Discovery of Pyrazole-5-yl-amide Derivatives Containing Cinnamamide Structural Fragments as Potential Succinate Dehydrogenase Inhibitors

• Published in: Journal of agricultural and food chemistry 2023-11, Vol.71 (45), p.16962-16971
• Main Authors: Cheng, Xiang, Xu, Zonghan, Cui, Hongyun, Zhang, Zhen, Chen, Wei, Wang, Fanglei, Li, Shanlu, Liu, Qixuan, Wang, Dandan, Lv, Xianhai, Chang, Xihao
• Format: Article
• Language: English
• Subjects: Agricultural and Environmental Chemistry
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.3c04355

To promote the development of novel agricultural succinate dehydrogenase inhibitor (SDHI) fungicides, we introduced cinnamamide and nicotinamide structural fragments into the structure of pyrazol-5-yl-amide by carbon chain extension and scaffold hopping, respectively, and synthesized a series of derivatives. The results of the biological activity assays indicated that most of the target compounds exhibited varying degrees of inhibitory activity against the tested fungi. Notably, compounds G22, G28, G34, G38, and G39 exhibited excellent in vitro antifungal activities against Valsa mali with EC50 values of 0.48, 0.86, 0.57, 0.73, and 0.87 mg/L, respectively, and this result was significantly more potent than boscalid (EC50 = 2.80 mg/L) and closer to the specialty control drug tebuconazole (EC50 = 0.30 mg/L). Compounds G22 and G34 also exhibited excellent in vivo protective and curative effects against V. mali at 40 mg/L. The SEM and TEM observations indicated that compounds G22 and G34 may affect normal V. mali mycelial morphology as well as the cellular ultrastructure. Molecular docking analysis results indicated that G22 and boscalid possessed a similar binding mode to that of SDH, and detailed SDH inhibition assays validated the feasibility of the designed compounds as potential SDH inhibitors. Compounds G22 and G3 were selected for theoretical calculations, and the terminal carboxylic acid group of this series of compounds may be a key region influencing the antifungal activity. Furthermore, toxicity tests on Apis mellifera l. revealed that compounds G22 and G34 exhibited low toxicity to A. mellifera l. populations. The above results demonstrated that these series of pyrazole-5-yl-amide derivatives are promising for development as potential low-risk drug-resistance agricultural SDHI fungicides.