Abstract
Based on the observed pharmacophoric structural features for the reported dual COX/15-LOX inhibitors and inspired by the abundance of COX/LOX inhibitory activities reported for the 1,2,4-triazine and quinoline scaffolds, we designed and synthesized novel 1,2,4-triazine-quinoline hybrids (8a-n). The synthesized hybrids were evaluated in vitro as dual COXs/15-LOX inhibitors. The new triazine-quinoline hybrids (8a-n) exhibited potent COX-2 inhibitory profiles (IC50 = 0.047-0.32 mu M, SI similar to 20.6-265.9) compared to celecoxib (IC50 = 0.045 mu M, SI similar to 326). Moreover, they revealed potent inhibitory activities against 15-LOX enzyme compared to reference quercetin (IC50 = 1.81-3.60 vs. 3.34 mu M). Hybrid 8e was the most potent and selective dual COX-2/15-LOX inhibitor (COX-2 IC50 = 0.047 mu M, SI = 265.9, 15-LOX IC50 = 1.81 mu M). These hybrids were further challenged by their ability to inhibit NO, ROS, TNF-alpha, IL-6 inflammatory mediators, and 15-LOX product, 15-HETE, production in LPS-activated RAW 264.7 macrophages cells. Compound 8e was the most potent hybrid in reducing ROS and 15-HETE levels showing IC50 values of 1.02 mu M (11-fold more potent than that of celecoxib, IC50 = 11.75 mu M) and 0.17 mu M (about 43 times more potent than celecoxib, IC50 = 7.46 mu M), respectively. Hybrid 8h exhibited an outstanding TNF-alpha inhibition with IC50 value of 0.40 mu M which was about 25 times more potent than that of celecoxib and diclofenac (IC50 = 10.69 and 10.27 mu M, respectively). Docking study of the synthesized hybrids into the active sites of COX-2 and 15-LOX enzymes ensures their favored binding affinity. To our knowledge, herein we reported the first 1,2,4-triazine-quinoline hybrids as dual COX/15-LOX inhibitors. (C) 2021 Elsevier Masson SAS. All rights reserved.