title: Synthesis and Structure-Activity Relationships of α-Amino-γ-lactone Ketolides: A Novel Class of Macrolide Antibiotics.
abstract: 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.
authors.affiliation: PLIVA Research Institute , Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.
authors.forename: Dražen
authors.initials: D
authors.lastname: Pavlović
authors.affiliation: PLIVA Research Institute , Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.
authors.forename: Stjepan
authors.initials: S
authors.lastname: Mutak
authors.affiliation: Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Andreotti
authors.affiliation: Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biondi
authors.affiliation: Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cardullo
authors.affiliation: Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Paio
authors.affiliation: Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Piga
authors.affiliation: Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.affiliation: Medicine Research Centre, GlaxoSmithKline , Via Fleming 4, I-37135 Verona, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lociuro
keywords: Macrolide antibiotics; ketolides; macrolide resistance; structure−activity relationships