Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction

A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of...

Descripción completa

Detalles Bibliográficos
Autores: Asproni, Battistina, Catto, Marco, Loriga, Giovanni, Murineddu, Gabriele, Corona, Paola, Purgatorio, Rosa, Cichero, Elena, Fossa, Paola, Scarano, Naomi, Martínez Rodríguez, Antón Leandro, Brea Floriani, José Manuel, Pinna, Gérard A.
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad de Santiago de Compostela (USC)
Repositorio:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
Idioma:inglés
OAI Identifier:oai:minerva.usc.gal:10347/45856
Acceso en línea:https://hdl.handle.net/10347/45856
Access Level:acceso abierto
Palabra clave:Acetylcholinesterase inhibitors
5-HT6 receptor ligands
Multitarget-directed ligands
Alzheimer’s disease
Thienocycloalkylpyridazinone derivatives
id ES_3cede1116dd412eeda92a9434bbfcb28
oai_identifier_str oai:minerva.usc.gal:10347/45856
network_acronym_str ES
network_name_str España
repository_id_str
spelling Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interactionAsproni, BattistinaCatto, MarcoLoriga, GiovanniMurineddu, GabrieleCorona, PaolaPurgatorio, RosaCichero, ElenaFossa, PaolaScarano, NaomiMartínez Rodríguez, Antón LeandroBrea Floriani, José ManuelPinna, Gérard A.Acetylcholinesterase inhibitors5-HT6 receptor ligandsMultitarget-directed ligandsAlzheimer’s diseaseThienocycloalkylpyridazinone derivativesA library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer’s disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT6 interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC50 in the 0.17–1.23 μM range, exhibiting low to poor activity for hBChE (IC50 = 4.13–9.70 μM). The introduction of 5-HT6 structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT6 thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT6 receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for ADElsevierUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica20232023-03-2120232023-03-21journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10347/45856reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostelainstname:Universidad de Santiago de Compostela (USC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2© 2023 The Authors. Published by Elsevier Ltd. This is an open access article distributed under the terms of the Creative Commons CC-BY licensehttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:minerva.usc.gal:10347/458562026-06-15T12:47:27Z
dc.title.none.fl_str_mv Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
title Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
spellingShingle Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
Asproni, Battistina
Acetylcholinesterase inhibitors
5-HT6 receptor ligands
Multitarget-directed ligands
Alzheimer’s disease
Thienocycloalkylpyridazinone derivatives
title_short Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
title_full Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
title_fullStr Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
title_full_unstemmed Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
title_sort Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT6 receptor interaction
dc.creator.none.fl_str_mv Asproni, Battistina
Catto, Marco
Loriga, Giovanni
Murineddu, Gabriele
Corona, Paola
Purgatorio, Rosa
Cichero, Elena
Fossa, Paola
Scarano, Naomi
Martínez Rodríguez, Antón Leandro
Brea Floriani, José Manuel
Pinna, Gérard A.
author Asproni, Battistina
author_facet Asproni, Battistina
Catto, Marco
Loriga, Giovanni
Murineddu, Gabriele
Corona, Paola
Purgatorio, Rosa
Cichero, Elena
Fossa, Paola
Scarano, Naomi
Martínez Rodríguez, Antón Leandro
Brea Floriani, José Manuel
Pinna, Gérard A.
author_role author
author2 Catto, Marco
Loriga, Giovanni
Murineddu, Gabriele
Corona, Paola
Purgatorio, Rosa
Cichero, Elena
Fossa, Paola
Scarano, Naomi
Martínez Rodríguez, Antón Leandro
Brea Floriani, José Manuel
Pinna, Gérard A.
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)
Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica
dc.subject.none.fl_str_mv Acetylcholinesterase inhibitors
5-HT6 receptor ligands
Multitarget-directed ligands
Alzheimer’s disease
Thienocycloalkylpyridazinone derivatives
topic Acetylcholinesterase inhibitors
5-HT6 receptor ligands
Multitarget-directed ligands
Alzheimer’s disease
Thienocycloalkylpyridazinone derivatives
description A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT6 receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer’s disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT6 interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC50 in the 0.17–1.23 μM range, exhibiting low to poor activity for hBChE (IC50 = 4.13–9.70 μM). The introduction of 5-HT6 structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT6 thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT6 receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-03-21
2023
2023-03-21
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/10347/45856
url https://hdl.handle.net/10347/45856
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
http://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 Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
instname:Universidad de Santiago de Compostela (USC)
instname_str Universidad de Santiago de Compostela (USC)
reponame_str Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
collection Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406407833419776
score 15.198674

Similares en LA Referencia