Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly
Copyright © 2023 Elsevier Masson SAS. All rights reserved..
A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is β, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC50 values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:259 |
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| Enthalten in: |
European journal of medicinal chemistry - 259(2023) vom: 05. Nov., Seite 115634 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hwang, Nicky [VerfasserIn] |
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| Links: |
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| Themen: |
1,2,3,4-Tetrahydroquinoxaline |
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| Anmerkungen: |
Date Completed 22.08.2023 Date Revised 29.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2023.115634 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359992676 |
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| 245 | 1 | 0 | |a Identification of novel tetrahydroquinoxaline derived phenyl ureas as modulators of the hepatitis B virus nucleocapsid assembly |
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| 500 | |a Date Completed 22.08.2023 | ||
| 500 | |a Date Revised 29.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is β, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC50 values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 1,2,3,4-Tetrahydroquinoxaline | |
| 650 | 4 | |a Capsid assembly | |
| 650 | 4 | |a Hepatitis B virus | |
| 650 | 4 | |a Phenyl ureas | |
| 650 | 7 | |a RNA, Viral |2 NLM | |
| 650 | 7 | |a DNA, Viral |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 700 | 1 | |a Wu, Shuo |e verfasserin |4 aut | |
| 700 | 1 | |a Ban, Haiqun |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Huixin |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Junjun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Qiong |e verfasserin |4 aut | |
| 700 | 1 | |a Laney, Jessilyn A |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Na |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Junyang |e verfasserin |4 aut | |
| 700 | 1 | |a Suresh, Manasa |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Liangxian |e verfasserin |4 aut | |
| 700 | 1 | |a Tolufashe, Gideon |e verfasserin |4 aut | |
| 700 | 1 | |a Viswanathan, Usha |e verfasserin |4 aut | |
| 700 | 1 | |a Kulp, John |e verfasserin |4 aut | |
| 700 | 1 | |a Lam, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Jinhong |e verfasserin |4 aut | |
| 700 | 1 | |a Clement, Jason A |e verfasserin |4 aut | |
| 700 | 1 | |a Menne, Stephan |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Ju-Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Yanming |e verfasserin |4 aut | |
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