Hydroxycinnamate-based Ionic liquids as bioactive compounds: physico-chemical characterization, biological activity and NMR insights into the effects on mutated cells metabolome

Nowadays, there is a strong collaboration between the research in drug discovery and drug delivery to improve pharmacokinetic and pharmacodynamic properties of new or use-consolidated drugs. With this purpose, several approaches have been proven to be fundamental for the developing of commercial drugs which are still in use. In this context, natural compounds such as Hydroxycinnamic acids (HCAs) are gaining increasing attention in pharmaceutical research due to their well-estabilished wide ranging benefits on health. HCAs are a group of phenolic products of plant secondary metabolism widely studied for their numerous biological properties, such as antioxidant, anti-inflammatory, anti-microbial, anti-collagenase, and anti-melanogenic activity. These features have made HCAs very attractive compounds for medicinal and pharmaceutical applications. However, their low water solubility represents a major drawback for their incorporation in hydrophilic topical formulations and thus, the search for new formulations with enhanced water solubility is of high priority in current research. The conversion of drugs or bioactive molecules into ionic liquids (ILs) rapresents a strategy to improve some issues related to solubility, polymorphism and bioavalibility. Indeed, by choosing an appropriate benign counterion, it is possible to obtain biocompatible and environmentally friendly ILs. In particular, ILs containing cholinium cation combined with hydroxycinnamic acid-based anion ([Cho][HCA] ILs) are promising compounds that are themselves components in active pharmaceutical ingredients (APIs) with potential applications in the formulation of pharmaceutical and cosmetic products due to the higher water solubility and antioxidant properties compared to their acidic precursors. In the present PhD thesis, I have synthesized six new derivatives of HCAs as [Cho][HCA] ILs. Several physico-chemical and biological properties of these compounds, considered important for their potential use in the pharmaceutical field, were studied: aqueous solubility, thermal stability, anti-oxidant activity, citotoxicity. To rationalize the experimental antioxidant activities, density functional theory (DFT) calculations were performed. Furthermore, some [Cho][HCA] ILs were also tested for their activity on mushroom tyrosinase, melanine production in human MNT 1 melanome cells and their impact of the cellular metabolome. Overall, this work successfully shows that [Cho][HCA] ILs may be good candidates as an alternative to HCAs in pharmaceutical field.