Synthesis and Antifungal Activity of Raspberry Ketone Ester Derivatives as Potential Fungicides.

Raspberry ketone is an aromatic phenolic natural product with a variety of bioactivities. To discover novel fungicide molecules based on raspberry ketone, a total of 25 raspberry ketone ester derivatives were synthesized, and their chemical structures were well characterized. Among them, most compounds have not been reported except for compounds 3a and 3n. Compound 3f exhibited the most significant antifungal activity against Valsa mali with the EC of 16.430 µM, indicating that its antifungal activity was 234.6 folds more potent than that of raspberry ketone (EC: 3854.401 µM). Compounds 3c and 3j displayed the broad-spectrum antifungal activity against three phytopathogenic fungi, which can be further optimized as the secondary lead compounds for the discovery of novel fungicide molecules. The structure-antifungal activity relationships indicated that acylation of the hydroxy group in the molecule of raspberry ketone could significantly improve its antifungal activity and the two methylene in the bridging chain is essential for its antifungal activity. This work will provide some reference for the development of novel fungicide candidates based on the natural product raspberry ketone.