Design, Synthesis, and Evaluation of Multitarget-Directed Resveratrol Derivatives for the Treatment of Alzheimer’s Disease

A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer’s disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced β-amyloid (Aβ) aggregation and Cu­(II)-induced Aβ_1–42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds <b>5d</b> and <b>10d</b> are potential lead compounds for AD therapy (<b>5d</b>, IC₅₀ = 7.56 μM and <b>10d</b>, IC₅₀ = 6.51 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured Aβ fibrils generated by self- and Cu­(II)-induced Aβ aggregation. Furthermore, <b>5d</b> crossed the blood–brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that <b>5d</b> is a very promising lead compound for AD

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 <b>7d</b>, one of the most potent acetylcholinesterase inhibitors (IC₅₀ values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC₅₀ = 1.586 μM), to possess rapid H₂O₂ and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν₀ = 123.5 μM 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, <b>7d</b> is able to penetrate the central nervous system

Multitarget-Directed Benzylideneindanone Derivatives: Anti-β-Amyloid (Aβ) Aggregation, Antioxidant, Metal Chelation, and Monoamine Oxidase B (MAO-B) Inhibition Properties against Alzheimer’s Disease

A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer’s disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ_1–42) aggregation (10.5–80.1%, 20 μM) and MAO-B activity (IC₅₀ of 7.5–40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75–9.37), and to function as metal chelators. In particular, compound <b>41</b> had the greatest ability to inhibit Aβ_1–42 aggregation (80.1%), and MAO-B (IC₅₀ = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu­(II)-induced Aβ_1–42 aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound <b>41</b> is an excellent multifunctional agent for the treatment of AD