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

doi:10.1016/j.ejmech.2019.02.013

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

Journal article

Peer reviewed

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 and Stephen G. Pyne

European Journal of Medicinal Chemistry, Vol.168, pp.386-404

2019

DOI: https://doi.org/10.1016/j.ejmech.2019.02.013

PMID: 30831407

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Abstract

Amphipathic

Antibacterial

Biaryl cationic amphiphiles

Membrane depolarization

Peptidomimetic

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.

Details

Title: Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles: synthesis, antibacterial evaluation and preliminary mechanism of action studies
Authors: Andrew J. Tague (Corresponding Author) - University of Wollongong
Papanin Putsathit (Author) - Edith Cowan University
Katherine A. Hammer (Author) - University of Western Australia
Steven M. Wales (Author) - University of Wollongong
Daniel R. Knight (Author) - Murdoch University
Thomas V. Riley (Author) - University of Western Australia
Paul A. Keller (Corresponding Author) - University of Wollongong
Stephen G. Pyne (Corresponding Author) - University of Wollongong
Publication details: European Journal of Medicinal Chemistry, Vol.168, pp.386-404
Publisher: Elsevier Masson
DOI: 10.1016/j.ejmech.2019.02.013
ISSN: 1768-3254
PMID: 30831407
Organisation Unit: Student Services and Engagement; School of Science, Technology and Engineering
Language: English
Record Identifier: 99707364402621
Output Type: Journal article

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Collaboration types: Domestic collaboration
Web Of Science research areas: Chemistry, Medicinal

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