Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability
Considering our previous experience in the design of new cholinesterase inhibitors, especially resveratrol analogs, in this research, the basic stilbene skeleton was used as a structural unit for new carbamates designed as potentially highly selective butyrylcholinesterase (BChE) inhibitors with exc...
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2025-01-01
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| author | Maja Sviben Ilijana Odak Danijela Barić Milena Mlakić Ottó Horváth Lajos Fodor Sunčica Roca Ivana Šagud Irena Škorić |
| author_facet | Maja Sviben Ilijana Odak Danijela Barić Milena Mlakić Ottó Horváth Lajos Fodor Sunčica Roca Ivana Šagud Irena Škorić |
| author_sort | Maja Sviben |
| collection | DOAJ |
| description | Considering our previous experience in the design of new cholinesterase inhibitors, especially resveratrol analogs, in this research, the basic stilbene skeleton was used as a structural unit for new carbamates designed as potentially highly selective butyrylcholinesterase (BChE) inhibitors with excellent absorption, distribution, metabolism, excretion and toxicity ADMET properties. The inhibitory activity of newly prepared carbamates <b>1</b>–<b>13</b> was tested toward the enzymes acetylcholinesterase (AChE) and BChE. In the tested group of compounds, the leading inhibitors were <b>1</b> and <b>7</b>, which achieved excellent selective inhibitory activity for BChE with IC<sub>50</sub> values of 0.12 ± 0.09 μM and 0.38 ± 0.01 μM, respectively. Both were much more active than the standard inhibitor galantamine against BChE. Molecular docking of the most promising inhibitor candidates, compounds <b>1</b> and <b>7</b>, revealed that stabilizing interactions between the active site residues of BChE and the ligands involve π-stacking, alkyl-π interactions, and, when the carbamate orientation allows, H-bond formation. MD analysis confirmed the stability of the obtained complexes. Some bioactive resveratrol-based carbamates displayed complex-forming capabilities with Fe<sup>3+</sup> ions as metal centers. Spectrophotometric investigation indicated that they coordinate one or two metal ions, which is in accordance with their chemical structure, offering two binding sites: an amine and a carboxylic group in the carbamate moiety. Based on the obtained in silico, experimental and computational results on biological activity in the present work, new carbamates <b>1</b> and <b>7</b> represent potential selective BChE inhibitors as new therapeutics for neurological disorders. |
| format | Article |
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| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj-art-a37252cb87f3453bafa5e84b94ac5eca2025-01-24T13:43:34ZengMDPI AGMolecules1420-30492025-01-0130231610.3390/molecules30020316Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation CapabilityMaja Sviben0Ilijana Odak1Danijela Barić2Milena Mlakić3Ottó Horváth4Lajos Fodor5Sunčica Roca6Ivana Šagud7Irena Škorić8Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Trg Marka Marulića 19, HR-10 000 Zagreb, CroatiaDepartment of Chemistry, Faculty of Science and Education, University of Mostar, Matice Hrvatske bb, 88 000 Mostar, Bosnia and HerzegovinaGroup for Computational Life Sciences, Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička Cesta 54, HR-10 000 Zagreb, CroatiaDepartment of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Trg Marka Marulića 19, HR-10 000 Zagreb, CroatiaEnvironmental and Inorganic Photochemistry Research Group, Center for Natural Sciences, Faculty of Engineering, University of Pannonia, P.O. Box 158, H-8201 Veszprém, HungaryEnvironmental and Inorganic Photochemistry Research Group, Center for Natural Sciences, Faculty of Engineering, University of Pannonia, P.O. Box 158, H-8201 Veszprém, HungaryNMR Center, Rudjer Bošković Institute, Bijenička Cesta 54, HR-10 000 Zagreb, CroatiaCroatian Agency for Medicinal Products and Medical Devices, Ksaverska Cesta 4, HR-10 000 Zagreb, CroatiaDepartment of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Trg Marka Marulića 19, HR-10 000 Zagreb, CroatiaConsidering our previous experience in the design of new cholinesterase inhibitors, especially resveratrol analogs, in this research, the basic stilbene skeleton was used as a structural unit for new carbamates designed as potentially highly selective butyrylcholinesterase (BChE) inhibitors with excellent absorption, distribution, metabolism, excretion and toxicity ADMET properties. The inhibitory activity of newly prepared carbamates <b>1</b>–<b>13</b> was tested toward the enzymes acetylcholinesterase (AChE) and BChE. In the tested group of compounds, the leading inhibitors were <b>1</b> and <b>7</b>, which achieved excellent selective inhibitory activity for BChE with IC<sub>50</sub> values of 0.12 ± 0.09 μM and 0.38 ± 0.01 μM, respectively. Both were much more active than the standard inhibitor galantamine against BChE. Molecular docking of the most promising inhibitor candidates, compounds <b>1</b> and <b>7</b>, revealed that stabilizing interactions between the active site residues of BChE and the ligands involve π-stacking, alkyl-π interactions, and, when the carbamate orientation allows, H-bond formation. MD analysis confirmed the stability of the obtained complexes. Some bioactive resveratrol-based carbamates displayed complex-forming capabilities with Fe<sup>3+</sup> ions as metal centers. Spectrophotometric investigation indicated that they coordinate one or two metal ions, which is in accordance with their chemical structure, offering two binding sites: an amine and a carboxylic group in the carbamate moiety. Based on the obtained in silico, experimental and computational results on biological activity in the present work, new carbamates <b>1</b> and <b>7</b> represent potential selective BChE inhibitors as new therapeutics for neurological disorders.https://www.mdpi.com/1420-3049/30/2/316ADMETcarbamatesbutyrylcholinesterase inhibitionbiometal complexationdockingmolecular dynamics |
| spellingShingle | Maja Sviben Ilijana Odak Danijela Barić Milena Mlakić Ottó Horváth Lajos Fodor Sunčica Roca Ivana Šagud Irena Škorić Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability Molecules ADMET carbamates butyrylcholinesterase inhibition biometal complexation docking molecular dynamics |
| title | Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability |
| title_full | Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability |
| title_fullStr | Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability |
| title_full_unstemmed | Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability |
| title_short | Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability |
| title_sort | resveratrol based carbamates as selective butyrylcholinesterase inhibitors design synthesis computational study and biometal complexation capability |
| topic | ADMET carbamates butyrylcholinesterase inhibition biometal complexation docking molecular dynamics |
| url | https://www.mdpi.com/1420-3049/30/2/316 |
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