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Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil

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dc.contributor.author Van Greunen, DG
dc.contributor.author Cordier, W
dc.contributor.author Nell, M
dc.contributor.author Van der Westhuyzen, Christiaan W
dc.contributor.author Steenkamp, V
dc.contributor.author Panayides, Jenny-Lee
dc.contributor.author Riley, DL
dc.date.accessioned 2017-09-26T09:33:41Z
dc.date.available 2017-09-26T09:33:41Z
dc.date.issued 2017-02
dc.identifier.citation Van Greunen, D.G., Cordier, W., Nell, M. et al. 2017. Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil. European Journal of Medicinal Chemistry, vol. 127: 671-690. doi.org/10.1016/j.ejmech.2016.10.036 en_US
dc.identifier.issn 0223-5234
dc.identifier.uri doi.org/10.1016/j.ejmech.2016.10.036
dc.identifier.uri http://www.sciencedirect.com/science/article/pii/S0223523416308984
dc.identifier.uri http://hdl.handle.net/10204/9596
dc.description Copyright: 2016 Elsevier. Due to copyright restrictions, the attached PDF file only contains the abstract of the full text item. For access to the full text item, kindly consult the publisher's website. en_US
dc.description.abstract 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 IC(sub50) value of 0.03 ± 0.07 µM against acetylcholinesterase with no cytotoxicity observed (IC(sub50) of >100 µM, SH-SY5Y cell line). In comparison donepezil had an IC(sub50) of 0.05 ± 0.06 µM and an observed cytotoxicity IC(sub50) of 15.54 ± 1.12 µM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase. en_US
dc.language.iso en en_US
dc.publisher Elsevier en_US
dc.relation.ispartofseries Worklist;19520
dc.subject Acetylcholinesterase en_US
dc.subject Alzheimer's disease en_US
dc.subject Cytotoxicity en_US
dc.subject Donepezil en_US
dc.subject Piperidine en_US
dc.title Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil en_US
dc.type Article en_US
dc.identifier.apacitation Van Greunen, D., Cordier, W., Nell, M., Van der Westhuyzen, C. W., Steenkamp, V., Panayides, J., & Riley, D. (2017). Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil. http://hdl.handle.net/10204/9596 en_ZA
dc.identifier.chicagocitation Van Greunen, DG, W Cordier, M Nell, Christiaan W Van der Westhuyzen, V Steenkamp, Jenny-Lee Panayides, and DL Riley "Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil." (2017) http://hdl.handle.net/10204/9596 en_ZA
dc.identifier.vancouvercitation Van Greunen D, Cordier W, Nell M, Van der Westhuyzen CW, Steenkamp V, Panayides J, et al. Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil. 2017; http://hdl.handle.net/10204/9596. en_ZA
dc.identifier.ris TY - Article AU - Van Greunen, DG AU - Cordier, W AU - Nell, M AU - Van der Westhuyzen, Christiaan W AU - Steenkamp, V AU - Panayides, Jenny-Lee AU - Riley, DL AB - 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 IC(sub50) value of 0.03 ± 0.07 µM against acetylcholinesterase with no cytotoxicity observed (IC(sub50) of >100 µM, SH-SY5Y cell line). In comparison donepezil had an IC(sub50) of 0.05 ± 0.06 µM and an observed cytotoxicity IC(sub50) of 15.54 ± 1.12 µM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase. DA - 2017-02 DB - ResearchSpace DP - CSIR KW - Acetylcholinesterase KW - Alzheimer's disease KW - Cytotoxicity KW - Donepezil KW - Piperidine LK - https://researchspace.csir.co.za PY - 2017 SM - 0223-5234 T1 - Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil TI - Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil UR - http://hdl.handle.net/10204/9596 ER - en_ZA


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