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 (<bold>6</bold>), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (<bold>2</bold>) and our final analogue in this series. While 4-desmethyl telithromycin (<bold>6</bold>) was found to be equipotent with telithromycin (<bold>2</bold>) 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 <bold>6</bold> 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 <bold>6</bold> with E. coli ribosomes confirmed <bold>6</bold> is indeed binding the ribosome.