New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking
The synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). N,N′-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an in...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/14901 |
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| author | Danuta Drozdowska Dawid Maliszewski Agnieszka Wróbel Artur Ratkiewicz Michał Sienkiewicz |
| author_facet | Danuta Drozdowska Dawid Maliszewski Agnieszka Wróbel Artur Ratkiewicz Michał Sienkiewicz |
| author_sort | Danuta Drozdowska |
| collection | DOAJ |
| description | The synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). N,N′-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an inhibitory concentration of AChE IC<sub>50</sub> = 0.056 µM, while the IC<sub>50</sub> for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC<sub>50</sub> value was 9.01 µM compared to that for quercetin, with IC<sub>50</sub> = 4.89 µM. Quantitative results identified this derivative to be the most promising. Molecular modeling was performed to elucidate the potential mechanism of action of this compound. Dynamic simulations showed that new ligands only had a limited stabilizing effect on AChE, but all clearly reduced the flexibility of the enzyme. It can, therefore, be concluded that a possible mechanism of inhibition increases the stiffness and decreases the flexibility of the enzyme, which obviously impedes its proper function. An analysis of the H-bonding patterns suggests a different mechanism (from other ligands) when interacting the most active derivative with the enzyme. |
| first_indexed | 2024-03-10T21:42:36Z |
| format | Article |
| id | doaj.art-46d502cb2934493eb8f902978b459ba8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:42:36Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-46d502cb2934493eb8f902978b459ba82023-11-19T14:32:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124191490110.3390/ijms241914901New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular DockingDanuta Drozdowska0Dawid Maliszewski1Agnieszka Wróbel2Artur Ratkiewicz3Michał Sienkiewicz4Department of Organic Chemistry, Medical University of Białystok, Mickiewicza Street 2A, 15-222 Białystok, PolandDepartment of Organic Chemistry, Medical University of Białystok, Mickiewicza Street 2A, 15-222 Białystok, PolandDepartment of Organic Chemistry, Medical University of Białystok, Mickiewicza Street 2A, 15-222 Białystok, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Białystok, Ciołkowskiego 1K Street, 15-245 Białystok, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Białystok, Ciołkowskiego 1K Street, 15-245 Białystok, PolandThe synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). N,N′-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an inhibitory concentration of AChE IC<sub>50</sub> = 0.056 µM, while the IC<sub>50</sub> for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC<sub>50</sub> value was 9.01 µM compared to that for quercetin, with IC<sub>50</sub> = 4.89 µM. Quantitative results identified this derivative to be the most promising. Molecular modeling was performed to elucidate the potential mechanism of action of this compound. Dynamic simulations showed that new ligands only had a limited stabilizing effect on AChE, but all clearly reduced the flexibility of the enzyme. It can, therefore, be concluded that a possible mechanism of inhibition increases the stiffness and decreases the flexibility of the enzyme, which obviously impedes its proper function. An analysis of the H-bonding patterns suggests a different mechanism (from other ligands) when interacting the most active derivative with the enzyme.https://www.mdpi.com/1422-0067/24/19/14901Alzheimer’s diseaseAChE inhibitorsBACE1 inhibitorsbenzamidesdual inhibitors |
| spellingShingle | Danuta Drozdowska Dawid Maliszewski Agnieszka Wróbel Artur Ratkiewicz Michał Sienkiewicz New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking International Journal of Molecular Sciences Alzheimer’s disease AChE inhibitors BACE1 inhibitors benzamides dual inhibitors |
| title | New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking |
| title_full | New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking |
| title_fullStr | New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking |
| title_full_unstemmed | New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking |
| title_short | New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking |
| title_sort | new benzamides as multi targeted compounds a study on synthesis ache and bace1 inhibitory activity and molecular docking |
| topic | Alzheimer’s disease AChE inhibitors BACE1 inhibitors benzamides dual inhibitors |
| url | https://www.mdpi.com/1422-0067/24/19/14901 |
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