Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates

Imidazoline I2 receptors (I2-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I2-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I2-IR is limited. In this framework, we have reported several new structural families...

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Detalles Bibliográficos
Autores: Bagán, Andrea, López Ruiz, Alba, Abás, Sònia, Molins, Elies, Pérez, Belén, Muneta Arrate, Itziar, Callado, Luis F., Escolano, Carmen
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/389811
Acceso en línea:http://hdl.handle.net/10261/389811
https://api.elsevier.com/content/abstract/scopus_id/105004860909
Access Level:acceso abierto
Palabra clave:(Pyrrolidine-2-yl)phosphonate
Imidazoline I2 receptor ligand
Phosphonic ester
Phosphoproline
pyrroline
α-aminophosphonate
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spelling Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)PhosphonatesBagán, AndreaLópez Ruiz, AlbaAbás, SòniaMolins, EliesPérez, BelénMuneta Arrate, ItziarCallado, Luis F.Escolano, Carmen(Pyrrolidine-2-yl)phosphonateImidazoline I2 receptor ligandPhosphonic esterPhosphoprolinepyrrolineα-aminophosphonateImidazoline I2 receptors (I2-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I2-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I2-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I2-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer's disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives.This work was supported by Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2022-1380790B-I00 MICIU/AEI/10.13039/501100011033 and FEDER, UE and PDC2022-133441-I00 MICIU/AEI/10.13039/501100011033 Europea Next GenerationEU/PRTR), the Basque Government (IT1512/22) and Generalitat de Catalunya (2021 SGR 00357). Financial support was provided for A.L.-R. (PRE2022-105091 Ministerio de Ciencia e Innovación).With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2023-001263-S).Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)European CommissionEusko JaurlaritzaGeneralitat de CatalunyaAbás, Sònia [0000-0002-3005-3539]Molins, Elies [0000-0003-1012-0551]Pérez, Belén [0000-0001-5801-1704]Escolano, Carmen [0000-0002-9117-8239]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/10261/389811https://api.elsevier.com/content/abstract/scopus_id/105004860909reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MICINN/Plan Estatal de investigación Científica y Técnica y de Innovación 2021-2023/PID2022-1380790B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PDC2022-133441-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de investigación Científica y Técnica y de Innovación 2021-2023/CEX2023-001263-SMolecules (Basel, Switzerland)http://doi.org/10.3390/molecules30092078Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3898112026-05-22T06:33:51Z
dc.title.none.fl_str_mv Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
title Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
spellingShingle Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
Bagán, Andrea
(Pyrrolidine-2-yl)phosphonate
Imidazoline I2 receptor ligand
Phosphonic ester
Phosphoproline
pyrroline
α-aminophosphonate
title_short Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
title_full Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
title_fullStr Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
title_full_unstemmed Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
title_sort Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
dc.creator.none.fl_str_mv Bagán, Andrea
López Ruiz, Alba
Abás, Sònia
Molins, Elies
Pérez, Belén
Muneta Arrate, Itziar
Callado, Luis F.
Escolano, Carmen
author Bagán, Andrea
author_facet Bagán, Andrea
López Ruiz, Alba
Abás, Sònia
Molins, Elies
Pérez, Belén
Muneta Arrate, Itziar
Callado, Luis F.
Escolano, Carmen
author_role author
author2 López Ruiz, Alba
Abás, Sònia
Molins, Elies
Pérez, Belén
Muneta Arrate, Itziar
Callado, Luis F.
Escolano, Carmen
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
European Commission
Eusko Jaurlaritza
Generalitat de Catalunya
Abás, Sònia [0000-0002-3005-3539]
Molins, Elies [0000-0003-1012-0551]
Pérez, Belén [0000-0001-5801-1704]
Escolano, Carmen [0000-0002-9117-8239]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv (Pyrrolidine-2-yl)phosphonate
Imidazoline I2 receptor ligand
Phosphonic ester
Phosphoproline
pyrroline
α-aminophosphonate
topic (Pyrrolidine-2-yl)phosphonate
Imidazoline I2 receptor ligand
Phosphonic ester
Phosphoproline
pyrroline
α-aminophosphonate
description Imidazoline I2 receptors (I2-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I2-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I2-IR is limited. In this framework, we have reported several new structural families embodying the iminophosphonate functional group that have an excellent affinity and selectivity for I2-IR, and selected members have demonstrated relevant pharmacological properties in murine models of neurodegeneration and Alzheimer's disease. Starting with these iminophosphonates, we continued to exploit their high degree of functionalization through a short and efficient synthesis to access unprecedented 2,3-di, 2,2,3-tri, 2,3,4-tri, and 2,2,3,4-tetrasubstituted diethyl (pyrrolidine-2-yl) phosphonates. The stereochemistry of the new compounds was unequivocally characterized by X-ray crystallographic analyses. Two selected compounds with structural features shared with the starting products were pharmacologically evaluated, allowing us to deduce the required key structural motifs for biologically active aminophosphonate derivatives.
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
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/389811
https://api.elsevier.com/content/abstract/scopus_id/105004860909
url http://hdl.handle.net/10261/389811
https://api.elsevier.com/content/abstract/scopus_id/105004860909
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MICINN/Plan Estatal de investigación Científica y Técnica y de Innovación 2021-2023/PID2022-1380790B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PDC2022-133441-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de investigación Científica y Técnica y de Innovación 2021-2023/CEX2023-001263-S
Molecules (Basel, Switzerland)
http://doi.org/10.3390/molecules30092078
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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