Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil.
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.
Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Pretoria, South Africa.
Divan G
DG
van Greunen
Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Bophelo Road, Pretoria, South Africa.
Werner
W
Cordier
Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Bophelo Road, Pretoria, South Africa.
Margo
M
Nell
Pioneering Health Sciences, CSIR Biosciences, Meiring Naudé Road, Pretoria, South Africa.
Chris
C
van der Westhuyzen
Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Bophelo Road, Pretoria, South Africa.
Vanessa
V
Steenkamp
Pioneering Health Sciences, CSIR Biosciences, Meiring Naudé Road, Pretoria, South Africa.
Jenny-Lee
JL
Panayides
Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Pretoria, South Africa. Electronic address: Darren.riley@up.ac.za.
Darren L
DL
Riley
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000077265:Donepezil; D004952:Esters / Q000737:chemistry; D006801:Humans; D007189:Indans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D004952:Esters; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase
Acetylcholinesterase; Alzheimer's disease; Cytotoxicity; Donepezil; Piperidine