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

Autor: Fabio Prati, Maria Luisa Introvigne, Magdalena A. Taracila, Emilia Caselli, Robert A. Bonomo
Rok vydání: 2020
Předmět:
Triazole
Microbial Sensitivity Tests
01 natural sciences
Biochemistry
beta-Lactamases
Article
Serine
chemistry.chemical_compound
Structure-Activity Relationship
Bacterial Proteins
Amide
Drug Discovery
Side chain
polycyclic compounds
antibiotic resistance
beta-lactamase inhibitors
boronic acids
click chemistry
Klebsiellae pneumoniae
General Pharmacology
Toxicology and Pharmaceutics
Beta-Lactamase Inhibitors
Pharmacology
chemistry.chemical_classification
Dose-Response Relationship
Drug
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
biochemical phenomena
metabolism
and nutrition
Triazoles
Combinatorial chemistry
Boronic Acids
0104 chemical sciences
Sulfonamide
Anti-Bacterial Agents
010404 medicinal & biomolecular chemistry
Klebsiella pneumoniae
Click chemistry
Molecular Medicine
Bioisostere
beta-Lactamase Inhibitors
Zdroj: ChemMedChem
ISSN: 1860-7187
Popis: 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.
Databáze: OpenAIRE
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