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Arch Pharm (Weinheim) ; 357(5): e2300693, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38332316

RESUMO

Aß1-42 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 (IC50 = 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 Aß1-42 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 AlCl3-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.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Peptídeos beta-Amiloides , Inibidores da Colinesterase , Desenho de Fármacos , Peixe-Zebra , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Relação Estrutura-Atividade , Acetilcolinesterase/metabolismo , Humanos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Donepezila/farmacologia , Donepezila/síntese química , Donepezila/química , Barreira Hematoencefálica/metabolismo , Estrutura Molecular , Flavanonas/farmacologia , Flavanonas/síntese química , Flavanonas/química , Relação Dose-Resposta a Droga , Comportamento Animal/efeitos dos fármacos
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