Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities

The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63–4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore,6bdcould cross the blood–brain barrier in vitro. More importantly, compared to edaravone,6bdhad stronger free-radical scavenging activity. Molecular docking studies revealed that6bdcould interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate6bdas a leading structure worthy of further investigation.Keywords:Alzheimer’s disease;Claulansine F–donepezil hybrids;AChE inhibitory activity;free-radical scavenging activity;neuroprotective effects