Natural products in crop protection: thiosemicarbazone derivatives of 3‐acetyl‐ N ‐benzylindoles as antifungal agents and their mechanism of action

Abstract Background Phytopathogenic fungi can cause a direct loss in economic value of agriculture. Especially Valsa mali Miyabe et Yamada, a devastating phytopathogenic disease especially threatening global apple production, is very difficult to control and manage. To discover new potential antifungal agents, a series of thiosemicarbazone derivatives of 3‐acetyl‐ N ‐benzylindoles were prepared. Their antifungal activities were first tested against six typically phytopathogenic fungi including Curvularia lunata , Valsa mali , Alternaria alternate , Fusarium graminearum , Botrytis cinerea and Fusarium solani . Then their mechanism of action against V. mali was investigated. Results Derivatives displayed potent antifungal activity against V. mali . Notably, 3‐acetyl‐ N ‐benzylindole thiosemicarbazone (IV‐1: EC 50 : 0.59 μ g mL −1 ), whose activity was comparable to that of a commercial fungicide carbendazim (EC 50 : 0.33 μ g mL −1 ), showed greater than 98‐fold antifungal activity of the precursor indole. Moreover, compound IV‐1 displayed good protective and therapeutic effects on apple Valsa canker disease. By scanning electron microscope (SEM) and RNA‐Seq analysis, it was demonstrated that compound IV‐1 can destroy the hyphal structure and regulate the homeostasis of metabolism of V. mali via the ergosterol biosynthesis and autophagy pathways. Conclusion 3‐Acetyl‐ N ‐(un)substituted benzylindoles thiosemicarbazones (IV‐1–IV‐5) can be studied as leads for further structural modification as antifungal agents against V. mali . Particularly, these ergosterol biosynthesis and autophagy pathways can be used as target receptors for design of novel green pesticides for management of congeneric phytopathogenic fungi. © 2023 Society of Chemical Industry.