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α‐Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs
Author(s) -
Introvigne Maria Luisa,
Taracila Magdalena A.,
Prati Fabio,
Caselli Emilia,
Bonomo Robert A.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000126
Subject(s) - chemistry , amide , bioisostere , stereochemistry , combinatorial chemistry , triazole , alkyne , azide , covalent bond , cefepime , cycloaddition , serine , click chemistry , sulfonamide , boronic acid , side chain , chemical synthesis , biochemistry , organic chemistry , enzyme , imipenem , antibiotics , antibiotic resistance , in vitro , catalysis , polymer
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 1 e , 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.