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

被引:34
作者
Hequet, Arnaud [1 ]
Burchak, Olga N. [2 ]
Jeanty, Matthieu [2 ,5 ]
Guinchard, Xavier [2 ,6 ]
Le Pihive, Emmanuelle [3 ]
Maigre, Laure [3 ]
Bouhours, Pascale [1 ]
Schneider, Dominique [3 ]
Maurin, Max [3 ,4 ]
Paris, Jean-Marc [1 ]
Denis, Jean-Noel [2 ]
Jolivalt, Claude [1 ]
机构
[1] Chim ParisTech, LCF, CNRS, UMR 7223, F-75005 Paris, France
[2] Univ Grenoble 1, Dept Chim Mol SeRCO, ICMG FR 2607, CNRS,UMR 5250, F-38041 Grenoble 9, France
[3] Univ Grenoble 1, Lab Adaptat & Pathogenie Microorganismes, Inst Jean Roget, CNRS,UMR 5163, F-38042 Grenoble 9, France
[4] Univ Grenoble 1, CHU Grenoble, F-38043 Grenoble 9, France
[5] NovAliX, Ctr Rech Pharma, F-27106 Val De Reuil, France
[6] CNRS, Ctr Rech, ICSN, F-91198 Gif Sur Yvette, France
关键词
antibiotics; efflux pumps; indoles; inhibitors; Staphylococcus aureus; structure-activity relationships; MULTIDRUG-RESISTANCE; ANTIBACTERIAL ACTIVITY; TRANSPORTER; CIPROFLOXACIN; ANTIBIOTICS; CONTRIBUTES; ALKALOIDS; PROTEINS; BACTERIA; ANALOGS;
D O I
10.1002/cmdc.201400042
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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-benzylidene2-(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.
引用
收藏
页码:1534 / 1545
页数:12
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