The pyridylureas are a novel class of antibacterial agents that target DNA gyrase, an essential enzyme in bacteria. Inhibition of DNA gyrase prevents DNA synthesis and subsequently leads to cell death.The pyridylureas were identified as a sub-series from known DNA gyrase inhibitors through virtual library enumeration utilizing x-ray co-crystal structures of the target protein. Focused libraries were designed and compounds were synthesized and tested for their biological activities. Enzymatic potency was measured as the IC50 against Staphylococcus aureus DNA gyrase ATPase activity, and cellular activity was measured as the minimum inhibitory concentration (MIC) against a panel of Gram-positive and Gram-negative bacteria. This effort led to the identification of a bis-pyridine ethyl urea compound containing a carboxylic acid as the initial lead with an IC50 = 0.85 �M against S. aureus DNA gyrase but with no MIC. Further optimization of the lead by modulating logD and replacing the carboxylic acid with an acidic heterocycle resulted in a very potent oxadiazolone-pyridyl compound, with an IC50 = 0.0005 �M and an MIC = 0.11 �M against S. aureus. The oxadiazolone compound also showed broad-spectrum antibacterial activity against other Gram-positive bacteria and fastidious Gram-negative bacteria such as Haemophilus influenza and Moraxella catarrhalis. Cross-resistance studies, radioactive precursor incorporation assays, and functional DNA supercoiling assays confirmed the mode of action. The oxadiazolone compound was efficacious  in a S. aureus mouse thigh model for infection reducing bacterial load by 4 log units.

Discovery and structure-activity relationship (SAR) of novel pyridylureas as potent antibacterial agents

247th National Meeting (2014)

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