Studies on synthesis, physicochemical properties, biological activities of two novel berberine-based salts with DL-mandelate and cinnamate anions

Abstract

Berberine (BBR) is a natural quaternary isoquinoline alkaloid which is derived from the traditional Chinese medicine Coptis chinensis and exerts various pharmacological effects. However, low solubility in water has greatly limited its clinical application. This study prepared two novel berberine-based salts (berberine DL-mandelate ([BBR][MAN]) and berberine cinnamate ([BBR][CIN])) to improve the physicochemical properties and bioavailability of berberine. Many techniques, like 1H and 13C NMR, FTIR, ESI-MS, and thermogravimetric analyzes were utilized to characterize two salts. The solubility and octanol/water partition coefficient in water and simulated body fluids (simulated body, simulated intestinal and simulated gastric fluids) were determined. Self-aggregation behaviors of two salts in water have been investigated by conductometry at different temperatures. The obtained critical aggregation concentration (cac) was used for the calculation of various thermodynamic properties namely standard Gibbs energy change (ΔGm0), enthalpy change (ΔHm0), and entropy change (ΔSm0) in the aggregation progress. The volumetric properties including the infinite dilution apparent molar volumes (V2,φ0), infinite dilution apparent molar expansibility (Eφ0) and thermal expansion coefficient (β) for [BBR][MAN] were also determined to study its solvation behavior in aqueous solution. In addition, the antibacterial effect of two salts on three strains (Staphylococcus aureus, Bacillus subtilis and Candida albicans) was measured, and the minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values were obtained. The results show that [BBR][MAN] has better antibacterial effect than [BBR][CIN]. The esterase-like activity assay demonstrated a decrease in enzyme activity of BSA in presence of two berberine-based salts. Cytotoxicity evaluation shows that two salts have potent in vitro anticancer activities against B16-F10 cancer cell lines.