Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling

Autores
Câmara, Viktor S.; Soares, Ana Julia; Biscussi, Brunella; Murray, Ana Paula; Guedes, Isabella A.; Dardenne, Laurent E.; Ruaro, Thaís C.; Zimmer, Aline R.; Ceschi, Marco A.
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
In the brain of patients with chronic Alzheimer's disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, development of new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)-lophine analogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions were performed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps for unsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of them inhibit AChE. All the compounds, except 7a, 7b and 7c, displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (half maximal inhibitory concentration (IC50) 32.25-0.03 μM). The enzyme kinetic and docking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studies showed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6 astroglial cell lines.
Fil: Câmara, Viktor S.. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Soares, Ana Julia. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Biscussi, Brunella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Guedes, Isabella A.. Laboratório Nacional de Computação Científica; Brasil
Fil: Dardenne, Laurent E.. Laboratório Nacional de Computação Científica; Brasil
Fil: Ruaro, Thaís C.. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Zimmer, Aline R.. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Ceschi, Marco A.. Universidade Federal do Rio Grande do Sul; Brasil
Materia
BIS(N)-LOPHINE ANALOGUES
BUTYRYLCHOLINESTERASE
CHOLINESTERASE INHIBITOR
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/211297
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/211297
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modellingCâmara, Viktor S.Soares, Ana JuliaBiscussi, BrunellaMurray, Ana PaulaGuedes, Isabella A.Dardenne, Laurent E.Ruaro, Thaís C.Zimmer, Aline R.Ceschi, Marco A.BIS(N)-LOPHINE ANALOGUESBUTYRYLCHOLINESTERASECHOLINESTERASE INHIBITORhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1In the brain of patients with chronic Alzheimer's disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, development of new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)-lophine analogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions were performed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps for unsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of them inhibit AChE. All the compounds, except 7a, 7b and 7c, displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (half maximal inhibitory concentration (IC50) 32.25-0.03 μM). The enzyme kinetic and docking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studies showed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6 astroglial cell lines.Fil: Câmara, Viktor S.. Universidade Federal do Rio Grande do Sul; BrasilFil: Soares, Ana Julia. Universidade Federal do Rio Grande do Sul; BrasilFil: Biscussi, Brunella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Guedes, Isabella A.. Laboratório Nacional de Computação Científica; BrasilFil: Dardenne, Laurent E.. Laboratório Nacional de Computação Científica; BrasilFil: Ruaro, Thaís C.. Universidade Federal do Rio Grande do Sul; BrasilFil: Zimmer, Aline R.. Universidade Federal do Rio Grande do Sul; BrasilFil: Ceschi, Marco A.. Universidade Federal do Rio Grande do Sul; BrasilSociedade Brasileira de Química2021-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/211297Câmara, Viktor S.; Soares, Ana Julia; Biscussi, Brunella; Murray, Ana Paula; Guedes, Isabella A.; et al.; Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling; Sociedade Brasileira de Química; Journal of the Brazilian Chemical Society; 32; 6; 1-2021; 1173-11850103-50531678-4790CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.scielo.br/j/jbchs/a/VKzV3Kqdvc7zNGnzVMJht8J/info:eu-repo/semantics/altIdentifier/url/https://s3.sa-east-1.amazonaws.com/static.sites.sbq.org.br/jbcs.sbq.org.br/pdf/2020-0519AR.pdfinfo:eu-repo/semantics/altIdentifier/doi/10.21577/0103-5053.20210018info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:09Zoai:ri.conicet.gov.ar:11336/211297instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:05:10.025CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
title Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
spellingShingle Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
Câmara, Viktor S.
BIS(N)-LOPHINE ANALOGUES
BUTYRYLCHOLINESTERASE
CHOLINESTERASE INHIBITOR
title_short Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
title_full Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
title_fullStr Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
title_full_unstemmed Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
title_sort Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling
dc.creator.none.fl_str_mv Câmara, Viktor S.
Soares, Ana Julia
Biscussi, Brunella
Murray, Ana Paula
Guedes, Isabella A.
Dardenne, Laurent E.
Ruaro, Thaís C.
Zimmer, Aline R.
Ceschi, Marco A.
author Câmara, Viktor S.
author_facet Câmara, Viktor S.
Soares, Ana Julia
Biscussi, Brunella
Murray, Ana Paula
Guedes, Isabella A.
Dardenne, Laurent E.
Ruaro, Thaís C.
Zimmer, Aline R.
Ceschi, Marco A.
author_role author
author2 Soares, Ana Julia
Biscussi, Brunella
Murray, Ana Paula
Guedes, Isabella A.
Dardenne, Laurent E.
Ruaro, Thaís C.
Zimmer, Aline R.
Ceschi, Marco A.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BIS(N)-LOPHINE ANALOGUES
BUTYRYLCHOLINESTERASE
CHOLINESTERASE INHIBITOR
topic BIS(N)-LOPHINE ANALOGUES
BUTYRYLCHOLINESTERASE
CHOLINESTERASE INHIBITOR
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv In the brain of patients with chronic Alzheimer's disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, development of new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)-lophine analogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions were performed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps for unsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of them inhibit AChE. All the compounds, except 7a, 7b and 7c, displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (half maximal inhibitory concentration (IC50) 32.25-0.03 μM). The enzyme kinetic and docking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studies showed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6 astroglial cell lines.
Fil: Câmara, Viktor S.. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Soares, Ana Julia. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Biscussi, Brunella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Guedes, Isabella A.. Laboratório Nacional de Computação Científica; Brasil
Fil: Dardenne, Laurent E.. Laboratório Nacional de Computação Científica; Brasil
Fil: Ruaro, Thaís C.. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Zimmer, Aline R.. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Ceschi, Marco A.. Universidade Federal do Rio Grande do Sul; Brasil
description In the brain of patients with chronic Alzheimer's disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, development of new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)-lophine analogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions were performed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps for unsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of them inhibit AChE. All the compounds, except 7a, 7b and 7c, displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (half maximal inhibitory concentration (IC50) 32.25-0.03 μM). The enzyme kinetic and docking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studies showed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6 astroglial cell lines.
publishDate 2021
dc.date.none.fl_str_mv 2021-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/211297
Câmara, Viktor S.; Soares, Ana Julia; Biscussi, Brunella; Murray, Ana Paula; Guedes, Isabella A.; et al.; Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling; Sociedade Brasileira de Química; Journal of the Brazilian Chemical Society; 32; 6; 1-2021; 1173-1185
0103-5053
1678-4790
CONICET Digital
CONICET
url http://hdl.handle.net/11336/211297
identifier_str_mv Câmara, Viktor S.; Soares, Ana Julia; Biscussi, Brunella; Murray, Ana Paula; Guedes, Isabella A.; et al.; Expedient microwave-assisted synthesis of Bis( n )-lophine analogues as selective butyrylcholinesterase inhibitors: Cytotoxicity evaluation and molecular modelling; Sociedade Brasileira de Química; Journal of the Brazilian Chemical Society; 32; 6; 1-2021; 1173-1185
0103-5053
1678-4790
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.scielo.br/j/jbchs/a/VKzV3Kqdvc7zNGnzVMJht8J/
info:eu-repo/semantics/altIdentifier/url/https://s3.sa-east-1.amazonaws.com/static.sites.sbq.org.br/jbcs.sbq.org.br/pdf/2020-0519AR.pdf
info:eu-repo/semantics/altIdentifier/doi/10.21577/0103-5053.20210018
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Sociedade Brasileira de Química
publisher.none.fl_str_mv Sociedade Brasileira de Química
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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