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Synthesis of novel vanillin derivatives: novel multi-targeted scaffold ligands against Alzheimer's disease.

Scipioni, Matteo; Kay, Graeme; Megson, Ian; Kong Thoo Lin, Paul

Authors

Matteo Scipioni

Graeme Kay

Ian Megson

Paul Kong Thoo Lin



Abstract

Alzheimer’s Disease (AD) is the most common cause of dementia worldwide, normally affecting people aged over 65. Due to the multifactorial nature of this disease, a “multi-target-directed ligands” (MTDLs) approach for the treatment of this illness has generated intense research interest in the past few years. Vanillin is a natural antioxidant and it provides a good starting point for the synthesis of new compounds with enhanced antioxidant properties, together with many biological activities, including ß-amyloid peptide aggregating and acetylcholinesterase inhibiting properties. Here we report novel vanillin derivatives, bearing a tacrine or a naphthalimido moiety. All compounds exhibited improved antioxidant properties using DPPH assay, with IC50 as low as 19.5 µM, FRAP and ORAC assays, with activities up to 1.54 and 6.4 Trolox equivalents, respectively. In addition, all compounds synthesized showed inhibitory activity toward acetylcholinesterase enzyme at µmolar concentrations using the Ellman assay. Computational docking studies of selected compounds showed interactions with both the catalytic anionic site and the peripheral anionic site of the enzyme. Furthermore, these compounds inhibited Aβ(1-42) amyloid aggregation using the fluorometric ThT assay, with compound 4 showing comparable inhibitory activity to the positive control, curcumin. At cellular level compound 4 (1 µM)showed significant protective effects of neuroblastoma SH-SY5Y cell line when treated with hydrogen peroxide (400 µM). In our opinion, vanillin derivatives could provide a viable platform for future development of multi-targeted ligands against AD.

Journal Article Type Article
Publication Date May 1, 2019
Journal MedChemComm
Print ISSN 2040-2503
Electronic ISSN 2040-2511
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 10
Issue 5
Pages 764-777
Institution Citation SCIPIONI, M., KAY, G., MEGSON, I.L. and KONG THOO LIN, P. 2019. Synthesis of novel vanillin derivatives: novel multi-targeted scaffold ligands against Alzheimer’s disease. MedChemComm [online], 10(5), pages 764-777. Available from: https://doi.org/10.1039/c9md00048h
DOI https://doi.org/10.1039/c9md00048h
Keywords Alzheimer’s disease; Synthetic antioxidants; AChE inhibitors; Multitarget-directed ligands; Vanillin derivatives