Novel pyrrolidine-2,4-dione derivatives containing pharmacophores of both hydrazine and diphenyl ether as potential antifungal agents: design, synthesis, biological evaluation, and 3D-QSAR study

Abstract

In order to screen novel fungicide leads, 19 pyrrolidine-2,4-dione derivatives containing the pharmacophores of both hydrazine and diphenyl ether were designed, synthesized, and characterized by FT-IR, ¹H NMR, ¹³C NMR, and HR-MS. The obtained target compounds were evaluated for their antifungal activity against Rhizoctonia solani (Rs), Botrytis cinerea (Bc), and Fusarium graminearum (Fg). The bioassay results indicated that the majority of the target compounds exhibited striking biological activities against the above-mentioned fungi. Strikingly, target compound 4h obviously inhibited the growth of Rs in vitro with an EC₅₀ value of 0.39 μg mL⁻¹, which was better than the commercialized fungicide boscalid (2.21 μg mL⁻¹). Subsequently, 4h was further evaluated for the in vivo anti-Rs effect on rice leaves, affording a control efficiency of 45.33% at 200 μg mL⁻¹. Scanning electron microscopy (SEM) was used for observing the changes in the mycelium morphology. Numerous abnormal branches and swellings were found on the hyphae that were treated with 4h. Based on the bioassay results against Rs, a comparative molecular similarity index analysis model was formulated to further analyze the quantitative structure–activity relationship (QSAR) of the target compounds. The above 3D-QSAR analyses revealed that introducing hydrophobic 4-FPh, 4-ClPh, or 4-BrPh fragments at the R² position could considerably increase the antifungal activity against Rs.