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Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

Norcross, Neil R. and Baragaña, Beatriz and Wilson, Caroline and Hallyburton, Irene and Osuna-Cabello, Maria and Norval, Suzanne and Riley, Jennifer and Stojanovski, Laste and Simeons, Frederick R. C. and Porzelle, Achim and Grimaldi, Raffaella and Wittlin, Sergio and Duffy, Sandra and Avery, Vicky M. and Meister, Stephan and Sanz, Laura and Jiménez-Díaz, Belén and Angulo-Barturen, Iñigo and Ferrer, Santiago and Martínez, María Santos and Gamo, Francisco Javier and Frearson, Julie A. and Gray, David W. and Fairlamb, Alan H. and Winzeler, Elizabeth A. and Waterson, David and Campbell, Simon F. and Willis, Paul and Read, Kevin D. and Gilbert, Ian H.. (2016) Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials. Journal of Medicinal Chemistry, 59 (13). pp. 6101-6120.

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:0022-2623
e-ISSN:1520-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:15 Nov 2016 14:22
Deposited On:15 Nov 2016 14:22

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