Scaffold Hopping for Pesticide Discovery: Design, Synthesis, and Biological Activity Research of Novel Raspberry Ketone Derivatives.

Plant diseases continuously threaten crop yield and quality. Given the overuse of chemical agents, developing antiviral and fungicidal agents from natural products represents a promising sustainable strategy. In this study, a series of raspberry ketone derivatives were designed, synthesized, and evaluated for their antiviral and fungicidal activities. Most compounds exhibited better antiviral activity than ribavirin; in particular, compounds 3iand 5h-5j showed significantly higher antiviral activity (EC50: 144-199 μg/mL) than ningnanmycin (EC50: 235 μg/mL) and thus emerged as novel antiviral candidates. Compound 3i was chosen for antiviral action mechanism research, which revealed that it can cause 20S coat protein (CP) polymerization, thereby affecting the assembly of TMV particles. The results of molecular docking and DFT calculations further provided a molecular basis for the observed antiviral activity. Additionally, these compounds displayed broad-spectrum fungicidal activity against six plant pathogens and met pesticide-likeness criteria in ADME predictions. This research advances the development of raspberry ketone derivatives as green pesticides.