Synthesis, bioevaluation and structure-activity relationship of podocarpamide derivatives from Zanthoxylum alkaloids (ZAs).

Natural products have become an important source for the innovation of new drugs and green pesticides due to their structural diversity and novelty. Some alkaloids of the genus Zanthoxylum with cinnamamide core usually exhibit a wide range of biological activities. The representative podocarpamide is isolated in trace amounts from the bark of Zanthoxylum podocarpum (Rutaceae). In this study, the synthetic method of podocarpamide was optimized to achieve large-scale preparation, and a series of podocarpamide derivatives were also designed and synthesized via a structure-activity relationships (SARs)-driven pharmacophore hopping strategy. Through systematic in vitro and in vivo biological evaluations, together with mechanistic studies including scanning electron microscopy (SEM), molecular docking, and DFT calculations, some podocarpamide derivatives with potential antifungal activity were discovered. Especially, compound 1f exhibited broad-spectrum antifungal effects, achieving an EC₅₀ of 9.63 μg/mL against B. cinerea and demonstrating the most potent activity against P. theae (EC₅₀ = 8.95 μg/mL). This work not only enables efficient resource utilization of natural products, but also provides a research basis for the design of structurally novel fungicidal agents derived from Zanthoxylum alkaloids.