期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 21, 期 1, 页码 135-145出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.10.053
关键词
Arylideneimidazolidine-2,4-dione; Arylidenehydantoin; Enterobacter aerogenes; Multidrug resistance; Efflux pump; AcrAB-TolC
资金
- COST action [BM0701]
- [501/N-COST/2009/0 (K/PMN/000031)]
- [Polonium 8127/2010]
- [ANR-11-BS07-019-02 'IBEF']
A series of amine-alkyl derivatives of 5-arylidenehydantoin 3-21 was evaluated for their ability to improve antibiotic effectiveness in two strains of Gram-negative Enterobacter aerogenes: the reference strain (ATCC-13048) and the chloramphenicol-resistant derivative over-producing the AcrAB-TolC efflux pump (CM-64). Three antibiotics, chloramphenicol, nalidixic acid and sparfloxacin were used as markers of efflux pump activity. New compounds (5-16) were obtained within 3-4 step synthesis using Knoevenagel condensation, Mitsunobu reaction and microwave aided N-alkylation. Molecular modeling based structure-activity relationship (SAR) studies were performed. The most active compounds: (Z)-5-(4-(diethylamino) benzylidene)-3-(2-hydroxy-3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (14) and (Z)-5-(2,4-dimethoxybenzylidene)-3-(2-hydroxy-3-(isopropylamino)propyl)imidazolidine-2,4-dione (15) induced fourfold decrease of minimal inhibition concentration (MIC) of all tested antibiotics in the strain CM-64 overexpressing the AcrAB-TolC pump. (C) 2012 Elsevier Ltd. All rights reserved.
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