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.