New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease
Copyright © 2017 Elsevier Masson SAS. All rights reserved..
A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2-b]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC50 of 49 nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in PC12 cells. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation. The advantages including synthetic accessibility, high potency and selectivity, low toxicity, adjunctive neuroprotective and Aβ aggregation inhibitory activity, make this compound as a new multifunctional lead for Alzheimer's disease drug discovery.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:139 |
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| Enthalten in: |
European journal of medicinal chemistry - 139(2017) vom: 20. Okt., Seite 280-289 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jalili-Baleh, Leili [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.10.2017 Date Revised 16.11.2017 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2017.07.072 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM274764431 |
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| 100 | 1 | |a Jalili-Baleh, Leili |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease |
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| 500 | |a Date Revised 16.11.2017 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2-b]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC50 of 49 nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in PC12 cells. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation. The advantages including synthetic accessibility, high potency and selectivity, low toxicity, adjunctive neuroprotective and Aβ aggregation inhibitory activity, make this compound as a new multifunctional lead for Alzheimer's disease drug discovery | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acetylcholinesterase | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a Neuroprotective activity | |
| 650 | 4 | |a Phthalazine | |
| 650 | 4 | |a Tacrine | |
| 650 | 4 | |a β-amyloid aggregation | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a Cholinesterase Inhibitors |2 NLM | |
| 650 | 7 | |a Neuroprotective Agents |2 NLM | |
| 650 | 7 | |a Phthalazines |2 NLM | |
| 650 | 7 | |a Protein Aggregates |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a pyrazolo(1,2-b)phthalazine |2 NLM | |
| 650 | 7 | |a Hydrogen Peroxide |2 NLM | |
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| 650 | 7 | |a Acetylcholinesterase |2 NLM | |
| 650 | 7 | |a EC 3.1.1.7 |2 NLM | |
| 650 | 7 | |a Butyrylcholinesterase |2 NLM | |
| 650 | 7 | |a EC 3.1.1.8 |2 NLM | |
| 700 | 1 | |a Nadri, Hamid |e verfasserin |4 aut | |
| 700 | 1 | |a Moradi, Alireza |e verfasserin |4 aut | |
| 700 | 1 | |a Bukhari, Syed Nasir Abbas |e verfasserin |4 aut | |
| 700 | 1 | |a Shakibaie, Mojtaba |e verfasserin |4 aut | |
| 700 | 1 | |a Jafari, Mandana |e verfasserin |4 aut | |
| 700 | 1 | |a Golshani, Mostafa |e verfasserin |4 aut | |
| 700 | 1 | |a Homayouni Moghadam, Farshad |e verfasserin |4 aut | |
| 700 | 1 | |a Firoozpour, Loghman |e verfasserin |4 aut | |
| 700 | 1 | |a Asadipour, Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Emami, Saeed |e verfasserin |4 aut | |
| 700 | 1 | |a Khoobi, Mehdi |e verfasserin |4 aut | |
| 700 | 1 | |a Foroumadi, Alireza |e verfasserin |4 aut | |
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