Synthesis and antibacterial activity of novel C12 ethyl ketolides Original Research Article

A novel series of C12 ethyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens, including those resistant to erythromycin. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with an ethyl group via chemical synthesis. From the C12 ethyl macrolide core, a series of C12 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 C12 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 C12 ethyl ketolides was demonstrated in a mouse infection model with Streptococcus pneumoniae as pathogen.