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Molecules 2016, 21(2), 132; doi:10.3390/molecules21020132

Graveoline Analogs Exhibiting Selective Acetylcholinesterase Inhibitory Activity as Potential Lead Compounds for the Treatment of Alzheimer’s Disease

1,†,* , 1,2,†
,
3
and
1
1
College of Pharmacy, Anhui Medical University, Hefei 230032, China
2
Department of Clinical Laboratory, Huaibei Miner’s General Hospital, Huaibei 235000, China
3
School of Pharmaceutical Sciences, Xiangnan University, Chenzhou 423000, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Michael Decker and Diego Muñoz-Torrero
Received: 11 December 2015 / Revised: 18 January 2016 / Accepted: 20 January 2016 / Published: 22 January 2016
(This article belongs to the Special Issue Molecules against Alzheimer)
View Full-Text   |   Download PDF [2471 KB, uploaded 22 January 2016]   |  

Abstract

This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (Selectivity Index from 45 to 486). When the two sites in the graveoline parent ring substituting phenyl and amino terminal had six chemical bonds (n = 3) and the terminal amino was piperidine, compound 5c showed the best activity. Furthermore, the mechanism of action and binding mode were explored by enzyme kinetic simulation, molecular docking, and thioflavin T-based fluorometric assay. Cytotoxicity assay showed that the low concentration of the analogs did not affect the viability of the neurocyte SH-SY5Y. View Full-Text
Keywords: graveoline analogs; acetylcholinesterase (AChE); butyrylcholine esterase (BuChE); structure–function relationships (SARs); mechanism graveoline analogs; acetylcholinesterase (AChE); butyrylcholine esterase (BuChE); structure–function relationships (SARs); mechanism
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Li, Z.; Mu, C.; Wang, B.; Jin, J. Graveoline Analogs Exhibiting Selective Acetylcholinesterase Inhibitory Activity as Potential Lead Compounds for the Treatment of Alzheimer’s Disease. Molecules 2016, 21, 132.

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