1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors. Issue 7 (26th March 2014)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: ChemMedChem. Volume 9:Issue 7(2014:Jul.)
• Page Start: 1534
• Page End: 1545
• Publication Date: 2014-03-26
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201400042
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>The synthesis of 37 1‐(1<italic>H</italic>‐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 <italic>Staphylococcus aureus</italic> 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 <italic>S. aureus</italic> NorA efflux pump. Among the compounds, (<italic>Z</italic>)‐<italic>N</italic>‐benzylidene‐2‐(<italic>tert</italic>‐butoxycarbonylamino)‐1‐(5‐iodo‐1<italic>H</italic>‐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 <sc>L</sc>⁻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, <italic>tert</italic>‐butyl (2‐(3‐hydroxyureido)‐2‐(1<italic>H</italic>‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found.</p> </abstract>