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Biguanide iridium(III) complexes with potent antimicrobial activity
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Chen, Feng, Moat, John, McFeely, Daniel, Clarkson, Guy J., Hands-Portman, Ian J., Furner-Pardoe, Jessica P., Harrison, Freya, Dowson, Christopher G. and Sadler, P. J. (2018) Biguanide iridium(III) complexes with potent antimicrobial activity. Journal of Medicinal Chemistry, 61 (16). pp. 7330-7344. doi:10.1021/acs.jmedchem.8b00906 ISSN 1520-4804.
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Official URL: https://doi.org/10.1021/acs.jmedchem.8b00906
Abstract
We have synthesized novel organoiridium(III) antimicrobial complexes containing a chelated biguanide, including the antidiabetic drug metformin. These 16- and 18-electron complexes were characterized by NMR, ESI-MS, elemental analysis, and X-ray crystallography. Several of these complexes exhibit potent activity against Gram-negative bacteria and Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus (MRSA)) and high antifungal potency toward C. albicans and C. neoformans, with minimum inhibitory concentrations (MICs) in the nanomolar range. Importantly, the complexes exhibit low cytotoxicity toward mammalian cells, indicating high selectivity. They are highly stable in broth medium, with a low tendency to generate resistance mutations. On coadministration, they can restore the activity of vancomycin against vancomycin-resistant Enterococci (VRE). Also the complexes can disrupt and eradicate bacteria in mature biofilms. Investigations of reactions with biomolecules suggest that these organometallic complexes deliver active biguanides into microorganisms, whereas the biguanides themselves are inactive when administered alone.
| Item Type: | Journal Article | |||||||||||||||||||||
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| Subjects: | R Medicine > RC Internal medicine | |||||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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| SWORD Depositor: | Library Publications Router | |||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Hypoglycemic agents, Organoiridium compounds | |||||||||||||||||||||
| Journal or Publication Title: | Journal of Medicinal Chemistry | |||||||||||||||||||||
| Publisher: | American Chemical Society (ACS) | |||||||||||||||||||||
| ISSN: | 1520-4804 | |||||||||||||||||||||
| Official Date: | 23 August 2018 | |||||||||||||||||||||
| Dates: |
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| Volume: | 61 | |||||||||||||||||||||
| Number: | 16 | |||||||||||||||||||||
| Page Range: | pp. 7330-7344 | |||||||||||||||||||||
| DOI: | 10.1021/acs.jmedchem.8b00906 | |||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||
| Reuse Statement (publisher, data, author rights): | “This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/page/policy/articlesonrequest/index.html].” | |||||||||||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||
| Date of first compliant deposit: | 11 September 2018 | |||||||||||||||||||||
| Date of first compliant Open Access: | 2 August 2019 | |||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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