Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling, and biological evaluation of 4,10-didesmethyl telithromyc...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2012-03, Vol.3 (3), p.211-215
Main Authors: Velvadapu, Venkata, Glassford, Ian, Lee, Miseon, Paul, Tapas, DeBrosse, Charles, Klepacki, Dorota, Small, Meagan C, MacKerell, Alexander D, Andrade, Rodrigo B
Format: Article
Language:English
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Letter
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Summary:Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling, and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the third-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10-didesmethyl telithromycin (4) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (3) in MIC assays. While less potent than telithromycin (2), the inclusion of the C-8 methyl group has improved biological activity, suggesting that it plays an important role in antibiotic function.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml200254h