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

被引：0

作者：

Noce, Beatrice ^{[1
]}

Marchese, Sara ^{[2
]}

Massari, Marta ^{[2
]}

Lambona, Chiara ^{[1
]}

Reis, Joana ^{[2
]}

Fiorentino, Francesco ^{[1
]}

Raucci, Alessia ^{[1
]}

Fioravanti, Rossella ^{[1
]}

Casteloa, Mariana ^{[3
]}

Mormino, Alessandro ^{[4
]}

Garofalo, Stefano ^{[4
]}

Limatola, Cristina ^{[4
]}

Basile, Lorenzo ^{[2
]}

Gottinger, Andrea ^{[2
]}

Binda, Claudia ^{[2
]}

Mattevi, Andrea ^{[2
]}

Mai, Antonello ^{[1
]}

Valente, Sergio ^{[1
]}

机构：

[1] Sapienza Univ Rome, Dept Drug Chem & Technol, I-00185 Rome, Italy

[2] Univ Pavia, Dept Biol & Biotechnol Lazzaro Spallanzani, I-27100 Pavia, Italy

[3] Univ Porto, Fac Sci, Dept Chem & Biochem, CIQUP IMS, P-4169007 Porto, Portugal

[4] Sapienza Univ Rome, Dept Physiol & Pharmacol, I-00185 Rome, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年

关键词：

SUPEROXIDE GENERATION; RESPIRATORY BURST; NOX ENZYMES; IDENTIFICATION; ACTIVATION; DISEASE; APOCYNIN; BINDING; DOMAIN;

D O I：

10.1021/acs.jmedchem.4c02644

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M, 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 mu M, 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-1 beta, 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.

引用

页码：6292 / 6311

页数：20