Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

被引：21

作者：

Cheng, Gang ^{[1
]}

Muench, Stephen P. ^{[2
]}

Zhou, Ying ^{[3
,4
,5
,6
]}

Afanador, Gustavo A. ^{[7
]}

Mui, Ernest J. ^{[3
,4
,5
,6
]}

Fomovska, Alina ^{[3
,4
,5
,6
]}

Lai, Bo Shiun ^{[3
,4
,5
,6
]}

Prigge, Sean T. ^{[7
]}

Woods, Stuart ^{[8
]}

Roberts, Craig W. ^{[8
]}

Hickman, Mark R. ^{[10
]}

Lee, Patty J. ^{[10
]}

Leed, Susan E. ^{[10
]}

Auschwitz, Jennifer M. ^{[10
]}

Rice, David W. ^{[9
]}

McLeod, Rima ^{[3
,4
,5
,6
]}

机构：

[1] Univ Illinois, Dept Med Chem & Pharmacognosy, Drug Discovery Program, Chicago, IL 60612 USA

[2] Univ Leeds, Sch Biomed Sci, Leeds LS2 9JT, W Yorkshire, England

[3] Univ Chicago, Inst Genom & Syst Biol, Comm Genet, Dept Ophthalmol & Visual Sci, Chicago, IL 60637 USA

[4] Univ Chicago, Inst Genom & Syst Biol, Comm Immunol, Dept Ophthalmol & Visual Sci, Chicago, IL 60637 USA

[5] Univ Chicago, Inst Genom & Syst Biol, Comm Mol Med, Dept Ophthalmol & Visual Sci, Chicago, IL 60637 USA

[6] Univ Chicago, Chicago, IL 60637 USA

[7] Johns Hopkins Sch Publ Hlth, Baltimore, MD 21205 USA

[8] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow G4 0RE, Lanark, Scotland

[9] Univ Sheffield, Dept Mol Biol & Biotechnol, Sheffield S10 2TN, S Yorkshire, England

[10] Walter Reed Army Inst Res, Dept Discovery, Div Expt Therapeut, Silver Spring, MD 20910 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 07期

基金：

英国惠康基金;

关键词：

TgENR; Triclosan; ADMET; Toxoplasma; CARRIER PROTEIN REDUCTASE; CONGENITAL TOXOPLASMOSIS; PLASMODIUM-FALCIPARUM; TREATED INFANTS; IDENTIFICATION; ARYLATION; CHILDREN; PHENOLS; GROWTH;

D O I：

10.1016/j.bmcl.2013.02.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2035 / 2043

页数：9

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