Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis.

Show simple item record Sutherland, Hamish S Lu, Guo-Liang Tong, Amy ST Conole, Daniel Franzblau, Scott G Upton, Anna M Lotlikar, Manisha U Cooper, Christopher B Palmer, Brian D Choi, Peter J Denny, William A
dc.coverage.spatial France 2022-02-09T22:14:44Z 2022-02-09T22:14:44Z 2021-12-21
dc.identifier.citation European journal of medicinal chemistry 229:114059 Feb 2022
dc.identifier.issn 0223-5234
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.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 2022-01-07T22:19:48Z
dc.rights.holder Copyright: 2021 The Authors. Published by Elsevier Masson SAS. en
pubs.publication-status Published
dc.rights.accessrights 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

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