☆ 4.7 Article

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

JOURNAL OF MEDICINAL CHEMISTRY (2008)

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JOURNAL OF MEDICINAL CHEMISTRY

卷 51, 期 12, 页码 3649-3653

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AMER CHEMICAL SOC

DOI: 10.1021/jm8001026

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Chemistry, Medicinal

资金

NIAID NIH HHS [AI26912, R21 AI053680-01, R01 AI053680, R01 AI053680-02, AI67670, R01 AI053680-01A2, R01 AI026912, R21 AI053680, R56 AI053680, R01 AI053680-03, R21 AI067670, AI053680] Funding Source: Medline
PHS HHS [MG00203] Funding Source: Medline

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摘要

A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor that is potent (K(I) = 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).

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