Design, synthesis, and biological evaluation of dual-target COX-2/5-LOX inhibitors for the treatment of inflammation

The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) have been considered to be associated with the occurrence and development of a variety of diseases, including inflammatory. Compared to classical NSAIDs, the dual COX-2/5-LOX inhibition is an effective strategy for designing compounds with more effective biological activities, fewer side effects, and a broader anti-inflammatory spectrum. In this study, we designed and synthesized a series of novel indole and indazole arylamide benzoic acid analogues as dual COX-2 / 5-LOX inhibitors and evaluated their anti-inflammatory properties in vivo. 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 indole arylamide benzoic acid analogs.