Synthesis and Evaluation of\nMulti-Target-Directed\nLigands against Alzheimer’s Disease Based on the Fusion of\nDonepezil and Ebselen

Abstract

A novel series of compounds obtained\nby fusing the cholinesterase\ninhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed\nligands against Alzheimer’s disease. An in vitro assay showed\nthat some of these molecules did not exhibit highly potent cholinesterase\ninhibitory activity but did have various other ebselen-related pharmacological\neffects. Among the molecules, compound <b>7d</b>, one of the\nmost potent acetylcholinesterase inhibitors (IC₅₀ values\nof 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase),\nwas found to be a strong butyrylcholinesterase inhibitor (IC₅₀ = 1.586 μM), to possess rapid H₂O₂ and\nperoxynitrite scavenging activity and glutathione peroxidase-like\nactivity (ν₀ = 123.5 μM min^–1), and to be a substrate of mammalian TrxR. A toxicity test in mice\nshowed no acute toxicity at doses of up to 2000 mg/kg. According to\nan in vitro blood–brain barrier model, <b>7d</b> is able\nto penetrate the central nervous system.