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

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 Aß(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 in 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.

Novel vanillin derivatives: Synthesis, anti-oxidant, DNA and cellular protection properties.

Antioxidants have been the subject of intense research interest mainly due to their beneficial properties associated with human health and wellbeing. Phenolic molecules, such as naturally occurring Resveratrol and Vanillin, are well known for their anti-oxidant properties, providing a starting point for the development of new antioxidants. Here we report, for the first time, the synthesis of a number of new vanillin through the reductive amination reaction between vanillin and a selection of amines. All the compounds synthesised, exhibited strong antioxidant properties in DPPH, FRAP and ORAC assays, with compounds 1b and 2c being the most active. The latter also demonstrated the ability to protect plasmid DNA from oxidative damage in the presence of the radical initiator AAPH. At cellular level, neuroblastoma SH-SY5Y cells were protected from oxidative damage (H2O2, 400 µM) with both 1b and 2c. The presence of a tertiary amino group, along with the number of vanillin moieties in the molecule contribute for the antioxidant activity. Furthermore, the delocalization of the electron pair of the nitrogen and the presence of an electron donating substituent to enhance the antioxidant properties of this new class of compounds. In our opinion, vanillin derivatives 1b and 2c described in this work can provide a viable platform for the development of antioxidant based therapeutics.