Cargando…

Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands

In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modelin...

Descripción completa

Detalles Bibliográficos
Autores principales: Thapa, Rajesh, Flores, Rafael, Cheng, Kwan H., Mochona, Bereket, Sikazwe, Donald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005056/
https://www.ncbi.nlm.nih.gov/pubmed/36903567
http://dx.doi.org/10.3390/molecules28052319
_version_ 1784904986198540288
author Thapa, Rajesh
Flores, Rafael
Cheng, Kwan H.
Mochona, Bereket
Sikazwe, Donald
author_facet Thapa, Rajesh
Flores, Rafael
Cheng, Kwan H.
Mochona, Bereket
Sikazwe, Donald
author_sort Thapa, Rajesh
collection PubMed
description In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418—a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro σ1R binding affinities of 2.18 and 9.54 μM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer’s disease (AD).
format Online
Article
Text
id pubmed-10005056
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100050562023-03-11 Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands Thapa, Rajesh Flores, Rafael Cheng, Kwan H. Mochona, Bereket Sikazwe, Donald Molecules Article In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418—a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro σ1R binding affinities of 2.18 and 9.54 μM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer’s disease (AD). MDPI 2023-03-02 /pmc/articles/PMC10005056/ /pubmed/36903567 http://dx.doi.org/10.3390/molecules28052319 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Thapa, Rajesh
Flores, Rafael
Cheng, Kwan H.
Mochona, Bereket
Sikazwe, Donald
Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands
title Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands
title_full Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands
title_fullStr Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands
title_full_unstemmed Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands
title_short Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands
title_sort design and synthesis of new acyl urea analogs as potential σ1r ligands
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10005056/
https://www.ncbi.nlm.nih.gov/pubmed/36903567
http://dx.doi.org/10.3390/molecules28052319
work_keys_str_mv AT thaparajesh designandsynthesisofnewacylureaanalogsaspotentials1rligands
AT floresrafael designandsynthesisofnewacylureaanalogsaspotentials1rligands
AT chengkwanh designandsynthesisofnewacylureaanalogsaspotentials1rligands
AT mochonabereket designandsynthesisofnewacylureaanalogsaspotentials1rligands
AT sikazwedonald designandsynthesisofnewacylureaanalogsaspotentials1rligands