Novel Citral-thiazolyl Hydrazine Derivatives as Promising Antifungal Agents against Phytopathogenic Fungi

To develop new antifungal agents against phytopathogenic fungi, a series of citral-thiazolyl hydrazine derivatives were designed, synthesized, and characterized by FT-IR, 1H NMR, 13C NMR, and HRMS. Antifungal activity results showed that most synthetic compounds exhibited broad-spectrum antifungal activities against six phytopathogenic fungi in vitro. Notably, compounds b and c15 exhibited remarkable antifungal activity against Colletotrichum gloeosprioides, Rhizoctonia solani, Phytophthora nicotianae var. nicotianae, Diplodia pinea, Colletotrichum acutatum, and Fusarium oxysporum f. sp. niveum, which were all superior to the positive control tricyclazole. Structure-activity relationship (SAR) studies demonstrated that introducing electron-withdrawing groups such as F on the benzene ring exhibited outstanding antifungal activities against all the tested fungi. Furthermore, compound b could effectively control rice sheath blight and showed higher curative activities against R. solani than validamycin·bacillus in vivo. In addition, the in vitro cytotoxicity results indicated that compound b possessed moderate cytotoxicity activity, and all citral-thiazolyl hydrazine derivatives exhibited lower or no cytotoxicity to the LO2 and HEK293 cell lines. In addition, the acute oral toxicity test showed that compound b had moderate toxicity (level II) with an LD50 value of 310 mg/kg bw (95% confidence limit: 175-550 mg/kg bw). Finally, a preliminary action mechanism study showed that causing obvious malformation of mycelium and increasing cell membrane permeability are two of the potential mechanisms by which compound b exerts antifungal activity. The present work indicates that some of these derivatives may serve as novel potential fungicides, and compound b is expected to be the leading structure for the development of new antifungal agents.