3‑Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer’s Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo

The challenges in the current treatment landscape for
Alzheimer’s
disease (AD) underscore the urgent need for novel therapeutic strategies
targeting multiple pathological pathways. Recent studies have implicated
iron in ROS-dependent neuronal injury through ferroptosis. Additionally,
overexpression of monoamine oxidase B (MAO-B) induces oxidative stress
and decreases cognitive function. In this study, we presented the
novel dual inhibitors of ferroptosis and MAO-B for AD management,
aiming to address both the symptomatic and neurodegenerative aspects
of this disease. Compound 21d emerged as a promising
candidate, exhibiting potent and selective MAO-B inhibitory activity
(IC50 = 87.47 nM, SI > 229), as well as excellent antiferroptosis
activity through modulation of the iron metabolic pathway and GSH-GPX4
axis in vitro. Importantly, 21d normalized
cognitive and memory impairments in a 3×Tg (APP/Tau/Ps1) AD mouse
model and reduced levels of AD-related proteins, including amyloid
precursor protein and phosphorylated Tau protein, in the brains of
AD mice.