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.
27 Jun 2016