DOI: https://doi.org/10.24959/ophcj.17.926

Synthesis and the activity assessment of adamantylcontaining thiazolium inhibitors of butyrylcholinesterase

A. D. Ocheretniuk, O. L. Kobzar, O. P. Kozachenko, V. S. Brovarets, A. I. Vovk

Abstract


Cholinesterase inhibitors can be used for treatment of neuropsychiatric symptoms and functional impairments in neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases.
Aim. To synthesize and assess the inhibitory activity of adamantyl-containing 5-substituted N-benzyl and N-phenacylthiazolium salts against butyrylcholinesterase and acetylcholinesterase.
Results and discussion. The synthesis of 3-aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts included preparation of 5-acyloxyethyl thiazole derivatives by the reaction of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole with the corresponding adamantoyl- or adamantylacetyl chlorides. The derivatives of 5-acyloxyethyl thiazole were quaternized in the reaction with benzyl or phenacyl halides. The studies in vitro have shown that the compounds synthesized inhibit butyrylcholinesterase with IC50 values in the micromolar range. Some of them exhibited selectivity over acetylcholinesterase. The molecular docking was performed for understanding the mechanisms of the enzyme-inhibitor complex formation.
Experimental part. The synthesis of the intermediate and target compounds was carried out by the classical methods. The structures of compounds were proven by NMR 1H-spectroscopy and elemental analysis. The methods of enzymatic kinetics were used for determination of the inhibitory effects of the compounds synthesized. Calculations by molecular docking were carried out using Autodock 4.2 program.
Conclusions. 3-Aroylmethyl- and 3-arylmethyl-5-(2-acyloxyethyl)-4-methylthiazolium salts with adamantylcontaining substituents in position 5 can selectively inhibit butyrylcholinesterase compared to their effect on acetylcholinesterase.


Keywords


butyrylcholinesterase; acetylcholinesterase; adamantan; inhibitor; thiazolium salt; molecular docking

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