Recent developments in matrine as a versatile molecular scaffold in small molecule drug discovery

Matrine, a classical quinolizidine alkaloid derived from Sophora flavescens and Sophora tonkinensis (Fabaceae), exhibits diverse pharmacological activities including anti-inflammatory, antiviral, antifibrotic, and antitumor effects. However, its natural structure faces limitations to restrict its clinical applications such as poor aqueous solubility, low bioavailability, and certain toxic side effects. Recent studies had focused on structural optimization strategies to enhance physicochemical properties and improve the bioactivities. Key structural modifications involved three parts of core skeleton remodeling (e.g. C-14 oxidation, N-1 alkylation, and D-ring opened derivatives), functional group incorporation into side chains (e.g. sulfonic acid, glycosyl, and amino acid conjugates), and heterocyclic fusion-based scaffold reconstruction. These modifications significantly improved targeting capability and chemical stability with enhancing antitumor and immunomodulatory activities through the regulation of NF-κB and PI3K/AKT signaling pathways. This review summarized the latest advances (2016-2025) in matrine structural modifications and pharmacological mechanisms. The clinical translation potential and future research insights had been proposed for the future drug development of matrine derivatives.