engleski

Design, synthesis and characterisation of quinuclidine carbamates

To investigate a new class of potentially bioactive 3-substituted quinuclidines, a series of mono- and disubstituted aliphatic (methyl and ethyl groups) and mono-substituted aromatic (phenyl groups) quinuclidine carbamates were prepared, as well as their quaternary analogues. The structural properties of the prepared compounds were studied by FT-IR, 1D and 2D 1H and 13C NMR spectroscopy. As it is known that compounds which contain 3- substituted quinuclidinium subunits possess a wide range of biological activities in the cholinergic system, all of the prepared carbamate derivatives were screened for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase activity. All carbamates displayed a time-dependent inhibition of both cholinesterases, demonstrating the formation of a covalent bond with the active site serine. The overall inhibition rate constants, which represent the measure of carbamate inhibition potency, was in 103 M-1min-1 range, which makes all tested carbamates fast cholinesterase inhibitors. The tested carbamates were equally potent inhibitors to acetyl and butyrylcholinesterases. Also, none of the cholinesterases showed pronounced stereoselectivity for tested quinuclidine carbamate enantiomers. To explain the differences of the determined carbamylation rates of compounds, extensive docking studies and quantum chemical calculations were used to determine intermediates and transition states in the course of the carbamylation reaction. Using the calculated potential energy surfaces for all compounds, multi-way decomposition methods were used to correlate kinetic data with theoretical results. A polynomial regression model was established and validated for all compounds.

quinuclidines ; carbamate derivatives ; cholinesterases

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