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HERO ID
2321095
Reference Type
Journal Article
Title
1-(1H-Indol-3-yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors
Author(s)
Hequet, A; Burchak, ON; Jeanty, M; Guinchard, X; Le Pihive, E; Maigre, L; Bouhours, P; Schneider, D; Maurin, M; Paris, JM; Denis, JN; Jolivalt, C
Year
2014
Is Peer Reviewed?
0
Journal
ChemMedChem
ISSN:
1860-7179
EISSN:
1860-7187
Publisher
John Wiley and Sons Ltd
Volume
9
Issue
7
Page Numbers
1534-1545
Language
English
PMID
24677763
DOI
10.1002/cmdc.201400042
Web of Science Id
WOS:000338991100022
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.
Keywords
antibiotics; efflux pumps; indoles; inhibitors; Staphylococcus aureus; structure-activity relationships; 1 (1h indol 3 yl)ethanamine derivative; antiinfective agent; carrier protein; ciprofloxacin; ethidium bromide; indole derivative; n (3 (( tert butoxycarbonyl)amino)propylidene) 1 phenylmethanamine oxide; NorA efflux pump; quinolone derivative; tert butyl (2 (1 benzyl 3 hydroxyureido) 2 (5 bromo 1h indol 3yl)ethyl)carbamate; tert butyl (2 (3 hydroxyureido) 2 (1h indol 3 yl)ethyl)carbamate; tert butyl (2 (4 bromophenyl)acetamido 2 (5 bromo 1h indol 3yl)ethyl)carbamate; tert butyl (2 (5 bromo 1h indol 3 yl) 2 (2,2,2 trifluoroacetamido)ethyl)carbamate; tert butyl (2 (5 bromo 1h indol 3 yl) 2 (nicotinamido)ethyl)carbamate; tert butyl (2 (benzylamino) 2 (5 bromo 1h indol 3 yl)ethyl)carbamate; tert butyl (2 acetamido 2 (1h indol 3 yl)ethyl)carbamate; tert butyl (2 acetamido 2 (5 bromo 1h indol 3 yl)ethyl)carbamate; tert butyl (2 amino 2 (1h indol 3 yl)ethyl)carbamate; tert butyl (2 amino 2 (5 bromo 1h indol 3 yl)ethyl)carbamate; tert butyl (2 benzamido 2 (5 bromo 1h indol 3 yl)ethyl)carbamate; tert butyl (2 formamido 2 (1h indol 3 yl)ethyl)carbamate; tert butyl (2 formamido 2 (5 bromo 1h indol 3 yl)ethyl)carbamate; tert butyl (3 (benzyl(hydroxy)amino) 3 (5 bromo 1h indol 3 yl)propyl)carbamate; tert butyl (3 oxopropyl)carbamate; unclassified drug; amine; antiinfective agent; bacterial protein; ciprofloxacin; indole; indole derivative; multidrug resistance protein; NorA protein, Staphylococcus; antibacterial activity; antibiotic resistance; article; bacterial strain; biological activity; cancer cell line; carbon nuclear magnetic resonance; colon tumor; drug structure; drug synthesis; growth inhibition; human; human cell; human cell culture; lung fibroblast; minimum inhibitory concentration; priority journal; proton nuclear magnetic resonance; Staphylococcus aureus; structure activity relation; antagonists and inhibitors; cell line; cell proliferation; chemistry; drug effects; metabolism; microbial sensitivity test; Staphylococcus aureus; synthesis; Amines; Anti-Bacterial Agents; Bacterial Proteins; Cell Line; Cell Proliferation; Ciprofloxacin; Drug Resistance, Bacterial; Humans; Indoles; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins; Staphylococcus aureus; Structure-Activity Relationship
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