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 analogue7was found to be equipotent with TEL (2) against a wild-typeE. colistrain, more potent than previously disclosed desmethyl TEL congeners3,4, and5, but fourfold less potent than TEL (2) against a mutantE. coliA2058G strain.
Department of Chemistry, Temple University, Philadelphia, PA 19122.
Bharat
B
Wagh
Department of Chemistry, Temple University, Philadelphia, PA 19122.
Tapas
T
Paul
Department of Chemistry, Temple University, Philadelphia, PA 19122.
Charles
C
Debrosse
Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607.
Dorota
D
Klepacki
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201.
Meagan C
MC
Small
Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201.
Alexander D
AD
Mackerell
Department of Chemistry, Temple University, Philadelphia, PA 19122.
Rodrigo B
RB
Andrade
antibiotic resistance; cethromycin; desmethyl analogues; ketolide antibiotics; molecular modeling; telithromycin; total synthesis