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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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/2/316 |
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| Summary: | 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. |
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| ISSN: | 1420-3049 |