Simplified Extraction of Berberine from <i>Coscinium fenestratum</i> Combined with Semi‐Synthesis of Derivatives: In Vitro Biological Activities and In silico Insights

Abstract Berberine (BBR), a major bioactive alkaloid in Coscinium fenestratum , exhibits diverse pharmacological properties. In this study, a simplified extraction method was optimized to obtain berberine‐rich crude extracts using 75% ethanol as a solvent under Soxhlet conditions. Based on BBR, structural modifications at C8 and C13 were applied to develop BBR derivatives with enhanced properties. BBR1 , an oxo‐berberine derivative obtained by alkaline oxidation, showed moderate α ‐amylase inhibition (IC 50 = 64.21 µg/mL) but negligible pancreatic lipase and antimicrobial activity, suggesting that the introduction of a ketone moiety at C8 may compromise its interaction with lipid‐processing enzymes and antimicrobial agents. In contrast, BBR2 synthesized through propargylation at the C13 position, displayed relatively balanced activity across both antidiabetic and antimicrobial assays. BBR2 showed an α ‐amylase inhibition (IC 50 = 98.06 µg/mL) that was weaker than that of BBR; however, it did an extremely high antimicrobial efficacy compared with BBR and BBR1 , particularly against Staphylococcus aureus (IC 50 = 35.12 µg/mL, MIC = 8.0 µg/mL), Lactobacillus fermentum (IC 50 = 18.36 µg/mL, MIC = 32.0 µg/mL), and Escherichia coli (IC 50 = 35.12 µg/mL, MIC = 32.0 µg/mL). Moreover, the interaction analysis of these derivatives with the NS2B‐NS3 protease highlighted their potential as lead compounds for the development of anti‐Zika therapeutic agents.