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Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease
In this work, we designed, synthesised and biologically investigated a novel series of 14 N- and O-phosphorylated tacrine derivatives as potential anti-Alzheimer’s disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydrox...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979514/ https://www.ncbi.nlm.nih.gov/pubmed/35361039 http://dx.doi.org/10.1080/14756366.2022.2045591 |
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author | Przybyłowska, Maja Dzierzbicka, Krystyna Kowalski, Szymon Demkowicz, Sebastian Daśko, Mateusz Inkielewicz-Stepniak, Iwona |
author_facet | Przybyłowska, Maja Dzierzbicka, Krystyna Kowalski, Szymon Demkowicz, Sebastian Daśko, Mateusz Inkielewicz-Stepniak, Iwona |
author_sort | Przybyłowska, Maja |
collection | PubMed |
description | In this work, we designed, synthesised and biologically investigated a novel series of 14 N- and O-phosphorylated tacrine derivatives as potential anti-Alzheimer’s disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products 6–13 and 16–21 that were characterised by (1)H, (13 )C, (31 )P NMR and MS. The results of the docking studies revealed that the designed phosphorus hybrids, in theory can bind to AChE and BChE. All compounds exhibited significantly lower AutoDock Vina scores compared to tacrine. The inhibitory potency evaluation was performed using the Ellman’s method. The most inhibitory activity against AChE exhibited compound 8 with an IC(50) value of 6.11 nM and against BChE 13 with an IC(50) value of 1.97 nM and they were 6- and 12-fold potent than tacrine. Compound 19 showed the lack of hepatocytotoxicity in MTT assay. |
format | Online Article Text |
id | pubmed-8979514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-89795142022-04-05 Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease Przybyłowska, Maja Dzierzbicka, Krystyna Kowalski, Szymon Demkowicz, Sebastian Daśko, Mateusz Inkielewicz-Stepniak, Iwona J Enzyme Inhib Med Chem Research Paper In this work, we designed, synthesised and biologically investigated a novel series of 14 N- and O-phosphorylated tacrine derivatives as potential anti-Alzheimer’s disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products 6–13 and 16–21 that were characterised by (1)H, (13 )C, (31 )P NMR and MS. The results of the docking studies revealed that the designed phosphorus hybrids, in theory can bind to AChE and BChE. All compounds exhibited significantly lower AutoDock Vina scores compared to tacrine. The inhibitory potency evaluation was performed using the Ellman’s method. The most inhibitory activity against AChE exhibited compound 8 with an IC(50) value of 6.11 nM and against BChE 13 with an IC(50) value of 1.97 nM and they were 6- and 12-fold potent than tacrine. Compound 19 showed the lack of hepatocytotoxicity in MTT assay. Taylor & Francis 2022-03-31 /pmc/articles/PMC8979514/ /pubmed/35361039 http://dx.doi.org/10.1080/14756366.2022.2045591 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Paper Przybyłowska, Maja Dzierzbicka, Krystyna Kowalski, Szymon Demkowicz, Sebastian Daśko, Mateusz Inkielewicz-Stepniak, Iwona Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease |
title | Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease |
title_full | Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease |
title_fullStr | Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease |
title_full_unstemmed | Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease |
title_short | Design, synthesis and biological evaluation of novel N-phosphorylated and O-phosphorylated tacrine derivatives as potential drugs against Alzheimer’s disease |
title_sort | design, synthesis and biological evaluation of novel n-phosphorylated and o-phosphorylated tacrine derivatives as potential drugs against alzheimer’s disease |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979514/ https://www.ncbi.nlm.nih.gov/pubmed/35361039 http://dx.doi.org/10.1080/14756366.2022.2045591 |
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