Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis
Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved..
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 MIC90 <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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:229 |
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| Enthalten in: |
European journal of medicinal chemistry - 229(2022) vom: 05. Feb., Seite 114059 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sutherland, Hamish S [VerfasserIn] |
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| Links: |
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| Themen: |
78846I289Y |
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| Anmerkungen: |
Date Completed 08.02.2022 Date Revised 09.02.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2021.114059 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM334989035 |
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| 520 | |a Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved. | ||
| 520 | |a 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 MIC90 <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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ATP synthase | |
| 650 | 4 | |a Structure-activity relationships | |
| 650 | 4 | |a Synthesis | |
| 650 | 4 | |a Tetrahydronaphthalenes | |
| 650 | 4 | |a Tuberculosis | |
| 650 | 7 | |a Amides |2 NLM | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Diarylquinolines |2 NLM | |
| 650 | 7 | |a Tetrahydronaphthalenes |2 NLM | |
| 650 | 7 | |a bedaquiline |2 NLM | |
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| 700 | 1 | |a Lu, Guo-Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Amy S T |e verfasserin |4 aut | |
| 700 | 1 | |a Conole, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Franzblau, Scott G |e verfasserin |4 aut | |
| 700 | 1 | |a Upton, Anna M |e verfasserin |4 aut | |
| 700 | 1 | |a Lotlikar, Manisha U |e verfasserin |4 aut | |
| 700 | 1 | |a Cooper, Christopher B |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Brian D |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Denny, William A |e verfasserin |4 aut | |
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