Merging structural frameworks of imidazolium, pyridinium, and cholinium ionic liquids with cinnamic acid to tune solution state behavior and properties

• New hybrid ionic liquids with cinnamic acid in the cation and anion were synthesized and characterized. • The synthesized hybrid ionic liquids showed improved water solubility and higher biological activity than non-modified cinnamic acid and original ionic liquids. • The concept of active pharmaceutical ingredients conjugate with ionic liquids (API-IL) was extended to the studied system. • API-IL with a short alkyl chain existed mainly in a folded form, possibly hindering their penetration into the cell membrane. • The presence of cinnamic acid in the cation had a more significant effect on cytotoxicity than in the IL anion. Solubility in water, interactions with the solvent medium and tuning of molecular conformation in the liquid phase are the key issues to discover new biologically active molecules and to understand the mechanisms of their action. In the present article, we report synthesis, structural and biological activity studies, and computational modeling of new ionic compounds. Structural frameworks of well-known imidazolium, pyridinium and cholinium ionic liquids (ILs) were combined with naturally occurring cinnamic acid (CA), which is known to possess a wide spectrum of biological activity. Different combinations of these two structural elements (IL and Cin (cinnamic moiety)) allowed modulating the solubility, physicochemical properties and biological activity of the resulting molecules. A significant increase in the biological activity was achieved for the three studied hybrid molecules - [C 4 mim-Cin][Cl], [C 4 py–Cin][Cl], and [C 4 mim-Cin][Cin]. Multiparameter cytotoxicity mapping was performed to visualize the biological activity of the 28 studied molecules. Detailed experimental investigation and molecular dynamics simulation were performed to gain insight into the structure–activity relationship. Of note, a folding conformational change in the structure of [C n mim-Cin][Cl] hybrid molecules in solution resulted in a substantial change in chemical reactivity, with the activation energy of the hydrolysis reaction decreasing from 32.1 to 23.9 kcal/mol.