
European Journal of Medicinal Chemistry p. 214 - 231 (2019)
Update date:2022-08-15
Topics:
Qiu, Yangyi
Chan, Shu Ting
Lin, Lin
Shek, Tsun Lam
Tsang, Tsz Fung
Barua, Nilakshi
Zhang, Yufeng
Ip, Margaret
Chan, Paul Kay-sheung
Blanchard, Nicolas
Hanquet, Gilles
Zuo, Zhong
Yang, Xiao
Ma, Cong
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-2 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 μg/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.
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