Journal article

Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents

Shane M Hickey, Trent D Ashton, Simren K Khosa, Ryan N Robson, Jonathan M White, Jian Li, Roger L Nation, Heidi Y Yu, Alysha G Elliott, Mark S Butler, Johnny X Huang, Matthew A Cooper, Frederick M Pfeffer

ORGANIC & BIOMOLECULAR CHEMISTRY | ROYAL SOC CHEMISTRY | Published : 2015

Abstract

A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL(-1) against Streptococcus pneumoniae, Enterococcus faeca..

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University of Melbourne Researchers

Grants

Awarded by ARC


Awarded by Australian Research Council through LIEF


Awarded by National Institute of Allergy and Infectious Diseases of the National Institutes of Health


Awarded by NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES


Funding Acknowledgements

F.M.P., S.M.H., S.K.K., R.N.R. & T.D.A. thank the ARC (DP140100227) and the Strategic Research Centre for Chemistry and Biotechnology (Deakin University) for financial support and a top-up scholarship for S.M.H. The authors would also like to thank Dr Damien Callahan for his assistance with the collection of HRMS and the Australian Research Council for funding Deakin University's Nuclear Magnetic Resonance Facility through LIEF grant LE110100141. J.L. & R.L.N. are supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI098771). J.L. is an Australian NHMRC Senior Research Fellow, while M.A.C. is an Australian NHMRC Principal Research Fellow. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The MIC screening was done in collaboration with CO-ADD (Community for Open Antimicrobial Drug Discovery, co-add.org) and we thank David L. Paterson (UQCCR, University of Queensland) for his kind donation of clinical Gram-positive isolates used for testing.