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Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G

Author(s): Kholoud F. Aliter and Rami A. Al-Horani*

Volume 20, Issue 10, 2024

Published on: 26 April, 2024

Page: [944 - 949] Pages: 6

DOI: 10.2174/0115734064300678240408084822

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Abstract

Background: Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, acute respiratory distress syndrome, and cystic fibrosis, among others.

Objective: We aim to develop a new class of CatG inhibitors and evaluate their potency and selectivity against a series of serine proteases.

Methods: We exploited chemical synthesis as well as chromogenic substrate hydrolysis assays to construct and evaluate the new inhibitors.

Results: In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin- 4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 μM. Inhibitor 2 was the most potent, with an IC50 of 0.84 ± 0.11 μM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIa, and kallikrein.

Conclusion: Thus, we propose this inhibitor as a lead molecule to guide subsequent efforts to develop clinically relevant potent and selective CatG inhibitors for use as anti-inflammatory agents.

Keywords: Cathepsin G, a serine protease, 4H-3, 1-benzoxazine-4-one, inflammation, CatG inhibitors, serine proteases, trypsin.

Graphical Abstract

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