Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum

J Med Chem. 2008 Jun 26;51(12):3649-53. doi: 10.1021/jm8001026. Epub 2008 Jun 4.

Abstract

A Plasmodium falciparum dihydroorotate dehydrogenase ( PfDHODH) inhibitor that is potent ( KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC50 = 79 nM).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Humans
  • Kinetics
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Protein Binding
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology

Substances

  • Antimalarials
  • Pyrimidines
  • Thiazoles
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase