Discovery of Novel α-Methylene-γ-Butyrolactone Derivatives Containing Vanillin Moieties as Antiviral and Antifungal Agents.

On the basis of the structure of nicotlactone A (), a series of novel α-methylene-γ-butyrolactone derivatives were designed and synthesized by structure simplification and active fragment replacement strategies, and their antiviral and antifungal activities were evaluated. The bioassay studies indicated that many target compounds possessed good to excellent antiviral activity against tobacco mosaic virus (TMV) and some of these compounds exhibited specific antifungal activities against and . Compound exhibited the best anti-TMV activity (inactivation effect, 88.9%; protection effect, 65.8%; curative effect, 52.8%) at 500 mg/L, which is significantly higher than that of commercial virucides ribavirin and ningnanmycin. The inhibition effect of compound was also visualized by the inoculation test using green fluorescent protein (GFP)-labeled TMV. The preliminary antiviral mechanism of compound was investigated. Transmission electron microscopy (TEM) showed that compound could destroy the integrity of virus particles. Then, molecular docking and isothermal titration calorimetry (ITC) analysis further demonstrated that compound exhibited a strong binding affinity to the TMV coat protein with a dissociation constant () of 3.06 μM, superior to ribavirin. Thus, we deduced that compound may interfere with the self-assembly of TMV particles by binding TMV coat protein (CP). In addition, compound showed good activity against with an inhibition rate of 90.9% at 50 mg/L, which was greater than that of fluxapyroxad (59.1%) but lower than that of the commercial fungicide carbendazim (96.8%). The present study provides support for the application of these α-methylene-γ-butyrolactone derivatives as novel antiviral and antifungal agents in crop protection.