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 Ki values ranging from 1 nM to 1 μM, and most of them are able to restore cefepime activity against K. pneumoniae harboring blaKPC-2. In particular, compound 1 e, bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (Ki=30 nM); it restored cefepime susceptibility in KPC-Kpn cells (MIC=0.5 μg/mL) with values similar to that of vaborbactam (Ki=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.

α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs / Introvigne, M. L.; Taracila, M. A.; Prati, F.; Caselli, E.; Bonomo, R. A.. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 15:14(2020), pp. 1283-1288. [10.1002/cmdc.202000126]

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

Introvigne M. L.;Prati F.;Caselli E.;
2020

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 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 Ki values ranging from 1 nM to 1 μM, and most of them are able to restore cefepime activity against K. pneumoniae harboring blaKPC-2. In particular, compound 1 e, bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (Ki=30 nM); it restored cefepime susceptibility in KPC-Kpn cells (MIC=0.5 μg/mL) with values similar to that of vaborbactam (Ki=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.
22-giu-2020
15
14
1283
1288
α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs / Introvigne, M. L.; Taracila, M. A.; Prati, F.; Caselli, E.; Bonomo, R. A.. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 15:14(2020), pp. 1283-1288. [10.1002/cmdc.202000126]
Introvigne, M. L.; Taracila, M. A.; Prati, F.; Caselli, E.; Bonomo, R. A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1207262
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