Design, synthesis and biological evaluation of novel 2- (indole arylamide) benzoic acid analogs as dual COX-2 / 5-LOX inhibitors

Abstract

Recently, the drug discovery paradigm has evolved from single-target inhibition to a multi-target design concept. This study designed, synthesized, and evaluated a series of novel 2-(indole arylamide) benzoic acid analogs for their in vivo anti-inflammatory properties. Compounds 7f and 7n showed significant anti-inflammatory activity in a xylene-induced mouse model of auricular edema. Furthermore, 7f and 7n exhibited moderate COX-2 inhibitory activity (IC50 = 537 and 321.5 nM) than celecoxib (IC50 = 10.04 nM) in vitro, among which 7n had higher COX-2 selectivity activity (selectivity index (COX-1/COX-2) = 7.89) and moderate 5-LOX inhibitory activity (IC50 = 222.1 nM). Compared to zileuton (IC50 = 36.46 nM), compound 7f was identified as the most potent 5-LOX inhibitor (IC50 = 77.37 nM). According to the biological results, compounds 7f and 7n have better inhibitory activities on the production of NO and PGE2 in LPS-induced RAW 264.7 cell macrophages than celecoxib and indomethacin. As demonstrated by docking studies, 7f and 7n have stronger interactions with key residues in the active pocket of COX-1 or COX-2, which is consistent with the activity results. Based on these results, further research into safer and more effective anti-inflammatory drugs might be possible using 2-(indole arylamide) benzoic acid analogs.