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

Based on the structural features of both succinate dehydrogenase inhibitors (SDHIs) and targeted covalent inhibitors, a series of -phenylpropiolamides containing a Michael acceptor moiety were designed to find new antifungal compounds. Nineteen compounds showed potent inhibition activity on nine species of plant pathogenic fungi. Compounds and showed higher activity on most of the fungi than the standard drug azoxystrobin. Compound could completely inhibit 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 is an SDH inhibitor with a median inhibitory concentration, IC, value of 0.55 μg/mL, comparable with that of the positive drug boscalid. Molecular docking studies revealed that 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, as the parent compound could destruct the mycelial structure of 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, -phenylpropiolamide emerged as a novel and promising lead scaffold for the development of new SDHIs for plant protection.