Novel β-Ionone Derivatives Containing Isoxazole Hydrazide Moiety: Design, Synthesis, Antifungal Activity, and Action...

In this work, a series of novel β-ionone derivatives bearing an isoxazole hydrazide moiety were designed, synthesized, and evaluated for their antifungal activities. In vitro bioassay results indicated that most of the synthesized compounds exhibited significant antifungal activity against seven tested phytopathogenic fungi. Notably, compound D28, bearing a 3,4-difluorophenyl group, showed good broad-spectrum antifungal effects against Rhizoctonia solani, Valsa mali, Gibberella zeae, Altenaria solani, Botrytis cinerea, and Colletotrichum orbiculare, with EC₅₀ (half-maximal effective concentration) values of 0.204, 0.586, 2.59, 1.87, 3.06, and 4.73 μg/mL, respectively. In vivo preventative effects of compound D28 against R. solani and V. mali revealed that it had potential as a novel antifungal agent. Mechanistic studies demonstrated that compound D28 exerted its antifungal activity against R. solani by disrupting mycelial morphology, increasing cell membrane permeability, inducing the production and accumulation of reactive oxygen species (ROS), and impairing mitochondrial function, ultimately leading to the inhibition of hyphal proliferation. Furthermore, compound D28 exhibited potent inhibitory activity against succinate dehydrogenase (SDH), with an IC₅₀ value of 5.38 μg/mL. Binding mode analysis further elucidated its binding mode with SDH, which closely resembles that of the SDHI fungicide boscalid. The above-mentioned results indicated that β-ionone derivatives containing isoxazole hydrazide moiety have the potential as novel SDH inhibitors.