Molecular hybridization of indoles and vanillins via α-hydroxyketone linking for discovering new inhibitor of PVY intercellular traffic

Potato virus Y (PVY) significantly reduces yield in economically important Solanaceae crops, while the limited availability of effective antiviral agents in the market highlights the necessity for exploring innovative antiviral lead structures. Herein, we disclose a new analogue of virucidal compounds, which are designed by molecular hybridization of natural indole and vanillin moieties. Most hybrid derivatives under bio-assay exhibit anti-PVY properties. Compound C7, in particular, shows superior inactivating effects to PVY, with a median effect concentration (EC₅₀) of 121.3 ± 4.9 μg/mL, which is significantly lower than that of controls ribavirin (EC₅₀ = 245.6 ± 10.3 μg/mL) and vanisulfane (EC₅₀ = 351.4 ± 4.8 μg/mL). The molecular docking result indicates formation of stable hydrogen-bonding between Arg²¹⁴ of PVY capsid protein (CP) and C7. Combining in vitro and in vivo assays allows Arg²¹⁴ to be identified as a functional residue modulating PVY systemic invasion in hosts. Further evidence provided by confocal microscope technique supports that C7 behaves as a potential inhibitor of virion intercellular movement. This study contributes an available lead structure for chemical blocking of viral cell-to-cell movement.