Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

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Norcross, Neil R
Baragana, Beatriz
Wilson, Caroline
Hallyburton, Irene
Osuna-Cabello, Maria
Norval, Suzanne
Riley, Jennifer
Stojanovski, Laste
Simeons, Frederick RC
Porzelle, Achim
Grimaldi, Raffaella
Wittlin, Sergio
Duffy, Sandra
Avery, Vicky M
Meister, Stephan
Sanz, Laura
Jimenez-Diaz, Belen
Angulo-Barturen, Inigo
Ferrer, Santiago
Santos Martinez, Maria
Javier Gamo, Francisco
Frearson, Julie A
Gray, David W
Fairlamb, Alan H
Winzeler, Elizabeth A
Waterson, David
Campbell, Simon F
Willis, Paul
Read, Kevin D
Gilbert, Ian H
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2016
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Abstract

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.

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Journal of Medicinal Chemistry

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59

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Medicinal and biomolecular chemistry

Medicinal and biomolecular chemistry not elsewhere classified

Organic chemistry

Pharmacology and pharmaceutical sciences

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