Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice

J Med Chem. 2009 Apr 9;52(7):1864-72. doi: 10.1021/jm801343r.


Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Dihydroorotate Dehydrogenase
  • Humans
  • In Vitro Techniques
  • Malaria / drug therapy*
  • Malaria / parasitology
  • Male
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Parasitic Sensitivity Tests
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / enzymology*
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology


  • (5-methyl(1,2,4)triazolo(1,5-a)pyrimidin-7-yl)(4-trifluoromethylphenyl)amine
  • Antimalarials
  • Dihydroorotate Dehydrogenase
  • Pyrimidines
  • Thiazoles
  • Triazoles
  • Oxidoreductases Acting on CH-CH Group Donors