Gohar_2026_ACS.Omega_11_39910

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, cholinergic dysfunction, and neuroinflammation. Multitarget-directed ligands (MTDLs) are increasingly recognized as promising therapeutic approaches for such multifactorial pathological disorders. Isoxazole-5-one derivatives represent a novel scaffold with potential neuroprotective activity. In current study, the cognitive and anti-inflammatory properties of a newly synthesized isoxazole-5-one derivative, (E)-3-((benzylamino)-methyl)-4-(3,4,5-trimethoxybenzylidene) isoxazol-5-(4H)-one (M5), were evaluated using scopolamine-induced mice models of AD and biochemical analysis, respectively. Behavioral performance was assessed using the Morris Water Maze (MWM) and Y-maze paradigms. Scopolamine administration significantly impaired spatial learning, memory consolidation, and spontaneous alternation behavior, while treatment with M5 produced dose-dependent memory improvements. At the highest dose (10 mg/kg), M5 markedly reduced escape latency and enhanced target quadrant occupancy in the MWM, as well as restored alternation rates in the Y-maze (p < 0.001 vs scopolamine), with effects comparable to donepezil, a standard cholinesterase inhibitor. Biochemical analyses further demonstrated that M5 significantly reduced hippocampal levels of TNF-alpha and IL-6, while downregulating COX-2 and NF-kappaB expression, confirming its potent anti-inflammatory action. Taken together, these findings suggest that M5 ameliorates memory impairment potentially through its anti-inflammatory actions. Therefore, M5 may represent might be a promising multitarget-directed ligand for Alzheimer's disease.