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

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

Desmethyl Macrolides: Synthesis and Evaluation of 4‑Desmethyl Telithromycin

Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (<b>6</b>), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (<b>2</b>) and our final analogue in this series. While 4-desmethyl telithromycin (<b>6</b>) was found to be equipotent with telithromycin (<b>2</b>) against wild-type bacteria, it was 4-fold less potent against the A2058G mutant. These findings reveal that strategically replacing the C4-methyl group with hydrogen (i.e., desmethylation) did not address this mechanism of resistance. Throughout the desmethyl series, the sequential addition of methyls to the 14-membered macrolactone resulted in improved bioactivity. Molecular modeling methods indicate that changes in conformational flexibility dominate the increased biological activity; moreover, they reveal <b>6</b> adopts a different conformation once bound to the A2058G ribosome, thus impacting noncovalent interactions reflected in a lower MIC value. Finally, fluorescence polarization experiments of <b>6</b> with <i>E. coli</i> ribosomes confirmed <b>6</b> is indeed binding the ribosome