4-吡啶酮作为潜在抗疟药物的合成及构效关系

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

作者信息

Yeates Clive L, Batchelor John F, Capon Edward C, Cheesman Neil J, Fry Mitch, Hudson Alan T, Pudney Mary, Trimming Helen, Woolven James, Bueno José M, Chicharro Jesús, Fernández Esther, Fiandor José M, Gargallo-Viola Domingo, Gómez de las Heras Federico, Herreros Esperanza, León María L

机构信息

Wellcome Research Laboratories, Langley Court, Beckenham, Kent, U.K.

出版信息

J Med Chem. 2008 May 8;51(9):2845-52. doi: 10.1021/jm0705760. Epub 2008 Apr 9.

DOI:10.1021/jm0705760

PMID:18396855

Abstract

A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium 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 bc1 complex.

摘要

一系列二芳基醚取代的4-吡啶酮已被确定具有强大的抗疟活性，在体外对恶性疟原虫以及在体内对约氏疟原虫的活性均优于氯喹。这些化合物是通过对抗球虫药氯吡醇侧链变化对活性影响的系统研究而衍生出来的。相对于氯吡醇，最具活性的化合物在体外对恶性疟原虫抑制的IC50提高了500倍以上，对小鼠体内约氏疟原虫的ED50提高了约100倍。这些化合物已在其他地方被证明是通过抑制细胞色素bc1复合物处的线粒体电子传递而具有选择性作用。