Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials.

  • Journal Article
  • Research Support, Non-U.S. Gov't

Journal of medicinal chemistry, Volume: 59, Issue: 13
July 14, 2016
Neil R Norcross NR, Beatriz Baragaña B, Caroline Wilson C, Irene Hallyburton I, Maria Osuna-Cabello M, Suzanne Norval S, Jennifer Riley J, Laste Stojanovski L, Frederick R C Simeons FR, Achim Porzelle A, Raffaella Grimaldi R, Sergio Wittlin S, Sandra Duffy S, Vicky M Avery VM, Stephan Meister S, Laura Sanz L, Belén Jiménez-Díaz B, Iñigo Angulo-Barturen I, Santiago Ferrer S, María Santos Martínez MS, Francisco Javier Gamo FJ, Julie A Frearson JA, David W Gray DW, Alan H Fairlamb AH, Elizabeth A Winzeler EA, David Waterson D, Simon F Campbell SF, Paul Willis P, Kevin D Read KD, Ian H Gilbert IH

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.

Courtesy of the U.S. National Library of Medicine