Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment\r\nof Alzheimerâ��s disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin\r\nanalogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives\r\nwere designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from\r\nelectrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellmanâ��s method using neostigmine methylsulphate\r\nand donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with Ki values\r\nin the micromolar range. 4b was found to be the most active compound with Ki value 0.028 �± 0.002 �µM and higher selectivity for\r\nAChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational studies, in which a primary\r\nbinding was proved to occur at the active gorge site, and a secondary binding was revealed at the peripheral anionic site. Structure\r\nactivity relationships of prepared compounds were also discussed.
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