Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: synthesis, antibacterial evaluation and preliminary mechanism of action studies

Andrew J. Tague*, Papanin Putsathit, Katherine A. Hammer, Steven M. Wales, Daniel R. Knight, Thomas V. Riley, Paul A. Keller, Stephen G. Pyne

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

13 Citations (Scopus)


Synthetic small molecular antimicrobial peptidomimetics represent a promising new class of potential antibiotics due to their membrane-disrupting ability and their decreased propensity for bacterial resistance. A library of 43 mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics was designed and synthesized based upon previously established lead biarylpeptidomimetics and a known pharmacophore. A reliable, facile and modular synthetic pathway allowed for the efficient synthesis of multiple unique scaffolds which were subjected to divergent derivatization to furnish the amphiphilic compounds. In vitro testing revealed enhanced antibacterial efficacy against a range of pathogenic bacteria, including bacterial isolates with methicillin, vancomycin, daptomycin, or multi-drug resistance. Preliminary time-kill kinetics and membrane-disruption assays revealed a likely membrane-active mechanism for the tested peptidomimetics. An optimal balance between hydrophobicity and cationic charge was found to be essential for reduced cytotoxicity/haemolysis (i.e. membrane selectivity) and enhanced Gram-negative activity. The cationic biaryl amphiphile 81 was identified as a potent, broad-spectrum peptidomimetic with activity against Gram-positive (methicillin-resistant Staphylococcus aureus - MIC = 2 μg/mL) and Gram-negative (Escherichia coli - MIC = 4 μg/mL) pathogenic bacteria.

Original languageEnglish
Pages (from-to)386-404
Number of pages19
JournalEuropean Journal of Medicinal Chemistry
Early online date13 Feb 2019
Publication statusPublished - 15 Apr 2019


  • Amphipathic
  • Antibacterial
  • Biaryl cationic amphiphiles
  • Membrane depolarization
  • Peptidomimetic
  • Triazoles/chemistry
  • Humans
  • Cations/chemistry
  • Anti-Bacterial Agents/chemical synthesis
  • Structure-Activity Relationship
  • Escherichia coli/drug effects
  • Dose-Response Relationship, Drug
  • Microbial Sensitivity Tests
  • Peptidomimetics/chemistry
  • Methicillin-Resistant Staphylococcus aureus/drug effects
  • HEK293 Cells
  • Molecular Structure
  • Kinetics
  • Surface-Active Agents/chemistry


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