Synthesis and antibacterial activity of novel C 12 ethyl ketolides

Abstract

A novel series of C 12 ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C 12 modification involves replacing the natural C 12 methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C 12 ethyl macrolide core, a series of C 12 ethyl ketolides were prepared and tested for antibacterial activity against a panel of relevant clinical isolates. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria, whether resistance was due to ribosome methylation ( erm) or efflux ( mef). In particular, the C 12 ethyl ketolides 4k, 4s, 4q, 4m, and 4t showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. The in vivo efficacy of several C 12 ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen.