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

• Inhibitors of bacterial DNA Gyrase were designed using de novo computational methods.
• Synthesis of a range of these pyridine-3-carboxamide-6-yl-ureas is described.
• Inhibitors with IC50s as low as 24 nM against DNA Gyrase were evaluated.
• Inhibitors were active against a range of Gram positive bacteria including Staphylococcus aureus.

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.

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