Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia, which arises due to low levels of acetyl and butyrylcholines, an increase in oxidative stress, inflammation, metal dyshomeostasis, Aβ and tau aggregations. The currently available drugs for AD treatment can provide only symptomatic relief without interfering with pathological hallmarks of the disease. In our ongoing efforts to develop naturally inspired novel multifunctional molecules for AD, systematic SAR studies on were caried out to improve its multifunctional properties. The rigorous medicinal efforts led to the development of , which displayed a 15-fold enhancement in antioxidant properties and a 2-fold increase in the activity against AChE and BChE over . Molecular docking and dynamics studies revealed the binding sites and stability of the complex of with AChE and BChE. The PAMPA-BBB assay clearly demonstrated that can easily cross the blood-brain barrier. Interestingly, also expresses promising metal chelation activity, while was found to be devoid of this property. Further, inhibited metal-induced or self Aβ aggregation. Observing the neuroprotection ability of against HO-induced oxidative stress in the PC-12 cell line is noteworthy. Furthermore, also inhibited NLRP3 inflammasome activation and attenuated mitochondrial-induced ROS and MMP damage caused by LPS and ATP in HMC-3 cells. In addition, is able to effectively reduce mitochondrial and cellular oxidative stress in the AD model. Finally, could reverse memory impairment in the scopolamine-induced AD mice model, as evident through and studies. These findings suggest that this compound may act as a promising candidate for further improvement in the management of AD.