Synthesis and Biological Evaluation of a Series of Dithiocarbamates as New Cholinesterase Inhibitors

In the present paper, a novel series of dithiocarbamates was synthesized via the treatment of 4‐(trifluoromethyl)benzyl chloride with appropriate sodium salts of N,N‐disubstituted dithiocarbamic acids. The chemical structures of the compounds were elucidated by 1H NMR, mass spectral data, and elemen...

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Published in:Archiv der Pharmazie (Weinheim) 2013-08, Vol.346 (8), p.571-576
Main Authors: Altıntop, Mehlika D., Gurkan-Alp, A. Selen, Özkay, Yusuf, Kaplancıklı, Zafer A.
Format: Article
Language:eng ; ger
Subjects:
Acetylcholinesterase
Acetylcholinesterase - chemistry
Acetylcholinesterase - metabolism
Anticholinesterase
Butyrylcholinesterase
Butyrylcholinesterase - chemistry
Butyrylcholinesterase - metabolism
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - pharmacology
Dithiocarbamate
Drug Design
Magnetic Resonance Spectroscopy
Molecular Docking Simulation
Molecular Structure
Protein Conformation
Spectrophotometry
Structure-Activity Relationship
Thiocarbamates - chemical synthesis
Thiocarbamates - pharmacology
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Summary:In the present paper, a novel series of dithiocarbamates was synthesized via the treatment of 4‐(trifluoromethyl)benzyl chloride with appropriate sodium salts of N,N‐disubstituted dithiocarbamic acids. The chemical structures of the compounds were elucidated by 1H NMR, mass spectral data, and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The most potent AChE inhibitor was found as compound 2g (IC50 = 0.53 ± 0.001 µM) followed by compounds 2f (IC50 = 0.74 ± 0.001 µM) and 2j (IC50 = 0.89 ± 0.002 µM) when compared with donepezil (IC50 = 0.048 ± 0.001 µM). Compounds 2f and 2g were more effective than donepezil (IC50 = 7.88 ± 0.52 µM) on BuChE inhibition. Compounds 2f and 2g exhibited the inhibitory effect on BuChE with IC50 values of 1.39 ± 0.041 and 3.64 ± 0.072 µM, respectively. A series of dithiocarbamates were synthesized and evaluated for their anticholinesterase activity. The most potent acetylcholinesterase inhibitor was found as compound 2g followed by compounds 2f and 2j when compared with donepezil. Compounds 2f and 2g were also more effective than donepezil on butyrylcholinesterase inhibition. Kinetic analysis and molecular docking studies of the most active compound (2g) were also carried out.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.201300045