Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase‑B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

We report here the first dual inhibitors of brain carbonic
anhydrases
(CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer’s
disease. Classical CA inhibitors (CAIs) such as methazolamide prevent
amyloid-β-peptide (Aβ)-induced overproduction of reactive
oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also
implicated in ROS production, cholinergic system disruption, and amyloid
plaque formation. In this work, we combined a reversible MAO-B inhibitor
of the coumarin and chromone type with benzenesulfonamide fragments
as highly effective CAIs. A hit-to-lead optimization led to a significant
set of derivatives showing potent low nanomolar inhibition of the
target brain CAs (KIs in the range of
0.1–90.0 nM) and MAO-B (IC50 in the range of 6.7–32.6
nM). Computational studies were conducted to elucidate the structure–activity
relationship and predict ADMET properties. The most effective multitarget
compounds totally prevented Aβ-related toxicity, reverted ROS
formation, and restored the mitochondrial functionality in an SH-SY5Y
cell model surpassing the efficacy of single-target drugs.