Amine-alkyl derivatives of hydantoin: New tool to combat resistant bacteria

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

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

A series of new 5,5-diphenylhydantoin derivatives with various amineealkyl terminal fragments at N1-position were synthesized. Then a series of twenty-eight compounds with the same hydantoin scaffold were evaluated for their potency to combat bacterial MultiDrug Resistance (MDR). Intrinsic antibacterial activities were first evaluated. As these compounds showed no direct activity on bacteria, their influence on minimal inhibitory concentration (MIC) of nalidixic acid was tested in two strains of Enterobacter aerogenes: the reference-strain ATCC-13048 and the CM-64 strain which over-produces AcrAB-TolC efflux pump. The compounds showed moderate-or low-anti-MDR properties. According to SAR-studies, hit compounds containing 2-methoxyphenylpiperazine at N1-terminal fragment and methylcarboxyl acid one at N3-position of hydantoin have been identified for further microbiological studies and pharma-comodulations to develop efflux pump inhibitors.

Keywords: Chemosensitizer; Antibiotic resistance; Hydantoin derivatives; Efflux pumps

Domains: Chemical Sciences; Medicinal Chemistry

Jadwiga Handzlik, Ewa Szymańska, Jacqueline Chevalier, Ewa Otrębska, Katarzyna Kieć-Kononowicz, et al.. Amine-alkyl derivatives of hydantoin: New tool to combat resistant bacteria. European Journal of Medicinal Chemistry, 2011, 46 (12), pp.5807-5816. ⟨10.1016/j.ejmech.2011.09.032⟩. ⟨hal-01425032⟩