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 (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.