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5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors
An efficient regioselective approach to novel functionalized bis(isoxazoles) with a variety of aromatic and aliphatic linkers was elaborated, based on the heterocyclization reaction of electrophilic alkenes under the treatment with tetranitromethane-triethylamine complex affording 3-EWG-5-nitroisoxa...
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/PMC10671298/ https://www.ncbi.nlm.nih.gov/pubmed/38003327 http://dx.doi.org/10.3390/ijms242216135 |
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author | Vasilenko, Dmitry A. Temnyakova, Nadezhda S. Dronov, Sevastian E. Radchenko, Eugene V. Grishin, Yuri K. Gabrel’yan, Alexey V. Zamoyski, Vladimir L. Grigoriev, Vladimir V. Averina, Elena B. Palyulin, Vladimir A. |
author_facet | Vasilenko, Dmitry A. Temnyakova, Nadezhda S. Dronov, Sevastian E. Radchenko, Eugene V. Grishin, Yuri K. Gabrel’yan, Alexey V. Zamoyski, Vladimir L. Grigoriev, Vladimir V. Averina, Elena B. Palyulin, Vladimir A. |
author_sort | Vasilenko, Dmitry A. |
collection | PubMed |
description | An efficient regioselective approach to novel functionalized bis(isoxazoles) with a variety of aromatic and aliphatic linkers was elaborated, based on the heterocyclization reaction of electrophilic alkenes under the treatment with tetranitromethane-triethylamine complex affording 3-EWG-5-nitroisoxazoles. The subsequent S(N)Ar reactions of 5-nitroisoxazoles with various O,O-, N,N- and S,S-bis(nucleophiles) provide a wide range of bis(isoxazole) derivatives in good isolated yields. Employing an elaborated method, a series of novel bis(3-EWG-isoxazoles) as the promising allosteric modulators of AMPA receptors were designed and synthesized. The effect of the compounds on the kainate-induced currents was studied in the patch clamp experiments, revealing modulator properties for several of them. The best positive modulator potency was found for dimethyl 5,5′-(ethane-1,2-diylbis(sulfanediyl))bis(isoxazole-3-carboxylate), which potentiated the kainate-induced currents in a wide concentration range (10(−12)–10(−6) M) with maximum potentiation of 77% at 10(−10) M. The results were rationalized using molecular docking and molecular dynamics simulations of modulator complexes with the dimeric ligand-binding domain of the GluA2 AMPA receptor. The predicted physicochemical, ADMET, and PAINS properties confirmed that the AMPA receptor modulators based on the bis(isoxazole) scaffold may serve as potential lead compounds for the development of neuroprotective drugs. |
format | Online Article Text |
id | pubmed-10671298 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106712982023-11-09 5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors Vasilenko, Dmitry A. Temnyakova, Nadezhda S. Dronov, Sevastian E. Radchenko, Eugene V. Grishin, Yuri K. Gabrel’yan, Alexey V. Zamoyski, Vladimir L. Grigoriev, Vladimir V. Averina, Elena B. Palyulin, Vladimir A. Int J Mol Sci Article An efficient regioselective approach to novel functionalized bis(isoxazoles) with a variety of aromatic and aliphatic linkers was elaborated, based on the heterocyclization reaction of electrophilic alkenes under the treatment with tetranitromethane-triethylamine complex affording 3-EWG-5-nitroisoxazoles. The subsequent S(N)Ar reactions of 5-nitroisoxazoles with various O,O-, N,N- and S,S-bis(nucleophiles) provide a wide range of bis(isoxazole) derivatives in good isolated yields. Employing an elaborated method, a series of novel bis(3-EWG-isoxazoles) as the promising allosteric modulators of AMPA receptors were designed and synthesized. The effect of the compounds on the kainate-induced currents was studied in the patch clamp experiments, revealing modulator properties for several of them. The best positive modulator potency was found for dimethyl 5,5′-(ethane-1,2-diylbis(sulfanediyl))bis(isoxazole-3-carboxylate), which potentiated the kainate-induced currents in a wide concentration range (10(−12)–10(−6) M) with maximum potentiation of 77% at 10(−10) M. The results were rationalized using molecular docking and molecular dynamics simulations of modulator complexes with the dimeric ligand-binding domain of the GluA2 AMPA receptor. The predicted physicochemical, ADMET, and PAINS properties confirmed that the AMPA receptor modulators based on the bis(isoxazole) scaffold may serve as potential lead compounds for the development of neuroprotective drugs. MDPI 2023-11-09 /pmc/articles/PMC10671298/ /pubmed/38003327 http://dx.doi.org/10.3390/ijms242216135 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 Vasilenko, Dmitry A. Temnyakova, Nadezhda S. Dronov, Sevastian E. Radchenko, Eugene V. Grishin, Yuri K. Gabrel’yan, Alexey V. Zamoyski, Vladimir L. Grigoriev, Vladimir V. Averina, Elena B. Palyulin, Vladimir A. 5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
title | 5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
title_full | 5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
title_fullStr | 5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
title_full_unstemmed | 5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
title_short | 5-Nitroisoxazoles in S(N)Ar Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
title_sort | 5-nitroisoxazoles in s(n)ar reactions: a novel chemo- and regioselective approach to isoxazole-based bivalent ligands of ampa receptors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671298/ https://www.ncbi.nlm.nih.gov/pubmed/38003327 http://dx.doi.org/10.3390/ijms242216135 |
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