Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

详细信息    查看全文

• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6101-6120
• 全文大小：732K
• 年卷期：0
• ISSN：1520-4804

文摘

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.