Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues

J Med Chem. 2004 Jun 17;47(13):3427-37. doi: 10.1021/jm031066i.

Abstract

Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives of d-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T. brucei 6PGDH with a Ki in the nanomolar range.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Butyrates / chemical synthesis
  • Butyrates / chemistry
  • Butyrates / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Gluconates / chemistry
  • Gluconates / metabolism
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Liver / enzymology
  • Oxidation-Reduction
  • Phosphogluconate Dehydrogenase / antagonists & inhibitors*
  • Phosphogluconate Dehydrogenase / chemistry
  • Sheep
  • Structure-Activity Relationship
  • Sulfoxides / chemical synthesis*
  • Sulfoxides / chemistry
  • Sulfoxides / pharmacology
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology
  • Trypanosoma brucei brucei / drug effects
  • Trypanosoma brucei brucei / enzymology*

Substances

  • 3-keto-6-phosphogluconic acid
  • Amides
  • Antimalarials
  • Butyrates
  • Enzyme Inhibitors
  • Gluconates
  • Hydroxamic Acids
  • Sulfoxides
  • Trypanocidal Agents
  • erythronic acid
  • Phosphogluconate Dehydrogenase