Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease. Metal ion dyshomeostasis and Aβ aggregation have been proposed to contribute to AD progression. Metal ions can bind to Aβ and promote Aβ aggregation, and ultimately lead to neuronal death. Bifunctional (metal chelation and Aβ interaction) compounds are showing promise against AD. In this work, eleven new 3,3'-diamino-2,2'-bipyridine derivatives 4a-4k were synthesized, and evaluated as bifunctional agents for AD treatment. In vitro Aβ aggregation inhibition assay confirmed that most of the synthesized compounds exhibited significant self-induced Aβ1-42 aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced Aβ1-42 aggregation with IC50 value of 9.4 µM, and it could selectively chelate with Cu2+ and exhibited 66.2% inhibition of Cu2+-induced Aβ1-42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against Aβ1-42 and Cu2+-treated Aβ1-42 induced cell damage. Moreover, compound 4d in high dose significantly reversed Aβ-induced memory impairment in mice.
Keywords: 2,2'-Bipyridyl derivatives; Alzheimer’s disease; Aβ aggregation; Bifunctional; Metal chelating.
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.