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27 Jun 2016

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold.  This led to compds. with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria.  The most promising compd. I showed a redn. 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 compd. is a potent inhibitor of cytochrome P 450 enzymes, probably due to a 4-​pyridyl substituent.  Nevertheless, this is a lead mol. with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.