Potential Fungicide Candidates: A Dual Action Mode Study of Novel Pyrazole-4-carboxamides against Gibberella zeae

Hydrazides are present in many bioactive molecules and exhibit a variety of biological activities, such as insecticidal, herbicidal, antifungal, antitumor, and antiviral effects. In this Review, we review the application of hydrazide and its derived structures in the agricultural fungicidal field, including monohydrazides, diacylhydrazines, hydrazide-hydrazones, and sulfonyl hydrazides. In addition, the antifungal mechanism of action of the hydrazide derivatives was analyzed and summarized, mainly involving succinate dehydrogenase inhibitors, laccase inhibitors, and targeting plasma membranes. Finally, based on the structural analysis of the novel fungicidal lead compounds, the structure−activity relationship of the hydrazide derivatives was constructed and the development trend of hydrazide structures in fungicidal applications was prospected. It is hoped that this Review can provide some significant guidance for the development of new hydrazide fungicides in the future.

Section: Summary and Future Prospectsmentioning

confidence: 99%

A Comprehensive Investigation of Hydrazide and Its Derived Structures in the Agricultural Fungicidal Field

Chang

Liu

Zhang

et al. 2023

“…As we previously reported, the morphological observations of V. mali hyphae which were treated with compound G22 (concentration = 0.48 mg/L) and G34 (concentration = 0.57 mg/L) were performed by scanning electron microscopy (SEM). 34 The detailed procedure was described in the Supporting Information. Meanwhile, as for transmission electron microscopy (TEM), 35 the detailed preliminary treatment procedure was consistent with the SEM.…”

Section: Scanning Electron Microscopy (Sem) and Transmission Electron...mentioning

confidence: 99%

Discovery of Pyrazole-5-yl-amide Derivatives Containing Cinnamamide Structural Fragments as Potential Succinate Dehydrogenase Inhibitors

Cheng,

Xu,

Cui

et al. 2023

To promote the development of novel agricultural succinate dehydrogenase inhibitor (SDHI) fungicides, we introduced cinnamamide and nicotinamide structural fragments into the structure of pyrazol-5-yl-amide by carbon chain extension and scaffold hopping, respectively, and synthesized a series of derivatives. The results of the biological activity assays indicated that most of the target compounds exhibited varying degrees of inhibitory activity against the tested fungi. Notably, compounds G22, G28, G34, G38, and G39 exhibited excellent in vitro antifungal activities against Valsa mali with EC 50 values of 0.48, 0.86, 0.57, 0.73, and 0.87 mg/L, respectively, and this result was significantly more potent than boscalid (EC 50 = 2.80 mg/L) and closer to the specialty control drug tebuconazole (EC 50 = 0.30 mg/L). Compounds G22 and G34 also exhibited excellent in vivo protective and curative effects against V. mali at 40 mg/L. The SEM and TEM observations indicated that compounds G22 and G34 may affect normal V. mali mycelial morphology as well as the cellular ultrastructure. Molecular docking analysis results indicated that G22 and boscalid possessed a similar binding mode to that of SDH, and detailed SDH inhibition assays validated the feasibility of the designed compounds as potential SDH inhibitors. Compounds G22 and G3 were selected for theoretical calculations, and the terminal carboxylic acid group of this series of compounds may be a key region influencing the antifungal activity. Furthermore, toxicity tests on Apis mellifera l. revealed that compounds G22 and G34 exhibited low toxicity to A. mellifera l. populations. The above results demonstrated that these series of pyrazole-5-yl-amide derivatives are promising for development as potential low-risk drug-resistance agricultural SDHI fungicides.

“…22,23 Among the commercialized SDH inhibitors, pyrazole-4-carboxamides containing a 3-CF 3 or 3-CHF 2 group take the largest proportion (10/25) (Figure 1a). 24 In recent years, there have been numerous studies conducted to optimize pyrazole-4-carboxamides through various effective strategies, including virtual screening, active substructure splicing, scaffold hopping, and bioisosterism. 22,25,26 These efforts have yielded a plethora of novel SDHIs with an impressive efficiency.…”

Section: ■ Introductionmentioning

confidence: 99%

Design, Synthesis, and Fungicidal Activities of Novel N-(Pyrazol-5-yl)benzamide Derivatives Containing a Diphenylamine Moiety

Ma,

Zhou,

Lin

et al. 2024

To accelerate the development of novel fungicides, a variety of N- (pyrazol-5-yl)benzamide derivatives with a diphenylamine moiety were designed and synthesized using a pharmacophore recombination strategy based on the structure of pyrazol-5-yl-aminophenyl-benzamides. The bioassay results demonstrated that most of the target compounds had excellent in vitro antifungal activities against Sclerotinia sclerotiorum, Valsa mali, and Botrytis cinerea. In particular, compound 5IIIh exhibited remarkable activity against S. sclerotiorum (EC 50 = 0.37 mg/L), which was similar to that of fluxapyroxad (EC 50 = 0.27 mg/L). In addition, compound 5IIIc (EC 50 = 1.32 mg/L) was observed to be more effective against V. mali than fluxapyroxad (EC 50 = 12.8 mg/L) and comparable to trifloxystrobin (EC 50 = 1.62 mg/L). Furthermore, compound 5IIIh demonstrated remarkable in vivo protective antifungal properties against S. sclerotiorum, with an inhibition rate of 96.8% at 100 mg/L, which was close to that of fluxapyroxad (99.6%). Compounds 5IIIc (66.7%) and 5IIIh (62.9%) exhibited good in vivo antifungal effects against V. mali at 100 mg/L, which were superior to that of fluxapyroxad (11.1%) but lower than that of trifloxystrobin (88.9%). The succinate dehydrogenase (SDH) enzymatic inhibition assay was conducted to confirm the mechanism of action. Molecular docking analysis further revealed that compound 5IIIh has significant hydrogen-bonding, π−π, and p−π conjugation interactions with ARG 43, SER 39, TRP 173, and TYR 58 in the binding site of SDH, and the binding mode was similar to that of the commercial fungicide fluxapyroxad. All of the results suggest that compound 5IIIh could be a potential SDH inhibitor, offering a valuable reference for future studies.