A multi-target directed ligands strategy for the treatment of Alzheimer's disease: Dimethyl fumarate plus Tranilast modified Dithiocarbate as AChE inhibitor and Nrf2 activator

Alzheimer's disease (AD) possessed intricate pathogenesis. Currently, multi-targeted drugs were considered to have the potential to against AD by simultaneously triggering molecules in functionally complementary pathways. Hence, a series of molecules based on the pharmacophoric features of Dimethyl fumarate, Tranilast, and Dithiocarbate were designed and synthesized. These compounds showed significant AChE inhibitory activity in vitro. Among them, compound 4c₂ displayed the mighty inhibitory activity to hAChE (IC₅₀ = 0.053 μM) and held the ability to cross the BBB. Kinetic study and molecular docking pointed out that 4c₂ bound well into the active sites of hAChE, forming steady and sturdy interactions with key residues in hAChE. Additionally, 4c₂ as an Nrf2 activator could promote the nuclear translocation of Nrf2 protein and induce the expressions of Nrf2-dependent Enzymes HO-1, NQO1, and GPX4. Moreover, 4c₂ rescued BV-2 cells from H₂O₂-induced injury and inhibited ROS accumulation. For the anti-neuroinflammatory potential of 4c₂, we observed that 4c₂ could lower the levels of pro-inflammatory cytokines (NO, IL-6 and TNF-α) and suppressed the expressions of iNOS and COX-2. In particular, 4c₂ was well tolerated in mice (2500 mg/kg, p.o.) and efficaciously recovered the memory impairment in a Scopolamine-induced mouse model. Overall, these results highlighted that 4c₂ was a promising multi-targeted agent for treating AD.