European Journal of Medicinal Chemistry p. 671 - 690 (2017)
Update date:2022-08-15
Topics:
van Greunen, Divan G.
Cordier, Werner
Nell, Margo
van der Westhuyzen, Chris
Steenkamp, Vanessa
Panayides, Jenny-Lee
Riley, Darren L.
A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer's disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer's disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50of 0.05 ± 0.06 μM and an observed cytotoxicity IC50of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.
View MoreBeijing Century Richap Chemistry Co.,Ltd
Contact:+86- 010-64455497
Address:Guannan County, Lianyungang City, Jiangsu Province, China
ShangHai Original Economy-Trade Develop Co.,Ltd.,
Contact:86-21-68552131
Address:shanghai
Shanxi Tongji Pharmaceuticals Co., Ltd.
Contact:+86-359-3024784
Address:Xikuang South Road, Ruicheng County , Shanxi
HANGZHOU TOYOND BIOTECH CO., LTD
Contact:+86-571-86965177
Address:No. 189, Fengqi East Road, Hangzhou, China
SHIJIAZHUANG HENRYTE CHEMICALS CO,.LTD
Contact:+86-311-85208698 311-80837698
Address:NO.166, yuhua west road, SHIJIAZHUANG, China
Doi:10.1016/j.tetlet.2003.09.005
(2003)Doi:10.1021/acs.orglett.6b02159
(2016)Doi:10.1021/jo00055a037
(1993)Doi:10.1016/S0223-5234(02)01370-3
(2002)Doi:10.1021/jo960017t
(1996)Doi:10.1002/jlcr.538
(2002)