| Summary: | Dementia is a neurological condition commonly correlated with Alzheimer’s disease (AD), and it is seen with many other central nervous system (CNS) disorders. The restricted number of medications is not appropriate to offer enough relief to enhance the quality of life of patients suffering from this symptom; thus, all therapeutic choices should be carefully assessed. In this study, new thiazolylhydrazone derivatives (<b>2a</b>–<b>2l</b>) were designed and synthesized based on the cholinergic hypothesis. Their chemical structures were confirmed by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and HRMS spectrometric techniques. The ADME (absorption, distribution, metabolism, elimination) parameters of the synthesized compounds were predicted by using QikProp 4.8 software. It was concluded that all compounds presented satisfactory drug-like characteristics. Furthermore, their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro were also tested by modified the Ellman spectrophotometric method. According to the results, all compounds showed a weak inhibitory effect on BChE. On the other hand, most of the compounds (<b>2a</b>, <b>2b</b>, <b>2d</b>, <b>2e</b>, <b>2g</b>, <b>2i</b>, and <b>2j</b>) had a certain AChE inhibitory activity, and the IC<sub>50</sub> values of them were calculated as 0.063 ± 0.003, 0.056 ± 0.002, 0.147 ± 0.006, 0.040 ± 0.001, 0.031 ± 0.001, 0.028 ± 0.001, and 0.138 ± 0.005 µM, respectively. Among these derivatives, compound <b>2i</b> was found to be the most active agent in the series with an IC<sub>50</sub> value of 0.028 ± 0.001 µM, which indicated an inhibition profile at a similar rate as the reference drug, donepezil. The potential binding modes of compounds <b>2a</b>, <b>2b</b>, <b>2e</b>, <b>2g</b>, and <b>2i</b> with AChE were investigated and compared with each other by the molecular docking studies. The results showed that these compounds were strongly bound up with the AChE enzyme active site with the optimal conformations.
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