Synthesis, Characterization, Molecular Dynamic Simulation and Neuroprotective Effects of Synthetic Isoxazolone Derivatives in Ethanol-Induced Neurodegeneration

Alcoholism and alcohol misuse are major public health concerns, and chronic alcohol consumption negatively impacts memory and can lead to neurodegeneration and neuroinflammation. Neuroinflammation is a prevalent characteristic of all neurological diseases, induced by oxidative stress and resulting in impaired neuronal function. Thus, targeting neuroinflammation and oxidative stress can be a pivotal mechanism for attenuating memory impairment. In the current study, new isoxazolone derivatives were synthesized, and their synthetic properties were characterized using proton nuclear magnetic resonance (¹H NMR) and Fourier transform infrared (FTIR) spectroscopy. The molecular simulation studies were performed on triggering receptors expressed on myeloid cells-1 (TREM-1) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3). Further, these derivatives were evaluated for neuroprotective potential in an ethanol-induced neuroinflammation model in male albino mice. Our results demonstrated ethanol-induced cognitive deficits, elevated inflammatory markers, ROS and altered endogenous antioxidant enzyme levels. At the same time, treatment with isoxazolone reversed the hyperactivated inflammatory markers, including NLRP3, and modulated the TREM-2 expression. Further, the antioxidant and anti-cholinesterase potential of these derivatives was also evaluated using in vitro assays. Our results suggested that these derivatives may help reduce neuroinflammation by acting on several stages of the inflammatory process in an ethanol-induced neurodegenerative model.