Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials.
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.
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Neil R
NR
Norcross
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Beatriz
B
Baragaña
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Caroline
C
Wilson
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Irene
I
Hallyburton
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Maria
M
Osuna-Cabello
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Suzanne
S
Norval
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Jennifer
J
Riley
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Laste
L
Stojanovski
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Frederick R C
FR
Simeons
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Achim
A
Porzelle
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Raffaella
R
Grimaldi
Swiss Tropical and Public Health Institute (Swiss TPH) , Socinstrasse 57, 4051 Basel, Switzerland.|University of Basel , CH-4003 Basel, Switzerland.
Sergio
S
Wittlin
Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Sandra
S
Duffy
Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University , Nathan, Queensland 4111, Australia.
Vicky M
VM
Avery
Department of Pediatrics, University of California, San Diego School of Medicine , 9500 Gilman Drive, 0741, La Jolla, California 92093, United States.
Stephan
S
Meister
Diseases of the Developing World-Tres Cantos Medicines Development Campus, GlaxoSmithKline , c/Severo Ochoa, 2, Tres Cantos, 28760, Madrid, Spain.
Laura
L
Sanz
Diseases of the Developing World-Tres Cantos Medicines Development Campus, GlaxoSmithKline , c/Severo Ochoa, 2, Tres Cantos, 28760, Madrid, Spain.
Belén
B
Jiménez-Díaz
Diseases of the Developing World-Tres Cantos Medicines Development Campus, GlaxoSmithKline , c/Severo Ochoa, 2, Tres Cantos, 28760, Madrid, Spain.
Iñigo
I
Angulo-Barturen
Diseases of the Developing World-Tres Cantos Medicines Development Campus, GlaxoSmithKline , c/Severo Ochoa, 2, Tres Cantos, 28760, Madrid, Spain.
Santiago
S
Ferrer
Diseases of the Developing World-Tres Cantos Medicines Development Campus, GlaxoSmithKline , c/Severo Ochoa, 2, Tres Cantos, 28760, Madrid, Spain.
María Santos
MS
Martínez
Diseases of the Developing World-Tres Cantos Medicines Development Campus, GlaxoSmithKline , c/Severo Ochoa, 2, Tres Cantos, 28760, Madrid, Spain.
Francisco Javier
FJ
Gamo
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Julie A
JA
Frearson
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
David W
DW
Gray
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Alan H
AH
Fairlamb
Department of Pediatrics, University of California, San Diego School of Medicine , 9500 Gilman Drive, 0741, La Jolla, California 92093, United States.
Elizabeth A
EA
Winzeler
Medicines for Malaria Venture , International Center Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
David
D
Waterson
Medicines for Malaria Venture , International Center Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
Simon F
SF
Campbell
Medicines for Malaria Venture , International Center Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, P.O. Box 1826, CH-1215, Geneva 15, Switzerland.
Paul
P
Willis
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Kevin D
KD
Read
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.
Ian H
IH
Gilbert
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D016513:Mice, SCID; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D000962:Antimalarials; D011743:Pyrimidines