Design, Synthesis, Molecular Docking and Biological Evaluation of Donepezil Analogues as Effective Anti-Alzheimer Agents.

Abstract

Discovering a cure for Alzheimer's disease remains an intricate endeavor. Acetylcholinesterase enzyme (AChE) inhibitors, such as donepezil, hold a crucial position in Alzheimer's therapy. Our present study focused on the innovative design and synthesis of new analogues of donepezil, employing a click chemistry approach. We characterized the molecular structures of these synthesized compounds through a combination of elemental analysis and various spectroscopic techniques, including FT-IR, 1H NMR, and 13C NMR methods. These substances underwent assessment to determine their ability to inhibit AChE activity. Most of the tested compounds demonstrated the capacity to effectively inhibit AChE. The in vitro experiments were utilized to determine the IC50 values for the most promising candidates, which were subsequently validated using molecular docking techniques. Interestingly, compound 15 displayed the best profile with IC50 of about IC50 = 0.392 μg/mL, in addition to its high docking score (-8.86 kcal/mol) and good in silico pharmacokinetic prediction. Therefore, 15 could be a promising compound that can be used for further development of novel drugs for Alzheimer's disease.