Open AccessDesmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin
Author(s) -
Bharat Wagh,
Tapas Paul,
Ian Glassford,
Charles W. DeBrosse,
Dorota Klepacki,
Meagan C. Small,
Alexander D. MacKerell,
Rodrigo Andrade
Publication year - 2012
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/ml300230h
Subject(s) - telithromycin , ketolide , desmethyl , erythromycin , stereochemistry , antibiotics , chemistry , pharmacology , combinatorial chemistry , medicine , biochemistry , metabolite
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 4,8-didesmethyl telithromycin ( 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.