Synthesis and Structure–Activity Relationships
of α‑Amino-γ-lactone Ketolides: A Novel Class of
Macrolide Antibiotics
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Abstract
An
efficient synthesis of α-amino-γ-lactone ketolide (<b>3</b>) was developed, which provided a versatile intermediate
for the incorporation of a variety of aryl and heteroaryl groups onto
the C-21 position of clarithromycin via HBTU-mediated amidation. The
biological data for this important new class of macrolides revealed
significantly potent activity against erythromycin-susceptible strains
as well as efflux-resistant and erythromycin MLS<sub>B</sub>-resistant
strains of <i>S. pneumoniae</i> and <i>S. pyogenes</i>. In addition, ketolide <b>11o</b> showed excellent <i>in vitro</i> antibacterial activity against <i>H. influenzae</i> strain as compared to telithromycin. These results indicate that
C-21 substituted γ-lactone ketolides have potential as a next
generation macrolide antibiotics
