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

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 [C4mim-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 [Cnmim-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. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Solubility in water, interactions with the solvent medium, and tuning of molecular conformation in the liquid phase are crucial for the discovery of new biologically active molecules and the understanding of their mechanisms. This article presents the synthesis, structural and biological activity studies, and computational modeling of new ionic compounds. Combining the structural frameworks of well-known imidazolium, pyridinium, and cholinium ionic liquids with naturally occurring cinnamic acid allows for the modulation of solubility, physicochemical properties, and biological activity. The biological activity of the resulting molecules was significantly increased, and the structure-activity relationship was investigated through cytotoxicity mapping and molecular dynamics simulation.