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1-(1H-Indol-3-yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors

Hequet, Arnaud ; Burchak, Olga N. ; Jeanty, Matthieu ; Guinchard, Xavier ; Le Pihive, Emmanuelle ; Maigre, Laure ; Bouhours, Pascale ; Schneider, Dominique ; Maurin, Max ; Paris, Jean-Marc ; Denis, Jean-Noël ; Jolivalt, Claude

ChemMedChem, 2014-07, Vol.9 (7), p.1534-1545 [Periódico revisado por pares]

Weinheim: WILEY-VCH Verlag

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Título:
1-(1H-Indol-3-yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors
Autor: Hequet, Arnaud ; Burchak, Olga N. ; Jeanty, Matthieu ; Guinchard, Xavier ; Le Pihive, Emmanuelle ; Maigre, Laure ; Bouhours, Pascale ; Schneider, Dominique ; Maurin, Max ; Paris, Jean-Marc ; Denis, Jean-Noël ; Jolivalt, Claude
Assuntos: Amines - chemical synthesis ; Amines - chemistry ; Amines - pharmacology ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; antibiotics ; Bacterial Proteins - antagonists & inhibitors ; Bacterial Proteins - metabolism ; Biodiversity ; Cell Line ; Cell Proliferation - drug effects ; Ciprofloxacin - pharmacology ; Derivatives ; Drug Resistance, Bacterial - drug effects ; efflux pumps ; Humans ; indoles ; Indoles - chemistry ; inhibitors ; Life Sciences ; Medical research ; Microbial Sensitivity Tests ; Multidrug Resistance-Associated Proteins - antagonists & inhibitors ; Multidrug Resistance-Associated Proteins - metabolism ; Penicillin ; Populations and Evolution ; Staphylococcus aureus ; Staphylococcus aureus - drug effects ; Staphylococcus aureus - metabolism ; Structure-Activity Relationship ; structure-activity relationships
É parte de: ChemMedChem, 2014-07, Vol.9 (7), p.1534-1545
Notas: Agence Nationale de la Recherche ANR, France - No. ANR-08EBIO-012
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Descrição: The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5 mg L−1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found. A pump turn off: 1‐(1H‐Indol‐3‐yl)ethanamine derivatives such as the one shown here, were synthesized through simple chemical modifications and were shown to be efficient NorA efflux pump inhibitors. They are able to restore ciprofloxacin activity against fluoroquinolone‐resistant Staphylococcus aureus strains.
Editor: Weinheim: WILEY-VCH Verlag
Idioma: Inglês;Alemão

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1-(1H-Indol-3-yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors

Hequet, Arnaud ; Burchak, Olga N. ; Jeanty, Matthieu ; Guinchard, Xavier ; Le Pihive, Emmanuelle ; Maigre, Laure ; Bouhours, Pascale ; Schneider, Dominique ; Maurin, Max ; Paris, Jean-Marc ; Denis, Jean-Noël ; Jolivalt, Claude

Weinheim: WILEY-VCH Verlag

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