Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

被引：12

作者：

Norcross, Neil R. ^{[1
]}

Baragana, Beatriz ^{[1
]}

Wilson, Caroline ^{[1
]}

Hallyburton, Irene ^{[1
]}

Osuna-Cabello, Maria ^{[1
]}

Norval, Suzanne ^{[1
]}

Riley, Jennifer ^{[1
]}

Stojanovski, Laste ^{[1
]}

Simeons, Frederick R. C. ^{[1
]}

Porzelle, Achim ^{[1
]}

Grimaldi, Raffaella ^{[1
]}

Wittlin, Sergio ^{[2
,3
]}

Duffy, Sandra ^{[4
]}

Avery, Vicky M. ^{[4
]}

Meister, Stephan ^{[5
]}

Sanz, Laura ^{[6
]}

Jimenez-Diaz, Belen ^{[6
]}

Angulo-Barturen, Inigo ^{[6
]}

Ferrer, Santiago ^{[6
]}

Santos Martinez, Maria ^{[6
]}

Javier Gamo, Francisco ^{[6
]}

Frearson, Julie A. ^{[1
]}

Gray, David W. ^{[1
]}

Fairlamb, Alan H. ^{[1
]}

Winzeler, Elizabeth A. ^{[5
]}

Waterson, David ^{[7
]}

Campbell, Simon F. ^{[7
]}

Willis, Paul ^{[7
]}

Read, Kevin D. ^{[1
]}

Gilbert, Ian H. ^{[1
]}

机构：

[1] Univ Dundee, Sch Life Sci, Div Biol Chem & Drug Discovery, Drug Discovery Unit, Dundee DD1 5EH, Scotland

[2] Swiss Trop & Publ Hlth Inst Swiss TPH, Socinstr 57, CH-4051 Basel, Switzerland

[3] Univ Basel, CH-4003 Basel, Switzerland

[4] Griffith Univ, Eskitis Inst Drug Discovery, Discovery Biol, Nathan, Qld 4111, Australia

[5] Univ Calif San Diego, San Diego Sch Med, Dept Pediat, 9500 Gilman Dr 0741, La Jolla, CA 92093 USA

[6] GlaxoSmithKline, Dis Developing World Tres Cantos Med Dev Campus, C Severo Ochoa 2, Madrid 28760, Spain

[7] Int Ctr Cointrin, Med Malaria Venture, Entrance G, 3rd Floor,Route Pre Bois 20,POB 1826, CH-1215 Geneva 15, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 13期

基金：

英国惠康基金;

关键词：

DRUG DISCOVERY; GENERATION; MALARIA;

D O I：

10.1021/acs.jmedchem.6b00028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：6101 / 6120

页数：20

共 22 条

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