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

• Published in: European journal of medicinal chemistry 2019-09, Vol.178, p.214-231
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antimicrobial activity; Chemical Sciences; Diarylamine; Diarylimine; Inhibitor; Life Sciences; Methicillin-resistant Staphylococcus aureus; Protein-protein interaction
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.05.090

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. [Display omitted] •Diarylimines and –amines were designed to target the specific NusB-NusE interaction in bacteria.•Representative compounds displayed excellent antimicrobial activity against MRSA strains.•Representative compounds showed low cytotoxicity to Human A549 and HaCaT cells.•Compounds 27 and 28 demonstrated excellent pharmacokinetic properties.