Synthesis and in vitro evaluation of vanillin derivatives as multi-target therapeutics for the treatment of Alzheimer's disease. Issue 21 (1st November 2020)

• Record Type: Journal Article
• Authors: Blaikie, Laura; Kay, Graeme; Kong Thoo Lin, Paul
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 21(2020)
• Publication Date: 2020-11-01
• Subjects: Alzheimer's disease -- Vanillin derivatives -- Antioxidant -- Cholinesterase inhibitor -- Binding conformation -- Multi-target strategy; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127505
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A series of naphthalimido and phthalimido vanillin derivatives were designed and synthesised using a multi-target hybrid-based strategy. Compound 2a presented strong antioxidant activity. Compound 2a exhibited potent BuChE selectivity with an IC50 of 0.27 µM. Abstract: 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.