Discovery of Novel Quinazolinone-2-carbohydrazide Derivatives as Effective Succinate Dehydrogenase Inhibitors and...

To develop potent and safe antifungal agents in agriculture, a total of 48 novel quinazolinone-2-carbohydrazide derivatives were designed and synthesized based on the pharmacophore hybridization method. The bioassay results demonstrated that many compounds exhibited powerful and broad-spectrum inhibition activities in vitro against the tested fungi. For instance, compounds E23 and F23 possessed EC₅₀ (half-maximal effective concentration) values of 0.41 and 0.47 μg/mL against Rhizoctonia solani, comparable to that of the commercial fungicide Boscalid (EC₅₀ = 0.49 μg/mL). Additionally, compound E23 also demonstrated pronounced antifungal effects against Verticillium dahliae, Alternaria solani, and Colletotrichum gloeosporioides with EC₅₀ values of 0.27, 1.15, and 0.27 μg/mL, respectively. In vivo assays on rice plants revealed that this compound at 200 μg/mL exhibited nearly equipotent curative and protective effects against R. solani, as compared with the positive controls Boscalid and Carbendazim. Moreover, compound E23 had an obvious inhibition activity against fungal succinate dehydrogenase (SDH) from R. solani with the half-maximal inhibition concentration (IC₅₀) of 11.76 μM, and the interactions between compound E23 and SDH enzyme were further confirmed by molecular docking studies. Furthermore, the presence of compound E23 also triggered obvious morphological changes of fungal mycelia and increased the conductivity and permeability of fungal cell membranes. Interestingly, the built three-dimensional quantitative structure-activity relationship (3D-QSAR) models showed that the electrostatic effect played a more important role in maintaining anti-R. solani effects of target compounds than other effects. Finally, the biosafety assessment of compound E23 demonstrated its safety toward rice and zebrafish.