期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 8, 期 4, 页码 438-442出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.7b00030
关键词
BRD7S39; BRD918S; DHODH; malaria; diversity-oriented synthesis; Plasmodium falciparum
资金
- Bill & Melinda Gates Foundation [OPP1032518]
- National Science Foundation [DGE1144152]
- Harvard University's Graduate Prize Fellowship
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/25075-0]
- Bill and Melinda Gates Foundation [OPP1032518] Funding Source: Bill and Melinda Gates Foundation
Dihydroorotate dehydrogenase (DHODH) is an enzyme necessary for pyrimidine biosynthesis in protozoan parasites of the genus Plasmodium, the causative agents of malaria. We recently reported the identification of novel compounds derived from diversity-oriented synthesis with activity in multiple stages of the malaria parasite life cycle. Here, we report the optimization of a potent series of antimalarial inhibitors consisting of azetidine-2-carbonitriles, which we had previously shown to target P. falciparum DHODH in a biochemical assay. Optimized compound BRD9185 (27) has in vitro activity against multidrug-resistant blood-stage parasites (EC50 = 0.016 mu M) and is curative after just three doses in a P. berghei mouse model. BRD9185 has a long half-life (15 h) and low clearance in mice and represents a new structural class of DHODH inhibitors with potential as antimalarial drugs.
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