Novel small molecule inhibitors targeting the "switch region" of bacterial RNAP: structure-based optimization of a virtual screening hit.
Eur J Med Chem
; 65: 223-31, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23711833
ABSTRACT
Rising resistance against current antibiotics necessitates the development of antibacterial agents with alternative targets. The "switch region" of RNA polymerase (RNAP), addressed by the myxopyronins, could be such a novel target site. Based on a hit candidate discovered by virtual screening, a small library of 5-phenyl-3-ureidothiophene-2-carboxylic acids was synthesized resulting in compounds with increased RNAP inhibition. Hansch analysis revealed π (lipophilicity constant) and σ (Hammet substituent constant) of the substituents at the 5-phenyl moiety to be crucial for activity. The binding mode was proven by the targeted introduction of a moiety mimicking the enecarbamate side chain of myxopyronin into the hit compound, accompanied by enhanced RNAP inhibitory potency. The new compounds displayed good antibacterial activities against Gram positive bacteria and Gram negative Escherichia coli TolC and a reduced resistance frequency compared to the established antibiotic rifampicin.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Tiofenos
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RNA Polimerases Dirigidas por DNA
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Ácidos Carboxílicos
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Inibidores Enzimáticos
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Escherichia coli
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Bibliotecas de Moléculas Pequenas
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Ensaios de Triagem em Larga Escala
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Antibacterianos
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2013
Tipo de documento:
Article