaluation of 1,5-diaryl-1,2,4-triazole derivatives as selective cyclooxygenase-2 inhibitors.

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.