Diversity-oriented synthesis (DOS) yields small molecule libraries with stereochemical and skeletal diversity in contrast to typical screening libraries, which consist of flat, sp2-rich, hetero/aromatic compounds. 100,000 DOS compounds were screened against Plasmodium falciparum (malaria parasites, Dd2), and resulting positives were rescreened in dose against Dd2 and transgenic parasites overexpressing yeast dihydroorotate dehydrogenase (PfScDHODH). We identified a hit compound BRD7539 with an EC50 of 10 nM in Dd2 parasites but 8 µM in PfScDHODH parasites, indicative of a mitochondrial mechanism. BRD7539 has been biochemically-validated to target PfDHODH with &gt;7,500-fold specificity over HsDHODH, and dozens of analogs have been synthesized, many of which display nanomolar potency. These compounds display strong stability in vitro in mouse and human microsomes, exhibit no cytotoxicity against HepG2 cells, and show efficacy in in vivo models. Collectively, we show that BRD7539 is a strong lead candidate, although further studies are necessary to fully evaluate the preclinical candidacy of the compound and related analogs.

Discovery and structure-activity relationship (SAR) of BRD7539, a small molecule inhibitor of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH)

250th National Meeting (2015)

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