Isoindolinedione-Benzamide Pyridinium Derivatives for Targeting Alzheimer’s Disease

An Isoindolinedione-benzamide pyridinium derivatives were designed through a structure-based strategy and synthesized as novel multifunctional anti-Alzheimer agents. The inhibitory activities of all 17 derivatives against acetylcholinesterase and butyrylcholinesterase were evaluated. Results exhibited that compound <b>7j</b> displayed promising AChE inhibitory activity with an IC₅₀ value of 0.26 ± 0.07 μM, and compound <b>7c</b> exhibited an IC₅₀ value of 0.08 ± 0.01 μM against BChE with 132-fold better inhibitory activity in comparison with positive control. Next, the enzyme kinetics studies and detailed binding mode via molecular docking were performed for the most potent compounds. Additionally, molecular dynamics simulations were accomplished to further investigate the potent compound's interaction, orientation, and conformation over the related enzymes. The neurotoxicity of the most potent derivative was executed against SH-SY5Y, and the mRNA levels of GSK-3α and GSK-3β after treatment with <b>7c</b> on SH-SY5Y were evaluated. Results exhibited the mRNA levels of GSK-3β were decreased compared to the control group. All these results indicate that <b>7c</b> is a good starting point for developing a multifunctional anti-Alzheimer compound.