title: Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin.
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 (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 beeight timesmore active than previously prepared 4,8,10-tridesmethyl congener (3) andtwo timesmore 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.
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122.
authors.forename: Bharat
authors.initials: B
authors.lastname: Wagh
authors.forename: Tapas
authors.initials: T
authors.lastname: Paul
authors.forename: Ian
authors.initials: I
authors.lastname: Glassford
authors.forename: Charles
authors.initials: C
authors.lastname: Debrosse
authors.forename: Dorota
authors.initials: D
authors.lastname: Klepacki
authors.forename: Meagan C
authors.initials: MC
authors.lastname: Small
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Mackerell
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Andrade
keywords: antibiotic resistance; desmethyl analogues; ketolide antibiotics; molecular modeling; telithromycin; total synthesis