Biarylmethoxy 2-nitroimidazooxazine antituberculosis agents: Effects of proximal ring substitution and linker reversal on metabolism and efficacy.

Show simple item record Thompson, Andrew en Blaser, Adrian en Palmer, Brian en Franzblau, Scott G en Wan, Baojie en Wang, Yuehong en Ma, Zhenkun en Denny, William en 2018-10-15T03:09:38Z en 2015-09 en
dc.identifier.issn 0960-894X en
dc.identifier.uri 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 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 en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype Journal Article en
pubs.elements-id 495092 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en 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

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