Cholinium-Based Ionic Liquids from Hydroxycinnamic Acids as New Promising Bioactive Agents: A Combined Experimental and Theoretical Investigation

Monica Demurtas,Mariella Nieddu,Alessandra Scano,Flaminia Cesare Marincola,Valentina Onnis,Leon De Villiers Engelbrecht,Francesca Mocci,Paolo Zucca,Antonio Rescigno,Joanna Izabela Lachowicz,Guido Ennas

doi:10.1021/acssuschemeng.1c00090

Abstract

Cholinium-based ionic liquids (Cho-ILs) are very attractive compounds for medicinal and pharmaceutical applications as bioavailability enhancers in drug formulations and active components in pharmaceutical ingredients. In this study, we synthesized six Cho-ILs from hydroxycinnamic acids (HCA) ([Cho][HCA] ILs), a group of bioactive compounds with poor water solubility. [Cho][HCA] ILs and their parent acids were evaluated for solubility, thermal stability, and antioxidant activity. Furthermore, [Cho][HCA] ILs were screened for their cytotoxicity. To rationalize the experimental antioxidant activities, density functional theory (DFT) calculations were performed. The theoretical approach allowed for identification of the most likely radical scavenging mechanisms involving HCAs and the corresponding ionic forms under the studied experimental conditions and to rationalize the observed activity differences between salts and acids. Overall, our results revealed a higher solubility and free-radical scavenging activity for [Cho][HCA] ILs than corresponding HCAs, a relatively high thermal stability (melting temperature > 100 °C) and negligible cytotoxicity activity. Furthermore, DFT calculations showed that both the hydrogen atom transfer and the sequential proton loss electron transfer mechanisms are likely to occur in aqueous and ethanolic solutions. The picture emerging from our results supports the increasingly expressed idea that [Cho][HCA]ILs are promising candidates for applications in pharmaceutical formulation.

Highlights

Ionic liquids (ILs) are organic salts with a melting point below 100 °C
All the synthesized ILs and the acidic precursors were evaluated for their solubility, thermal stability, and antioxidant activity
Compared to the corresponding parent acid, [Cho][hydroxycinnamic acids (HCA)] ILs showed notably higher solubility and lower thermal stability, TD is above 100 °C

Summary

■ INTRODUCTION

Ionic liquids (ILs) are organic salts with a melting point below 100 °C. Due to this feature, ILs are known as “molten salts.” The remarkable properties of ILs, including extremely low vapor pressure, high thermal stability, wide temperature range as liquids, and tunable physicochemical characteristics,[1−5] make them suitable as solvents and/or reagents in many areas such as organic synthesis, catalysis, biocatalysis, and biomass pretreatment. The good correlation observed between the orders of experimental antioxidant activity and the calculated BDE values suggests that in the presence of the radical DPPH, both HCAs ‐ and HCAs can react with a single-step mechanism of the HAT type. The largest differences among solvents are observed for the acids For both HCA− and HCA compounds, the calculated IP values in PCM solvent are significantly larger than the corresponding BDE values, indicating that the HAT mechanism is thermodynamically favored compared to SET− PT. It should be noted that the BDE and ETE values for ferulic, sinapic, and m-coumaric are similar, and both mechanisms seem plausible

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES