Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases

Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synth...

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Autores: Bolognino, Isabella, Giangregorio, Nicola, Tonazzi, Annamaria, Martínez Rodríguez, Antón Leandro, Altomare, Cosimo D., Loza García, María Isabel, Sablone, Sara, Cellamare, Saverio, Catto, Marco
Tipo de recurso: artículo
Fecha de publicación:2021
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:10347/45055
Acceso en línea:https://hdl.handle.net/10347/45055
Access Level:acceso abierto
Palabra clave:Dantrolene analogues
Hydrazide and hydrazone derivatives
Multitarget activity
Carnitine/acylcarnitine carrier
Alzheimer's disease
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spelling Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseasesBolognino, IsabellaGiangregorio, NicolaTonazzi, AnnamariaMartínez Rodríguez, Antón LeandroAltomare, Cosimo D.Loza García, María IsabelSablone, SaraCellamare, SaverioCatto, MarcoDantrolene analoguesHydrazide and hydrazone derivativesMultitarget activityCarnitine/acylcarnitine carrierAlzheimer's diseaseDantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A or AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81 μM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined seriesWileyUniversidade 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 Farmacéutica20212021-05-2820212021-05-28journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10347/45055reponame: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© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Licensehttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:minerva.usc.gal:10347/450552026-06-15T12:47:27Z
dc.title.none.fl_str_mv Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
title Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
spellingShingle Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
Bolognino, Isabella
Dantrolene analogues
Hydrazide and hydrazone derivatives
Multitarget activity
Carnitine/acylcarnitine carrier
Alzheimer's disease
title_short Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
title_full Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
title_fullStr Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
title_full_unstemmed Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
title_sort Synthesis and biological evaluation of Dantrolene‐like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
dc.creator.none.fl_str_mv Bolognino, Isabella
Giangregorio, Nicola
Tonazzi, Annamaria
Martínez Rodríguez, Antón Leandro
Altomare, Cosimo D.
Loza García, María Isabel
Sablone, Sara
Cellamare, Saverio
Catto, Marco
author Bolognino, Isabella
author_facet Bolognino, Isabella
Giangregorio, Nicola
Tonazzi, Annamaria
Martínez Rodríguez, Antón Leandro
Altomare, Cosimo D.
Loza García, María Isabel
Sablone, Sara
Cellamare, Saverio
Catto, Marco
author_role author
author2 Giangregorio, Nicola
Tonazzi, Annamaria
Martínez Rodríguez, Antón Leandro
Altomare, Cosimo D.
Loza García, María Isabel
Sablone, Sara
Cellamare, Saverio
Catto, Marco
author2_role 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 Dantrolene analogues
Hydrazide and hydrazone derivatives
Multitarget activity
Carnitine/acylcarnitine carrier
Alzheimer's disease
topic Dantrolene analogues
Hydrazide and hydrazone derivatives
Multitarget activity
Carnitine/acylcarnitine carrier
Alzheimer's disease
description Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A or AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81 μM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-05-28
2021
2021-05-28
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/10347/45055
url https://hdl.handle.net/10347/45055
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 Wiley
publisher.none.fl_str_mv Wiley
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
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score 15,811543

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