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

Abstract

Cumulative evidence suggests that β-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 μΜ) and potent GPx-like activity (ν₀ = 183.0 μM min^-1). Aβ production experiment indicated that 13f could reduce the secretion of Aβ1-40 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.

Keywords: Alzheimer’s disease; Anti-inflammatory; Antioxidant; BACE-1; Neuroprotection; Nrf2.