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

Kholoud F Aliter; Rami A Al-Horani

doi:10.2174/0115734064300678240408084822

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

Med Chem. 2024 Apr 26. doi: 10.2174/0115734064300678240408084822. Online ahead of print.

Authors

Kholoud F Aliter¹, Rami A Al-Horani²

Affiliations

¹ Department of Chemistry, School of STEM, Dillard University, New Orleans, LA, 70122.
² Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans LA 70125.

PMID: 38676528
DOI: 10.2174/0115734064300678240408084822

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: 1-benzoxazine-4-one; 4H-3; Cathepsin G; a serine protease; inflammation..