Journal article

Synthesis of norbornane bisether antibiotics via silver-mediated alkylation

Shane M Hickey, Trent D Ashton, 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

RSC ADVANCES | ROYAL SOC CHEMISTRY | Published : 2015

Abstract

A small series of norbornane bisether diguanidines have been synthesized and evaluated as antibacterial agents. The key transformation-bisalkylation of norbornane diol 6-was not successful using Williamson methodology but has been accomplished using Ag2O mediated alkylation. Further functionalization to incorporate two guanidinium groups gave rise to a series of structurally rigid cationic amphiphiles; several of which (16d, 16g and 16h) exhibited antibiotic activity. For example, compound 16d was active against a broad range of bacteria including Pseudomonas aeruginosa (MIC = 8 µg/mL), Escherichia coli (MIC = 8 µg/mL) and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL).

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. & 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 Magnetic Resonance Facility through LIEF grant LE110100141. J.L. and 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. 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 (The Community for Open Access Drug Discovery) and we thank David L. Paterson (UQCCR) for his kind donation of clinical Gram-positive strains used for testing.