Fragment‐based hit‐to‐lead optimization and preliminary mechanistic investigation of fungicidal thioester derivatives

BACKGROUND Plant pathogenic fungi cause substantial crop yield losses worldwide, and chemical fungicides remain indispensable for maintaining crop productivity and food security. However, the widespread use of fungicides with similar chemical structures and modes of action has accelerated the development of cross‐resistance, highlighting the urgent need for novel fungicidal scaffolds. RESULTS A total of 48 thioester derivatives were designed and synthesized. Among them, compound B22 exhibited the highest antifungal activity against Rhizoctonia solani , with a half‐maximal effective concentration (EC 50 ) value of 0.124 μg mL −1 , showing approximately tenfold greater potency than fenfuram (EC 50 = 1.480 μg mL −1 ), although it was less active than fluxapyroxad (EC 50 = 0.041 μg mL −1 ). At 100 μg mL −1 , compound B22 also showed 79.2% protective control against rice sheath blight under greenhouse conditions. Scanning electron microscopy revealed pronounced morphological abnormalities in R . solani hyphae following B22 treatment. Integrated transcriptomic and proteomic analyses indicated substantial perturbations in energy metabolism‐related processes, while a preliminary biochemical assay showed that B22 inhibited porcine heart succinate dehydrogenase (SDH) activity. Molecular docking further suggested that B22 could be accommodated in the SDH‐binding pocket through hydrogen‐bonding and cation–π interactions. CONCLUSION Bioactivity screening and antifungal mechanism studies suggested the potential of thioester derivatives as promising candidates for the development of novel fungicidal agents.