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 R1 and R2 substituents played a crucial role in modulating GSK-3β inhibitory activity. Docking studies demonstrated that all novel derivatives fit well within the active site, with Val135 and Lys85 contributing prominently to ligand stabilization. On the basis of the docking results, compound 3b was selected for behavioural testing. Compound 3b significantly ameliorated spatial learning and memory deficits in a rat model of AD. 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.