1. 4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis.
- Author
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Arnold MA, Gerasyuto AI, Wang J, Du W, Gorske YJK, Arasu T, Baird J, Almstead NG, Narasimhan J, Peddi S, Ginzburg O, Lue SW, Hedrick J, Sheedy J, Lagaud G, Branstrom AA, Weetall M, Prasad JVNV, and Karp GM
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Azabicyclo Compounds metabolism, Azabicyclo Compounds pharmacology, Azabicyclo Compounds therapeutic use, DNA chemistry, Drug Evaluation, Preclinical, Escherichia coli drug effects, Escherichia coli pathogenicity, 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 metabolism, Niacin pharmacology, Niacin therapeutic use, Pyridines metabolism, Pyridines pharmacology, Pyridines therapeutic use, Structure-Activity Relationship, Anti-Bacterial Agents metabolism, Azabicyclo Compounds chemistry, DNA metabolism, Niacin analogs & derivatives, Pyridines chemistry
- Abstract
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 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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