Synthesis and Evaluation of Multi-Target-Directed Ligands against Alzheimer's Disease Based on the Fusion of Donepezil and Ebselen

A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 mu M for Electrophorus electricus acetylcholinesterase and 0.097 mu M for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 mu M), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (nu(0) = 123.5 mu M min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.