4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis.
Bioorg Med Chem Lett
; 27(22): 5014-5021, 2017 11 15.
Article
in En
| MEDLINE
| ID: mdl-29032026
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 MIC90 value of 8⯵g/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8â¯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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyridines
/
DNA
/
Azabicyclo Compounds
/
Anti-Bacterial Agents
/
Niacin
Limits:
Animals
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2017
Document type:
Article