dc.contributor.author |
Sutherland, Hamish S |
|
dc.contributor.author |
Tong, Amy ST |
|
dc.contributor.author |
Choi, Peter J |
|
dc.contributor.author |
Blaser, Adrian |
|
dc.contributor.author |
Franzblau, Scott G |
|
dc.contributor.author |
Cooper, Christopher B |
|
dc.contributor.author |
Upton, Anna M |
|
dc.contributor.author |
Lotlikar, Manisha |
|
dc.contributor.author |
Denny, William A |
|
dc.contributor.author |
Palmer, Brian D |
|
dc.coverage.spatial |
England |
|
dc.date.accessioned |
2022-02-09T21:22:48Z |
|
dc.date.available |
2022-02-09T21:22:48Z |
|
dc.date.issued |
2020-1 |
|
dc.identifier.citation |
Bioorganic & medicinal chemistry 28(1):115213 Jan 2020 |
|
dc.identifier.issn |
0968-0896 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/58128 |
|
dc.description.abstract |
Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition. |
|
dc.format.medium |
Print-Electronic |
|
dc.language |
eng |
|
dc.publisher |
Elsevier BV |
|
dc.relation.ispartofseries |
Bioorganic & medicinal chemistry |
|
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. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
|
dc.subject |
Animals |
|
dc.subject |
Humans |
|
dc.subject |
Mycobacterium tuberculosis |
|
dc.subject |
Antitubercular Agents |
|
dc.subject |
Microbial Sensitivity Tests |
|
dc.subject |
Molecular Structure |
|
dc.subject |
Structure-Activity Relationship |
|
dc.subject |
Dose-Response Relationship, Drug |
|
dc.subject |
Diarylquinolines |
|
dc.subject |
CFU, colony-forming units |
|
dc.subject |
HPLC, high-peformance liquid chromatography |
|
dc.subject |
LDA, lithium diisopropylamide |
|
dc.subject |
LORA, low oxygen recovery assay |
|
dc.subject |
LiTMP, lithium tetramethylpiperidide |
|
dc.subject |
M.tb, Mycobacterium tuberculosis |
|
dc.subject |
MABA, microplate alamar blue assay |
|
dc.subject |
MIC(90), minimum concentration for 90% inhibition |
|
dc.subject |
TB, tuberculosis |
|
dc.subject |
hERG, the alpha subunit of a K+ channel that contributes to the electrical activity of the heart |
|
dc.subject |
Animals |
|
dc.subject |
Antitubercular Agents |
|
dc.subject |
Diarylquinolines |
|
dc.subject |
Dose-Response Relationship, Drug |
|
dc.subject |
Humans |
|
dc.subject |
Microbial Sensitivity Tests |
|
dc.subject |
Molecular Structure |
|
dc.subject |
Mycobacterium tuberculosis |
|
dc.subject |
Structure-Activity Relationship |
|
dc.subject |
Science & Technology |
|
dc.subject |
Life Sciences & Biomedicine |
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dc.subject |
Physical Sciences |
|
dc.subject |
Biochemistry & Molecular Biology |
|
dc.subject |
Chemistry, Medicinal |
|
dc.subject |
Chemistry, Organic |
|
dc.subject |
Pharmacology & Pharmacy |
|
dc.subject |
Chemistry |
|
dc.subject |
CFU |
|
dc.subject |
colony-forming units hERG |
|
dc.subject |
the alpha subunit of a K plus channel that contributes to the electrical activity of the heart |
|
dc.subject |
HPLC |
|
dc.subject |
high-peformance liquid chromatography LDA |
|
dc.subject |
lithium diisopropylamide LiTMP |
|
dc.subject |
lithium tetramethylpiperidide LORA |
|
dc.subject |
low oxygen recovery assay MABA |
|
dc.subject |
microplate alamar blue assay MIC90 |
|
dc.subject |
minimum concentration for 90% inhibition M.tb |
|
dc.subject |
Mycobacterium tuberculosis TB |
|
dc.subject |
tuberculosis |
|
dc.subject |
MULTIDRUG-RESISTANT TUBERCULOSIS |
|
dc.subject |
ASSAY |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.subject |
Biomedical |
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dc.subject |
Basic Science |
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dc.subject |
Cardiovascular |
|
dc.subject |
5.1 Pharmaceuticals |
|
dc.subject |
0304 Medicinal and Biomolecular Chemistry |
|
dc.subject |
0305 Organic Chemistry |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.title |
Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1016/j.bmc.2019.115213 |
|
pubs.issue |
1 |
|
pubs.begin-page |
115213 |
|
pubs.volume |
28 |
|
dc.date.updated |
2022-01-10T00:56:47Z |
|
dc.rights.holder |
Copyright: 2019 Elsevier Ltd. All rights reserved. |
en |
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/31810890 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
Research Support, U.S. Gov't, Non-P.H.S. |
|
pubs.subtype |
Journal Article |
|
pubs.elements-id |
790182 |
|
dc.identifier.eissn |
1464-3391 |
|
dc.identifier.pii |
S0968-0896(19)31505-6 |
|
pubs.number |
115213 |
|