Design and Synthesis of Novel Small Molecule Phthalide and Thiophthalide Derivatives as Potential Antifungal Agents

Twenty-two novel small molecule phthalide and thiophthalide derivatives were synthesized via a series of chemical reactions, including acylation, nitration, reduction, hydrolysis, bromination, and sulfuration. The antifungal activity assays revealed that compounds 2e, 2f, S2, S3, S4, and S9 exhibited moderate to excellent inhibitory activity against several phytopathogenic fungi. Notably, compound S9 demonstrated the most prominent antifungal effect against six fungi, with EC₅₀ values ranging from 2.86 to 7.55 µg/mL. Specifically, its activity against Fusarium solani, Botryosphaeria dothidea, and Valsa mali surpassed that of the commercial fungicide chlorothalonil. Furthermore, compound S9 provided superior protective and curative efficacies against B. dothidea-infected apples compared to chlorothalonil. Preliminary structure-activity relationship (SAR) studies indicated that replacing the carbonyl oxygen in the n-butylphthalide with sulfur atoms facilitated enhancement of antifungal activity. This research provides a structurally simple and highly efficient candidate compound for controlling phytopathogenic fungi.