Discovery of Antimalarial Azetidine-2-carbonitriles That InhibitDihydroorotate Dehydrogenase.
Authors | |
Abstract | Dihydroorotate dehydrogenase (DHODH) is an enzyme necessary for pyrimidine biosynthesis in protozoan parasites of the genus, 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 targetDHODH in a biochemical assay. Optimized compound BRD9185 () hasactivity against multidrug-resistant blood-stage parasites (EC= 0.016 μM) and is curative after just three doses in amouse 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. |
Year of Publication | 2017
|
Journal | ACS Med Chem Lett
|
Volume | 8
|
Issue | 4
|
Pages | 438-442
|
Date Published | 2017 Apr 13
|
ISSN | 1948-5875
|
DOI | 10.1021/acsmedchemlett.7b00030
|
PubMed ID | 28435533
|
PubMed Central ID | PMC5392761
|
Links |