α-triazolylboronic acids: a promising scaffold for effective inhibitors of KPCs.

α-triazolylboronic acids: a promising scaffold for effective inhibitors of KPCs.
ChemMedChem. 2020 May 27;:
Authors: Introvigne ML, Taracila MA, Prati F, Caselli E, Bonomo RA
Abstract
Boronic Acids are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain mimicking the β-lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids where the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two steps synthesis which relies on the solid and versatile coppercatalyzed azide-alkyne cycloaddition (CuAAC) followed by boronate deprotection. All of the compounds show very good inhibition of KPC2, with Kis ranging from 1 nM to 1 µM and most of them are able to restore cefepime activity against Klebsiella pneumoniae harboring blaKPC-2. In particular, compound 1e bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (Ki 30  nM) and it restored cefepime susceptibility in KPC-Kpn cells (MIC =  0.5 µg/mL) with values similar to vaborbactam (Ki 20 nM, MIC in KPC-Kp1 0.5 µg/mL). Our findings suggest that α-triazolylboronates might represent an effective scaffold for the treatment of KPC-mediated infections.
PMID: 32459878 [PubMed - as supplied by publisher]

Source: ChemMedChem - May 26, 2020 Category: Chemistry Authors: Introvigne ML, Taracila MA, Prati F, Caselli E, Bonomo RA Tags: ChemMedChem Source Type: research