dc.contributor.author |
Sutherland, Hamish S |
|
dc.contributor.author |
Lu, Guo-Liang |
|
dc.contributor.author |
Tong, Amy ST |
|
dc.contributor.author |
Conole, Daniel |
|
dc.contributor.author |
Franzblau, Scott G |
|
dc.contributor.author |
Upton, Anna M |
|
dc.contributor.author |
Lotlikar, Manisha U |
|
dc.contributor.author |
Cooper, Christopher B |
|
dc.contributor.author |
Palmer, Brian D |
|
dc.contributor.author |
Choi, Peter J |
|
dc.contributor.author |
Denny, William A |
|
dc.coverage.spatial |
France |
|
dc.date.accessioned |
2022-02-09T22:14:44Z |
|
dc.date.available |
2022-02-09T22:14:44Z |
|
dc.date.issued |
2021-12-21 |
|
dc.identifier.citation |
European journal of medicinal chemistry 229:114059 Feb 2022 |
|
dc.identifier.issn |
0223-5234 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/58134 |
|
dc.description.abstract |
Drug resistant tuberculsosis (TB) is global health crisis that demands novel treatment strategies. Bacterial ATP synthase inhibitors such as bedaquiline and next-generation analogues (such as TBAJ-876) have shown promising efficacy in patient populations and preclinical studies, respectively, suggesting that selective targeting of this enzyme presents a validated therapeutic strategy for the treatment of TB. In this work, we report tetrahydronaphthalene amides (THNAs) as a new class of ATP synthase inhibitors that are effective in preventing the growth of Mycobacterium tuberculosis (M.tb) in culture. Design, synthesis and comprehensive structure-activity relationship studies for approximately 80 THNA analogues are described, with a small selection of compounds exhibiting potent (in some cases MIC<sub>90</sub> <1 μg/mL) in vitro M.tb growth inhibition taken forward to pharmacokinetic and off-target profiling studies. Ultimately, we show that some of these THNAs possess reduced lipophilic properties, decreased hERG liability, faster mouse/human liver microsomal clearance rates and shorter plasma half-lives compared with bedaquiline, potentially addressing of the main concerns of persistence and phospholipidosis associated with bedaquiline. |
|
dc.format.medium |
Print-Electronic |
|
dc.language |
eng |
|
dc.publisher |
Elsevier BV |
|
dc.relation.ispartofseries |
European journal of 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.rights.uri |
https://creativecommons.org/licenses/by/4.0/ |
|
dc.subject |
ATP synthase |
|
dc.subject |
Structure-activity relationships |
|
dc.subject |
Synthesis |
|
dc.subject |
Tetrahydronaphthalenes |
|
dc.subject |
Tuberculosis |
|
dc.subject |
0304 Medicinal and Biomolecular Chemistry |
|
dc.subject |
0305 Organic Chemistry |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.title |
Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1016/j.ejmech.2021.114059 |
|
pubs.begin-page |
114059 |
|
pubs.volume |
229 |
|
dc.date.updated |
2022-01-07T22:19:48Z |
|
dc.rights.holder |
Copyright: 2021 The Authors. Published by Elsevier Masson SAS. |
en |
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/34963068 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Journal Article |
|
pubs.elements-id |
878097 |
|
dc.identifier.eissn |
1768-3254 |
|
dc.identifier.pii |
S0223-5234(21)00908-9 |
|
pubs.number |
114059 |
|