Synthesis of novel halogenated triarylpyrazoles as selective COX-2 inhibitors: Anti-inflammatory activity, histopatholgical profile and in-silico studies

Abstract

A novel series of halogenated triarylpyrazoles 12a-l was designed and synthesized. All target compounds showed good in vitro COX-2 inhibitory activity (IC50 = 0.043–0.17 µM) over COX-1 (IC50 = 7.8 – 15.4 µM) relative to celecoxib (COX-1/IC50 = 9.87, COX-2/IC50 = 0.055), with acceptable selectivity index values (SI = 50.6–253.1). Also, they displayed moderate to potent in vivo anti-inflammatory activity (% edema inhibition = 16.9–87.9) comparable to celecoxib (% edema inhibition = 46.6–72.1) as standard drug. Three fluorinated pyrazoles 12a, 12g and 12j, exhibited superior anti-inflammatory activity at all time intervals (% edema inhibition = 42.1–87.9) with better gastric profile (UI = 1.25–2.5) than the traditional NSAID; indomethacin (UI = 14) and were close to the selective COX–2 inhibitor; celecoxib (UI = 1.75). In-silico docking and ADME studies of 12a, 12g and 12j supported the obtained biological data and pointed out their potential use for the development of bio-available, safe and potent anti-inflammatory drugs.