Bioactive Phenolate Salts: Thymol Salts

Fine tuning via salt formation: The present work summarizes the synthesis and characterization of thymol-metal/ammonium salts as representative phenol-containing bioactive molecules. The solubility, thermal properties, and evaporation rate of thymol salts were studied relative to native thymol. The in vitro release of copper from Cu-thymol in water and in solution of various pH values was thoroughly studied.

Abstract

Phenolate salts of bioactive agents have been reported only scarcely. This is the first report on the formation and characterization of thymol phenolate salts as representatives of phenol-containing bioactive molecules. Thymol has been used in medicine and agriculture for decades owing to its excellent therapeutic properties. However, in light of its poor aqueous solubility, thermal instability, and especially its high chemical volatility, the utility of thymol is hampered. The present work focuses on tuning the physicochemical properties of thymol by modifying its chemical structure through salt formation. In this context, a series of metal (Na, K, Li, Cu, and Zn) and ammonium (tetrabutylammonium and choline) salts of thymol were synthesized and characterized using IR, NMR, CHN elemental analysis, and DSC analyses. The molecular formulae of thymol salts were determined based on CHN analysis and thymol quantification studies from UV-Vis spectrometric analysis. In most cases, the thymol phenolate was prepared as a 1 : 1 molar ratio with metal/ammonium ion. Only the Cu salt of thymol was isolated at a ratio of two phenolate units per copper ion. Most of the synthesized thymol salts were found to have increased thermal stability relative to thymol. The physicochemical properties such as solubility, thermal stability, and evaporation rate of thymol salts were thoroughly studied in comparison with thymol. The in vitro release studies of Cu from the copper salt of thymol is pH-dependent: rapid release of copper was observed in the lower pH release medium (100 % release at pH 1 for 12 days) and the rates of release were slower at higher pH values (5 % release at pH 2, and <1 % release at pH 4, 6, 8, and 10) over a period of about three weeks.

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