Methoxyphenol derivatives as reversible inhibitors of myeloperoxidase as potential antiatherosclerotic agents

Future Med Chem. 2020 Jan;12(2):95-110. doi: 10.4155/fmc-2019-0080. Epub 2019 Nov 26.

Abstract

Aim: To evaluate new chemical entities, based on ferulic acid scaffolds, as reversible myeloperoxidase inhibitors (MPOI). Methodology & results:In silico docking studies are performed with MPO protein as a target for several ferulic acid analogs followed by multiple in vitro assays to validate this approach. Two lead compounds 2a and 3 are identified with optimum docking and IC50 values: -7.95 kcal/mol, 0.9 μM and -8.35 kcal/mol, 8.5 μM, respectively. These MPOIs are able to inhibit oxidation of high-density lipoprotein and further promoted functionality of high-density lipoprotein. Conclusion: Lead analogs are potent MPOIs that exert specific effects on MPO-mediated oxidation as well as inflammatory pathways. It also acts as promoters of cholesterol efflux that sheds light on pharmacological approach in atherosclerosis treatment.

Keywords: HDL; LDL; cardiovascular; ferulic acid; hypochlorous acid; methoxyphenol; myeloperoxidase; proline.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arteriosclerosis / drug therapy*
  • Arteriosclerosis / metabolism
  • Coumaric Acids / chemical synthesis
  • Coumaric Acids / chemistry
  • Coumaric Acids / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Oxidation-Reduction
  • Peroxidase / antagonists & inhibitors*
  • Peroxidase / metabolism
  • Phenols / chemical synthesis
  • Phenols / chemistry
  • Phenols / pharmacology*

Substances

  • Coumaric Acids
  • Enzyme Inhibitors
  • Phenols
  • ferulic acid
  • Peroxidase