Isolation, synthesis and structure-activity relationships of gallotannin derivatives as cathepsin C inhibitor

Cathepsin C (CatC), a key enzyme in neutrophil serine protease activation, is a promising target for treating neutrophilic inflammatory diseases like acute lung injury, ARDS, and COVID-19. Despite its therapeutic potential, no CatC inhibitors are currently available. In this study, a series of gallotannin derivatives were isolated from the traditional Chinese medicine Rhois Galla. Among these, 1,2,3,6-tetra-O-galloyl-β-d-glucose (1) inhibited CatC with an IC₅₀ of 32.69 ± 2.95 nM. Subsequently, fifteen derivatives of 1 were synthesized and evaluated, revealing key structure-activity relationships. Compound 1 emerged as a potent and selective CatC inhibitor, while a novel synthetic derivative, 15, demonstrated dual inhibitory effects on CatC and cathepsin L. Structural features, including O-galloyl groups at positions 1, 2, and 6 of β-glucose and a hydrogen donor at position 4, were identified as favorable for CatC inhibition. These findings provide valuable insights for developing novel CatC inhibitors.