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

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

Author information

1
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA. margaret.phillips@UTSouthwestern.edu

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).

PMID:
18522386
PMCID:
PMC2624570
DOI:
10.1021/jm8001026
[Indexed for MEDLINE]
Free PMC Article

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