Beatrice Noce, Sara Marchese, Marta Massari, Chiara Lambona, Joana Reis, Francesco Fiorentino, Alessia Raucci, Rossella Fioravanti, Mariana Castelôa, Alessandro Mormino, Stefano Garofalo, Cristina Limatola, Lorenzo Basile, Andrea Gottinger, Claudia Binda, Andrea Mattevi, Antonello Mai, and Sergio Valente
Journal of Medicinal Chemistry 2025
DOI: 10.1021/acs.jmedchem.4c02644
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.
