Molecular docking and SARs guiding the gradual development of thiazole-2-yl amide derivatives containing biphenyl groups as promising antifungal scaffolds.

Background: The antifungal activities ofthe initially synthesized thiazol-2-ylbenzamide derivatives were relatively limited, suggesting potential for structural optimization. Inspired by the promising bioactivities of biphenyl scaffolds, and guided by molecular docking and structure-activity relationships (SARs), 42 thiazol-2-ylamide derivatives containing a biphenyl scaffold were synthesized through gradual structural modification, and their antifungal and anti-oomycete activities were assessed. Furthermore, the most potent compound G41 was selected for preliminary mechanistic studies.

Results: Bioassay results indicated that compound G41 [half maximal effective concentration (EC) values of 0.16, 0.20, 0.23, 0.11,] and 0.28 mg L, respectively] exhibited broader antifungal spectrum and stronger effects against Sclerotinia scleotiorum, Botrytis cinerea, Fusarium graminearum, Pythium graminicola and Curvularia lunata than boscalid (EC values of 0.16, 0.93, >10, >10 and 0.35 mg L, respectively) and thifluzamide (EC values of 0.97, >10, >10, >10 and 3.14 mg L, respectively). Additionally, treatment with compound G41 (100 mg L) effectively suppressed further infection by B. cinerea on cherry tomatoes. Preliminary mechanistic investigations demonstrated that compound G41 significantly altered the hyphal surface morphology and compromised the cellular ultrastructure of B. cinerea, leading to severe damage to the fungal cell membrane. Moreover, G41 drastically diminished or disrupted mitochondrial membrane potential, triggering premature apoptosis in B. cinerea cells. Integrated analyses combining enzyme activity assays, molecular docking and molecular dynamics simulations revealed that G41 specifically targets succinate dehydrogenase, thereby interfering with normal growth and reproduction of B. cinerea.

Conclusion: Compound G41 provided critical insights and established a technical foundation for developing these derivatives as novel efficient SDHIs fungicides for crop protection. © 2025 Society of Chemical Industry.