Design and Mechanistic Insights into α-Helical p -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 p -terphenyl scaffolds with guanidine side chains. These p -terphenyl guanidines 1 , 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, 1a , 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 K a calculations, we elucidated the mechanisms underlying their antifreeze properties.