One-Step Organic Synthesis of 18β-Glycyrrhetinic Acid-Anthraquinone Ester Products: Exploration of Antibacterial Activity and Structure–Activity Relationship, Toxicity Evaluation in Zebrafish

Abstract

To combine the activity characteristics of 18β-glycyrrhetinic acid (18β-GA) and anthraquinone compounds (rhein and emodin), reduce toxicity, and explore the structure–activity relationship (SAR) of anthraquinones, 18β-GA-anthraquinone ester compounds were synthesized by one-step organic synthesis. The products were separated and purified by HPLC and characterized by NMR and EI-MS. It was finally determined as di-18β-GA-3-rhein ester (1, New), GA dimer (2, known), 18β-GA-3-emodin ester (3, known), and di-18β-GA-1-emodin ester (4, new). The MIC of three reactants and four products against Escherichia coli and Staphylococcus aureus were detected in vitro. Its developmental toxicity and cardiotoxicity were assessed using zebrafish embryos. The experimental results showed that rhein had the best antibacterial activity against Staphylococcus aureus with MIC₅₀ of 2.4 mM, and it was speculated that –COOH, –OH, and intramolecular hydrogen bonds in anthraquinone compounds would enhance the antibacterial effect, while the presence of-CH₃ might weaken the antibacterial activity. Product 1 increased the hatching rate and survival rate of zebrafish embryos and reduced the malformation rate and cardiomyocyte apoptosis. This experiment lays the foundation for further studying the SAR of anthraquinones and providing new drug candidates.