Ruthenium-Catalyzed Cycloaddition for Introducing Chemical Diversity in Second-Generation β-Lactamase Inhibitors
Flavie Bouchet1, Jean-Philippe Barnier2, Ines Sayah2
1Université Paris Cité, CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, 75006, Paris, France.
Abstract:
Ruthenium(II) alkyne azide cycloaddition (RuAAC) is an attractive reaction to access 1,5-triazole derivatives and is applicable to internal alkynes. Here, we explore RuAAC to introduce molecular diversity on the diazabicyclooctane (DBO) scaffold of β-lactamase inhibitors. The methodology presented is fully regioselective and enabled synthesis of a series of 1,5-triazole DBOs and trisubstituted analogues. Molecular modelling and biological evaluation revealed that the DBO substituents provided putative stabilizing interactions in the active site of broad-spectrum β-lactamase KPC-2 and promising activity against a hyperpermeable strain of Escherichia coli producing KPC-2.
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