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

Qiu, Y; Chan, ST; Lin, L; Shek, TL; Tsang, TF; Barua, N; Zhang, Y; Ip, M; Chan, PKS; Blanchard, N; Hanquet, G; Zuo, Z; Yang, X; Ma, C

Title:	Design, synthesis and biological evaluation of antimicrobial diarylimine and –amine compounds targeting the interaction between the bacterial NusB and NusE proteins
Authors:	Qiu, Y Chan, ST Lin, L Shek, TL Tsang, TF Barua, N Zhang, Y Ip, M Chan, PKS Blanchard, N Hanquet, G Zuo, Z Yang, X Ma, C
Issue Date:	15-Sep-2019
Source:	European journal of medicinal chemistry, 15 Sept. 2019, v. 178, p. 214-231
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-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.
Keywords:	Antimicrobial activity Diarylamine Diarylimine Inhibitor Methicillin-resistant Staphylococcus aureus Protein-protein interaction
Publisher:	Elsevier Masson
Journal:	European journal of medicinal chemistry
ISSN:	0223-5234
EISSN:	1768-3254
DOI:	10.1016/j.ejmech.2019.05.090
Appears in Collections:	Journal/Magazine Article

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