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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Sep 10

PMID 24015325

Citations 7

Authors

Bharat Wagh

Tapas Paul

Ian Glassford

Charles DeBrosse

Dorota Klepacki

Meagan C Small

Alexander D MacKerell Jr

Rodrigo B Andrade

Affiliations

Soon will be listed here.

Abstract

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 (), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (), which is an FDA-approved semisynthetic derivative of erythromycin (). We found 4,8-didesmethyl telithromycin () to be more active than previously prepared 4,8,10-tridesmethyl congener () and more active than 4,10-didesmethyl regioisomer () in MIC assays. While less potent than telithromycin () and paralleling the observations made in the previous study of 4,10-didesmethyl analogue (), the inclusion of a single methyl group improves biological activity thus supporting its role in antibiotic activity.

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