Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials

被引：108

作者：

Yeates, Clive L. ^{[1
]}

Batchelor, John F. ^{[1
]}

Capon, Edward C. ^{[1
]}

Cheesman, Neil J. ^{[1
]}

Fry, Mitch ^{[1
]}

Hudson, Alan T. ^{[1
]}

Pudney, Mary ^{[1
]}

Trimming, Helen ^{[1
]}

Woolven, James ^{[1
]}

Bueno, Jose M. ^{[2
]}

Chicharro, Jesus ^{[2
]}

Fernandez, Esther ^{[2
]}

Fiandor, Jose M. ^{[2
]}

Gargallo-Viola, Domingo ^{[2
]}

de las Heras, Federico Gomez ^{[2
]}

Herreros, Esperanza ^{[2
]}

Leon, Maria L. ^{[2
]}

机构：

[1] Wellcome Res Labs, Beckenham, Kent, England

[2] GlaxoSmithKline R&D, Ctr Dis Dev World, Cantos 28760, Spain

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 09期

关键词：

D O I：

10.1021/jm0705760

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasinodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc(1) complex.

引用

页码：2845 / 2852

页数：8

共 43 条

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