title: Search for new tools to combat Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin.
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.
authors.affiliation: Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. jhandzli@cm-uj.krakow.pl
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
authors.forename: Ewa
authors.initials: E
authors.lastname: Szymańska
authors.forename: Sandrine
authors.initials: S
authors.lastname: Alibert
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Chevalier
authors.forename: Ewa
authors.initials: E
authors.lastname: Otrębska
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Pagès
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D021902:Enterobacter aerogenes / Q000187:drug effects*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy*; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D006827:Hydantoins