dc.contributor.author |
Tong, Amy ST |
en |
dc.contributor.author |
Choi, Peter |
en |
dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Sutherland, Hamish |
en |
dc.contributor.author |
Tsang, Sophia KY |
en |
dc.contributor.author |
Guillemont, Jerome |
en |
dc.contributor.author |
Motte, Magali |
en |
dc.contributor.author |
Cooper, Christopher B |
en |
dc.contributor.author |
Andries, Koen |
en |
dc.contributor.author |
Van den Broeck, Walter |
en |
dc.contributor.author |
Franzblau, Scott G |
en |
dc.contributor.author |
Upton, Anna M |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
Conole, Daniel |
en |
dc.date.accessioned |
2018-11-13T03:31:10Z |
en |
dc.date.issued |
2017-10 |
en |
dc.identifier.issn |
1948-5875 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/44180 |
en |
dc.description.abstract |
Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1. |
en |
dc.format.medium |
Electronic-eCollection |
en |
dc.language |
eng |
en |
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 |
6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/acsmedchemlett.7b00196 |
en |
pubs.issue |
10 |
en |
pubs.begin-page |
1019 |
en |
pubs.volume |
8 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
29057044 |
en |
pubs.end-page |
1024 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
rapid-communication |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
677822 |
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 |
1948-5875 |
en |
pubs.record-created-at-source-date |
2017-10-24 |
en |
pubs.dimensions-id |
29057044 |
en |