2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2021 Jul 5:219:113457. doi: 10.1016/j.ejmech.2021.113457.
Amany M Ghanim 1,  Samar Rezq 2,  Tarek S Ibrahim 3,  Damian G Romero 4,  Hend Kothayer 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
  • 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt; Departments of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, USA; Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, USA; Cardio Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA.
  • 3 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
  • 4 Departments of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, USA; Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, USA; Cardio Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA.
  • 5 Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Egypt. Electronic address: hendo1311@hotmail.com.
PMID: 33892270 DOI: 10.1016/j.ejmech.2021.113457
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.

Keywords

1,2,4-Triazine; Docking; Dual COX-2/15-LOX inhibitors; Invitro anti-inflammatory; Quinoline.

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