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

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 ?-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 ?M, 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 ?molar 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 A?(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 ?M) showed significant protective effects in neuroblastoma SH-SY5Y cell line when treated with hydrogen peroxide (400 ?M). In our opinion, vanillin derivatives could provide a viable platform for future development of multi-targeted ligands against AD.

SUBMITTER: Scipioni M

PROVIDER: S-EPMC6533886 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Scipioni Matteo M Kay Graeme G Megson Ian L IL Kong Thoo Lin Paul P

MedChemComm 20190408 5

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, in ...[more]

PMID: 31191867

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Project description:A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the N1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the in vivo hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with 6 and 8 portraying IC50 values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC50: 2-5 μM). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound 6 was the most potent multifunctional agent showing better inhibitory activity than ladostigil in vitro on all enzymes tested (hMAO-A IC50 = 4.31 μM, hMAO-B IC50 = 2.62 μM, eeAChE IC50 = 3.70 μM, eqBuChE IC50 = 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound 6 to be more stable than its diethyl-carbamate containing counterpart compound 8. Compound 6 also exerted significant neuroprotection (52.62% at 1 μM) against MPP+ insult to SH-SY5Y neural cells and has good in silico predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties in vivo and the potent neuroprotective ability of compound 6 make it a promising compound for further development.

Dataset Information

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

Publications

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

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