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Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease
A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT(4)R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget dire...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033111/ https://www.ncbi.nlm.nih.gov/pubmed/32080261 http://dx.doi.org/10.1038/s41598-020-59805-7 |
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author | Lalut, Julien Payan, Hugo Davis, Audrey Lecoutey, Cédric Legay, Rémi Sopkova-de Oliveira Santos, Jana Claeysen, Sylvie Dallemagne, Patrick Rochais, Christophe |
author_facet | Lalut, Julien Payan, Hugo Davis, Audrey Lecoutey, Cédric Legay, Rémi Sopkova-de Oliveira Santos, Jana Claeysen, Sylvie Dallemagne, Patrick Rochais, Christophe |
author_sort | Lalut, Julien |
collection | PubMed |
description | A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT(4)R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT(4)R. |
format | Online Article Text |
id | pubmed-7033111 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70331112020-02-27 Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease Lalut, Julien Payan, Hugo Davis, Audrey Lecoutey, Cédric Legay, Rémi Sopkova-de Oliveira Santos, Jana Claeysen, Sylvie Dallemagne, Patrick Rochais, Christophe Sci Rep Article A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT(4)R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT(4)R. Nature Publishing Group UK 2020-02-20 /pmc/articles/PMC7033111/ /pubmed/32080261 http://dx.doi.org/10.1038/s41598-020-59805-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Lalut, Julien Payan, Hugo Davis, Audrey Lecoutey, Cédric Legay, Rémi Sopkova-de Oliveira Santos, Jana Claeysen, Sylvie Dallemagne, Patrick Rochais, Christophe Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease |
title | Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease |
title_full | Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease |
title_fullStr | Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease |
title_full_unstemmed | Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease |
title_short | Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT(4) receptors activities for the treatment of Alzheimer’s disease |
title_sort | rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-ht(4) receptors activities for the treatment of alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033111/ https://www.ncbi.nlm.nih.gov/pubmed/32080261 http://dx.doi.org/10.1038/s41598-020-59805-7 |
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