Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholineste...

Descripción completa

Detalles Bibliográficos
Autores: Bortolami, Martina, Pandolfi, Fabiana, Tudino, Valeria, Messore, Antonella, Madia, Valentina Noemi, De Vita, Daniela, Di Santo, Roberto, Costi, Roberta, Romeo, Isabella, Alcaro, Stefano, Colone, Marisa, Stringaro, Annarita, Espargaró Colomé, Alba, Sabaté Lagunas, Raimon, Scipione, Luigi
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/191491
Acceso en línea:https://hdl.handle.net/2445/191491
Access Level:acceso abierto
Palabra clave:Malaltia d'Alzheimer
Amiloïdosi
Agregació (Química)
Alzheimer's disease
Amyloidosis
Aggregation (Chemistry)
id ES_9d8ec8b75fd9d1a55a63ffcfdbd72bf0
oai_identifier_str oai:diposit.ub.edu:2445/191491
network_acronym_str ES
network_name_str España
repository_id_str
spelling Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitorsBortolami, MartinaPandolfi, FabianaTudino, ValeriaMessore, AntonellaMadia, Valentina NoemiDe Vita, DanielaDi Santo, RobertoCosti, RobertaRomeo, IsabellaAlcaro, StefanoColone, MarisaStringaro, AnnaritaEspargaró Colomé, AlbaSabaté Lagunas, RaimonScipione, LuigiMalaltia d'AlzheimerAmiloïdosiAgregació (Química)Alzheimer's diseaseAmyloidosisAggregation (Chemistry)Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ42 and tau and to be able to chelate Cu2+ and Fe3+ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line.MDPI2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/191491Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/ph15060673Pharmaceuticals, 2022, vol. 15, num. 6, p. 673https://doi.org/10.3390/ph15060673cc-by (c) Bortolami, Martina et al., 2022https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1914912026-05-27T06:46:51Z
dc.title.none.fl_str_mv Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
title Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
spellingShingle Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
Bortolami, Martina
Malaltia d'Alzheimer
Amiloïdosi
Agregació (Química)
Alzheimer's disease
Amyloidosis
Aggregation (Chemistry)
title_short Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
title_full Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
title_fullStr Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
title_full_unstemmed Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
title_sort Design, synthesis, and in vitro, in silico and in cellulo evaluation of new pyrimidine and pyridine amide and carbamate derivatives as multi-functional cholinesterase inhibitors
dc.creator.none.fl_str_mv Bortolami, Martina
Pandolfi, Fabiana
Tudino, Valeria
Messore, Antonella
Madia, Valentina Noemi
De Vita, Daniela
Di Santo, Roberto
Costi, Roberta
Romeo, Isabella
Alcaro, Stefano
Colone, Marisa
Stringaro, Annarita
Espargaró Colomé, Alba
Sabaté Lagunas, Raimon
Scipione, Luigi
author Bortolami, Martina
author_facet Bortolami, Martina
Pandolfi, Fabiana
Tudino, Valeria
Messore, Antonella
Madia, Valentina Noemi
De Vita, Daniela
Di Santo, Roberto
Costi, Roberta
Romeo, Isabella
Alcaro, Stefano
Colone, Marisa
Stringaro, Annarita
Espargaró Colomé, Alba
Sabaté Lagunas, Raimon
Scipione, Luigi
author_role author
author2 Pandolfi, Fabiana
Tudino, Valeria
Messore, Antonella
Madia, Valentina Noemi
De Vita, Daniela
Di Santo, Roberto
Costi, Roberta
Romeo, Isabella
Alcaro, Stefano
Colone, Marisa
Stringaro, Annarita
Espargaró Colomé, Alba
Sabaté Lagunas, Raimon
Scipione, Luigi
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Amiloïdosi
Agregació (Química)
Alzheimer's disease
Amyloidosis
Aggregation (Chemistry)
topic Malaltia d'Alzheimer
Amiloïdosi
Agregació (Química)
Alzheimer's disease
Amyloidosis
Aggregation (Chemistry)
description Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ42 and tau and to be able to chelate Cu2+ and Fe3+ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/191491
url https://hdl.handle.net/2445/191491
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/ph15060673
Pharmaceuticals, 2022, vol. 15, num. 6, p. 673
https://doi.org/10.3390/ph15060673
dc.rights.none.fl_str_mv cc-by (c) Bortolami, Martina et al., 2022
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Bortolami, Martina et al., 2022
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869414752973750272
score 15,300724

Similares en LA Referencia