Synthesis and antibacterial activity of novel C12 ethyl ketolides

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 16; pp. 5592 - 5604
• Main Authors: BURGER, Matthew T, HIEBERT, Christy, SEID, Mehran, CHU, Daniel T, BARKER, Lynn, LANGHORNE, Mike, SHAWAR, Ribhi, KIDNEY, Jolene, DESAI, Manoj C, PLATTNER, Jacob J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 15.08.2006
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Erythromycin - analogs & derivatives; Erythromycin - chemical synthesis; Erythromycin - pharmacology; General aspects; Ketolides - chemical synthesis; Ketolides - pharmacology; Medical sciences; Methylation; Mice; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Respiratory Tract Infections - drug therapy; Respiratory Tract Infections - microbiology; Ribosomes - metabolism; Streptococcus pneumoniae - drug effects; Structure-Activity Relationship; Ribosome; Ketolide antibiotic; Macrolide antibiotic; Antiinfective; Organic carbamate; Antimicrobial agent; Pyridine derivatives; Imidazopyridine derivatives; Bacteria; Micrococcales; Antiinfectious; Chemical synthesis; Clinical isolate; Rodentia; Telithromycin; Erythromycin; In vitro; Macrolide; Biological activity; Streptococcus pneumoniae; Infection; Resistance; Streptococcaceae; In vivo; Vertebrata; Experimental disease; Antibiotic; Mammalia; Mouse; Animal; Antibacterial agent; Methylation; Ketolide
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.04.032

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.