Design, Synthesis and Biological Evaluation of Antimicrobial Diarylimine and -amine Compounds Targeting the Interaction between the Bacterial NusB and NusE Proteins

Yangyi Qiu (1) , Shu Ting Chan (1) , Lin Lin (2) , Tsun Lam Shek (3) , Tsz Fung Tsang (2) , Nilakshi Barua (2) , Yufeng Zhang (3) , Margaret Ip (2) , Kay-Sheung Paul (4) , Nicolas Blanchard (5) , Gilles Hanquet (5) , Zhong Zuo (4) , Xiao Yang (4) , Cong Ma (1)

1 POLYU - The Hong Kong Polytechnic University [Hong Kong]
2 Department of Mathematics [Berkeley]
3 HIT - Harbin Institute of Technology
4 CUHK - The Chinese University of Hong Kong [Hong Kong]
5 LIMA - Laboratoire d'innovation moléculaire et applications

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.

Domaines: Chimie; Sciences du Vivant [q-bio]

Yangyi Qiu, Shu Ting Chan, Lin Lin, Tsun Lam Shek, Tsz Fung Tsang, et al.. Design, Synthesis and Biological Evaluation of Antimicrobial Diarylimine and -amine Compounds Targeting the Interaction between the Bacterial NusB and NusE Proteins. European Journal of Medicinal Chemistry, 2019, 178, pp.214-231. ⟨10.1016/j.ejmech.2019.05.090⟩. ⟨hal-03079069⟩