Structure-activity relationship of 2,4,5-trioxoimidazolidines as inhibitors of thymidine phosphorylase

Eur J Med Chem. 2011 Apr;46(4):1165-71. doi: 10.1016/j.ejmech.2011.01.035. Epub 2011 Jan 31.

Abstract

Novel non-nucleobase-derived inhibitors of the angiogenic enzyme, thymidine phosphorylase, have been identified using molecular modelling, synthesis and biological evaluation. These inhibitors are 2,4,5-trioxoimidazolidines bearing N-(substituted)phenylalkyl groups, together with, in most cases, N'-(CH(2))(n)-carboxylic acid, ester or amide side chains. The best compound from this series is 3-(2,4,5-trioxo-3-phenylethyl-imidazolodin-1-yl)propionamide, with an IC(50) of 40 μM against Escherichia coli TP. Molecular modelling suggests that this ligand, when complexed with closed-cleft human TP, would have the phenylalkyl group in the active site region normally occupied by a thymine-containing structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydantoins / chemistry
  • Imidazolidines / chemical synthesis
  • Imidazolidines / chemistry*
  • Imidazolidines / pharmacology*
  • Models, Molecular
  • Protein Conformation
  • Structure-Activity Relationship
  • Thymidine Phosphorylase / antagonists & inhibitors*
  • Thymidine Phosphorylase / chemistry

Substances

  • Enzyme Inhibitors
  • Hydantoins
  • Imidazolidines
  • Thymidine Phosphorylase