TY - JOUR
T1 - Trisubstituted Pyrimidines as Efficacious and Fast-acting Antimalarials
AU - Norcross, Neil R.
AU - Baragana, Beatriz
AU - Wilson, Caroline
AU - Hallyburton, Irene
AU - Osuna-Cabello, Maria
AU - Norval, Suzanne
AU - Riley, Jennifer
AU - Stojanovski, Laste
AU - Simeons, Frederick R. C.
AU - Porzelle, Achim
AU - Grimaldi, Raffaella
AU - Wittlin, Sergio
AU - Duffy, Sandra
AU - Avery, Vicky M.
AU - Meister, Stephan
AU - Sanz, Laura
AU - Jimenez-Diaz, Belen
AU - Angulo-Barturen, Inigo
AU - Ferrer, Santiago
AU - Santos Marinez, Maria
AU - Javier Gamo, Francisco
AU - Frearson, Julie A.
AU - Gray, David W.
AU - Fairlamb, Alan H.
AU - Winzeler, Elizabeth A.
AU - Waterson, David
AU - Campbell, Simon F.
AU - Willis, Paul
AU - Read, Kevin D.
AU - Gilbert, Ian H.
PY - 2016/7/14
Y1 - 2016/7/14
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.6b00028
DO - 10.1021/acs.jmedchem.6b00028
M3 - Article
C2 - 27314305
SN - 0022-2623
VL - 59
SP - 6101
EP - 6120
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -