Design, Synthesis, Antifungal Evaluation, and Three-Dimensional Quantitative Structure–Activity Relationship of Novel 5-Sulfonyl-1,3,4-thiadiazole Flavonoids

Plant pathogenic fungi frequently disrupt the normal physiological and biochemical functions of plants, leading to diseases, compromising plant health, and ultimately reducing crop yield. This study aimed to address this challenge by identifying antifungal agents with innovative structures and novel mechanisms of action. We designed and synthesized a series of flavonoid derivatives substituted with 5-sulfonyl-1,3,4-thiadiazole and evaluated their antifungal activity against five phytopathogenic fungi. Most flavonoid derivatives demonstrated excellent antifungal activity against <i>Botrytis cinerea</i> (<i>B. cinerea</i>), <i>Alternaria solani</i> (<i>A. solani</i>), <i>Rhizoctorzia solani</i> (<i>R. solani</i>), <i>Fusarium graminearum</i> (<i>F. graminearum</i>), and <i>Colletotrichum orbiculare</i> (<i>C. orbiculare</i>). Specifically, the EC₅₀ values of 38 target compounds against <i>R. solani</i> were below 4 μg/mL, among which the compounds <b>C13</b> (EC₅₀ = 0.49 μg/mL), <b>C15</b> (EC₅₀ = 0.37 μg/mL), and <b>C19</b> (EC₅₀ = 0.37 μg/mL) had the most prominent antifungal activity, superior to that of the control drug carbendazim (EC₅₀ = 0.52 μg/mL). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of the cellular ultrastructures of <i>R. solani</i> mycelia and cells after treatment with the compound <b>C19</b> revealed sprawling growth of hyphae, a distorted outline of their cell walls, and reduced mitochondrial numbers. Studying the 3D-QSAR between the molecular structure and antifungal activity of 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoid derivatives could significantly improve conventional drug molecular design pathways and facilitate the development of novel antifungal leads.