Van Greunen, DGCordier, WNell, MVan der Westhuyzen, Christiaan WSteenkamp, VPanayides, Jenny-LeeRiley, DL2017-09-262017-09-262017-02Van 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.2016.10.0360223-5234doi.org/10.1016/j.ejmech.2016.10.036http://www.sciencedirect.com/science/article/pii/S0223523416308984http://hdl.handle.net/10204/9596Copyright: 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.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.enAcetylcholinesteraseAlzheimer's diseaseCytotoxicityDonepezilPiperidineArticleVan 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/10204/9596Van 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/10204/9596Van 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.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 -