Discovery of Novel Coumarin Derivatives as Potential Eco-Friendly Antivirals against Cucumber Mosaic Virus

Coumarins are widely distributed natural products with diverse biological activities. In this study, 54 novel coumarin derivatives bearing benzyl chloride and dithioacetal moieties were designed, synthesized, and evaluated for antiviral activity against cucumber mosaic virus (CMV). Several compounds exhibited superior efficacy compared to the commercial agent ningnanmycin. Notably, compound <b>E27</b> showed the strongest <i>in vivo</i> protective activity, outperforming both ningnanmycin and chitosan oligosaccharide (COS). Mechanistic studies revealed that <b>E27</b> enhanced defense-related enzyme activities, increased chlorophyll accumulation, and mitigated CMV-induced photosynthetic damage. Transcriptomic analysis demonstrated that <b>E27</b> significantly upregulated photosynthesis-related pathways, with chlorophyll <i>a</i>/<i>b</i>-binding protein (CAB) identified as a key responsive gene. Functional assays confirmed that CAB silencing reduced host resistance, whereas CAB overexpression suppressed CMV proliferation. In addition, <i>in silico</i> ADME analysis indicated favorable pharmacokinetic properties and low ecological risk. These results highlight <b>E27</b> as a promising lead for eco-friendly antiviral agrochemical development.