Desmethyl Macrolides: Synthesis and Evaluation of 4-Desmethyl Telithromycin
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- 作者：Ian Glassford ; Miseon Lee ; Bharat Wagh ; Venkata Velvadapu ; Tapas Paul ; Gary Sandelin ; Charles DeBrosse ; Dorota Klepacki ; Meagan C. Small ; Alexander D. MacKerell ; Jr. ; Rodrigo B. Andrade
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2014
- 出版时间：September 11, 2014
- 年：2014
- 卷：5
- 期：9
- 页码：1021-1026
- 全文大小：418K
- ISSN：1948-5875
文摘
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.