{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Noce B"],"funding":["Associazione Italiana per la Ricerca sul Cancro","Ateneo Sapienza Project 2020","Sapienza Grandi Attrezzature Scientifiche 2021","Ministero dell&apos;Universit? e della Ricerca","Funda??o para a Ci?ncia e a Tecnologia"],"pagination":["6292-6311"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11956017"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["68(6)"],"pubmed_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 <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."],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Design of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor."],"pmcid":["PMC11956017"],"funding_grant_id":["IG26172","28098","2020CW39SJ","IG19808","P2022FESRR","RG120172B8E53D03","2022.13356.BD","GA12117A8711CC9F","26648","IG31139"],"pubmed_authors":["Valente S","Noce B","Raucci A","Fioravanti R","Binda C","Gottinger A","Fiorentino F","Reis J","Massari M","Lambona C","Marchese S","Garofalo S","Mormino A","Mattevi A","Limatola C","Casteloa M","Basile L","Mai A"],"additional_accession":[]},"is_claimable":false,"name":"Design of Benzyl-triazolopyrimidine-Based NADPH Oxidase Inhibitors Leads to the Discovery of a Potent Dual Covalent NOX2/MAOB Inhibitor.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Mar","modification":"2026-06-02T12:02:02.833Z","creation":"2026-04-18T03:11:03.154Z"},"accession":"S-EPMC11956017","cross_references":{"pubmed":["40042998"],"doi":["10.1021/acs.jmedchem.4c02644"]}}