dc.contributor.author |
Thompson, Andrew |
en |
dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
Franzblau, Scott G |
en |
dc.contributor.author |
Wan, Baojie |
en |
dc.contributor.author |
Wang, Yuehong |
en |
dc.contributor.author |
Ma, Zhenkun |
en |
dc.contributor.author |
Denny, William |
en |
dc.date.accessioned |
2018-10-15T03:09:38Z |
en |
dc.date.issued |
2015-09 |
en |
dc.identifier.issn |
0960-894X |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/41658 |
en |
dc.description.abstract |
Certain biaryl analogues of antitubercular drug PA-824 displayed enhanced in vivo efficacies yet retained some susceptibility towards oxidative metabolism; therefore, two new strategies were explored to address this. Ortho-substitution of the proximal aryl ring with larger electron-withdrawing substituents maintained or improved compound stability but reduced aerobic potency; however, fluoro and cyano were well tolerated. In vivo, only 2'- or 3'-fluoro mono-substitution preserved high efficacy against acute infection, although one example was twofold more effective than delamanid against chronic infection. Reversal of the 6-oxymethylene linkage also permitted high potency and improved stability towards human liver microsomes, albeit, in vivo results were inferior. These novel findings provide further insight into the preferred structural features for lead candidates in this important drug class. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
Bioorganic & 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.subject |
Microsomes, Liver |
en |
dc.subject |
Animals |
en |
dc.subject |
Mice, Inbred Strains |
en |
dc.subject |
Humans |
en |
dc.subject |
Mice |
en |
dc.subject |
Mycobacterium tuberculosis |
en |
dc.subject |
Nitroimidazoles |
en |
dc.subject |
Oxazoles |
en |
dc.subject |
Antitubercular Agents |
en |
dc.subject |
Microbial Sensitivity Tests |
en |
dc.subject |
Molecular Structure |
en |
dc.subject |
Structure-Activity Relationship |
en |
dc.subject |
Dose-Response Relationship, Drug |
en |
dc.title |
Biarylmethoxy 2-nitroimidazooxazine antituberculosis agents: Effects of proximal ring substitution and linker reversal on metabolism and efficacy. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1016/j.bmcl.2015.07.084 |
en |
pubs.issue |
18 |
en |
pubs.begin-page |
3804 |
en |
pubs.volume |
25 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
26253632 |
en |
pubs.end-page |
3809 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
495092 |
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 |
dc.identifier.eissn |
1464-3405 |
en |
pubs.record-created-at-source-date |
2015-08-17 |
en |
pubs.dimensions-id |
26253632 |
en |