2,4-Disubstituted 5-Nitroimidazoles Potent against Clostridium difficile

Abstract

Metronidazole is one of the first-line treatments for non-severe Clostridium difficile infections (CDI). However, resistance limits its use in cases of severe and complicated CDI. Structure-activity relationships previously described for the 5-nitroimidazole series have shown that functionalization at the 2- and 4-positions can impart better activity against parasites and anaerobic bacteria than metronidazole. Herein we report the synthesis of new 2,4-disubstituted 5-nitroimidazole compounds that show potent antibacterial activity against C. difficile. We used a vicarious nucleophilic substitution of hydrogen (VNS) reaction to introduce a phenylmethylsulfone at the 4-position and a unimolecular radical nucleophilic substitution (S_RN 1) reaction to introduce an ethylenic function at the 2-position of the 5-nitroimidazole scaffold.

Keywords: Clostridium difficile; antibiotics; medicinal chemistry; nitrogen heterocycles; radical reactions.