Multi-target vanillin-derived hydrazones: Cholinesterase and MAO-A inhibition, antioxidant activity and molecular modeling toward Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurological condition that predominantly affects the elderly population. Cholinesterase inhibitors (ChEIs) are effective medications for palliative and symptomatic relief in the management of AD. A series of new vanillin-based hydrazones 5(a-n) was synthesized and assessed for their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase A (MAO-A), along with their antioxidant properties. Compounds 5c and 5n were potent inhibitors of AChE and BChE, with IC50 = 0.88 & micro;M (Ki = 0.65 +/- 0.01 & micro;M) and 14.33 & micro;M (Ki = 12.30 +/- 0.50 & micro;M), respectively. In contrast, compound 5l showed significant MAO-A inhibition (IC50 = 0.16 & micro;M) and strong antioxidant metal chelating activity (IC50 = 26.98 & micro;g/ mL), surpassing the reference drug Clorgyline (IC50 = 1.98 & micro;M) and EDTA (IC50 = 59.26 & micro;g/mL), respectively. Molecular docking analysis revealed that compound 5c showed more favorable binding energies than the other synthesized derivatives across all three targets, forming key interactions within the catalytic active sites of AChE, BChE, and MAO-A. Molecular dynamics simulations (100 ns) confirmed that 5c remained stably bound within the active sites, maintaining consistent interactions with critical amino acid residues throughout the simulation period. The BChE-5c complex exhibited the highest structural stability (RMSD = 1.7 & Aring;), followed by AChE (2.23 & Aring;) and MAO-A (2.38 & Aring;), indicating minimal conformational deviation and stable protein-ligand interactions.