5-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> 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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/22/16135 |
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| author | Dmitry A. Vasilenko Nadezhda S. Temnyakova Sevastian E. Dronov Eugene V. Radchenko Yuri K. Grishin Alexey V. Gabrel’yan Vladimir L. Zamoyski Vladimir V. Grigoriev Elena B. Averina Vladimir A. Palyulin |
| author_facet | Dmitry A. Vasilenko Nadezhda S. Temnyakova Sevastian E. Dronov Eugene V. Radchenko Yuri K. Grishin Alexey V. Gabrel’yan Vladimir L. Zamoyski Vladimir V. Grigoriev Elena B. Averina Vladimir A. Palyulin |
| author_sort | Dmitry A. Vasilenko |
| collection | DOAJ |
| 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 <i>S<sub>N</sub>Ar</i> reactions of 5-nitroisoxazoles with various <i>O</i>,<i>O</i>-, <i>N</i>,<i>N</i>- and <i>S</i>,<i>S</i>-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<sup>−12</sup>–10<sup>−6</sup> M) with maximum potentiation of 77% at 10<sup>−10</sup> 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. |
| first_indexed | 2024-03-09T16:45:49Z |
| format | Article |
| id | doaj.art-4c62fbf241dc43be808116070224f40e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:45:49Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4c62fbf241dc43be808116070224f40e2023-11-24T14:46:09ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124221613510.3390/ijms2422161355-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA ReceptorsDmitry A. Vasilenko0Nadezhda S. Temnyakova1Sevastian E. Dronov2Eugene V. Radchenko3Yuri K. Grishin4Alexey V. Gabrel’yan5Vladimir L. Zamoyski6Vladimir V. Grigoriev7Elena B. Averina8Vladimir A. Palyulin9Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaInstitute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, 142432 Chernogolovka, Moscow Region, RussiaInstitute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, 142432 Chernogolovka, Moscow Region, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, RussiaAn 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 <i>S<sub>N</sub>Ar</i> reactions of 5-nitroisoxazoles with various <i>O</i>,<i>O</i>-, <i>N</i>,<i>N</i>- and <i>S</i>,<i>S</i>-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<sup>−12</sup>–10<sup>−6</sup> M) with maximum potentiation of 77% at 10<sup>−10</sup> 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.https://www.mdpi.com/1422-0067/24/22/16135heterocyclizationregioselectivetetranitromethaneisoxazolebivalent ligandAMPA receptor |
| spellingShingle | Dmitry A. Vasilenko Nadezhda S. Temnyakova Sevastian E. Dronov Eugene V. Radchenko Yuri K. Grishin Alexey V. Gabrel’yan Vladimir L. Zamoyski Vladimir V. Grigoriev Elena B. Averina Vladimir A. Palyulin 5-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors International Journal of Molecular Sciences heterocyclization regioselective tetranitromethane isoxazole bivalent ligand AMPA receptor |
| title | 5-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
| title_full | 5-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
| title_fullStr | 5-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
| title_full_unstemmed | 5-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
| title_short | 5-Nitroisoxazoles in <i>S<sub>N</sub>Ar</i> Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors |
| title_sort | 5 nitroisoxazoles in i s sub n sub ar i reactions a novel chemo and regioselective approach to isoxazole based bivalent ligands of ampa receptors |
| topic | heterocyclization regioselective tetranitromethane isoxazole bivalent ligand AMPA receptor |
| url | https://www.mdpi.com/1422-0067/24/22/16135 |
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