Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities

J Enzyme Inhib Med Chem. 2016 Dec;31(6):1602-11. doi: 10.3109/14756366.2016.1158713. Epub 2016 Mar 30.

Abstract

A set of 1,2,4-triazine derivatives were designed as cyclooxygenase-2 (COX-2) inhibitors. These compounds were synthesized and screened for inhibition of cyclooxygenases (COX-1 and COX-2) based on a cellular assay using human whole blood (HWB) and lipoxygenase (LOX-15) that are key enzymes in inflammation. The results showed that 3-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (G11) was identified as the most potent COX-2 inhibitor (78%) relative to COX-1 (50%). Ferric reducing anti-oxidant power (FRAP) assay revealed that compound G10 possesses the highest anti-oxidant activity. The compound G3 with IC50 value of 124 μM was the most potent compound in LOX inhibitory assay. Molecular docking was performed and a good agreement was observed between computational and experimental results.

Keywords: 1,2,4-triazine; 15-lipoxygenase; Cyclooxygenase; FRAP assay; molecular modeling.

MeSH terms

  • Antioxidants / chemistry*
  • Antioxidants / pharmacology
  • Cyclooxygenase 2 Inhibitors / chemistry*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Humans
  • Lipoxygenase Inhibitors / chemistry*
  • Lipoxygenase Inhibitors / pharmacology*
  • Mass Spectrometry
  • Molecular Docking Simulation*
  • Molecular Structure
  • Proton Magnetic Resonance Spectroscopy
  • Spectrophotometry, Infrared
  • Triazines / chemistry*
  • Triazines / pharmacology*

Substances

  • Antioxidants
  • Cyclooxygenase 2 Inhibitors
  • Lipoxygenase Inhibitors
  • Triazines
  • 1,2,4-triazine