New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling

Eur J Med Chem. 2018 Feb 25:146:577-587. doi: 10.1016/j.ejmech.2018.01.054. Epub 2018 Jan 31.

Abstract

In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX-2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE2 production. Among them, compound 5d exhibited the most potent inhibitory activity with a PGE2 inhibition compared to NS-398 (79% and 88% respectively) and showed non-inhibitory activity towards the COX-1 enzyme. Docking studies revealed the capacity of this compound to occupy the selective COX-2 cavity establishing additional hydrogen bonds between the oxygen of the methoxy group and the His90 and Arg513 of the binding site of the enzyme.

Keywords: Anti-inflammatory; COX-1/COX-2 inhibition; COX-2 inhibitors; Cyclocoumarol; Cyclooxygenase; Docking study.

MeSH terms

  • 4-Hydroxycoumarins / chemical synthesis
  • 4-Hydroxycoumarins / chemistry
  • 4-Hydroxycoumarins / pharmacology*
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / chemical synthesis
  • Cyclooxygenase 2 Inhibitors / chemistry
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • 4-Hydroxycoumarins
  • Cyclooxygenase 2 Inhibitors
  • cyclocumarol
  • Cyclooxygenase 2