Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ.
Bioorg Med Chem Lett
; 24(1): 353-9, 2014 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-24287381
ABSTRACT
The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oxazóis
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Staphylococcus aureus
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Proteínas de Bactérias
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Benzamidas
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Desenho de Fármacos
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Proteínas do Citoesqueleto
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Antibacterianos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Reino Unido