Design of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor

NADPH oxidases (NOXs)
are enzymes dedicated to reactive oxygen
species (ROS) production and are implicated in cancer, neuroinflammation,
and neurodegenerative diseases. VAS2870 is a covalent inhibitor of
mainly NOX2 and NOX5. It alkylates a conserved active-site cysteine,
blocking productive substrate binding. To enhance potency and selectivity
toward NOXs, we conducted some chemical modifications, leading to
the discovery of compound 9a that preferentially inhibits
NOX2 with an IC50 of 0.155 μM, and only upon its
preactivation. We found that 9a, bearing a pargyline
moiety, is also able to selectively inhibit MAOB over MAOA (465-fold)
with an IC50 of 0.182 μM, being the first-in-class
dual NOX2/MAOB covalent inhibitor. Tested in the BV2 microglia neuroinflammation
model, 9a decreased ROS production and downregulated
proinflammatory cytokines as iNOS, IL-1β, and IL-6 expression
more efficiently than the single target inhibitors (rasagiline for
MAOB and VAS2870 for NOXs) but also, more importantly, than their
combination.