Design and Mechanistic Insights into α-Helical <i>p</i>-Terphenyl Guanidines as Potent Small-Molecule Antifreeze Agents

Ice formation is a critical challenge across multiple fields, from industrial applications to biological preservation. Inspired by natural antifreeze proteins, we designed and synthesized a new class of small-molecule antifreezes based on α-helical <i>p</i>-terphenyl scaffolds with guanidine side chains. These <i>p</i>-terphenyl guanidines <b>1</b>, among the smallest molecules that mimic α-helical structures, exhibit potent ice recrystallization inhibition (IRI) activity, similar to that of existing large α-helical antifreeze compounds. The most effective compound, <b>1a</b>, with four C1-carbon guanidine moieties, demonstrated a superior IRI activity of 0.46 (1 mg/mL). Using molecular dynamics simulations with density-functional theory and separate p<i>K</i>_a calculations, we elucidated the mechanisms underlying their antifreeze properties.