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 telithromycin (<b>4</b>), a novel desmethyl analogue of the third-generation drug telithromycin (<b>2</b>). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (<b>1</b>). We found 4,10-didesmethyl telithromycin (<b>4</b>) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (<b>3</b>) in MIC assays. While less potent than telithromycin (<b>2</b>), the inclusion of the C-8 methyl group has improved biological activity, suggesting that it plays an important role in antibiotic function