Synthesis and structure-activity relationships for tetrahydroisoquinoline-based inhibitors of Mycobacterium tuberculosis
Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved..
A series of 5,8-disubstituted tetrahydroisoquinolines were shown to be effective inhibitors of M. tb in culture and modest inhibitors of M. tb ATP synthase. There was a broad general trend of improved potency with higher lipophilicity. Large substituents (e.g., Bn) at the tetrahydroquinoline 5-position were well-tolerated, while N-methylpiperazine was the preferred 8-substituent. Structure-activity relationships for 7-linked side chains showed that the nature of the 7-linking group was important; -CO- and -COCH2- linkers were less effective than -CH2- or -CONH- ones. This suggests that the positioning of a terminal aromatic ring is important for target binding. Selected compounds showed much faster rates of microsomal clearance than did the clinical ATP synthase inhibitor bedaquiline, and modest inhibition of mycobacterial ATP synthase.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Bioorganic & medicinal chemistry - 28(2020), 22 vom: 15. Nov., Seite 115784 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lu, Guo-Liang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.07.2021 Date Revised 21.07.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmc.2020.115784 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a A series of 5,8-disubstituted tetrahydroisoquinolines were shown to be effective inhibitors of M. tb in culture and modest inhibitors of M. tb ATP synthase. There was a broad general trend of improved potency with higher lipophilicity. Large substituents (e.g., Bn) at the tetrahydroquinoline 5-position were well-tolerated, while N-methylpiperazine was the preferred 8-substituent. Structure-activity relationships for 7-linked side chains showed that the nature of the 7-linking group was important; -CO- and -COCH2- linkers were less effective than -CH2- or -CONH- ones. This suggests that the positioning of a terminal aromatic ring is important for target binding. Selected compounds showed much faster rates of microsomal clearance than did the clinical ATP synthase inhibitor bedaquiline, and modest inhibition of mycobacterial ATP synthase | ||
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| 650 | 4 | |a Synthesis | |
| 650 | 4 | |a Tetrahydroquinolines | |
| 650 | 4 | |a Tuberculosis | |
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| 650 | 7 | |a Tetrahydroisoquinolines |2 NLM | |
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| 700 | 1 | |a Conole, Daniel |e verfasserin |4 aut | |
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| 700 | 1 | |a Choi, Peter J |e verfasserin |4 aut | |
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| 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 Denny, William A |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Brian D |e verfasserin |4 aut | |
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