Document Type

Journal Article

Publication Title

European Journal of Medicinal Chemistry


Elsevier Masson SAS


School of Medical and Health Sciences




© 2019. This manuscript version is made Available under the CC-BY-NC-ND 4.0 license

This is an Author's Accepted Manuscript of: Tague, A. J., Putsathit, P., Hammer, K. A., Wales, S. M., Knight, D. R., Riley, T. V., . . . Pyne, S. G. (2019). Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: Synthesis, antibacterial evaluation and preliminary mechanism of action studies. European Journal of Medicinal Chemistry, 386-404. Available here


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. © 2019 Elsevier Masson SAS



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