Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

S.M. Wales; K.A. Hammer; A.M. King; A.J. Tague; D. Lyras; T.V. Riley; P.A. Keller; S.G. Pyne

doi:10.1039/c5ob00576k

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Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

Journal article

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Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria

S.M. Wales, K.A. Hammer, A.M. King, A.J. Tague, D. Lyras, T.V. Riley, P.A. Keller and S.G. Pyne

Organic & Biomolecular Chemistry, Vol.13(20), pp.5743-5756

2015

DOI: https://doi.org/10.1039/c5ob00576k

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Abstract

Clostridium difficile (C. difficile) is a problematic Gram positive bacterial pathogen causing moderate to severe gastrointestinal infections. Based on a lead binaphthyl-tripeptide dicationic antimicrobial, novel mono-, di- and tri-peptidomimetic analogues targeting C. difficile were designed and synthesized incorporating one, two or three d-configured cationic amino acid residues, with a common 1,2,3-triazole ester isostere at the C-terminus. Copper- and ruthenium-click chemistry facilitated the generation of a 46 compound library for in vitro bioactivity assays, with structure-activity trends over the largest compound subset revealing a clear advantage to triazole-substitution with a linear or branched hydrophobic group. The most active compounds were dicationic-dipeptides where the triazole was substituted with a 4- or 5-cyclohexylmethyl or 4,5-diphenyl moiety, providing MICs of 4 μg mL-1 against three human isolates of C. difficile. Further biological screening revealed significant antimicrobial activity for several compounds against other common bacterial pathogens, both Gram positive and negative, including S. aureus (MICs ≥2 μg mL-1), S. pneumoniae (MICs ≥1 μg mL-1), E. coli (MICs ≥4 μg mL-1), A. baumannii (MICs ≥4 μg mL-1) and vancomycin-resistant E. faecalis (MICs ≥4 μg mL-1).

Details

Title: Binaphthyl-1,2,3-triazole peptidomimetics with activity against Clostridium difficile and other pathogenic bacteria
Authors/Creators: S.M. Wales (Author/Creator) - University of Wollongong
K.A. Hammer (Author/Creator) - The University of Western Australia
A.M. King (Author/Creator) - Monash University
A.J. Tague (Author/Creator) - University of Wollongong
D. Lyras (Author/Creator) - Monash University
T.V. Riley (Author/Creator) - The University of Western Australia
P.A. Keller (Author/Creator) - University of Wollongong
S.G. Pyne (Author/Creator) - University of Wollongong
Publication Details: Organic & Biomolecular Chemistry, Vol.13(20), pp.5743-5756
Publisher: Royal Society of Chemistry
Identifiers: 991005541359507891
Copyright: © 2015 The Royal Society of Chemistry.
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: 2 Chemistry; 2.1 Synthesis; 2.1.1402 Click Chemistry
Web Of Science research areas: Chemistry, Organic
ESI research areas: Chemistry