Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitors with Potent and Selective Activity against the Malaria Parasite Plasmodium falciparum
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- 作者：Margaret A. Phillips ; Ramesh Gujjar ; Nicholas A. Malmquist ; John White ; Farah El Mazouni ; Jeffrey Baldwin ; Pradipsinh K. Rathod
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：June 26, 2008
- 年：2008
- 卷：51
- 期：12
- 页码：3649 - 3653
- 全文大小：530K
- 年卷期：v.51,no.12(June 26, 2008)
- ISSN：1520-4804
文摘
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).