Network-Based Drug Optimization toward the Treatment of Parkinson’s Disease: NRF2, MAO-B, Oxidative Stress, and Chronic Neuroinflammation

Parkinson’s disease (PD), the second most common
neurodegenerative
disorder, affects around 10 million people worldwide. It is a multifactorial
disease marked by dopaminergic neuron loss with oxidative stress (OS)
and neuroinflammation as key pathological drivers. Current treatments
focus on dopamine replacement and are symptomatic, underscoring the
urgent need for disease-modifying therapies. Here, we present a novel
class of dual MAO-B inhibitors and NRF2 inducers with neuroprotective
properties in in vitro PD models. Through an optimization program,
we enhanced their MAO-B inhibitory potency, selectivity, and NRF2
induction capacity while achieving favorable pharmacokinetic profiles.
Virtual library screening identified two core derivatives, leading
to the development of compound 11, which exhibited potent
anti-inflammatory and neuroprotective activity in OS-related in vitro
models. Compound 11 also demonstrated high liver microsomal
stability and favorable pharmacokinetics in mice, making it a promising
candidate for further investigation as a potential PD therapy.