1. 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
- Author
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Samar Rezq, Tarek S. Ibrahim, Damian G. Romero, Hend Kothayer, and Amany M. Ghanim
- Subjects
Lipopolysaccharides ,Anti-Inflammatory Agents ,Pharmacology ,Nitric Oxide ,01 natural sciences ,Article ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Diclofenac ,Catalytic Domain ,Drug Discovery ,medicine ,Animals ,Arachidonate 15-Lipoxygenase ,Lipoxygenase Inhibitors ,IC50 ,030304 developmental biology ,Inflammation ,chemistry.chemical_classification ,0303 health sciences ,Binding Sites ,Cyclooxygenase 2 Inhibitors ,Triazines ,010405 organic chemistry ,Macrophages ,Organic Chemistry ,Quinoline ,General Medicine ,0104 chemical sciences ,Molecular Docking Simulation ,RAW 264.7 Cells ,Enzyme ,chemistry ,Cyclooxygenase 2 ,Docking (molecular) ,Drug Design ,Quinolines ,Celecoxib ,Cytokines ,lipids (amino acids, peptides, and proteins) ,Tumor necrosis factor alpha ,Quercetin ,medicine.drug - 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 μM, SI ∼ 20.6–265.9) compared to celecoxib (IC50 = 0.045 μM, SI ∼ 326). Moreover, they revealed potent inhibitory activities against 15-LOX enzyme compared to reference quercetin (IC50 = 1.81–3.60 vs. 3.34 μM). Hybrid 8e was the most potent and selective dual COX-2/15-LOX inhibitor (COX-2 IC50 = 0.047 μM, SI = 265.9, 15-LOX IC50 = 1.81 μM). 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 1.02 μM (11-fold more potent than that of celecoxib, IC50 = 11.75 μM) and 0.17 μM (about 43 times more potent than celecoxib, IC50 = 7.46 μM), respectively. Hybrid 8h exhibited an outstanding TNF-α inhibition with IC50 value of 0.40 μM which was about 25 times more potent than that of celecoxib and diclofenac (IC50 = 10.69 and 10.27 μM, 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.
- Published
- 2021