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

• Published in: Bioorganic & medicinal chemistry letters 2017-11, Vol.27 (22), p.5014-5021
• Main Authors: Arnold, Michael A., Gerasyuto, Aleksey I., Wang, Jiashi, Du, Wu, Gorske, Yi Jin Kim, Arasu, Tamil, Baird, John, Almstead, Neil G., Narasimhan, Jana, Peddi, Srinivasa, Ginzburg, Olya, Lue, Stanley W., Hedrick, Jean, Sheedy, Josephine, Lagaud, Guy, Branstrom, Arthur A., Weetall, Marla, Prasad, J.V.N. Vara, Karp, Gary M.
• Format: Article
• Language: English
• Subjects: 4-Hydroxy-2-pyridone; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibacterial; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - metabolism; Azabicyclo Compounds - pharmacology; Azabicyclo Compounds - therapeutic use; DNA - chemistry; DNA - metabolism; DNA synthesis inhibitor; Drug Evaluation, Preclinical; Escherichia coli - drug effects; Escherichia coli - pathogenicity; Gram-negative; Gram-Negative Bacteria - drug effects; Gram-Negative Bacterial Infections - drug therapy; Gram-Negative Bacterial Infections - microbiology; Gram-Negative Bacterial Infections - veterinary; Half-Life; Mice; Microbial Sensitivity Tests; Niacin - analogs & derivatives; Niacin - metabolism; Niacin - pharmacology; Niacin - therapeutic use; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Pyridines - therapeutic use; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.10.006

[Display omitted] 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 MIC90 value of 8 μg/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 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.