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 structure-activity relationships.

Abstract

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 the 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.

• Authors: Paul S Charifson, Anne-Laure Grillot, Trudy H Grossman, Jonathan D Parsons, Michael Badia, Steve Bellon, David D Deininger, Joseph E Drumm, Christian H Gross, Arnaud LeTiran, Yusheng Liao, Nagraj Mani, David P Nicolau, Emanuele Perola, Steven Ronkin, Dean Shannon, Lora L Swenson, Qing Tang, Pamela R Tessier, Ski-Kai Tian, Martin Trudeau, Tiansheng Wang, Yunyi Wei, Hong Zhang, Dean Stamos
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 17 Pg. 5243-63 (Sep 11 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18690678 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Benzimidazoles
• Topoisomerase II Inhibitors
• Urea
• benzimidazole
• DNA Topoisomerase IV

Topics

• Animals
• Anti-Bacterial Agents (chemistry, pharmacology)
• Bacterial Proteins
• Benzimidazoles (chemistry, pharmacology)
• Binding Sites
• DNA Topoisomerase IV (antagonists & inhibitors)
• Drug Design
• Microbial Sensitivity Tests
• Rodentia
• Structure-Activity Relationship
• Topoisomerase II Inhibitors
• Urea (analogs & derivatives, pharmacology)