Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease

Cumulative evidence suggests that beta-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 mu M) and potent GPx-like activity (v(0) = 183.0 mu M min(-1)). Ab production experiment indicated that 13f could reduce the secretion of A beta 1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

The selenium-containing compound 13f, based on ebselen and verubecestat, showed potential anti-Alzheimer's disease and antioxidant stress effects by reducing beta-amyloid production and alleviating oxidative stress. Furthermore, 13f also demonstrated anti-inflammatory and cytoprotective effects, making it a promising candidate for AD treatment.