A rational approach for the design and synthesis of 1-acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles as a new class of potential non-purine xanthine oxidase inhibitors

Bioorg Med Chem. 2011 Mar 15;19(6):1950-8. doi: 10.1016/j.bmc.2011.01.058. Epub 2011 Feb 23.

Abstract

Xanthine oxidase is a complex molybdoflavoprotein that catalyses the hydroxylation of xanthine to uric acid. Fifty three analogues of 1-acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles were rationally designed and synthesized and evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Some notions about structure activity relationships are presented. Six compounds 41, 42, 44, 46, 55 and 59 were found to be most active against XO with IC(50) ranging from 5.3 μM to 15.2 μM. The compound 59 emerged as the most potent XO inhibitor (IC(50)=5.3 μM). Some of the important interactions of 59 with the amino acid residues of active site of XO have been figured out by molecular modeling.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Computer Simulation
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Isomerism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship
  • Xanthine Oxidase / antagonists & inhibitors*
  • Xanthine Oxidase / metabolism

Substances

  • Enzyme Inhibitors
  • Pyrazoles
  • Xanthine Oxidase