Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7486-9. doi: 10.1016/j.bmcl.2012.10.045. Epub 2012 Oct 17.


We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole's 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters.

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemistry*
  • Lactoylglutathione Lyase / antagonists & inhibitors*
  • Lactoylglutathione Lyase / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Structure-Activity Relationship


  • 7-azaindole dimer
  • Enzyme Inhibitors
  • Indoles
  • Pyridones
  • Lactoylglutathione Lyase