Discovery of N -Phenylpropiolamide as a Novel Succinate Dehydrogenase Inhibitor Scaffold with Broad-Spectrum Antifungal Activity on Phytopathogenic Fungi

作者：Yuhao Zhang, S Samuel Yang, Qi Zhang, Tiantian Zhang, Tianyi Zhang, Bohang Zhou, Le Zhou · 发表于：Journal of Agricultural and Food Chemistry · 年份：2023 · DOI：10.1021/acs.jafc.2c07712 · 被引用次数：51 · 研究领域：Fungal Plant Pathogen Control、Microbial Natural Products and Biosynthesis、Cancer therapeutics and mechanisms

Based on the structural features of both succinate dehydrogenase inhibitors (SDHIs) and targeted covalent inhibitors, a series of N -phenylpropiolamides containing a Michael acceptor moiety were designed to find new antifungal compounds. Nineteen compounds showed potent inhibition activity in vitro on nine species of plant pathogenic fungi. Compounds 9 and 13 showed higher activity on most of the fungi than the standard drug azoxystrobin. Compound 13 could completely inhibit Physalospora piricola infection on apples at 200 μg/mL concentration over 7 days and showed high safety to seed germination and seedling growth of plants at ≤100 μg/mL concentration. The action mechanism showed that 13 is an SDH inhibitor with a median inhibitory concentration, IC 50, value of 0.55 μg/mL, comparable with that of the positive drug boscalid. Molecular docking studies revealed that 13 can bind well to the ubiquinone-binding region of SDH by hydrogen bonds and undergoes π–alkyl interaction and π–cation interaction. At the cellular level, 1 as the parent compound could destruct the mycelial structure of P. piricola and partly dissolve the cell wall and/or membrane. Structure–activity relationship analysis showed that the acetenyl group should be a structure determinant for the activity, and the substitution pattern of the phenyl ring can significantly impact the activity. Thus, N -phenylpropiolamide emerged as a novel and promising lead scaffold for the development of new SDHIs for plant prote...