Search for new tools to combat Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin

Jadwiga Handzlik (1) , Ewa Szymańska (1) , Sandrine Alibert (2) , Jacqueline Chevalier (2) , Ewa Otrębska (1) , Elżbieta Pękala (1) , Jean-Marie Pagès (2) , Katarzyna Kieć-Kononowicz (1)

1 Department of Technology and Biotechnology of Drugs
2 TMCD2 - Transporteurs membranaires, chimioresistance et drug-design

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)imidaz-olidine-2,4-dione (14) and (Z)-5-(2,4-dimethoxybenzylidene)-3-(2-hydroxy-3-(isopropylamino)pro-pyl)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.

Keywords: AcrAB-TolC; Multidrug resistance; Efflux pump; Arylideneimidazolidine-2; 4-dione; Arylidenehydantoin; Enterobacter aerogenes

Domains: Chemical Sciences; Medicinal Chemistry

Jadwiga Handzlik, Ewa Szymańska, Sandrine Alibert, Jacqueline Chevalier, Ewa Otrębska, et al.. Search for new tools to combat Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin. Bioorganic and Medicinal Chemistry, 2013, 21 (1), pp.135 - 145. ⟨10.1016/j.bmc.2012.10.053⟩. ⟨hal-01425050⟩