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Design, synthesis, and evaluation of 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for Alzheimer’s disease

BACKGROUND: Alzheimer’s disease (AD) is thought to be a complex, multifactorial syndrome with many related molecular lesions contributing to its pathogenesis. Thus, multi-target-directed ligands are considered an effective way of treating AD. This study sought to evaluate 8-aminoquinoline-melatonin...

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Detalles Bibliográficos
Autores principales: Chen, Ziwei, Yu, Xuefeng, Chen, Lei, Xu, Lexing, Cai, Yu, Hou, Shanshan, Zheng, Miaodan, Liu, Fuhe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011219/
https://www.ncbi.nlm.nih.gov/pubmed/35433950
http://dx.doi.org/10.21037/atm-22-730
Descripción
Sumario:BACKGROUND: Alzheimer’s disease (AD) is thought to be a complex, multifactorial syndrome with many related molecular lesions contributing to its pathogenesis. Thus, multi-target-directed ligands are considered an effective way of treating AD. This study sought to evaluate 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for AD. METHODS: Thioflavin-T fluorescence assays were used to detect the inhibitory potency of 8-aminoquinoline-melatonin hybrids (a1–a5, b1–b5, and c1–c5) on self- and acetylcholinesterase (AChE)-induced amyloid-β (Aβ) aggregation. The AChE and butyrylcholinesterase (BuChE) inhibitory potency within the compounds was evaluated by Ellman’s assays. Methyl thiazolyl tetrazolium (MTT) assays were performed to evaluate the cytotoxicity of the compounds to C17.2 cells. MTT assay was used to detect the cell viability of HT22 cells to evaluate the antioxidant effect of the compounds. Metal chelation property was measured by ultraviolet-visible spectrophotometry. RESULTS: Compounds c3 and c5 had superior inhibitory activity against self-induced Aβ aggregation (with inhibitory rates of 41.4±2.1 and 25.5±3.2 at 10 µM, respectively) compared to the other compounds. Compounds in the carbamate group (i.e., a4, a5, b4, b5, c4, and c5) showed significant BuChE inhibitory activity and excellent selectivity over AChE. Most of the compounds exhibited low cytotoxicity in the C17.2 cells. Notably, a2, a3, b2, and b3 and series c (c1–c5) exhibited strong protective effects. Additionally, a3 and c1 specifically chelated with copper ions. CONCLUSIONS: Taking all of the promising results together, 8-aminoquinoline-melatonin hybrids can serve as lead molecules in the further development of new multi-functional anti-AD agents.