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

摘要

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 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX-2 IC₅₀ = 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.