α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs

Boronic acids are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain that mimics the β- lactam’s amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids in which the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two-step synthesis that relies on the solid and versatile copper-catalyzed azide-alkyne cycloaddition (CuAAC) followed by boronate deprotection. All of the compounds show very good inhibition of the Klebsiella pneumoniae carbapenemase KPC-2, with K(i) values ranging from 1 nM to 1 μM, and most of them are able to restore cefepime activity against K. pneumoniae harboring bla(KPC-2). In particular, compound 1e, bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (K(i)=30 nM); it restored cefepime susceptibility in KPC-Kpn cells (MIC=0.5 μg/ mL) with values similar to that of vaborbactam (K(i)=20 nM, MIC in KPC-Kpn 0.5 μg/mL). Our findings suggest that α-triazolylboronates might represent an effective scaffold for the treatment of KPC-mediated infections.