Synthesis, antiviral activity and mechanistic insights into cytidine derivatives

BACKGROUND Tobacco mosaic virus (TMV) is one of the most destructive plant pathogens. The modification of nucleosides is an effective method to develop anti‐TMV agents. A series of novel cytidine derivatives were designed and synthesized, and their antiviral activities against TMV were evaluated systematically. RESULTS Activity assays revealed that 5z exhibited excellent protective and curative effects, with a half‐effective concentration (EC 50 ) of 191.84 μg mL −1 , outperforming the control commercial agents ningnanmycin (240.79 μg mL −1 ) and ribavirin (622.22 μg mL −1 ). The mode of action (MoA) of 5z was thoroughly investigated through a multifaceted approach involving TMV‐GFP agrobacterium infiltration inoculation, chlorophyll content measurement, defense enzyme activity analysis and molecular docking. Mechanistic studies revealed that 5z exerts its multi‐target antiviral effects by specifically binding to the TMV coat protein (TMV‐CP), while simultaneously triggering the plant's defense enzyme system and boosting photosynthetic efficiency. CONCLUSION Structure–activity relationships (SARs) were established for the cytidine derivatives, providing guidance for the design of cytidine‐based antiviral agents. Given its potent antiviral activity and unique mechanism of action, 5z shows strong promise as a novel antiviral agent.