Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-target Agents for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series of 4-flexible amino-2-arylethenylquinoline derivatives as multi-target agents was efficiently synthesized and evaluated for the treatment of AD. Among these synthesized derivatives, some compounds exhibited strong self-induced Aβ aggregation inhibition and antioxidant activity. The structure-activity relationship was summarized, which confirmed that the introduction of a flexible amino group featuring a ,-dimethylaminoalkylamino moiety at the 4-position increased the Aβ aggregation inhibition activity, with an inhibition ratio of 95.3% at 20 μM concentration. Compound ₁, the optimal compound, was able to selectively chelate copper (II), and inhibit Cu-induced Aβ aggregation effectively. It also could disassemble the self-induced Aβ aggregation fibrils with a ratio of 64.3% at 20 μM concentration. Moreover, compound ₁ showed low toxicity and a good neuroprotective effect against Aβ-induced toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated compound ₁ significantly reversed scopolamine-induced memory deficit in mice. Taken together, these results suggested that compound ₁ was a promising multi-target compound worthy of further study for AD.