Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors

<p>New coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and <i>in vitro</i> tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (<b>6c</b>, IC<sub>50</sub> value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that <b>6c</b> was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for <b>6c</b> showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound <b>6c</b> is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.</p>