4-Chlorobenzylamine Containing Maleic Acid Derivatives: Synthesis, <i>In Silico</i> Studies, and Anti-Alzheimer’s Activity

One way to protect neurons is to protect them from oxidative damage by reducing lipid peroxidation (LPO). Therapeutic medicines that target the inflammatory response have antioxidant activities and can also block inflammatory cascade pathways and counteract cell lyses. The goal of this investigation was to see if new maleic acid derivatives could protect the brain from scopolamine-induced amnesia. To evaluate and characterize the maleic acid derivatives, spectroscopic techniques such as ¹H NMR and Fourier Transform Infrared Spectroscopy (FTIR) were used. To further evaluate the synthesized compounds, an in vitro DPPH antioxidant assay was performed, compound 2f exhibited the best antioxidant potential, and along this side, an acetylcholinesterase (ACE) inhibition assay was performed. Compounds 2a and 2f showed promising results with IC₅₀ 20.15 and 22.09 nM, respectively. Scopolamine-treated rats trigger neurodegeneration, raise the level of antioxidant enzymes, and increase oxidative stress. The elevated levels of Tumor Necrosis Factor α (TNF-α), cyclooxygenase-2 (COX-2), Jun N-terminal kinase (JNK), and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFκB), which are neuroinflammatory mediators, along with neuronal damage, were also seen. The anti-Alzheimer's activity of maleic acid derivatives was performed in these rats by performing the Y-maze test, Morris water maze (MWM) models, immunohistochemistry, and hematoxylin and eosin staining. In vivo antioxidant assays revealed that compounds 2a and 2f significantly restored enzymatic defenses and reduced lipid peroxidation, with 2a showing slightly superior activity. The maleic acid derivatives (2a and 2f) cause increased spontaneous changes in the rat behavior and the number of entries of rats in the Y-maze test. The observation from the MWM model showed a decrease in the escape latency time in the rats. Finally, the AutoDock Vina program was used to check ligand-protein interaction using COX-2, and TNF-α, JNK, NFκB, GSK-3β, and ACE were used as targets.