Search for new tools to combat Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin |
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Authors: | Jadwiga Handzlik Ewa Szymańska Sandrine Alibert Jacqueline Chevalier Ewa Otrębska Elżbieta Pękala Jean-Marie Pagès Katarzyna Kieć-Kononowicz |
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Affiliation: | 1. Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland;2. UMR-MD1, Transporteurs Membranaires, Chimiorésistance et Drug Design, Aix-Marseille Université/IRBA, Facultés de Médecine et de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille cedex 05, France;3. COST Action BM0701 (ATENS), Brussels, Belgium |
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Abstract: | 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. |
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