Synthesis and Antibacterial Activity of Novel C12 Vinyl Ketolides

• Published in: Journal of medicinal chemistry Vol. 49; no. 5; pp. 1730 - 1743
• Main Authors: Burger, Matthew T, Lin, Xiaodong, Chu, Daniel T, Hiebert, Christy, Rico, Alice C, Seid, Mehran, Carroll, Georgia L, Barker, Lynn, Huh, Kay, Langhorne, Mike, Shawar, Ribhi, Kidney, Jolene, Young, Kelly, Anderson, Scott, Desai, Manoj C, Plattner, Jacob J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 09.03.2006
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Biological Availability; Drug Resistance, Bacterial; Enterococcus faecalis - drug effects; Haemophilus Infections - drug therapy; Haemophilus influenzae - drug effects; Half-Life; Ketolides - chemical synthesis; Ketolides - pharmacokinetics; Ketolides - pharmacology; Lung Diseases - drug therapy; Lung Diseases - microbiology; Male; Microbial Sensitivity Tests; Pneumococcal Infections - drug therapy; Rats; Rats, Sprague-Dawley; Staphylococcus aureus - drug effects; Streptococcus pneumoniae - drug effects; Streptococcus pyogenes - drug effects; Structure-Activity Relationship; Vinyl Compounds - chemical synthesis; Vinyl Compounds - pharmacokinetics; Vinyl Compounds - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051157a

A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.