Design, Synthesis, Molecular Dynamics Analysis, and Biological Evaluation of New Urea Derivatives in an Animal Model of Alzheimer Disease.

Background: Alzheimer disease (AD), first described by Alois Alzheimer more than a century ago, remains a major global health challenge. Glycogen synthase kinase-3β (GSK-3β) plays an important role in AD pathophysiology. Dysregulation of GSK-3β is associated with beta-amyloid accumulation, tau hyperphosphorylation, neurodegeneration, and cognitive impairment. Objectives: This study aimed to design and synthesize 17 arylalkyl urea derivatives as GSK-3β inhibitors and evaluate them in an animal model of AD. Methods: New arylalkyl derivatives were designed on the basis of the pharmacophores of GSK-3β inhibitors. Molecular docking and molecular dynamics simulations were used to evaluate the interactions of the designed compounds within the ATP-binding pocket of GSK-3β. The compounds were then synthesized by reacting substituted anilines with benzyl isocyanate, and their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and liquid chromatography-mass spectrometry. The radial arm water maze was used to assess the effects of a selected compound on learning and memory deficits in an intracerebroventricular streptozotocin-induced rat model of sporadic Alzheimer-like disease. Results: Structure-activity relationship analysis indicated that variations in the R Conclusions: Compound 3b emerged as a promising lead in this series, combining favorable GSK-3β binding properties with robust cognition-enhancing effects in vivo. These findings may inform therapeutic design, clinical translation, and strategic development in the evolving field of AD drug discovery.