Design, Synthesis and Biological Evaluation of Trypanosoma brucei Trypanothione Synthetase Inhibitors

被引：38

作者：

Spinks, Daniel ^{[1
]}

Torrie, Leah S. ^{[1
]}

Thompson, Stephen ^{[1
]}

Harrison, Justin R. ^{[1
]}

Frearson, Julie A. ^{[1
]}

Read, Kevin D. ^{[1
]}

Fairlamb, Alan H. ^{[1
]}

Wyatt, Paul G. ^{[1
]}

Gilbert, Ian H. ^{[1
]}

机构：

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

来源：

CHEMMEDCHEM | 2012年 / 7卷 / 01期

基金：

英国惠康基金;

关键词：

antiprotozoal agents; drug design; Trypanosoma brucei; trypanothione synthetase; HUMAN AFRICAN TRYPANOSOMIASIS; DRUG TARGET; METABOLISM; REDUCTASE; BIOSYNTHESIS; LEISHMANIA; LEAD;

D O I：

10.1002/cmdc.201100420

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62?000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids.

引用

页码：95 / 106

页数：12

共 29 条

[11] TRYPANOTHIONE - A NOVEL BIS(GLUTATHIONYL)SPERMIDINE COFACTOR FOR GLUTATHIONE-REDUCTASE IN TRYPANOSOMATIDS [J].