Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease
Autor(a) principal: | |
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Data de Publicação: | 2020 |
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/10316/106464 https://doi.org/10.3390/molecules25040985 |
Resumo: | A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD. |
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Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Diseasehydroxyphenyl-benzimidazoledonepezilanti-neurodegenerativesAlzheimer´s diseasemultifunctional drugsmetal chelationAcetylcholinesteraseAlzheimer DiseaseAmyloid beta-PeptidesAntioxidantsChelating AgentsCholinesterase InhibitorsDonepezilHumansIndazolesLigandsMolecular Docking SimulationMolecular StructurePiperazinePiperidinesStructure-Activity RelationshipA series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.MDPI2020-02-22info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/106464http://hdl.handle.net/10316/106464https://doi.org/10.3390/molecules25040985eng1420-3049Chaves, SílviaResta, SimonettaRinaldo, FedericaCosta, MarinaJosselin, RomaneGwizdala, KarolinaPiemontese, LucaCapriati, VitoSantos, A. Raquel PereiraCardoso, Sandra M.Santos, 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:RCAAP2023-04-04T20:37:44Zoai:estudogeral.uc.pt:10316/106464Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:22:54.922321Repositório 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 |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease |
title |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease |
spellingShingle |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Chaves, Sílvia hydroxyphenyl-benzimidazole donepezil anti-neurodegeneratives Alzheimer´s disease multifunctional drugs metal chelation Acetylcholinesterase Alzheimer Disease Amyloid beta-Peptides Antioxidants Chelating Agents Cholinesterase Inhibitors Donepezil Humans Indazoles Ligands Molecular Docking Simulation Molecular Structure Piperazine Piperidines Structure-Activity Relationship |
title_short |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease |
title_full |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease |
title_fullStr |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease |
title_full_unstemmed |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease |
title_sort |
Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease |
author |
Chaves, Sílvia |
author_facet |
Chaves, Sílvia Resta, Simonetta Rinaldo, Federica Costa, Marina Josselin, Romane Gwizdala, Karolina Piemontese, Luca Capriati, Vito Santos, A. Raquel Pereira Cardoso, Sandra M. Santos, M. Amélia |
author_role |
author |
author2 |
Resta, Simonetta Rinaldo, Federica Costa, Marina Josselin, Romane Gwizdala, Karolina Piemontese, Luca Capriati, Vito Santos, A. Raquel Pereira Cardoso, Sandra M. Santos, M. Amélia |
author2_role |
author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Chaves, Sílvia Resta, Simonetta Rinaldo, Federica Costa, Marina Josselin, Romane Gwizdala, Karolina Piemontese, Luca Capriati, Vito Santos, A. Raquel Pereira Cardoso, Sandra M. Santos, M. Amélia |
dc.subject.por.fl_str_mv |
hydroxyphenyl-benzimidazole donepezil anti-neurodegeneratives Alzheimer´s disease multifunctional drugs metal chelation Acetylcholinesterase Alzheimer Disease Amyloid beta-Peptides Antioxidants Chelating Agents Cholinesterase Inhibitors Donepezil Humans Indazoles Ligands Molecular Docking Simulation Molecular Structure Piperazine Piperidines Structure-Activity Relationship |
topic |
hydroxyphenyl-benzimidazole donepezil anti-neurodegeneratives Alzheimer´s disease multifunctional drugs metal chelation Acetylcholinesterase Alzheimer Disease Amyloid beta-Peptides Antioxidants Chelating Agents Cholinesterase Inhibitors Donepezil Humans Indazoles Ligands Molecular Docking Simulation Molecular Structure Piperazine Piperidines Structure-Activity Relationship |
description |
A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer's disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-02-22 |
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/10316/106464 http://hdl.handle.net/10316/106464 https://doi.org/10.3390/molecules25040985 |
url |
http://hdl.handle.net/10316/106464 https://doi.org/10.3390/molecules25040985 |
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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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