Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials

Neil R. Norcross, Beatriz Baragana, Caroline Wilson, Irene Hallyburton, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Laste Stojanovski, Frederick R. C. Simeons, Achim Porzelle, Raffaella Grimaldi, Sergio Wittlin, Sandra Duffy, Vicky M. Avery, Stephan Meister, Laura Sanz, Belen Jimenez-Diaz, Inigo Angulo-Barturen, Santiago Ferrer, Maria Santos MarinezFrancisco Javier Gamo, Julie A. Frearson, David W. Gray, Alan H. Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul Willis, Kevin D. Read (Lead / Corresponding author), Ian H. Gilbert (Lead / Corresponding author)

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13 Citations (Scopus)
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In this paper we describe the optimisation of a phenotypic hit against Plasmodium falciparum, based on a tri-substituted 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 parasitaemia 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 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 optimised or used for target hunting.
Original languageEnglish
Pages (from-to)6101-6120
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number13
Early online date17 Jun 2016
Publication statusPublished - 14 Jul 2016


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