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

Abstract

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, Nphenylpropiolamide emerged as a novel and promising lead scaffold for the development of new SDHIs for plant protection.

Design, Synthesis, Antifungal Activity, and Action Mechanism of Pyrazole-4-carboxamide Derivatives Containing Oxime Ether Active Fragment As Succinate Dehydrogenase Inhibitors

“…This ligand carboxyl is a typical SDH inhibitor. As a protein structure, 2FBW has been reported to be used to study the SDHIs by numerous scientists. ,,,− Based on the above analysis, 2FBW was selected as the receptor protein for molecular docking and MD simulations in this work.…”

Discovery of Trifluorobutene Amide Derivatives as Potential Nematicides: Design, Synthesis, Nematicidal Activity Evaluation, SAR, and Mode of Action Study

“…Partial least-squares (PLS) analysis was used to establish statistical parameters including q 2 (cross-validated correlation), r 2 (optimum number of components), noncrossvalidated correlation (ONC), standard error of estimate (SEE), and F-value to evaluate the statistical significance and predictive ability of the CoMFA model. 24 Biological Activity and SAR. In Vitro Nematicidal Activity of Compounds C1−C22 against M. incognita.…”

“…21 Target-based molecule design has been a widely used approach in pesticide discovery in recent years. 24 However, the lack of information on nematode targets makes it difficult to design new nematicidal molecules based on this approach; therefore, scaffold hopping design strategies are a very useful tool in the finding of nematicidal lead. Among such strategies, the reversal of functional groups is a common method with a great track record of delivering new innovations in drug and pesticide design.…”

Design and optimization of novel succinate dehydrogenase inhibitors against agricultural fungi based on Transformer model

“…Third, after selecting molecules with amide bond structures, a total of 72,319 molecules were found. The reason for this step of screening is that the amide bond is part of the chemical structure of the classic SDHI fungicide [42]. Fourth, after selecting compounds with F atoms and Cl atoms, a total of 1,188 compounds were found.…”