Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: Structure based design, synthesis, SAR and antimicrobial activity

• DOI: 10.1016/j.ejmech.2014.08.025
• Publication Date: 2014-08-07T20:05:48Z
• Authors: Ian A. Yule; Lloyd G. Czaplewski; Stephanie Pommier; David T. Davies; Sarah K. Narramore; Colin W.G. Fishwick
• Keywords: Carboxamide; Structure–activity relationship; Topoisomerase IV

The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy.