Synthesis of Diversely Substituted Diethyl (Pyrrolidin-2-Yl)Phosphonates
Bagán, Andrea (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
López-Ruiz, Alba (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Abás, Sònia (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Molins, Elies (Institut de Ciència de Materials de Barcelona)
Pérez, Belén (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Muneta-Arrate, Itziar (Universidad del País Vasco. Departamento de Farmacología)
Callado, Luis F. (Universidad del País Vasco. Departamento de Farmacología)
Escolano, Carmen (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)

Date:	2025
Abstract:	Imidazoline I receptors (I-IR) are untapped therapeutic targets lacking a structural description. Although the levels of I-IR are dysregulated in a plethora of illnesses, the arsenal of ligands that can modulate I-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 I-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.
Grants:	Agencia Estatal de Investigación PID2022-1380790B-I00 Agencia Estatal de Investigación PDC2022-133441-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00357
Note:	Altres ajuts: Basque Government (IT1512/22)
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	α-aminophosphonate ; Pyrroline ; Phosphonic ester ; (Pyrrolidine-2-yl)phosphonate ; Phosphoproline ; Imidazoline I2 receptor ligand
Published in:	Molecules, Vol. 30 Núm. 9 (May 2025) , p. 2078, ISSN 1420-3049

DOI: 10.3390/molecules30092078
PMID: 40363884

18 p, 2.3 MB

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