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

摘要: A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer’s disease. An in vitro assay showed that some these molecules did not exhibit highly potent inhibitory activity but have various other ebselen-related pharmacological effects. Among molecules, compound 7d, one most acetylcholinesterase inhibitors (IC50 values 0.042 μM for Electrophorus electricus 0.097 human acetylcholinesterase), was found to be a strong butyrylcholinesterase = 1.586 μM), possess rapid H2O2 peroxynitrite scavenging glutathione peroxidase-like (ν0 123.5 min–1), substrate mammalian TrxR. toxicity test mice no acute at doses up 2000 mg/kg. According an blood–brain barrier model, 7d is able penetrate central nervous system.