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

Margaret A. Phillips, Ramesh Gujjar, Nicholas A. Malmquist, John White, Farah El Mazouni, Jeffrey Baldwin, Pradipsinh K. Rathod

Research output: Contribution to journalArticle

150 Scopus citations

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 (EC 50 = 79 nM).

Original languageEnglish (US)
Pages (from-to)3649-3653
Number of pages5
JournalJournal of Medicinal Chemistry
Volume51
Issue number12
DOIs
StatePublished - Jun 26 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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