Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability

Sviben, Maja; Odak, Ilijana; Barić, Danijela; Mlakić, Milena; Horváth, Ottó; Fodor, Lajos; Roca, Sunčica; Šagud, Ivana; Škorić, Irena (2025) Resveratrol-Based Carbamates as Selective Butyrylcholinesterase Inhibitors: Design, Synthesis, Computational Study and Biometal Complexation Capability. Molecules, 30 (2). ISSN 1420-3049

	PDF - Published Version - article Available under License Creative Commons Attribution. Download (8MB)
	PDF - Submitted Version - article Available under License Creative Commons Attribution. Download (2MB)

Abstract

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 IC50 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 1 and 7, 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 Fe3+ 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.

Item Type:	Article
Uncontrolled Keywords:	ADMET; carbamates; butyrylcholinesterase inhibition; biometal complexation; docking; molecular dynamics; synthesis
Subjects:	NATURAL SCIENCES
Divisions:	Division of Physical Chemistry NMR Center
Depositing User:	Ana Zečević
Date Deposited:	28 Apr 2025 06:59
URI:	http://fulir.irb.hr/id/eprint/9755
DOI:	10.3390/molecules30020316

Actions (login required)

View Item