Open AccessDesmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin
Author(s) -
Bharat Wagh,
Tapas Paul,
Charles W. DeBrosse,
Dorota Klepacki,
Meagan C. Small,
Alexander D. MacKerell,
Rodrigo Andrade
Publication year - 2013
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml400337t
Subject(s) - desmethyl , telithromycin , erythromycin , antibiotics , macrolide antibiotics , mutant , strain (injury) , chemistry , stereochemistry , microbiology and biotechnology , bacteria , combinatorial chemistry , biology , biochemistry , genetics , gene , anatomy , metabolite
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.