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

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

Volume: 20

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

Affiliation:

• Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans LA 70125

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.

Cite this article as:

Aliter F. Kholoud and Al-Horani A. Rami*, Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G, Medicinal Chemistry 2024; 20 () . https://dx.doi.org/10.2174/0115734064300678240408084822

DOI https://dx.doi.org/10.2174/0115734064300678240408084822	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638