Design, Creation, and Biological Screening of Newer Coumarin-Coupled Heterocyclic Hybrids as Acetylcholinesterase Inhibitors that may be Useful in the Treatment of Alzheimer's Disease

A group of 7-hydroxycoumarin derivatives was designed and synthesised as novel acetylcholinesterase (AChE) inhibitors that may be useful in the treatment of Alzheimer's disease. Among the 15 coumarin-derived compounds tested against human acetylcholinesterase (hAChE), 7-(2-(9H-carbazol-9-yl)-2-oxoethoxy)-2H-chromen-2-one (compound 4d) had the greatest AChE inhibitory effect (IC50 1.322 +/- 0.014 mM), according to docking studies of the most potent compound 4d extended to the PAS of hAChE. The ligand was stalked by establishing a polar pi-pi interaction between the carbazole moiety and Tyr 331A of the CAS site in the receptor. In the CAS, molecule 4d also created an interaction with Phe 327 A and Phe 328 A. Ahydrophobic pi-pi stacking was formed between the phenyl ring of the coumarin moiety and Trp 81A of the receptor in the acyl binding pocket of the receptor. As seen in compound 4d, one intriguing property of AChE inhibitors is their capacity to form interactions with both sites of the enzyme.