Design, synthesis, and evaluation of dual-target inhibitors for the treatment of Alzheimer's disease

Aβ 1−42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC 50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aβ 1−42 and protect nerve cells, and it can also penetrate the blood–brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl 3 -induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.