Synthesis and Evaluation of Piceatannol Derivatives as Novel Arginase Inhibitors with Radical Scavenging Activity and Their Potential for Collagen Reduction in Dermal Fibroblasts

Abstract

High arginase activity is associated with several pathological conditions, including TGF-β-induced fibrosis, by increasing levels of the proline precursor L-ornithine, thereby promoting collagen biosynthesis and increasing oxidative stress due to nitric oxide synthase (NOS) uncoupling. The natural piceatannol has been shown to have beneficial effects on collagen deposition, fibrosis and oxidative stress. In this study, we present an in-depth structure-activity relationship study on arginase I, which resulted in the thioamide derivative 12a with dual catechol rings that displays potent inhibitory activity with IC₅₀ values of 9 μM and 55 μM for bovine and human arginase I, respectively. Quantum chemical modelling suggested that the sulphur atom in the thioamide group plays a crucial role in binding affinity by forming a stable hydrogen bond within the active site of the enzyme. In addition, compound 12a demonstrated high radical scavenging activity and effectively normalised collagen and procollagen levels at 5 μM in an in vitro cell model of a dermal fibrosis.