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Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation
Alzheimer's disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholin...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Leibniz Research Centre for Working Environment and Human Factors
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192883/ https://www.ncbi.nlm.nih.gov/pubmed/34121977 http://dx.doi.org/10.17179/excli2021-3569 |
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author | Nazari, Maryam Rezaee, Elham Hariri, Roshanak Akbarzadeh, Tahmineh Tabatabai, Sayyed Abbas |
author_facet | Nazari, Maryam Rezaee, Elham Hariri, Roshanak Akbarzadeh, Tahmineh Tabatabai, Sayyed Abbas |
author_sort | Nazari, Maryam |
collection | PubMed |
description | Alzheimer's disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound 6n with an IC(50) value of 5.07 µM and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound 6n properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to in silico ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer's agents (Figure 1(Fig. 1)). |
format | Online Article Text |
id | pubmed-8192883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Leibniz Research Centre for Working Environment and Human Factors |
record_format | MEDLINE/PubMed |
spelling | pubmed-81928832021-06-11 Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation Nazari, Maryam Rezaee, Elham Hariri, Roshanak Akbarzadeh, Tahmineh Tabatabai, Sayyed Abbas EXCLI J Original Article Alzheimer's disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound 6n with an IC(50) value of 5.07 µM and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound 6n properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to in silico ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer's agents (Figure 1(Fig. 1)). Leibniz Research Centre for Working Environment and Human Factors 2021-05-18 /pmc/articles/PMC8192883/ /pubmed/34121977 http://dx.doi.org/10.17179/excli2021-3569 Text en Copyright © 2021 Nazari et al. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ) You are free to copy, distribute and transmit the work, provided the original author and source are credited. |
spellingShingle | Original Article Nazari, Maryam Rezaee, Elham Hariri, Roshanak Akbarzadeh, Tahmineh Tabatabai, Sayyed Abbas Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation |
title | Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation |
title_full | Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation |
title_fullStr | Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation |
title_full_unstemmed | Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation |
title_short | Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation |
title_sort | novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: design, synthesis and biological evaluation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192883/ https://www.ncbi.nlm.nih.gov/pubmed/34121977 http://dx.doi.org/10.17179/excli2021-3569 |
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