Discovery of New 1,2,4-Triazole/1,3,4-Oxadiazole-Decorated Quinolinones as Agrochemical Alternatives for Controlling Viral Infection by Inhibiting the Viral Replication and Self-Assembly Process

Tobacco mosaic virus (TMV), a representative plant virus, is widely known and causes severe crop losses worldwide. In order to ensure the demand for crop and food security, the exploration of novel antiviral agents with outstanding activity and unique mechanisms of action is necessary. Herein, 40 new azole-quinolinone molecules were elaborately designed and systematically evaluated for their anti-TMV activity. Notably, compound <b>A</b>_<b>21</b> had significant therapeutic activity against TMV (EC₅₀ value = 200 μg/mL), which was superior to commercial ningnanmycin (280 μg/mL). Studies on the anti-TMV mechanism showed that compound <b>A</b>_<b>21</b> could suppress the expression level of important TMV genes and affect the assembly of TMV viral particles by disrupting the self-assembly process of TMV coat protein (TMV-CP). In-depth antiviral behaviors were verified by molecular docking, fluorescence titration analysis, and TMV assembly assays, suggesting that compound <b>A</b>_<b>21</b> strongly interacted with TMV coat protein through various interactions. Overall, this promising work discloses a new paradigm for the exploitation of 2-quinolinone-based virucidal agents for hindering plant viral infection through triggering versatile antiviral behavior.