Desmethyl Macrolides: Synthesis and Evaluation of 4-Desmethyl Telithromycin

作者：Glassford Ian; Lee Miseon; Wagh Bharat; Velyadapu Venkata; Paul Tapas; Sandelin Gary; DeBrosse Charles; Klepacki Dorota; Small Meagan C; MacKerell Alexander D Jr; Andrade Rodrigo B^*

来源：ACS Medicinal Chemistry Letters, 2014, 5(9): 1021-1026.

DOI：10.1021/ml5002097

• Total synthesis
• ketolide antibiotics
• antibiotic resistance
• telithromycin
• molecular modeling
• desmethyl analogues

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 (%26lt;bold%26gt;6%26lt;/bold%26gt;), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (%26lt;bold%26gt;2%26lt;/bold%26gt;) and our final analogue in this series. While 4-desmethyl telithromycin (%26lt;bold%26gt;6%26lt;/bold%26gt;) was found to be equipotent with telithromycin (%26lt;bold%26gt;2%26lt;/bold%26gt;) 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 %26lt;bold%26gt;6%26lt;/bold%26gt; 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 %26lt;bold%26gt;6%26lt;/bold%26gt; with E. coli ribosomes confirmed %26lt;bold%26gt;6%26lt;/bold%26gt; is indeed binding the ribosome.

• 出版日期2014-9