6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis.

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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

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