Total Synthesis, Configuration, and Antiplasmodium Activity of Fusarihexin D and E and Analogues

Fusarihexins C-E, a group of cyclodepsipeptides that contain a characteristic 2-hydroxy-4-methyl-pentanoic acid (HICA) residue, were recently isolated from the endophytic fungus <i>Fusarium</i> sp. The absolute stereochemistry of HICA was determined to be <i>R</i> in fusarihexin C using a modified Mosher's method. It was assumed that HICA in fusarihexins D and E would have the same configuration, as they are derived from the same biological source. Herein, we report the first total synthesis of the proposed structures of fusarihexins D and E as well as three new analogues. The compounds were synthesized by employing solid phase peptide synthesis (SPPS) and high dilution macrolactamization and characterized by NMR spectroscopy and high-resolution mass spectrometry (HRMS). Comparing the ¹H and ¹³C NMR spectra of synthesized and natural compounds revealed that the HICA residue has the <i>S</i>-configuration in fusarihexin D. The antiplasmodium activity on <i>Plasmodium falciparum</i> and antitumor activity against MCF7 and A431 cells were also investigated. Encouragingly, fusarihexin D (with <i>S</i>-HICA) displayed potent antiplasmodium activity by interfering with the ring stage of the <i>Plasmodium falciparum</i> parasite life cycle (IC₅₀ at 650 nM).