N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease
As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer's diseas...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2025 |
| País: | España |
| Recursos: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositório: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/402078 |
| Acesso em linha: | http://hdl.handle.net/10261/402078 https://api.elsevier.com/content/abstract/scopus_id/105017041855 |
| Access Level: | Acceso aberto |
| Palavra-chave: | ADME Alzheimer’s disease Biological evaluation Molecular modelling |
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N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease |
| title |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease |
| spellingShingle |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease Bautista-Aguilera, Óscar M. ADME Alzheimer’s disease Biological evaluation Molecular modelling |
| title_short |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease |
| title_full |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease |
| title_fullStr |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease |
| title_full_unstemmed |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease |
| title_sort |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease |
| dc.creator.none.fl_str_mv |
Bautista-Aguilera, Óscar M. Manik, Aleksandra Diez-Iriepa, Daniel Szałaj, Natalia Zaręba, Paula Więckowska, Anna Żmudzki, Paweł Honkisz-Orzechowska, Ewelina Knez, Damijan Gobec, Stanislav Sałat, Kinga Martínez-Alonso, Borja Guarnizo-Herrero, Víctor Durán, Guillermo Torrado Torrado-Salmerón, Carlos Bellver-Sanchis, Aina Nsiona-Defise, Inaya Ribalta-Vilella, Marta Pallàs, Mercè López-Muñoz, Francisco Griñán-Ferré, Christian Marco-Contelles, José Iriepa, Isabel |
| author |
Bautista-Aguilera, Óscar M. |
| author_facet |
Bautista-Aguilera, Óscar M. Manik, Aleksandra Diez-Iriepa, Daniel Szałaj, Natalia Zaręba, Paula Więckowska, Anna Żmudzki, Paweł Honkisz-Orzechowska, Ewelina Knez, Damijan Gobec, Stanislav Sałat, Kinga Martínez-Alonso, Borja Guarnizo-Herrero, Víctor Durán, Guillermo Torrado Torrado-Salmerón, Carlos Bellver-Sanchis, Aina Nsiona-Defise, Inaya Ribalta-Vilella, Marta Pallàs, Mercè López-Muñoz, Francisco Griñán-Ferré, Christian Marco-Contelles, José Iriepa, Isabel |
| author_role |
author |
| author2 |
Manik, Aleksandra Diez-Iriepa, Daniel Szałaj, Natalia Zaręba, Paula Więckowska, Anna Żmudzki, Paweł Honkisz-Orzechowska, Ewelina Knez, Damijan Gobec, Stanislav Sałat, Kinga Martínez-Alonso, Borja Guarnizo-Herrero, Víctor Durán, Guillermo Torrado Torrado-Salmerón, Carlos Bellver-Sanchis, Aina Nsiona-Defise, Inaya Ribalta-Vilella, Marta Pallàs, Mercè López-Muñoz, Francisco Griñán-Ferré, Christian Marco-Contelles, José Iriepa, Isabel |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Ministerio de Ciencia e Innovación (España) Ministerio de Economía, Industria y Competitividad (España) Generalitat de Catalunya European Commission National Science Centre (Poland) Ministry of Education, Science and Sport (Slovenia) Bautista-Aguilera, Óscar M. [0000-0002-1327-1681] Diez-Iriepa, Daniel [0000-0002-8575-1246] Żmudzki, Paweł [0000-0003-3594-124] Honkisz-Orzechowska, Ewelina [0000-0002-2046-4879] Knez, Damijan [0000-0001-9917-1384] Gobec, Stanislav [0000-0002-9678-3083] Martínez-Alonso, Borja [0009-0002-9124-5507] Guarnizo-Herrero, Víctor [0000-0001-9323-3388] Nsiona-Defise, Inaya [0009-0001-0596-315] Pallàs, Mercè [0000-0003-3095-4254] Marco-Contelles, José [0000-0003-0690-0328] Iriepa, Isabel [0000-0003-3475-9624] Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
ADME Alzheimer’s disease Biological evaluation Molecular modelling |
| topic |
ADME Alzheimer’s disease Biological evaluation Molecular modelling |
| description |
As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer's disease. We synthesized MBA-159 and conducted comprehensive in vitro and in vivo evaluations. In in vivo studies MBA-159 demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, MBA-159 showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2025 2025 |
| 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 |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/402078 https://api.elsevier.com/content/abstract/scopus_id/105017041855 |
| url |
http://hdl.handle.net/10261/402078 https://api.elsevier.com/content/abstract/scopus_id/105017041855 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
https://doi.org/10.1016/j.biopha.2025.118603 Sí |
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info:eu-repo/semantics/openAccess |
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openAccess |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
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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 |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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1869425418347479040 |
| spelling |
N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's diseaseBautista-Aguilera, Óscar M.Manik, AleksandraDiez-Iriepa, DanielSzałaj, NataliaZaręba, PaulaWięckowska, AnnaŻmudzki, PawełHonkisz-Orzechowska, EwelinaKnez, DamijanGobec, StanislavSałat, KingaMartínez-Alonso, BorjaGuarnizo-Herrero, VíctorDurán, Guillermo TorradoTorrado-Salmerón, CarlosBellver-Sanchis, AinaNsiona-Defise, InayaRibalta-Vilella, MartaPallàs, MercèLópez-Muñoz, FranciscoGriñán-Ferré, ChristianMarco-Contelles, JoséIriepa, IsabelADMEAlzheimer’s diseaseBiological evaluationMolecular modellingAs part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer's disease. We synthesized MBA-159 and conducted comprehensive in vitro and in vivo evaluations. In in vivo studies MBA-159 demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, MBA-159 showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model.II thanks AEI (Government of Spain; Grant PID2019–105813RB- C22). JMC thanks AEI (Government of Spain; Grant PID2019–105813RB-C21) and UCJC [Grant: “In vivo analysis of new analogues of Contilisant (MITOPI) (2022)”] for support. This study was also supported by the Ministerio de Economía, Industria y Com- petitividad (Agencia Estatal de Investigación, AEI; to CGF, and MP) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) (PID2022–139016OA-I00, PDC2022–133441-I00, to CGF, and MP), Generalitat de Catalunya (2021 SGR 00357; to CGF and MP). This study was co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya 2022 (Producte 0092; Llavor 005 and 007; to CGF). The Government of Catalonia (2021 SGR 00357 to C.G.-F and M.P.). II and OMBA thank Laura Contreras andCristina García for their collaboration. II and OMBA thank subsidies for the implementation of the research program within the framework of the recovery, transformation and resilience plan – financed by the Eu- ropean Union – Next Generation EU. CAM. K.S. and E.H.-O. thank JUMC for support (Grant N42/DBS/000290 and N42/DBS/000332). ADMET studies were financed by the National Science Centre Poland (Grant No. 2019/34/E/NZ7/00090). The ADMET research/study were carried out with the use of research infrastructure co-financed by the Smart Growth Operational Programme POIR 4.2 project no. POIR.04.02.00–00-D023/ 20. The financial support from the Slovenian Research and Innovation Agency (Research Core Funding grant P1–0208) is gratefully acknowl- edged. This research was supported by the Ministry of Education, Sci- ence, and Sport (MIZˇS) and the European Regional Development Fund OP20.05187 RI-SI-EATRIS. BMA, VGH, CTS and GTD, thanks UAH CEA and CEMAETA CAI for the in vivo pharmacokinetics studies which were carried out with the use of their research infrastructure.Peer reviewedElsevierMinisterio de Ciencia e Innovación (España)Ministerio de Economía, Industria y Competitividad (España)Generalitat de CatalunyaEuropean CommissionNational Science Centre (Poland)Ministry of Education, Science and Sport (Slovenia)Bautista-Aguilera, Óscar M. [0000-0002-1327-1681]Diez-Iriepa, Daniel [0000-0002-8575-1246]Żmudzki, Paweł [0000-0003-3594-124]Honkisz-Orzechowska, Ewelina [0000-0002-2046-4879]Knez, Damijan [0000-0001-9917-1384]Gobec, Stanislav [0000-0002-9678-3083]Martínez-Alonso, Borja [0009-0002-9124-5507]Guarnizo-Herrero, Víctor [0000-0001-9323-3388]Nsiona-Defise, Inaya [0009-0001-0596-315]Pallàs, Mercè [0000-0003-3095-4254]Marco-Contelles, José [0000-0003-0690-0328]Iriepa, Isabel [0000-0003-3475-9624]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/402078https://api.elsevier.com/content/abstract/scopus_id/105017041855reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1016/j.biopha.2025.118603Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4020782026-05-22T06:33:51Z |
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15,811543 |