Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors

Eur J Med Chem. 2015 Aug 28:101:573-83. doi: 10.1016/j.ejmech.2015.07.011. Epub 2015 Jul 15.

Abstract

In this work the synthesis, structure-activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 μm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization.

Keywords: 5-Lipoxygenase inhibitor; Caffeic acid; Inflammation; Polyphenol; Triazole; Zileuton.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Caffeic Acids / chemical synthesis
  • Caffeic Acids / chemistry
  • Caffeic Acids / pharmacology*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Male
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • U937 Cells

Substances

  • Caffeic Acids
  • Lipoxygenase Inhibitors
  • Triazoles
  • Arachidonate 5-Lipoxygenase
  • caffeic acid