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dc.contributor.authorNorcross, Neil R
dc.contributor.authorBaragana, Beatriz
dc.contributor.authorWilson, Caroline
dc.contributor.authorHallyburton, Irene
dc.contributor.authorOsuna-Cabello, Maria
dc.contributor.authorNorval, Suzanne
dc.contributor.authorRiley, Jennifer
dc.contributor.authorStojanovski, Laste
dc.contributor.authorSimeons, Frederick RC
dc.contributor.authorPorzelle, Achim
dc.contributor.authorGrimaldi, Raffaella
dc.contributor.authorWittlin, Sergio
dc.contributor.authorDuffy, Sandra
dc.contributor.authorAvery, Vicky M
dc.contributor.authorMeister, Stephan
dc.contributor.authorSanz, Laura
dc.contributor.authorJimenez-Diaz, Belen
dc.contributor.authorAngulo-Barturen, Inigo
dc.contributor.authorFerrer, Santiago
dc.contributor.authorSantos Martinez, Maria
dc.contributor.authorJavier Gamo, Francisco
dc.contributor.authorFrearson, Julie A
dc.contributor.authorGray, David W
dc.contributor.authorFairlamb, Alan H
dc.contributor.authorWinzeler, Elizabeth A
dc.contributor.authorWaterson, David
dc.contributor.authorCampbell, Simon F
dc.contributor.authorWillis, Paul
dc.contributor.authorRead, Kevin D
dc.contributor.authorGilbert, Ian H
dc.description.abstractIn 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.
dc.publisherAmerican Chemical Society
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchMedicinal and biomolecular chemistry not elsewhere classified
dc.subject.fieldofresearchOrganic chemistry
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.titleTrisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorDuffy, Sandra
gro.griffith.authorAvery, Vicky M.

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