Title |
Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials
|
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Published in |
Journal of Medicinal Chemistry, June 2016
|
DOI | 10.1021/acs.jmedchem.6b00028 |
Pubmed ID | |
Authors |
Neil R. Norcross, Beatriz Baragaña, Caroline Wilson, Irene Hallyburton, Maria Osuna-Cabello, Suzanne Norval, Jennifer Riley, Laste Stojanovski, Frederick R. C. Simeons, Achim Porzelle, Raffaella Grimaldi, Sergio Wittlin, Sandra Duffy, Vicky M. Avery, Stephan Meister, Laura Sanz, Belén Jiménez-Díaz, Iñigo Angulo-Barturen, Santiago Ferrer, María Santos Martínez, Francisco Javier Gamo, Julie A. Frearson, David W. Gray, Alan H. Fairlamb, Elizabeth A. Winzeler, David Waterson, Simon F. Campbell, Paul Willis, Kevin D. Read, Ian H. Gilbert |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United Kingdom | 2 | 20% |
France | 1 | 10% |
Switzerland | 1 | 10% |
Unknown | 6 | 60% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 5 | 50% |
Scientists | 3 | 30% |
Science communicators (journalists, bloggers, editors) | 1 | 10% |
Practitioners (doctors, other healthcare professionals) | 1 | 10% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 43 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 10 | 23% |
Student > Ph. D. Student | 9 | 21% |
Other | 5 | 12% |
Student > Doctoral Student | 3 | 7% |
Professor > Associate Professor | 3 | 7% |
Other | 7 | 16% |
Unknown | 6 | 14% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 17 | 40% |
Biochemistry, Genetics and Molecular Biology | 3 | 7% |
Medicine and Dentistry | 2 | 5% |
Unspecified | 2 | 5% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 5% |
Other | 7 | 16% |
Unknown | 10 | 23% |