Novel 1,2,4-triazine-quinoline hybrids: The privileged scaffolds as potent multi-target inhibitors of LPS-induced inflammatory response via dual COX-2 and 15-LOX inhibition.

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 invitro as dual COXs/15-LOX inhibitors. The new triazine-quinoline hybrids (8a-n) exhibited potent COX-2 inhibitory profiles (IC50=0.047-0.32μM, SI∼20.6-265.9) compared to celecoxib (IC50=0.045μM, SI∼326). Moreover, they revealed potent inhibitory activities against 15-LOX enzyme compared to reference quercetin (IC50=1.81-3.60 vs. 3.34μM). Hybrid 8e was the most potent and selective dual COX-2/15-LOX inhibitor (COX-2 IC50=0.047μM, SI=265.9, 15-LOX IC50=1.81μM). These hybrids were further challenged by their ability to inhibit NO, ROS, TNF-α, 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 1.02μM (11-fold more potent than that of celecoxib, IC50=11.75μM) and 0.17μM (about 43 times more potent than celecoxib, IC50=7.46μM), respectively. Hybrid 8h exhibited an outstanding TNF-α inhibition with IC50 value of 0.40μM which was about 25 times more potent than that of celecoxib and diclofenac (IC50=10.69 and 10.27μM, 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.