Etemadi_2023_Chem.Biodivers__e202300075

Indanone derivatives containing meta/para-substituted aminopropoxy benzyl/benzylidene moieties were designed based on the structures of donepezil and ebselen analogues as the cholinesterase inhibitors. The designed compounds were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were measured. Inhibitory potencies (IC50 values) for the synthesized compounds ranged from 0.12 to 11.92 microM and 0.04 to 24.36 microM against AChE and BChE, respectively. Compound 5c showed the highest AChE inhibitory potency with IC50 value of 0.12 microM, whereas the highest BChE inhibition was achieved by structure 7b (IC50= 0.04 microM). Structure-activity relationship (SAR) analysis revealed that there is no significant difference between meta and para-substituted derivatives in AChE and BChE inhibition. However, the most potent AChE inhibitor 5c belongs to meta-substituted compounds, while the most active BChE inhibitor is para-substituted derivative 7b. The order of enzyme inhibition potency based on the substituted amine group is dimethyl amine > piperidine > morpholine. Compounds containing C=C linkage are more potent AChE inhibitors than the corresponding saturated structures. Molecular docking studies indicated that 5c interacts with AChE in a very similar way to that observed experimentally for donepezil. The introduced indanone-aminopropoxy benzylidenes could be used in drug-discovery development against Alzheimer's disease.