Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives

Autores
Biscussi, Brunella; Cueto Díaz, Eduardo J.; Pérez, Concepción; Rodríguez Franco, María Isabel; Murray, Ana Paula
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and teophylline derived compounds was designed and synthesized applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (n= 3, 5-8) and subsequently, the brominated intermediary reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective in vitro AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC50 values in the low nanomolar scale. The kinetic study of compound 28 in hAChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and dynamic molecular modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS site, whereas the xanthine fragment of each inhibitor interacted with the Trp286 in the PAS site. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their in silico good pharmacokinetic profile, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementia
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: Cueto Díaz, Eduardo J.. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; España
Fil: Pérez, Concepción. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; España
Fil: Rodríguez Franco, María Isabel. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; España
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
Materia
Caffeine analogues
Metylxanthines
Acetylcholinesterase inhibitors
Theobromine
Teophylline
Nivel de accesibilidad
acceso embargado
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/288823
Acceder
id CONICETDig_97dcebcf531ed96c383e6193daec86ab
oai_identifier_str oai:ri.conicet.gov.ar:11336/288823
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivativesBiscussi, BrunellaCueto Díaz, Eduardo J.Pérez, ConcepciónRodríguez Franco, María IsabelMurray, Ana PaulaCaffeine analoguesMetylxanthinesAcetylcholinesterase inhibitorsTheobromineTeophyllinehttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and teophylline derived compounds was designed and synthesized applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (n= 3, 5-8) and subsequently, the brominated intermediary reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective in vitro AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC50 values in the low nanomolar scale. The kinetic study of compound 28 in hAChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and dynamic molecular modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS site, whereas the xanthine fragment of each inhibitor interacted with the Trp286 in the PAS site. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their in silico good pharmacokinetic profile, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementiaFil: 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: Cueto Díaz, Eduardo J.. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; EspañaFil: Pérez, Concepción. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; EspañaFil: Rodríguez Franco, María Isabel. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; EspañaFil: 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; ArgentinaRoyal Society of Chemistry2025-02info:eu-repo/date/embargoEnd/2026-08-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/288823Biscussi, Brunella; Cueto Díaz, Eduardo J.; Pérez, Concepción; Rodríguez Franco, María Isabel; Murray, Ana Paula; Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives; Royal Society of Chemistry; RSC Medicinal Chemistry; 16; 5; 2-2025; 2098-21162632-8682CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1039/D5MD00031Ainfo:eu-repo/semantics/embargoedAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:35:49Zoai:ri.conicet.gov.ar:11336/288823instacron: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:34982026-08-25 14:35:49.625CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
title Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
spellingShingle Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
Biscussi, Brunella
Caffeine analogues
Metylxanthines
Acetylcholinesterase inhibitors
Theobromine
Teophylline
title_short Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
title_full Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
title_fullStr Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
title_full_unstemmed Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
title_sort Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives
dc.creator.none.fl_str_mv Biscussi, Brunella
Cueto Díaz, Eduardo J.
Pérez, Concepción
Rodríguez Franco, María Isabel
Murray, Ana Paula
author Biscussi, Brunella
author_facet Biscussi, Brunella
Cueto Díaz, Eduardo J.
Pérez, Concepción
Rodríguez Franco, María Isabel
Murray, Ana Paula
author_role author
author2 Cueto Díaz, Eduardo J.
Pérez, Concepción
Rodríguez Franco, María Isabel
Murray, Ana Paula
author2_role author
author
author
author
dc.subject.none.fl_str_mv Caffeine analogues
Metylxanthines
Acetylcholinesterase inhibitors
Theobromine
Teophylline
topic Caffeine analogues
Metylxanthines
Acetylcholinesterase inhibitors
Theobromine
Teophylline
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and teophylline derived compounds was designed and synthesized applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (n= 3, 5-8) and subsequently, the brominated intermediary reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective in vitro AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC50 values in the low nanomolar scale. The kinetic study of compound 28 in hAChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and dynamic molecular modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS site, whereas the xanthine fragment of each inhibitor interacted with the Trp286 in the PAS site. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their in silico good pharmacokinetic profile, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementia
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: Cueto Díaz, Eduardo J.. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; España
Fil: Pérez, Concepción. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; España
Fil: Rodríguez Franco, María Isabel. Consejo Superior de Investigaciones Científicas. Instituto de Química Médica; España
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
description Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and teophylline derived compounds was designed and synthesized applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (n= 3, 5-8) and subsequently, the brominated intermediary reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective in vitro AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC50 values in the low nanomolar scale. The kinetic study of compound 28 in hAChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and dynamic molecular modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS site, whereas the xanthine fragment of each inhibitor interacted with the Trp286 in the PAS site. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their in silico good pharmacokinetic profile, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementia
publishDate 2025
dc.date.none.fl_str_mv 2025-02
info:eu-repo/date/embargoEnd/2026-08-05
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/11336/288823
Biscussi, Brunella; Cueto Díaz, Eduardo J.; Pérez, Concepción; Rodríguez Franco, María Isabel; Murray, Ana Paula; Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives; Royal Society of Chemistry; RSC Medicinal Chemistry; 16; 5; 2-2025; 2098-2116
2632-8682
CONICET Digital
CONICET
url http://hdl.handle.net/11336/288823
identifier_str_mv Biscussi, Brunella; Cueto Díaz, Eduardo J.; Pérez, Concepción; Rodríguez Franco, María Isabel; Murray, Ana Paula; Novel potent and selective dual acetylcholinesterase inhibitors: N -substituted theobromine and theophylline derivatives; Royal Society of Chemistry; RSC Medicinal Chemistry; 16; 5; 2-2025; 2098-2116
2632-8682
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1039/D5MD00031A
dc.rights.none.fl_str_mv info:eu-repo/semantics/embargoedAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv embargoedAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry
publisher.none.fl_str_mv Royal Society of Chemistry
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 13.265058

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