Design, synthesis, and biological evaluation of benzyl pyridinium derivatives as novel AChE inhibitors with anti Alzheimer effect

Abstract

Introduction: Alzheimer's disease is the most common type of neurodegenerative disease and the most important cause of dementia in the elderly population. Aims: Alzheimer's disease is expected to be one of the leading causes of death in the world in the coming years. As a result, the design, synthesis, and biological evaluation of compounds that have anti-Alzheimer's effects would be a valuable approach. Methods: In this study, new benzyl-pyridinium derivatives were designed and synthesized, and biologically evaluated. The acetylcholinesterase inhibitory activity of the synthesized compounds was evaluated by Ellman method. The compounds capabilities to inhibit β-amyloid aggregation,exert neuroprotective effect, interact with the PAS domain of AChE , and penetrate artificial membrane were tested. Finally, some physicochemical properties of the synthesized compounds were investigated. Results: The synthesized compounds were identified by IR, 1H NMR, 13C NMR and LC-Mass spectroscopy and all were confirmed. The results of biological tests showed that all derivatives were selective for AChE and among them, compounds 7d and 7j showed the highest inhibitory effect on AChE enzyme. In addition, the 7j derivative, three times more potent than dopezil, inhibited Aβ aggregation. Also, compound 7j showed good neuroprotective activity against H2O2 induced oxidative stress. This derivative also had the highest power in displacing propidium iodide from PAS site, and showed acceptable BBB permeability. Based on docking studies, it has been shown that the orientation of the most active compounds 7d and 7j at the active site of the AChE enzyme is similar to that of donepezil. In addition, these compounds can interact simultaneously with both the catalytic (CAS) and anionic (PAS) domains of the enzyme.

Conclusion: The results obtained in this work showed that the thiazole-pyridinium structure may represent a new useful scaffold for the development of novel anti-Alzheimer agents.