Synthesis and antibacterial activity of novel C12 vinyl ketolides

Journal of Medicinal Chemistry
Matthew T BurgerJ J Plattner

Abstract

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.

References

Mar 1, 1992·The Journal of Antibiotics·P A LarteyJ J Plattner
Apr 15, 1971·Experientia·P KurathT J Perun

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Citations

Jul 22, 2010·Expert Opinion on Therapeutic Patents·Herbert A Kirst
Feb 28, 2013·Expert Opinion on Drug Discovery·Zhi-Xiong RuanWei-Min Chen
Jan 19, 2008·Expert Opinion on Pharmacotherapy·Françoise Van BambekePaul M Tulkens
Mar 18, 2017·Bioorganic & Medicinal Chemistry·Hany Fakhry AnwarKjell Undheim
Aug 21, 2010·The Journal of Pharmacy and Pharmacology·Kohei TogamiKazuhiro Morimoto
Sep 3, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kjell Undheim

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