Discovery of a Furoyloxy‐Oleanolic Acid Conjugate with Spermidine as a Potent Inhibitor of Influenza Viruses, Including Avian Flu

A series of 3 β ‐furoyloxy‐oleanolic acid derivatives modified at C‐28 by linear and cyclic amines was synthesized and evaluated for antiviral properties. The 3 β ‐furoyloxy‐oleanolic acid spermidine amide 2 exhibited potent inhibition of influenza viruses, with IC 50 values of 20 µM (SI 22) against A/Puerto Rico/8/1934 (H1N1) and 12 µM (SI 38) against A/Mallard/Pennsylvania/1984 (H5N2). Structure–activity relationship analysis revealed that introduction of a furoyloxy‐group at C‐3 improves selectivity, while spermidine conjugation at C‐28 confers broad‐spectrum activity with low toxicity. In contrast, substitution with cyclic amines (cyclohexylamine, N ‐methylpiperazine, morpholine) significantly reduced activity and increased cytotoxicity. Time‐of‐addition assays demonstrated that compound 2 acts at the early stage of the viral cycle by interfering with hemagglutinin (HA)‐mediated attachment. Molecular docking supported binding near the HA fusion peptide with favorable complexation energy (213 kcal/mol). These results identify the 3 β ‐furoyloxy‐oleanolic acid spermidine amide moetiy as a key pharmacophore for developing new triterpenoid‐based influenza entry inhibitors.