Design, synthesis and biological evaluation of antimicrobial diarylimine and -amine compounds targeting the interaction between the bacterial NusB and NusE proteins.
Eur J Med Chem
; 178: 214-231, 2019 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-31185412
ABSTRACT
Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model. Inhibitory activity against the NusB-NusE binding, circular dichroism of compound treated NusB, antimicrobial activity, cytotoxicity, hemolytic property and cell permeability using Caco-2â¯cells were measured. Structure-activity relationship and quantitative structure-activity relationship were also concluded and discussed. Some of the derivatives demonstrated improved antimicrobial activity than the hit compound against a panel of clinically important pathogens, lowering the minimum inhibition concentration to 1-2⯵g/mL against Staphylococcus aureus, including clinical strains of methicillin-resistant Staphylococcus aureus at a level comparable to some of the marketed antibiotics. Given the improved antimicrobial activity, specific inhibition of target protein-protein interaction and promising pharmacokinetic properties without significant cytotoxicity, this series of diaryl compounds have high potentials and deserve for further studies towards a new class of antimicrobial agents in the future.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ligação Proteica
/
Bases de Schiff
/
Benzilaminas
/
Compostos de Anilina
/
Antibacterianos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article