Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit P-falciparum Dihydroorotate Dehydrogenase

Autor(es)

Maetani, Micah ; Kato, Nobutaka ; Jabor, Valquiria A. P. ; Calil, Felipe A. ; Nonato, Maria Cristina ; Scherer, Christina A. ; Schreiber, Stuart L.

• Tipo de documento: Artigo Científico
• Fonte: ACS Medicinal Chemistry Letters; v. 8, n. 4, p. 438-442, APR 2017.
• Citações Web of Science: 17

Resumo

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. (AU)

• Processo FAPESP: 12/25075-0 - Desenvolvimento de moléculas com ação leishmanicida baseado na inibição seletiva da enzima diidroorotato desidrogenase
• Beneficiário: Maria Cristina Nonato
• Modalidade de apoio: Auxílio à Pesquisa - Regular