Design And Synthesis Multifunctional Tacrine-quinoline Hybrids With Cholinergic, Aβ-reducing, And Metal Chelating Properties For The Treatment Of Alzheimer’s Disease

Alzheimer’s disease (AD) is a kind of progressive memory and cognitive dysfunction in neurodegenerative diseases, and the disease has a great impact on people’s health. The most important anti-Alzheimer’s disease drug is still cholinesterase inhibitors from the current clinical drugs. There has four kinds of cholinesterase inhibitors for the treatment of Alzheimer’s disease in five kinds of drugs approved by the FDA. However, the pathogenesis of AD have multiple mechanisms, multi-factor and other characteristics. Because of these features make the clinical efficacy of the drug is limited, and for multifactorial disease, multi-target therapy is an effective strategy. Therefore, the development of multi-target anti-AD drug candidates become a research focus. A large number of relevant literature have been reported about multi-target anti-AD drug candidates research. But the literature of AChE and metal ions as a target is relatively few. The paper based on tacrine molecules cholinesterase inhibition activity, and 8-hydroxy(amine) quinoline was added as a molecular metal chelating groups. A series of tacrine-8-hydroxy(amine) quinoline derivatives were designed and synthesized as multi-target anti-AD drug candidates. In vitro activity tests show that the target compound has cholinesterase and Aβ self-induced polymerization inhibitory activity, and metal ion chelating ability.The method used in this paper is chemical synthesis, spectral analysis, cholinesterase inhibitors activity test in vitro. A series of tacrine-8-hydroxy(amine) quinoline derivatives were designed and synthesized as multi-target cholinesterase inhibitors that based on cholinesterase inhibitor tacrine.19 final products have been synthesized, and all of these compounds are new.The activity test results show that most of the compounds have cholinesterase inhibiting activity, and better than tacrine. Meanwhile, the compounds also have good inhibitory effect for β-amyloid protein (Aβ) self-induced polymerization, and better than the positive control curcumin. The best compound of tacrine-8-hydroxy(amine) quinoline hybrids has good inhibitory activity of acetylcholinesterase and butyrylcholinesterase, and IC50 values are 0.052μM and 0.018μM respectively, and the the highest value inhibitory activity of Aβ1-42 aggregation is 94.6% when the concentration is 20uM. Furthermore, the test of copper ion chelating properties results show that most of the the compound molecules have the ability to chelate copper ions, the ligand ratio was 2:1. The results also prove the design conception of multi-target anti-Alzheimer’s disease. The test results can show that these compounds have the potential as an anti-Alzheimer’s drug candidate.