Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease.

A novel series of donepezil based multi-functional agents "(E)-5,6-dimethoxy-2-(4-(4-substituted piperazin-1-yl)benzylidene)-2,3-dihydro-1H-inden-1-ones" have been designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compounds demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivatives are also endowed with admirable antioxidant activity. Among the entire series compounds IP-9, IP-13 and IP-15 appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicate that IP-13 and IP-15 showed better AChE inhibitory activity than the standard drug donepezil and IP-9, IP-13 as well as IP-15 exhibited better Aβ aggregation inhibitory activity than curcumin. These compounds (IP-9, IP-13 and IP-15) successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ induced toxicity in SH-SY5Y cells in a concentration dependent manner. Moreover, these derivatives did not exert any significant toxicity in neuronal SH-SY5Y cells in cytotoxicity assay. To elucidate the plausible binding mode of the compounds IP-9, IP-13 and IP-15, molecular docking studies and molecular dynamics (MD) simulation studies were also performed and the results indicate their significant interactions with the active sites of AChE as well as Aβ1-42 peptide. Thus, the present study evidently showed that IP-9, IP-13 and IP-15 are potent multi-functional agents against Alzheimer's disease and might serve as promising lead candidates for anti-Alzheimer drug development. Copyright Â