Optimal synthesis conditions for NBF-modified 8,13-dihydroberberine derivatives

Berberine is a natural alkaloid with a broad spectrum of biological activity. Derivatives of berberine with reduced structural stability are particularly promising for pharmacological applications. However, synthesizing disubstituted berberines poses a challenging task. The order and rate of reagent addition, mixing rate and trace amounts of acids in the atmosphere affect the purity and degradation. In this study, we developed a flow synthesis of 8,13-disubstituted berberines, which are particularly difficult to obtain in the batch. The reaction was performed in a 3D printed microfluidic chip, incorporating modules for rapid reagent mixing, optical diagnostics and a delay line to regulate the overall reaction time. The microfluidic flow system allowed us to synthesize hybrid berberine derivatives with an NBF fragment at the C-13 position, resulting in up to a 30% increase in product yields compared to classical batch synthesis. These substances exhibited high antioxidant activity without toxic effects on cell cultures, thus being potential candidates for novel pharmacological agents. The microfluidic approach, coupled with UV-Vis diagnostics, is a promising tool for optimizing and screening synthesis conditions of alkaloid derivatives that are challenging to obtain using conventional methods.