Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin.

Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, 2) and cethromycin (CET, 6), both of which are semi-synthetic derivatives of flagship macrolide antibiotic erythromycin (1). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8,10-tridesmethyl cethromycin (7). In MIC assays, CET analogue 7 was found to be equipotent with TEL (2) against a wild-type E. coli strain, more potent than previously disclosed desmethyl TEL congeners 3, 4, and 5, but fourfold less potent than TEL (2) against a mutant E. coli A2058G strain.