Structure-guided design of antibacterials that allosterically inhibit DNA gyrase

被引：23

作者：

Thalji, Reema K. ^{[1
]}

Raha, Kaushik ^{[1
]}

Andreotti, Daniele ^{[2
]}

Checchia, Anna ^{[2
]}

Cui, Haifeng ^{[1
]}

Meneghelli, Giovanni ^{[2
,5
]}

Profeta, Roberto ^{[2
,5
]}

Tonelli, Federica ^{[2
]}

Tommasi, Simona ^{[2
,5
]}

Bakshi, Tania ^{[1
]}

Donovan, Brian T. ^{[1
]}

Howells, Alison ^{[3
]}

Jain, Shruti ^{[3
]}

Nixon, Christopher ^{[1
]}

Quinque, Geoffrey ^{[1
]}

McCloskey, Lynn ^{[1
]}

Bax, Benjamin D. ^{[4
,6
]}

Neu, Margarete ^{[4
]}

Chan, Pan F. ^{[1
]}

Stavenger, Robert A. ^{[1
]}

机构：

[1] GlaxoSmithKline, Collegeville, PA 19426 USA

[2] EVOTEC Ctr Drug Discovery & Dev, I-37135 Verona, Italy

[3] Inspiralis Ltd, Innovat Ctr, Norwich NR4 7GJ, Norfolk, England

[4] GlaxoSmithKline, Stevenage SG1 2NYH, Herts, England

[5] FIS, I-36075 Vicenza, Italy

[6] Cardiff Univ, Med Discovery Inst, Main Bldg,Pk Pl, Cardiff CF10 3AT, S Glam, Wales

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 11期

关键词：

Antibacterial; Topoisomerase; CLEAVAGE COMPLEXES;

D O I：

10.1016/j.bmcl.2019.03.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.

引用

页码：1407 / 1412

页数：6

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