Abstract: Documento escrito por un elevado número de autores/as, solo se referencia el/la que aparece en primer lugar y los/as autores/as pertenecientes a la UC3M. ; 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. ; We acknowledge Medicines for Malaria for financial support. The University of Dundee also acknowledges support from the Wellcome Trust (Grant 100476 and a Principal Research Fellowship to A.H.F.). This work is partially funded by the MSD Scottish Life Sciences Fund. As part of an ongoing contribution to Scottish life sciences, Merck Sharp & Dohme (MSD) Ltd. (known as Merck & Co., Inc., Kenilworth, NJ, U.S., in the United States and Canada) has given substantial monetary funding to the Scottish Funding Council (SFC) for distribution via the Scottish Universities Life Sciences Alliance (SULSA) to develop and deliver a high quality drug discovery research and training program.
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