title: Synthesis and antibacterial activity of novel C12 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.
authors.affiliation: Chiron Corporation, Biopharma Research, Emeryille, CA 94608-2916, USA. matthew_burger@chiron.com
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burger
authors.forename: Christy
authors.initials: C
authors.lastname: Hiebert
authors.forename: Mehran
authors.initials: M
authors.lastname: Seid
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chu
authors.forename: Lynn
authors.initials: L
authors.lastname: Barker
authors.forename: Mike
authors.initials: M
authors.lastname: Langhorne
authors.forename: Ribhi
authors.initials: R
authors.lastname: Shawar
authors.forename: Jolene
authors.initials: J
authors.lastname: Kidney
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Desai
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004917:Erythromycin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D048628:Ketolides / Q000138:chemical synthesis / Q000494:pharmacology*; D008745:Methylation; D051379:Mice; D008826:Microbial Sensitivity Tests; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology; D012270:Ribosomes / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D004917:Erythromycin; C106791:telithromycin