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 <b>9a</b> that preferentially inhibits NOX2 with an IC<sub>50</sub> of 0.155 μM, and only upon its preactivation. We found that <b>9a</b>, bearing a pargyline moiety, is also able to selectively inhibit MAOB over MAOA (465-fold) with an IC<sub>50</sub> of 0.182 μM, being the first-in-class dual NOX2/MAOB covalent inhibitor. Tested in the BV2 microglia neuroinflammation model, <b>9a</b> 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.
Authors
- Mariana Castelôa (ORCID: https://orcid.org/0000-0002-0913-3219)
- Marta Massari (ORCID: https://orcid.org/0000-0002-7731-7626)
- Joana Reis (ORCID: https://orcid.org/0000-0003-3124-4377)
- Cristina Limatola (ORCID: https://orcid.org/0000-0001-7504-8197)
- Francesco Fiorentino (ORCID: https://orcid.org/0000-0003-3550-1860)
- Antonello Mai (ORCID: https://orcid.org/0000-0001-9176-2382)
- Andrea Mattevi (ORCID: https://orcid.org/0000-0002-9523-7128)
- Stefano Garofalo (ORCID: https://orcid.org/0000-0002-5370-3506)
- Sara Marchese (ORCID: https://orcid.org/0000-0002-9722-2616)
- Alessandro Mormino (ORCID: https://orcid.org/0000-0003-1090-1569)
- Rossella Fioravanti
- Beatrice Noce
- Andrea Gottinger (ORCID: https://orcid.org/0000-0002-0859-5569)
- Claudia Binda (ORCID: https://orcid.org/0000-0003-2038-9845)
- Lorenzo Basile
- Sérgio Valente (ORCID: https://orcid.org/0000-0002-2241-607X)
- Chiara Lambona (ORCID: https://orcid.org/0000-0002-3415-4126)
- Alessia Raucci (ORCID: https://orcid.org/0000-0003-4182-4420)
Institutions
- Universidade do Porto (PT)
- University of Pavia (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02644
- Citations
- 5
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.99
Funders
- Associazione Italiana per la Ricerca sul Cancro
- Ministero dell'Università e della Ricerca
- Fundação para a Ciência e a Tecnologia