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

Xiao-Qin Wang,Chu-Ping Zhao,Mei-Gui Liang,De-Ling Zhu,De-Hao Mai,Ming-Hua He,Long-Cheng Zhong

doi:10.3390/molecules23123100

Abstract

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.

Highlights

Alzheimer’s disease (AD) is a chronic and age-related neurodegenerative disorder characterized by memory loss and cognitive impairments [1,2]
Aβ peptide is produced through proteolytic cleavage of the amyloid precursor protein (APP) by α, β or γ-secretase, which can aggregate into oligomers, protofibrils, and insoluble fibrils
In order to improve Aβ aggregation inhibition properties of the compound, in this work, based on the structure-activity relationships (SAR) of our previous work, we introduced the flexible amino substituent at the 4-position of the quinoline ring, and synthesized a series of 4-flexible amino-2-arylethenylquinoline derivatives (Figure 1B), we optimized the synthesis method of the target compounds, which improved the yield and shortened the reaction time; and evaluated their biological activities, including inhibition of Aβ aggregation, antioxidative activity, metal chelating property, neuroprotection and cytotoxicity

Summary

Introduction

Alzheimer’s disease (AD) is a chronic and age-related neurodegenerative disorder characterized by memory loss and cognitive impairments [1,2]. Among these pathogenic factors of AD, Aβ production and aggregation in the brain play a crucial role in AD pathogenesis [12]. Aβ peptide is produced through proteolytic cleavage of the amyloid precursor protein (APP) by α, β or γ-secretase, which can aggregate into oligomers, protofibrils, and insoluble fibrils. These aggregates can result in the formation of senile plaques, and lead to the neuronal loss and dementia [15,16]. Aβ aggregates can produce neurotoxicity in many ways [17]

Methods

Discussion

Conclusion