Synthesis and evaluation of 1-hydroxy/methoxy-4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid derivatives as non-purine xanthine oxidase inhibitors

Eur J Med Chem. 2015 Oct 20:103:343-53. doi: 10.1016/j.ejmech.2015.08.056. Epub 2015 Sep 3.

Abstract

Xanthine oxidase is a key enzyme that catalyses hypoxanthine and xanthine to uric acid, whose overproduction leads to the gout-causing hyperuricemia. In this study, a series of 1-hydroxy/methoxy-4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid derivatives (4a-4k and 6a-6k) was synthesized and evaluated for their inhibitory potency against xanthine oxidase. The 1-hydroxyl substituted derivatives 4a-4k showed excellent inhibitory potency with IC50 values ranging from 0.003 μM to 1.2 μM, with compounds 4d (IC₅₀ = 0.003 μM), 4e (IC₅₀ = 0.003 μM), and 4f (IC₅₀ = 0.006 μM) manifesting the most potent xanthine oxidase inhibitory potency that were comparable with that of Febuxostat (IC₅₀ = 0.01 μM). Lineweaver-Burk plot analysis revealed that representative compound 4f acted as a mixed-type inhibitor for xanthine oxidase. The basis of significant inhibition of xanthine oxidase by 4f was rationalized by its molecular docking into the active site of xanthine dehydrogenase.

Keywords: 4-Methyl-2-phenyl-1H-imidazole-5-carboxylic acid; Gout; Xanthine oxidase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • Cattle
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Xanthine Oxidase / antagonists & inhibitors*
  • Xanthine Oxidase / metabolism

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Imidazoles
  • imidazole
  • Xanthine Oxidase