4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis.

The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c , derived from the N -debenzylation of 1b , preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q , identified through further optimization of the series, had an MIC 90 value of 8 μg/mL against a panel of highly resistant strains of E. coli . In a murine septicemia model, compound 6q exhibited a PD 50 of 8 mg/kg in mice infected with a lethal dose of E. coli . This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections. [ABSTRACT FROM AUTHOR]