dc.contributor.author |
Thompson, Andrew |
en |
dc.contributor.author |
Bonnet, M |
en |
dc.contributor.author |
Lee, Ho |
en |
dc.contributor.author |
Franzblau, SG |
en |
dc.contributor.author |
Wan, B |
en |
dc.contributor.author |
Wong, GS |
en |
dc.contributor.author |
Cooper, CB |
en |
dc.contributor.author |
Denny, William |
en |
dc.date.accessioned |
2018-11-22T00:16:37Z |
en |
dc.date.issued |
2017 |
en |
dc.identifier.issn |
1948-5875 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/44558 |
en |
dc.description.abstract |
A published study of structural features associated with the aerobic and anaerobic activities of 4- and 5-nitroimidazoles had found that the 3-nitro isomer of pretomanid, 8, displayed interesting potencies, including against nitroreductase-mutant Mycobacterium tuberculosis. However, recent NMR analyses of two trace byproducts, isolated from early process op-timization studies toward a large-scale synthesis of pretomanid, raised structural assignment queries, particularly for 8, stimulating further investigation. Following our discovery that the reported compound was a 6-nitroimidazooxazole derivative, we developed a de novo synthesis of authentic 8 via nitration of the chiral des-nitro imidazooxazine alcohol 26 in trifluoroacetic or acetic anhydride, and verified its identity through an X ray crystal structure. Unfortunately, 8 displayed no antitubercular activity (MICs >128 µM), whereas the second byproduct (3’-methyl pretomanid) was 8-fold more potent than pretomanid in the aerobic assay. These findings further clarify target specificities for bicyclic nitroimidazoles, which may become important in the event of any future clinical resistance. |
en |
dc.publisher |
American Chemical Society |
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dc.relation.ispartofseries |
ACS Medicinal Chemistry Letters |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/acsmedchemlett.7b00356 |
en |
pubs.issue |
12 |
en |
pubs.begin-page |
1275 |
en |
pubs.volume |
8 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
29259747 |
en |
pubs.end-page |
1280 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
719442 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2017-12-20 |
en |
pubs.online-publication-date |
2017-11-13 |
en |
pubs.dimensions-id |
29259747 |
en |