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 A beta aggregation have been proposed to contribute to AD progression. Metal ions can bind to A beta and promote A beta aggregation, and ultimately lead to neuronal death. Bifunctional (metal chelation and A beta 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 A beta aggregation inhibition assay confirmed that most of the synthesized compounds exhibited significant self-induced A beta(1- 42) aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced A beta(1- 42) aggregation with -IC50 value of 9.4 mu M, and it could selectively chelate with -Cu2+ and exhibited 66.2% inhibition of -Cu2+-induced A beta 1- 42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against A beta 1- 42 and -Cu2+-treated A beta 1- 42 induced cell damage. Moreover, compound 4d in high dose significantly reversed A beta-induced memory impairment in mice.