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 Aβ1⁻42 aggregation inhibition and antioxidant activity. The structure-activity relationship was summarized, which confirmed that the introduction of a flexible amino group featuring a N,N-dimethylaminoalkylamino moiety at the 4-position increased the Aβ1⁻42 aggregation inhibition activity, with an inhibition ratio of 95.3% at 20 μM concentration. Compound 6b₁, the optimal compound, was able to selectively chelate copper (II), and inhibit Cu2+-induced Aβ aggregation effectively. It also could disassemble the self-induced Aβ1⁻42 aggregation fibrils with a ratio of 64.3% at 20 μM concentration. Moreover, compound 6b₁ showed low toxicity and a good neuroprotective effect against Aβ1⁻42-induced toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated compound 6b₁ significantly reversed scopolamine-induced memory deficit in mice. Taken together, these results suggested that compound 6b₁ was a promising multi-target compound worthy of further study for AD.