Liquid-Phase Peptide Synthesis of Tropolone-Peptide Hybrid Antimalarials

Tropolones are non-benzenoid aromatics with broad bioactivity, yet their inherent planarity and metal-chelating properties pose challenges to a medicinal chemistry campaign. We developed a liquid-phase peptide synthesis strategy that leveraged a hydrophobic TAG carrier to streamline condensation, deprotection, and purification steps, overcoming challenges that hinder traditional solution-phase derivatization of tropolones. Among the synthesized tropolone-peptide hybrid derivatives, the lead analogue exceeded antimalarial potency of puberulic acid and artemisinin, highlighting the advantage of three-dimensional peptide hybridization.