Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives
We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca<sup>+2</sup> channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/20/7652 |
| _version_ | 1797550791003734016 |
|---|---|
| author | Irene Pachón Angona Helene Martin Solene Daniel Ignacio Moraleda Alexandre Bonet Artur Wnorowski Maciej Maj Krzysztof Jozwiak Isabel Iriepa Bernard Refouvelet José Marco-Contelles Lhassane Ismaili |
| author_facet | Irene Pachón Angona Helene Martin Solene Daniel Ignacio Moraleda Alexandre Bonet Artur Wnorowski Maciej Maj Krzysztof Jozwiak Isabel Iriepa Bernard Refouvelet José Marco-Contelles Lhassane Ismaili |
| author_sort | Irene Pachón Angona |
| collection | DOAJ |
| description | We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca<sup>+2</sup> channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate <b>3a-p</b>, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL <b>3h</b> [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca<sup>+2</sup> channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H<sub>2</sub>O<sub>2,</sub> and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents. |
| first_indexed | 2024-03-10T15:34:26Z |
| format | Article |
| id | doaj.art-5b73fff50c8c4937a77a76dd85a55f53 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:34:26Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5b73fff50c8c4937a77a76dd85a55f532023-11-20T17:19:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120765210.3390/ijms21207652Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and NeuroprotectivesIrene Pachón Angona0Helene Martin1Solene Daniel2Ignacio Moraleda3Alexandre Bonet4Artur Wnorowski5Maciej Maj6Krzysztof Jozwiak7Isabel Iriepa8Bernard Refouvelet9José Marco-Contelles10Lhassane Ismaili11Neurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, FrancePEPITE EA4267, Laboratoire de Toxicologie Cellulaire, Univ. Bourgogne Franche-Comté, F-25000 Besançon, FranceNeurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, FranceDepartment of Organic Chemistry and Inorganic Chemistry, School Sciences, University of Alcalá, Ctra. Barcelona, Km. 33.6, 28871 Alcalá de Henares, SpainPEPITE EA4267, Laboratoire de Toxicologie Cellulaire, Univ. Bourgogne Franche-Comté, F-25000 Besançon, FranceDepartment of Biopharmacy, Medical University of Lublin, ul. W. Chodzki 4a, 20-093 Lublin, PolandDepartment of Biopharmacy, Medical University of Lublin, ul. W. Chodzki 4a, 20-093 Lublin, PolandDepartment of Biopharmacy, Medical University of Lublin, ul. W. Chodzki 4a, 20-093 Lublin, PolandDepartment of Organic Chemistry and Inorganic Chemistry, School Sciences, University of Alcalá, Ctra. Barcelona, Km. 33.6, 28871 Alcalá de Henares, SpainNeurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, FranceLaboratory of Medicinal Chemistry (IQOG, CSIC), Juan de la Cierva, 3, 28006-Madrid, SpainNeurosciences Intégratives et Cliniques EA 481, Pôle de Chimie Organique et Thérapeutique, Univ. Bourgogne Franche-Comté, UFR Santé, 19, rue Ambroise Paré, F-25000 Besançon, FranceWe report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca<sup>+2</sup> channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate <b>3a-p</b>, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL <b>3h</b> [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca<sup>+2</sup> channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H<sub>2</sub>O<sub>2,</sub> and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.https://www.mdpi.com/1422-0067/21/20/7652Alzheimer’s diseaseCa<sup>+2</sup> channel antagonistsHantzsch reactionmultitarget directed ligandsneuroprotectionoxidative stress |
| spellingShingle | Irene Pachón Angona Helene Martin Solene Daniel Ignacio Moraleda Alexandre Bonet Artur Wnorowski Maciej Maj Krzysztof Jozwiak Isabel Iriepa Bernard Refouvelet José Marco-Contelles Lhassane Ismaili Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives International Journal of Molecular Sciences Alzheimer’s disease Ca<sup>+2</sup> channel antagonists Hantzsch reaction multitarget directed ligands neuroprotection oxidative stress |
| title | Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives |
| title_full | Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives |
| title_fullStr | Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives |
| title_full_unstemmed | Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives |
| title_short | Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives |
| title_sort | synthesis of hantzsch adducts as cholinesterases and calcium flux inhibitors antioxidants and neuroprotectives |
| topic | Alzheimer’s disease Ca<sup>+2</sup> channel antagonists Hantzsch reaction multitarget directed ligands neuroprotection oxidative stress |
| url | https://www.mdpi.com/1422-0067/21/20/7652 |
| work_keys_str_mv | AT irenepachonangona synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT helenemartin synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT solenedaniel synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT ignaciomoraleda synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT alexandrebonet synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT arturwnorowski synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT maciejmaj synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT krzysztofjozwiak synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT isabeliriepa synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT bernardrefouvelet synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT josemarcocontelles synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives AT lhassaneismaili synthesisofhantzschadductsascholinesterasesandcalciumfluxinhibitorsantioxidantsandneuroprotectives |