Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease
Autor(a) principal: | |
---|---|
Data de Publicação: | 2021 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/105262 https://doi.org/10.3390/molecules26061658 |
Resumo: | Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides. |
id |
RCAP_0003637f3e7bf608ca52a4d7c25e5313 |
---|---|
oai_identifier_str |
oai:estudogeral.uc.pt:10316/105262 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Diseasearylsulfonamidedonepezilanti-neurodegenerativesAlzheimer´s diseaseAChE inhibitorsAβ aggregationAcetylcholinesteraseAlzheimer DiseaseAmyloid beta-PeptidesCell Line, TumorCholinesterase InhibitorsDonepezilHumansLigandsPiperazinesPiperidinesStructure-Activity RelationshipSulfonamidesAlzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.MDPI2021-03-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/105262http://hdl.handle.net/10316/105262https://doi.org/10.3390/molecules26061658eng1420-3049Queda, FaustoCalò, SoniaGwizdala, KarolinaMagalhães, João D.Cardoso, Sandra M.Chaves, SílviaPiemontese, LucaSantos, M. Améliainfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-02-13T11:20:15Zoai:estudogeral.uc.pt:10316/105262Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:21:51.623813Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease |
title |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease |
spellingShingle |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease Queda, Fausto arylsulfonamide donepezil anti-neurodegeneratives Alzheimer´s disease AChE inhibitors Aβ aggregation Acetylcholinesterase Alzheimer Disease Amyloid beta-Peptides Cell Line, Tumor Cholinesterase Inhibitors Donepezil Humans Ligands Piperazines Piperidines Structure-Activity Relationship Sulfonamides |
title_short |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease |
title_full |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease |
title_fullStr |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease |
title_full_unstemmed |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease |
title_sort |
Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease |
author |
Queda, Fausto |
author_facet |
Queda, Fausto Calò, Sonia Gwizdala, Karolina Magalhães, João D. Cardoso, Sandra M. Chaves, Sílvia Piemontese, Luca Santos, M. Amélia |
author_role |
author |
author2 |
Calò, Sonia Gwizdala, Karolina Magalhães, João D. Cardoso, Sandra M. Chaves, Sílvia Piemontese, Luca Santos, M. Amélia |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Queda, Fausto Calò, Sonia Gwizdala, Karolina Magalhães, João D. Cardoso, Sandra M. Chaves, Sílvia Piemontese, Luca Santos, M. Amélia |
dc.subject.por.fl_str_mv |
arylsulfonamide donepezil anti-neurodegeneratives Alzheimer´s disease AChE inhibitors Aβ aggregation Acetylcholinesterase Alzheimer Disease Amyloid beta-Peptides Cell Line, Tumor Cholinesterase Inhibitors Donepezil Humans Ligands Piperazines Piperidines Structure-Activity Relationship Sulfonamides |
topic |
arylsulfonamide donepezil anti-neurodegeneratives Alzheimer´s disease AChE inhibitors Aβ aggregation Acetylcholinesterase Alzheimer Disease Amyloid beta-Peptides Cell Line, Tumor Cholinesterase Inhibitors Donepezil Humans Ligands Piperazines Piperidines Structure-Activity Relationship Sulfonamides |
description |
Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-03-16 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/105262 http://hdl.handle.net/10316/105262 https://doi.org/10.3390/molecules26061658 |
url |
http://hdl.handle.net/10316/105262 https://doi.org/10.3390/molecules26061658 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1420-3049 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799134108865003520 |