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

141 Citations (Scopus)

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

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Falciparum Malaria
Plasmodium falciparum
Parasites
Antimalarials
Toxicity
Screening
Throughput
Association reactions
Enzymes
dihydroorotate dehydrogenase

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. / Phillips, Margaret A.; Gujjar, Ramesh; Malmquist, Nicholas A.; White, John; El Mazouni, Farah; Baldwin, Jeffrey; Rathod, Pradipsinh K.

In: Journal of Medicinal Chemistry, Vol. 51, No. 12, 26.06.2008, p. 3649-3653.

Research output: Contribution to journalArticle

Phillips, Margaret A. ; Gujjar, Ramesh ; Malmquist, Nicholas A. ; White, John ; El Mazouni, Farah ; Baldwin, Jeffrey ; Rathod, Pradipsinh K. / Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 12. pp. 3649-3653.
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AU - El Mazouni, Farah

AU - Baldwin, Jeffrey

AU - Rathod, Pradipsinh K.

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