Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin

There is an urgent need for novel sources of antibiotics to address the incessant and inevitable onset of bacterial resistance. To this end, we have initiated a structure-based drug design program that features a desmethylation strategy (i.e., replacing methyl groups with hydrogens). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8-didesmethyl telithromycin ( 5 ), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin ( 2 ), which is an FDA-approved semisynthetic derivative of erythromycin ( 1 ). We found 5 to be eight times more active than previously prepared 4,8,10-tridesmethyl congener ( 3 ) and two times more active than 4,10-didesmethyl regioisomer ( 4 ) in MIC assays. While less potent than telithromycin ( 2 ) and paralleling the observations made in the previous study of 4,10-didesmethyl analogue ( 4 ), the inclusion of a single methyl group improves biological activity, thus supporting its role in antibiotic activity.