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Open AccessArticle

Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-Target Agents for the Treatment of Alzheimer’s Disease

School of Pharmacy, Guangdong Medical University, Dongguan 523808, Guangdong, China
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Authors to whom correspondence should be addressed.
Academic Editors: Diego Muñoz-Torrero and Michael Decker
Molecules 2018, 23(12), 3100; https://doi.org/10.3390/molecules23123100
Received: 30 October 2018 / Revised: 23 November 2018 / Accepted: 24 November 2018 / Published: 27 November 2018
(This article belongs to the Special Issue Molecules against Alzheimer II)
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. View Full-Text
Keywords: Alzheimer’s disease; 2-arylethenylquinoline derivatives; multi-target; Aβ aggregation; antioxidant; neuroprotection Alzheimer’s disease; 2-arylethenylquinoline derivatives; multi-target; Aβ aggregation; antioxidant; neuroprotection
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MDPI and ACS Style

Wang, X.-Q.; Zhao, C.-P.; Zhong, L.-C.; Zhu, D.-L.; Mai, D.-H.; Liang, M.-G.; He, M.-H. Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-Target Agents for the Treatment of Alzheimer’s Disease. Molecules 2018, 23, 3100.

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