Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors

Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes...

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Autores: Svobodova, Barbora, Mezeiova, Eva, Hepnarova, Vendula, Hrabinova, Martina, Muckova, Lubica, Kobrlova, Tereza, Jun, Daniel, Soukup, Ondrej, Jimeno, M. Luisa, Marco-Contelles, José, Korábečný, Jan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/188938
Acceso en línea:http://hdl.handle.net/10261/188938
Access Level:acceso abierto
Palabra clave:Tacrine
Bis(7)-tacrine
6-chlorotacrine
7-methoxytacrine
Squaramides
Alzheimer’s disease
Cholinesterases
In vitro
In silico
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spelling Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitorsSvobodova, BarboraMezeiova, EvaHepnarova, VendulaHrabinova, MartinaMuckova, LubicaKobrlova, TerezaJun, DanielSoukup, OndrejJimeno, M. LuisaMarco-Contelles, JoséKorábečný, JanTacrineBis(7)-tacrine6-chlorotacrine7-methoxytacrineSquaramidesAlzheimer’s diseaseCholinesterasesIn vitroIn silicoTacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.This project was conceived by JMC (IQOG, CSIC, Madrid, Spain), initially carried out experimentally by EM, in Madrid, thanks to a Short-Term Scientific Mission (from 30 January until the 28 April 2017) granted by EU COST Action (CA15135: “Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig)”), and continued in Hradec Kralove (Czech Republic) by EM in collaboration with BS, under the supervision of JK, who organized and planned all the biological analysis and wrote the manuscript. JMC is very thankful to EM, BS, and JK for their collaboration, and to the COST Action CA15135 for supporting this project. The study was supported by a grant of Ministry of Defence “Long Term Development Plan” Medical Aspects of Weapons of Mass Destruction of the Faculty of Military Health Sciences, University of Defence, by the Ministry of Education, Youth and Sports of Czech Republic (project ERDF no. CZ.02.1.01/0.0/0.0/18_069/0010054) and by MH CZ - DRO (University Hospital Hradec Kralove, No. 00179906). JMC thanks MINECO (Government of Spain) (SAF2015-65586-R) for support.Peer reviewedMultidisciplinary Digital Publishing InstituteEuropean Cooperation in Science and TechnologyMinistry of Defence (UK)Ministry of Education, Youth and Sports (Czech Republic)Ministerio de Economía y Competitividad (España)University of Defence (Czech Republic)University Hospital Hradec KrálovéConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2019201920192019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/188938reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-65586-Rhttps://doi.org/10.3390/biom9080379Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1889382026-05-22T06:33:51Z
dc.title.none.fl_str_mv Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
title Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
spellingShingle Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
Svobodova, Barbora
Tacrine
Bis(7)-tacrine
6-chlorotacrine
7-methoxytacrine
Squaramides
Alzheimer’s disease
Cholinesterases
In vitro
In silico
title_short Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
title_full Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
title_fullStr Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
title_full_unstemmed Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
title_sort Exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors
dc.creator.none.fl_str_mv Svobodova, Barbora
Mezeiova, Eva
Hepnarova, Vendula
Hrabinova, Martina
Muckova, Lubica
Kobrlova, Tereza
Jun, Daniel
Soukup, Ondrej
Jimeno, M. Luisa
Marco-Contelles, José
Korábečný, Jan
author Svobodova, Barbora
author_facet Svobodova, Barbora
Mezeiova, Eva
Hepnarova, Vendula
Hrabinova, Martina
Muckova, Lubica
Kobrlova, Tereza
Jun, Daniel
Soukup, Ondrej
Jimeno, M. Luisa
Marco-Contelles, José
Korábečný, Jan
author_role author
author2 Mezeiova, Eva
Hepnarova, Vendula
Hrabinova, Martina
Muckova, Lubica
Kobrlova, Tereza
Jun, Daniel
Soukup, Ondrej
Jimeno, M. Luisa
Marco-Contelles, José
Korábečný, Jan
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Cooperation in Science and Technology
Ministry of Defence (UK)
Ministry of Education, Youth and Sports (Czech Republic)
Ministerio de Economía y Competitividad (España)
University of Defence (Czech Republic)
University Hospital Hradec Králové
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Tacrine
Bis(7)-tacrine
6-chlorotacrine
7-methoxytacrine
Squaramides
Alzheimer’s disease
Cholinesterases
In vitro
In silico
topic Tacrine
Bis(7)-tacrine
6-chlorotacrine
7-methoxytacrine
Squaramides
Alzheimer’s disease
Cholinesterases
In vitro
In silico
description Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/188938
url http://hdl.handle.net/10261/188938
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-65586-R
https://doi.org/10.3390/biom9080379
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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