Synthesis and Structure-Activity Relationships of α-Amino-γ-lactone Ketolides: A Novel Class of Macrolide Antibiotics.

An efficient synthesis of α-amino-γ-lactone ketolide (3) 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 MLSB-resistant strains of S. pneumoniae and S. pyogenes. In addition, ketolide 11o showed excellent in vitro antibacterial activity against H. influenzae strain as compared to telithromycin. These results indicate that C-21 substituted γ-lactone ketolides have potential as a next generation macrolide antibiotics.