Discovery and optimization of antibacterial AccC inhibitors.
Bioorg Med Chem Lett
; 19(23): 6507-14, 2009 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-19875284
ABSTRACT
The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo[d]imidazole-5-carboxamide (1), which was identified using our proprietary Automated Ligand Identification System (ALIS).(1) The X-ray co-crystal structure of 1 was solved and revealed several key interactions and opportunities for further optimization in the ATP site of AccC. Structure Based Drug Design (SBDD) and parallel synthetic approaches resulted in a novel series of AccC inhibitors, exemplified by (R)-2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo[4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC(50) of 20 nM and a MIC of 0.8 microg/mL against a sensitized strain of Escherichia coli (HS294 E. coli).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
/
Carbono-Nitrogênio Ligases
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Inibidores Enzimáticos
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Escherichia coli
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Descoberta de Drogas
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Imidazóis
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Antibacterianos
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Ácidos Nicotínicos
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos