Design and Mechanistic\nInsights into α‑Helical <i>p</i>‑Terphenyl\nGuanidines as Potent Small-Molecule Antifreeze\nAgents

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