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Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin.

ABSTRACT: Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10-didesmethyl telithromycin (4) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (3) in MIC assays. While less potent than telithromycin (2), the inclusion of the C-8 methyl group has improved biological activity suggesting it plays an important role in antibiotic function.

SUBMITTER: Velvadapu V

PROVIDER: S-EPMC3374412 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin.

Velvadapu Venkata V Glassford Ian I Lee Miseon M Paul Tapas T Debrosse Charles C Klepacki Dorota D Small Meagan C MC Mackerell Alexander D AD Andrade Rodrigo B RB

ACS medicinal chemistry letters 20120115 3

Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10-didesmethyl telithromy ...[more]

PMID: 22708010

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Desmethyl macrolides: synthesis and evaluation of 4-desmethyl telithromycin.

Project description:Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (6), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2) and our final analogue in this series. While 4-desmethyl telithromycin (6) was found to be equipotent with telithromycin (2) against wild-type bacteria, it was 4-fold less potent against the A2058G mutant. These findings reveal that strategically replacing the C4-methyl group with hydrogen (i.e., desmethylation) did not address this mechanism of resistance. Throughout the desmethyl series, the sequential addition of methyls to the 14-membered macrolactone resulted in improved bioactivity. Molecular modeling methods indicate that changes in conformational flexibility dominate the increased biological activity; moreover, they reveal 6 adopts a different conformation once bound to the A2058G ribosome, thus impacting noncovalent interactions reflected in a lower MIC value. Finally, fluorescence polarization experiments of 6 with E. coli ribosomes confirmed 6 is indeed binding the ribosome.

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