Design, Synthesis, and Antifungal Activity of Novel Thiazole-2-carboxamide Derivatives Bearing Flexible Diaryl Linkers as Succinate Dehydrogenase Inhibitors

Abstract

To develop eco-friendly succinate dehydrogenase inhibitors with good fungicidal activity, various diaryl-substituted thiazole-2-carboxamide derivatives were designed and synthesized based on structure–activity relationships (SARs) and molecular docking. At 20 mg/L, most target compounds exhibited ≥80% inhibition against Valsa mali, Botrytis cinerea, Curvularia lunata, and Phytophthora capsici. Notably, compound G33 showed potent activity against B. cinerea (EC50 = 0.17 mg/L) and P. capsici (EC50 = 0.42 mg/L), outperforming commercial fungicides thifluzamide and boscalid. At 100 mg/L, G33 effectively suppressed B. cinerea infection on strawberries. Mechanistic studies revealed that G33 disrupted hyphal morphology and ultrastructure, compromised cell membrane integrity, dissipated mitochondrial membrane potential, and inhibited mycelial growth. Enzyme activity assays, molecular docking, and molecular dynamics (MD) simulations further confirmed that G33 directly targets succinate dehydrogenase. Combined with favorable theoretical calculation results and low toxicity, G33 emerges as a promising lead compound for developing highly efficient and environmentally benign agricultural fungicides.