Design, Synthesis, and Biological Evaluation of New 1H-Imidazole-2-Carboxylic Acid Derivatives as Metallo-ß-Lactamase Inhibitors.
Bioorg Med Chem
; 72: 116993, 2022 10 15.
Article
em En
| MEDLINE
| ID: mdl-36084491
ABSTRACT
As one of important mechanisms to ß-lactam antimicrobial resistance, metallo-ß-lactamases (MBLs) have been receiving increasing worldwide attentions. Ambler subclass B1 MBLs are most clinically relevant, because they can hydrolyze almost all ß-lactams with the exception of monobactams. However, it is still lacking of clinically useful drugs to combat MBL-medicated resistance. We previously identified 1H-imidazole-2-carboxylic acid as a core metal-binding pharmacophore (MBP) to target multiple B1 MBLs. Herein, we report structural optimization of 1H-imidazole-2-carboxylic acid and substituents. Structure-activity relationship (SAR) analyses revealed that replacement of 1H-imidazole-2-carboxylic acid with other structurally highly similar MBPs excepting thiazole-4-carboxylic acid resulted in decreased MBL inhibition. Further SAR studies identified more potent inhibitors to MBLs, of which 28 manifested IC50 values of 0.018 µM for both VIM-2 and VIM-5. The microbiological tests demonstrated that the most tested compounds showed improved synergistic effects; some compounds at 1 µg/ml were able to reduce meropenem MIC by at least 16-fold, which will be worth further development of new potent inhibitors particularly targeting VIM-type MBLs.
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MEDLINE
Assunto principal:
Beta-Lactamases
/
Inibidores de beta-Lactamases
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article