Structure-Based Discovery of New Succinate Dehydrogenase Inhibitors via Scaffold Hopping Strategy

Abstract

Scaffold hopping strategy has become one of the most successful methods in the process of molecular design. Seeking to develop novel succinate dehydrogenase inhibitors (SDHIs), we employed a scaffold hopping strategy to design compounds featuring geminate dichloralkenes (gem-dichloralkenes) fragment. After stepwise modifications, a series of N-cyclopropyl-dichloralkenes-pyrazole-carboxamide derivatives was synthesized. Among them, compounds G28 (IC50 = 26.00 nM) and G40 (IC50 = 27.00 nM) were identified as the best inhibitory activity against porcine SDH, with IC50 values reaching the nanomolar range, outperforming the lead compound pydiflumetofen. Additionally, the greenhouse assay indicated that compounds G37 (EC90 = 0.031 mg/L) and G34 (EC90 = 1.67 mg/L) displayed extremely high activities against wheat powdery mildew (WPM) and cucumber powdery mildew (CPM), respectively. Computational results further revealed that the gem-dichloralkene fragment and fluorine substituted pyrazole form an extra hydrophobic interaction and dipolar–dipolar interaction with SDH. In summary, our study provides a novel gem-dichloralkene scaffold with outstanding fungicidal properties, obtained through scaffold hopping, that holds great potential for future research on PM control.

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.…”

Recent Advances in Design and Development of Diazole and Diazine Based Fungicides (2014–2023)

“…Huang et al employed a scaffold hopping strategy in order to design novel SDH inhibitor N -cyclopropyldichloralkenes-pyrazole-carboxamides bearing geminate dichloralkenes fragments. After testing against porcine SDH, compounds 24a and 24b were selected as the most active compounds, with IC 50 values of 26.00 and 27.00 nM, respectively (Figure b).…”

Discovery of Novel Acethydrazide-Containing Flavonol Derivatives as Potential Antifungal Agents

“…Phytopathogenic fungi pose a significant threat to agricultural productivity and ecosystem health. They infect various parts of plants, including the leaves, stems, roots, and fruits, leading to devastating crop yield losses. − To mitigate agricultural losses caused by pathogenic fungi, fungicides have been widely employed as a protective strategy in agricultural practices. − Succinate dehydrogenase (SDH) serves as an ideal target for fungicides, and SDH inhibitors (SDHIs) exert their antifungal activity by disrupting the mitochondrial tricarboxylic acid cycle and respiratory chain. − The antifungal mechanism of SDHIs makes them a class of effective fungicides. However, long-term application of SDHIs can lead to reduced efficacy, plant toxicity, and environmental pollution .…”