Sviben_2025_Molecules_30_

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 1-13 was tested toward the enzymes acetylcholinesterase (AChE) and BChE. In the tested group of compounds, the leading inhibitors were 1 and 7, which achieved excellent selective inhibitory activity for BChE with IC(50) values of 0.12 +/- 0.09 microM and 0.38 +/- 0.01 microM, respectively. Both were much more active than the standard inhibitor galantamine against BChE. Molecular docking of the most promising inhibitor candidates, compounds 1 and 7, revealed that stabilizing interactions between the active site residues of BChE and the ligands involve Pi-stacking, alkyl-Pi 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(3+) 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 1 and 7 represent potential selective BChE inhibitors as new therapeutics for neurological disorders.