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

Full text
Author(s):	Maetani, Micah ; Kato, Nobutaka ; Jabor, Valquiria A. P. ; Calil, Felipe A. ; Nonato, Maria Cristina ; Scherer, Christina A. ; Schreiber, Stuart L. Total Authors: 7
Document type:	Journal article
Source:	ACS Medicinal Chemistry Letters; v. 8, n. 4, p. 438-442, APR 2017.
Web of Science Citations:	17
Abstract
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)

FAPESP's process:	12/25075-0 - Development of leishmanicidal drugs based on the selective inhibition of the enzyme dihydroorotate dehydrogenase
Grantee:	Maria Cristina Nonato
Support Opportunities:	Regular Research Grants