Design, synthesis and pharmacobiological evaluation of novel acrylic acid derivatives acting as lipoxygenase and cyclooxygenase-1 inhibitors with antioxidant and anti-inflammatory activities

Eur J Med Chem. 2011 Jan;46(1):191-200. doi: 10.1016/j.ejmech.2010.10.035. Epub 2010 Nov 4.

Abstract

A series of novel acrylic acid derivatives bearing at the 3 position thienyl, furfuryl and 3,5-ditert-butyl-4-hydroxyphenyl substituents have been designed, synthesized and tested as potential dual lipoxygenase/cyclooxygenase-1 (LOX/COX-1) inhibitors and as antioxidant and anti-inflammatory agents. Some compounds have shown moderate antioxidant and COX-1 inhibitory activities, very good anti-inflammatory activity and an inhibition of soybean lipoxygenase (LOX) higher than caffeic acid. In particular, compound 4I disclosed a moderate in vitro LOX inhibition with an IC(50) = 100 μM whereas compounds 1I and 2II exhibited the best, albeit poor, activity as COX-1 inhibition (75% inhibition at 100 μM). Good radical scavenging properties were shown by compounds 4I, 3I and 1II. Docking simulations performed on LOX inhibitor 4I and COX-1 inhibitor 1I indicated that hydrophobic key interactions may govern the enzyme-inhibitor binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylates / chemical synthesis*
  • Acrylates / chemistry
  • Acrylates / pharmacology*
  • Acrylates / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Antioxidants / therapeutic use
  • Binding Sites
  • Cyclooxygenase 1 / chemistry
  • Cyclooxygenase 1 / metabolism*
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cyclooxygenase Inhibitors / therapeutic use
  • Drug Design*
  • Female
  • Free Radical Scavengers / chemical synthesis
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / pharmacology
  • Free Radical Scavengers / therapeutic use
  • Glycine max / enzymology
  • Inflammation / drug therapy
  • Lipoxygenase / chemistry
  • Lipoxygenase / metabolism
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Lipoxygenase Inhibitors / therapeutic use
  • Male
  • Models, Molecular
  • Protein Conformation
  • Rats

Substances

  • Acrylates
  • Anti-Inflammatory Agents
  • Antioxidants
  • Cyclooxygenase Inhibitors
  • Free Radical Scavengers
  • Lipoxygenase Inhibitors
  • Lipoxygenase
  • Cyclooxygenase 1
  • acrylic acid