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Synfacts 2017; 13(07): 0675
DOI: 10.1055/s-0036-1590519
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Dihydroorotate Dehydrogenase Inhibitor BRD9185

Contributor(s):
Philip Kocienski
Maetani M. Kato N. Jabor VA. P. Calil FA. Nonato MC. Scherer CA. Schreiber SL. * Harvard University, Broad Institute, and Howard Hughes Medical Institute, Cambridge, USA; University of São Paulo, Brazil
Discovery of Antimalarial Azetidine-2-carbonitriles that Inhibit P. falciparum Dihydroorotate Dehydrogenase.

ACS Med. Chem. Lett. 2017;
8: 438-442
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Further Information

Publication History

Publication Date:
19 June 2017 (online)

 
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Key words

BRD9185 - dihydroorotate dehydrogenase - azetidine-2-carbonitriles - 4-exo-tet cyclization

Significance

Dihydroorotate dehydrogenase (DHODH) is necessary for pyrimidine biosynthesis in protozoan parasites of the genus Plasmodium, the causative agents of malaria. BRD9185 is a DHODH inhibitor that 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.


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Comment

The key step in the synthesis depicted was the construction of the azetidine-2-carbo­nitrile core by a 4-exo-tet cyclization of the anion derived from D. The stereochemistry of the cyclization depended on the base. Treatment of D with LiHMDS at –50 °C provided the products Ea and Eb in a ratio of approximately 15:1 as a separable mixture. Alternatively, exposure of D to KHMDS at –78 °C gave nearly exclusively Eb (Ea/Eb ≈ 1:20). The conversion of A into E is described in a preceding paper: J. T. Lowe et al. J. Org. Chem. 2012, 77, 7187.


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