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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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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 |
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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 |
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