Design, synthesis, and evaluation of 2,2'-bipyridyl derivatives as bifunctional agents against Alzheimer's disease.

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 Aβ _1-42 aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced Aβ _1-42 aggregation with IC ₅₀ value of 9.4 µM, and it could selectively chelate with Cu ²⁺ and exhibited 66.2% inhibition of Cu ²⁺ -induced Aβ _1-42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against Aβ _1-42 and Cu ²⁺ -treated Aβ _1-42 induced cell damage. Moreover, compound 4d in high dose significantly reversed Aβ-induced memory impairment in mice.
(© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)