Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials.

J Med Chem 2016 07 17;59(13):6101-20. Epub 2016 Jun 17.

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.

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http://dx.doi.org/10.1021/acs.jmedchem.6b00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947981PMC
July 2016
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