Portal de Periódicos da CAPES

Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

2016; American Chemical Society; Volume: 59; Issue: 13 Linguagem: Inglês

10.1021/acs.jmedchem.6b00028

1520-4804

Neil R. Norcross, Beatriz Baragaña, 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 M. Sanz, Belén Jiménez-Díaz, Íñigo Angulo‐Barturen, Santiago Ferrer, María Santos Martínez, Francisco‐Javier Gamo, Julie A. Frearson, David W. Gray, Alan H. Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul Willis, Kevin D. Read, Ian H. Gilbert,

Hepatitis C virus research

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.