Design, synthesis and biological evaluation of antimicrobial diarylimine and –amine compounds targeting the interaction between the bacterial NusB and NusE proteins

Yangyi Qiu, Shu Ting Chan, Lin Lin, Tsun Lam Shek, Tsz Fung Tsang, Nilakshi Barua, Yufeng Zhang, Margaret Ip, Paul Kay sheung Chan, Nicolas Blanchard, Gilles Hanquet, Zhong Zuo, Xiao Yang, Cong Ma

Research output: Journal article publicationJournal articleAcademic researchpeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)214-231
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 15 Sep 2019


  • Antimicrobial activity
  • Diarylamine
  • Diarylimine
  • Inhibitor
  • Methicillin-resistant Staphylococcus aureus
  • Protein-protein interaction

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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