Synthesis, Biological Evaluation, and 3D-QSAR Studies of N-(Substituted pyridine-4-yl)-1-(substituted phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide Derivatives as Potential Succinate Dehydrogenase Inhibitors
- 22 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Agricultural and Food Chemistry
- Vol. 69 (4), 1214-1223
- https://doi.org/10.1021/acs.jafc.0c05702
Abstract
A series of new fungicides that can inhibit the succinate dehydrogenase (SDH) was classified and named as SDH inhibitors by the Fungicide Resistance Action Committee in 2009. To develop more potential SDH inhibitors, we designed and synthesized a novel series of N-(substituted pyridine-4-yl)-1-(substituted phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide derivatives, 4a–4i, namely, 5a–5h, 6a–6h, and 7a–7j. The bioassay results demonstrated that some title compounds exhibited excellent antifungal activity against four tested phytopathogenic fungi (Gibberella zea, Fusarium oxysporum, Cytospora mandshurica, and Phytophthora infestans). The EC50 values were 1.8 μg/mL for 7a against G. zeae, 1.5 and 3.6 μg/mL for 7c against F. oxysporum and C. mandshurica, respectively, and 6.8 μg/mL for 7f against P. infestans. The SDH enzymatic activity testing revealed that the IC50 values of 4c, 5f, 7f, and penthiopyrad were 12.5, 135.3, 6.9, and 223.9 μg/mL, respectively. The molecular docking results of this series of title compounds with SDH model demonstrated that the compounds could completely locate inside of the pocket, the body fragment formed H bonds, and the phenyl ring showed a π–π interaction with Arg59, suggesting that these novel 5-trifluoromethyl-pyrazole-4-carboxamide derivatives might target SDH. These results could provide a benchmark for understanding the antifungal activity against the phytopathogenic fungus P. infestans and prompt us to discover more potent SDH inhibitors.Keywords
Funding Information
- Ministry of Science and Technology of the People's Republic of China (2014BAD23B01)
- Guizhou Science and Technology Department ([2017]5788)
- National Natural Science Foundation of China (21662008, 21877021)
This publication has 35 references indexed in Scilit:
- Succinate Dehydrogenase: An Ideal Target for Fungicide DiscoveryACS Symposium Series, 2015
- A Review of Current Knowledge of Resistance Aspects for the Next-Generation Succinate Dehydrogenase Inhibitor FungicidesPhytopathology®, 2013
- Biological activity of sedaxane – a novel broad‐spectrum fungicide for seed treatmentPest Management Science, 2012
- Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungiCrop Protection, 2010
- Effect of the new pyrazole carboxamide fungicide penthiopyrad on late leaf spot and stem rot of peanutPest Management Science, 2008
- Structural and Computational Analysis of the Quinone-binding Site of Complex II (Succinate-Ubiquinone Oxidoreductase)Online Journal of Public Health Informatics, 2006
- Development of a Systemic Fungicide, FlutolanilJournal of Pesticide Science, 1993
- Systemic Fungicide Benodanil for Control of Pine-Oak Rust on Pine Seedlings in the NurseryPlant Disease, 1984
- Mode of action of oxathiin systemic fungicidesPesticide Biochemistry and Physiology, 1971
- Systemic Fungicidal Activity of 1,4-Oxathiin DerivativesScience, 1966