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

Citation data:

Organic & Biomolecular Chemistry, ISSN: 1477-0520, Vol: 13, Issue: 20, Page: 5743-5756

Publication Year:
2015
Usage 73
Downloads 43
Abstract Views 27
Link-outs 3
Citations 10
Citation Indexes 10
Repository URL:
https://research-repository.uwa.edu.au/en/publications/ec00c08f-fadc-49a0-a84d-3dbbfac609fb; http://ro.uow.edu.au/smhpapers/2853
PMID:
25901416
DOI:
10.1039/c5ob00576k
Author(s):
Wales, Steven M; Hammer, Katherine A; King, Amy M; Tague, Andrew J; Lyras, Dena; Riley, Thomas V; Keller, Paul A; Pyne, Stephen G
Publisher(s):
Royal Society of Chemistry (RSC); The Royal Society of Chemistry
Tags:
Biochemistry, Genetics and Molecular Biology; Chemistry; Medicine and Health Sciences; Social and Behavioral Sciences
article description
© 2015 The Royal Society of Chemistry. 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).