Discovery of Novel Pyrazole/Thiazole Derivatives Containing Cyano/Thiocyanato Groups as Fungicide Candidates

The introduction of groups with high drug activity is an effective strategy for discovering novel succinate dehydrogenase inhibitor (SDHI) fungicides, providing insights for the future design of SDHI fungicides with higher efficacy and resistance. In this study, we designed and synthesized a series of novel pyrazole/thiazole derivatives containing cyano/thiocyanato groups and evaluated them for antifungal activity. Some of the designed compounds exhibited promising antifungal activities against tested fungi, among them, compounds B31 and B35 displayed excellent in vitro activity against Rhizoctonia solani with EC50 values of 1.83 and 1.08 μg/mL, which were in close proximity to the commercial fungicide boscalid (EC50 = 0.87 μg/mL). For Altemaria solani, compound B35 (11.14 μg/mL) showed good antifungal activity against Altemaria solani with EC50 values below boscalid (15.31 μg/mL). SAR studies further reveal that induced and conjugated interactions between B35 and the target receptor facilitate an electron transport process, contributing to its antifungal activity. In preliminary mechanistic studies, compound B35 induced the mycelium and cells of Rhizoctonia solani showed irregular abnormal state under SEM and TEM observation and caused the production and accumulation of ROS. Molecular docking results and SDH enzyme assays indicate that compound B35 has the potential to be an effective SDHI fungicide.