Design, Synthesis and Anti-Alzheimer's Activity of Some Hybrid Molecule of Oxymatrine Through TGF-β

This study aimed to investigate novel therapeutic approaches for Alzheimer's disease (AD) by targeting the Transforming Growth Factor-β (TGF-β) pathway using hybrid compounds derived from oxymatrine and amino acids.

AD remains a significant challenge in neurodegenerative disorders, necessitating innovative treatments that can mitigate its devastating effects. The TGF-β pathway has been implicated in AD pathogenesis, making it a promising target for therapeutic intervention.

The objective of this study was to synthesize and evaluate the anti-AD activity of hybrid molecules combining oxymatrine with different amino acids. These compounds were designed to enhance blood-brain barrier permeability and selectively modulate TGF-β signaling.

Hybrid compounds were synthesized based on molecular docking studies. Characterization of synthesized compounds was performed using thin-layer chromatography (TLC), infrared spectroscopy (IR), and nuclear magnetic resonance (NMR) spectroscopy. Anti-AD activity was assessed using an AD rat model induced by a high-cholesterol diet, employing behavioral tests (radial arm maze and Hebb's Williams maze) and biochemical assays to measure Aβ and TGF-β levels.

All hybrid molecules exhibited significant anti-AD activity, with compound 3B demonstrating the highest efficacy at a dose of 100 mg/kg. Biochemical analyses revealed modulation of Aβ and TGF-β levels, indicating the compounds' potential therapeutic effects against AD.

This study unveils a new class of hybrid compounds derived from oxymatrine and amino acids that effectively target the TGF-β pathway, offering promising therapeutic potential for AD. These compounds demonstrate neuroprotective properties, suggesting they may mitigate ADrelated pathology, including tau deposition, synaptic dysfunction, and cognitive decline.