Discovery of Novel Pyrazole-4-carboxamide Derivatives with Thioether Moiety as Potential SDHI Agents for Crop...

In the ongoing search for more potent succinate dehydrogenase inhibitors (SDHIs) for agricultural applications, 30 pyrazole-4-carboxamide derivatives bearing a thioether group were designed and synthesized via bioisosteric replacement and scaffold-hopping based on the structure of two SDHIs lead compounds in our previous work. The antifungal efficacy of these target compounds was evaluated against five major plant pathogenic fungi, and the results indicated that the majority of the synthesized compounds exhibited strong antifungal activities, particularly against Rhizoctonia solani and Sclerotinia sclerotiorum. Among these, compound 8e emerged as the most promising candidate, displaying exceptional antifungal potency against R. solani (EC₅₀ = 0.012 μg/mL) and S. sclerotiorum (EC₅₀ = 0.123 μg/mL), significantly superior to boscalid (EC₅₀ = 0.464 μg/mL and 0.159 μg/mL, respectively) and comparable to fluxapyroxad (EC₅₀ = 0.036 μg/mL and 0.104 μg/mL). Additionally, detached leaf assays revealed that compound 8e effectively inhibited the growth of R. solani on rice leaves and S. sclerotiorum on oilseed rape leaves, achieving significant protective efficacies of 89.1% and 93.9%, respectively, at 100 μg/mL, which were superior to boscalid (68.8% and 90.5%) and comparable to fluxapyroxad (86.4% and 98.6%), indicating a promising potential for crop protection in the field, particularly for rice and oilseed rape. Furthermore, SDH enzymatic inhibition assays showed that compound 8e exhibited potent SDH inhibition (IC₅₀ = 1.30 μM), which was more effective than boscalid (IC₅₀ = 1.53 μM) and close to fluxapyroxad (IC₅₀ = 0.35 μM), confirming its role as an effective SDHI. SEM analysis showed that compound 8e caused significant structural disruption and morphological damage to the hyphae of R. solani, further supporting its antifungal activity. The results of molecular docking and DFT and ESP calculations demonstrated that compound 8e had a similar antifungal mechanism to fluxapyroxad. These findings suggested that compound 8e held great promise as a potential SDHI candidate for protection of crops such as rice and oilseed rape, warranting further investigation.