biostudies-literatureNoce BAssociazione Italiana per la Ricerca sul CancroAteneo Sapienza Project 2020Sapienza Grandi Attrezzature Scientifiche 2021Ministero dell'Universit? e della RicercaFunda??o para a Ci?ncia e a Tecnologia6292-6311https://www.ebi.ac.uk/biostudies/studies/S-EPMC11956017biostudies-literatureUnknown68(6)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.Journal of medicinal chemistryDesign of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor.PMC11956017IG26172280982020CW39SJIG19808P2022FESRRRG120172B8E53D032022.13356.BDGA12117A8711CC9F26648IG31139Valente SNoce BRaucci AFioravanti RBinda CGottinger AFiorentino FReis JMassari MLambona CMarchese SGarofalo SMormino AMattevi ALimatola CCasteloa MBasile LMai AfalseDesign 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.2025-01-01T00:00:00Z2025 Mar2026-06-02T12:02:02.833Z2026-04-18T03:11:03.154ZS-EPMC119560174004299810.1021/acs.jmedchem.4c02644