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Synthesis and in vitro evaluation of vanillin derivatives as multi-target therapeutics for the treatment of Alzheimer’s disease.

Blaikie, Laura; Kay, Graeme; Kong Thoo Lin, Paul


Laura Blaikie


A number of novel naphthalimido and phthalimido vanillin derivatives were synthesised, and evaluated as antioxidants and cholinesterase inhibitors in vitro. Antioxidant activity was assessed using DPPH, FRAP, and ORAC assays. All compounds demonstrated enhanced activity compared to the parent compound, vanillin. They also exhibited BuChE selectivity in Ellman’s assay. A lead compound, 2a(2-(3-(bis(4-hydroxy-3-methoxybenzyl)amino)propyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione), was identified and displayed strong antioxidant activity (IC50 of 16.67 µM in the DPPH assay, a 25-fold increase in activity compared to vanillin in the FRAP assay, and 9.43 TE in the ORAC assay). Furthermore, 2a exhibited potent BuChE selectivity, with an IC50 of 0.27 µM which was around 53-fold greater than the corresponding AChE inhibitory activity. Molecular modelling studies showed that molecules with bulkier groups, as in 2a, exhibited better BuChE selectivity. This work provides a promising basis for the development of multi-target hybrid compounds based on vanillin as potential AD therapeutics.


BLAIKIE, L., KAY, G. and KONG THOO LIN, P. 2020. Synthesis and in vitro evaluation of vanillin derivatives as multi-target therapeutics for the treatment of Alzheimer's disease. Bioorganic and medical chemistry letters [online], 30(21), article ID 127505. Available from:

Journal Article Type Article
Acceptance Date Aug 17, 2020
Online Publication Date Aug 19, 2020
Publication Date Nov 1, 2020
Deposit Date Aug 25, 2020
Publicly Available Date Aug 20, 2021
Journal Bioorganic and medicinal chemistry letters
Print ISSN 0960-894X
Electronic ISSN 1464-3405
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 30
Issue 21
Article Number 127505
Keywords Alzheimer’s disease; Vanillin derivatives; Antioxidant; Cholinesterase inhibitor; Binding conformation; Multi-target strategy
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