Discovery of Terpene-Derived Quaternary Ring Compounds Containing an Oxime Moiety as Potential Fungicides

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Structural diversity derivatization from natural products is an important and effective method of discovering novel green pesticides. Cinnamic acids are abundant in plants, and their unparalleled structures endow them with various excellent biological activities. A series of novel cinnamic oxime esters were designed and synthesized to develop high antifungal agrochemicals. The antifungal activity, structure−activity relationship, and action mechanism were systematically studied. Compounds 7i, 7u, 7v, and 7x exhibited satisfactory activity against Gaeumannomyces graminis var. tritici, with inhibition rates of ≥90% at 50 μg/mL. Compounds 7z and 7n demonstrated excellent activities against Valsa mali and Botrytis cinerea, with median effective concentration (EC 50 ) values of 0.71 and 1.41 μg/mL, respectively. Compound 7z exhibited 100% protective and curative activities against apple Valsa canker at 200 μg/mL. The control effects of 7n against gray mold on tomato fruits and leaves were all >96%, exhibiting superior or similar effects to those of the commercial fungicide boscalid. Furthermore, the quantitative structure−activity relationship was established to guide the further design of higher-activity compounds. The preliminary results on the action mechanism revealed that 7n treatment could disrupt the function of the nucleus and mitochondria, leading to reactive oxygen species accumulation and cell membrane damage. Its primary biochemical mechanism may be inhibiting fungal ergosterol biosynthesis. The novel structure, simple synthesis, and excellent activity of cinnamic oxime esters render them promising potential fungicides.

Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Novel Cinnamic Acid Derivatives as Fungicide Candidates

Liu,

Cai,

Zhang

et al. 2024

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“…The molecular structure optimization and minimum energy calculations were performed by the Density Functional Theory (DFT) method of Discovery Studio 2021. Finally, the tested compound’s highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO and LUMO) and molecular electrostatic potential (MEP) were obtained, plotted, and visualized. − …”

Section: Methodsmentioning

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.

“…Natural products can be a good arsenal for discovering agriculturally active agents due to their distinct structures, potent biological activities, and environmental friendliness. − The α-methylene-γ-butyrolactone (MBL) is a significant structural scaffold in pharmaceutics and agriculture. , Up to now, more than 5000 MBL-containing natural products have been confirmed, the majority of which exhibit vital pharmacologically potential and attractive biological characteristics, , such as anti-inflammatory, anticancer, antioxidant, insecticidal, bacteriostatic, antiviral, and antifungal activities. − In addition, MBL has been used as a key pharmacophore in a variety of pharmaceutical preparations and chemical probes. − Compounds containing MBL fragments have been reported to exert their biological effects by acting as Michael receptors in the sulfhydryl reactions with biophilic reagents . The remarkable biological activities of MBL containing compounds have been widely used in the pharmaceutical sector; in contrast, little research has been done in the pesticide field.…”

Section: Introductionmentioning

confidence: 99%

Heterocycle-Substituted α-Methylene-γ-Butyrolactones Derivatives Synthesis, Antifungal Activity, and 3D-QSAR

Yang

et al. 2023

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Developing fungicides from active botanical skeletons is one of the effective methods to tackle the resistance of plant pathogens. Based on our previous discoveries, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing heterocycles and phenyl rings were designed according to the antifungal molecule carabrone first discovered in plant Carpesium macrocephalum. The target compounds were synthesized, and the inhibitory activity against pathogenic fungi as well as the mechanism of action were then systematically investigated. Several compounds showed promising inhibitory activities against a variety of fungi. The most potent compound 38 exhibited the EC50 value of 0.50 mg/L against Valsa mali (V. mali), which was more effective than that of commercial fungicide famoxadone. The protective effect of compound 38 against V. mali on apple twigs was superior to that of famoxadone, with an inhibition rate of 47.9% at 50 mg/L. The physiological and biochemical results showed that compound 38 inhibits V. mali by causing cell deformation and contraction, reducing the number of intracellular mitochondria, thickening the cell wall, as well as increasing the permeability of the cell membrane. Based on three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses, it was shown that the introduction of the bulky and negatively charged groups favored the antifungal activity of the novel MBL derivatives. These findings suggest that compound 38 can be a potential candidate for novel fungicides worthy of further investigation further.