2. Academic Validation
  3. Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit P. falciparum Dihydroorotate Dehydrogenase

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

  • ACS Med Chem Lett. 2017 Feb 27;8(4):438-442. doi: 10.1021/acsmedchemlett.7b00030.
Micah Maetani 1 2,  Nobutaka Kato 2,  Valquiria A P Jabor 3,  Felipe A Calil 3,  Maria Cristina Nonato 3,  Christina A Scherer 2,  Stuart L Schreiber 1 2 4
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
  • 2 Broad Institute, Cambridge, Massachusetts 02142, United States.
  • 3 School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14040-903, Brazil.
  • 4 Howard Hughes Medical Institute, Cambridge, Massachusetts 02138, United States.
PMID: 28435533 DOI: 10.1021/acsmedchemlett.7b00030
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 μM) 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.

Keywords

BRD7539; BRD9185; DHODH; Plasmodium falciparum; diversity-oriented synthesis; malaria.

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