Synthesis and inhibitory effects of triarylpyrazoles on LPS-induced NO and PGE(2) productions in RAW 264.7 macrophages

Abstract

The inhibition of nitric oxide and prostaglandin E-2 productions is a very interesting research topic in the field of anti-inflammatory drug development. In the current study, a new series of 1,3,4-triarylpyrazole derivatives was synthesized and evaluated for their capabilities to inhibit nitric oxide and prostaglandin E-2 productions in lipopolysaccharide-induced RAW 264.7 macrophages. Among all the target analogs, the diarylurea hydroxyl compounds 1f and 1h possessing phenyl and 3-( trifluoromethyl) phenyl terminal moiety, respectively, showed the highest inhibitory effect on the production of prostaglandin E-2. Both compounds exerted equal activity to the reference compound NS-398 at 3 mu M concentration. This effect was due to inhibition cyclooxygenase-2 enzyme activity not inhibition of cyclooxygenase-2 protein expression. The IC50 value of compound 1f against lipopolysaccharide-induced prostaglandin E2 production in the macrophages was 1.12 mu M. In addition, compound 1j with urea linker, hydroxyl group, and 3,5-bis( trifluoromethyl) phenyl terminal ring was the strongest nitric oxide inhibitor. Western blot study showed that it exerted that effect through inhibition of inducible nitric oxide synthase protein expression.