Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease

丁酰胆碱酯酶 乙酰胆碱酯酶 β淀粉样蛋白 多奈哌齐 塔克林 体外 阿尔茨海默病 淀粉样β 体内 乙酰胆碱酯酶抑制剂 淀粉样蛋白(真菌学) 阿切
作者
Chandra Bhushan Mishra,Apra Manral,Shikha Kumari,Vikas Saini,Manisha Tiwari
出处
期刊:Bioorganic & Medicinal Chemistry [Elsevier]
卷期号:24 (16): 3829-3841 被引量:29
标识
DOI:10.1016/j.bmc.2016.06.027
摘要

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1H-indene-1,3(2H)-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27-38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC50=0.048μM: 34; 0.036μM: 38), Aβ aggregation (max% inhibition 82.2%, IC50=9.2μM: 34; max% inhibition 80.9%, IC50=10.11μM: 38) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H2O2 and Aβ induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future.
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