Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: Intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships

被引：223

作者：

Charifson, Paul S. ^{[1
]}

Grillot, Anne-Laure ^{[1
]}

Grossman, Trudy H. ^{[1
]}

Parsons, Jonathan D. ^{[1
]}

Badia, Michael ^{[1
]}

Bellon, Steve ^{[1
]}

Deininger, David D. ^{[1
]}

Drumm, Joseph E. ^{[1
]}

Gross, Christian H. ^{[1
]}

LeTiran, Arnaud ^{[1
]}

Liao, Yusheng ^{[1
]}

Mani, Nagraj ^{[1
]}

Nicolau, David P. ^{[2
]}

Perola, Emanuele ^{[1
]}

Ronkin, Steven ^{[1
]}

Shannon, Dean ^{[1
]}

Swenson, Lora L. ^{[1
]}

Tang, Qina ^{[1
]}

Tessier, Pamela R. ^{[2
]}

Tian, Ski-Kai ^{[1
]}

Trudeau, Martin ^{[1
]}

Wang, Tiansheng ^{[1
]}

Wei, Yunyi ^{[1
]}

Zhang, Hong ^{[1
]}

Stamos, Dean ^{[1
]}

机构：

[1] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA

[2] Hartford Hosp, Ctr Antiinfect Res & Dev, Hartford, CT 06102 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 17期

关键词：

D O I：

10.1021/jm800318d

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all Currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic Subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to file ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.

引用

页码：5243 / 5263

页数：21

共 38 条

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