Triazole-substituted phenylboronic acids as tunable lead inhibitors of KPC-2 antibiotic resistance.
Eur J Med Chem
; 240: 114571, 2022 Oct 05.
Article
em En
| MEDLINE
| ID: mdl-35792385
ABSTRACT
Inhibition of ß-lactamases is a promising strategy to overcome antimicrobial resistance to commonly used ß-lactam antibiotics. Boronic acid derivatives have proven to be effective inhibitors of ß-lactamases due to their direct interaction with the catalytic site of these enzymes. We synthesized a series of phenylboronic acid derivatives and evaluated their structure-activity relationships as Klebsiella pneumoniae carbapenemase (KPC-2) inhibitors. We identified potent KPC-2 inhibitors 2e & 6c (Ki = 0.032 µM and 0.038 µM, respectively) that enhance the activity of cefotaxime in KPC-2 expressing Escherichia coli. The measured acid dissociation constants (pKa) of selected triazole-containing phenylboronic acids was broad (5.98-10.0), suggesting that this is an additional property of the compounds that could be tuned to optimize the target interaction and/or the physicochemical properties of the compounds. These findings will help to guide the future development of boronic acid compounds as inhibitors of KPC-2 and other target proteins.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Triazóis
/
Klebsiella pneumoniae
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2022
Tipo de documento:
Article