title: 1-(1H-indol-3-yl)ethanamine derivatives as potent Staphylococcus aureus NorA efflux pump inhibitors.
abstract: 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.
authors.affiliation: Laboratoire Charles Friedel (LCF), CNRS UMR 7223, Chimie ParisTech, 11 rue Pierre et Marie Curie, 75005 Paris (France).
authors.forename: Arnaud
authors.initials: A
authors.lastname: Hequet
authors.forename: Olga N
authors.initials: ON
authors.lastname: Burchak
authors.forename: Matthieu
authors.initials: M
authors.lastname: Jeanty
authors.forename: Xavier
authors.initials: X
authors.lastname: Guinchard
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Le Pihive
authors.forename: Laure
authors.initials: L
authors.lastname: Maigre
authors.forename: Pascale
authors.initials: P
authors.lastname: Bouhours
authors.forename: Dominique
authors.initials: D
authors.lastname: Schneider
authors.forename: Max
authors.initials: M
authors.lastname: Maurin
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Paris
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Denis
authors.forename: Claude
authors.initials: C
authors.lastname: Jolivalt
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002939:Ciprofloxacin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C075040:NorA protein, Staphylococcus; C030374:indole
keywords: Staphylococcus aureus; antibiotics; efflux pumps; indoles; inhibitors; structure-activity relationships