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Design, Synthesis and Bioactivity of New Anti-Alzheimer's Drugs Based on Vasicinone

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Tutor: JiangYuRen
School: Central South University
Course: Chemical Engineering and Technology
Keywords: vasicinone,virtual screening,Alziheimer,bioactivity
CLC: R914.5
Type: Master's thesis
Year:  2013
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Alzheimer¡¯s disease (AD) is a highly prevalent progressive neurodegenerative disease, characterized initially by selective loss of cholinergic neurons in the basal fore-brain, followed by cognitive and hehaviorol impairments that progres-sively disrupt activities of daily living, and finally resulted in institutionalization and eventually death. Acetylcholinesterase inhibitors (AChEIs) are currently used as drugs for the treatment of Alzheimer¡¯s disease. The methanol extracts of the seeds from genus peganum were found to show significant inhibitory activity to acetylcholinesterase enzyme (AChE) using an in vitro TLC-bioautogra-phic assay.Acetylcholinesterase enzyme involved several active sites which included central catalytic site and peripheral anionic site.The crystal structure of TcAChE1QTI, obtained from the Protein Data Bank, was chosen as protein acceptor, and the molecular docking as well as visual screening were carried out among the derivatives of vasicine with the respective linkage of O,=CH, CH2and NH. Such derivatives are able to interact with active sites in the TcAChE, not only central catalytic site and peripheral site favorably but also other active sites reported recently.On the basis of virtual screening, three possible synthetic route of parent structure by method of retrosynthetic analysis.eight compounds with potential bioactivity were synthesized, At the same time, H-NMR and LC-MS were conducted to ensure structure characterization of these compounds and intermediates, in which,four of them have not been seen in the literature,proved to be new kinds of compounds.The Ellman colorimetric method is adopted for synthesized compounds to test biological activity in vitro, the results show that biological activity of branched chain derived compounds higher than those derived before, Among which compounds V got the IC50As low as3.9nM, compared with the positive control galantamine which IC50is0.991¦Ì M, the bioactivity has raised more than two hundred times.
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