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

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

  • J Med Chem. 2025 Mar 27;68(6):6292-6311. doi: 10.1021/acs.jmedchem.4c02644.
Beatrice Noce 1,  Sara Marchese 2,  Marta Massari 2,  Chiara Lambona 1,  Joana Reis 2,  Francesco Fiorentino 1,  Alessia Raucci 1,  Rossella Fioravanti 1,  Mariana Castelôa 3,  Alessandro Mormino 4,  Stefano Garofalo 4,  Cristina Limatola 4,  Lorenzo Basile 2,  Andrea Gottinger 2,  Claudia Binda 2,  Andrea Mattevi 2,  Antonello Mai 1,  Sergio Valente 1
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, Rome 00185, Italy.
  • 2 Department of Biology and Biotechnology Lazzaro Spallanzani, University of Pavia, Via Adolfo Ferrata 9A, Pavia 27100, Italy.
  • 3 CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, Porto 4169-007, Portugal.
  • 4 Department of Physiology and Pharmacology, Sapienza University of Rome, P.le Aldo Moro 5, Rome 00185, Italy.
PMID: 40042998 DOI: 10.1021/acs.jmedchem.4c02644
Abstract

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.

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