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

Abstract

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 <i>in vitro</i>. Notably, compounds <b>b</b> and <b>c15</b> exhibited remarkable antifungal activity against <i>Colletotrichum gloeosprioides</i>, <i>Rhizoctonia solani</i>, <i>Phytophthora nicotianae</i> var. <i>nicotianae</i>, <i>Diplodia pinea</i>, <i>Colletotrichum acutatum</i>, and <i>Fusarium oxysporum</i> f. sp. <i>niveum</i>, 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>b</b> could effectively control rice sheath blight and showed higher curative activities against <i>R. solani</i> than validamycin·bacillus <i>in vivo</i>. In addition, the <i>in vitro</i> cytotoxicity results indicated that compound <b>b</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>b</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>b</b> exerts antifungal activity. The present work indicates that some of these derivatives may serve as novel potential fungicides, and compound <b>b</b> is expected to be the leading structure for the development of new antifungal agents.