Succinate Dehydrogenase Inhibitor Research Articles

Accumulation and growth toxicity mechanisms of fluxapyroxad revealed by physiological, hepatopancreas transcriptome, and gut microbiome analysis in Pacific white shrimp (Litopenaeus vannamei)

Fluxapyroxad (FX), a typical succinate dehydrogenase inhibitor fungicide, is causing increased global concerns due to its fungicide effects. However, the accumulation and grow toxicity of FX to Litopenaeus vannamei (L. vannamei) is poorly understand. Therefore, the accumulation pattern of FX in L. vannamei was investigated for the first time in environmental concentrations. FX accumulated rapidly in shrimp muscle. Meanwhile, growth inhibition was observed and the mechanism derived by primarily accelerated glycolipid metabolism and reduced glycolipid content. Moreover, exposure to environmental concentrations of FX induced significant growth inhibition and oxidative stress and inhibited oxidative phosphorylation and TCA cycle in L. vannamei. The endocytosis signaling pathway genes were activated, thereby driving growth toxicity. Oxidative phosphorylation and cytosolic gene expression were further rescued in elimination experiments, demonstrating the mechanism of growth toxicity by FX exposure. The results revealed that FX persistently altered the gut microbiome of L. vannamei using gut microbiome sequencing, particularly with increased Garcinia Purple Pseudoalteromonas luteoviolacea for organic pollutant degradation. This study provided new insights into the potential toxicity of FX to marine organisms, emphasizing the need for further investigation and potential regulatory considerations.

Adsorption–desorption and leaching behavior of benzovindiflupyr in different soil types

Benzovindiflupyr is a succinate dehydrogenase inhibitor fungicide that targets mitochondrial function for disease control. In this study, we investigated the adsorption–desorption and leaching behavior of benzovindiflupyr in eight soil types using the batch equilibrium method and the soil column leaching method. A Freundlich model (r2 > 0.9959) was used to better characterize the adsorption-desorption process in eight soil types, with adsorption coefficients (KF-ads) ranging from 2.303 to 17.886. KF-ads was significantly and positively correlated (p < 0.05) with the organic carbon content. High temperatures and increased initial pH of aqueous solutions led to a decrease in benzovindiflupyr adsorption in the soil. The adsorption was also influenced by factors such as ionic strength, humic acid, surfactant type, microplastic type, and particle size and concentration. Moreover, benzovindiflupyr exhibited low leachability in all four soils selected, but different leaching solutions affected the risk of benzovindiflupyr migration to groundwater. Overall, this study provides insights into the adsorption characteristics of benzovindiflupyr in different soils and provides key information for environmental risk assessment.

Profitability of foliar fungicides in double crop soybean under low-disease environments

Double-crop soybean production involves planting soybean (Glycine max) directly following winter wheat (Triticum aestivum) harvest. Frogeye leaf spot (FLS), caused by Cercospora sojina, is an important late-season foliar disease affecting soybean fields in the United States. In some instances, foliar fungicides have been used in double-crop soybean production with little to no FLS present, raising questions on the profitability of these applications. This study analyzed yield data from 25 fungicide trials across five states (Illinois, Indiana, Kentucky, Missouri, and Tennessee) conducted under low FLS pressure, from 2008 to 2021, on double-crop soybean. Fungicide classes evaluated in the trials included quinone outside inhibitors (QoI), demethylation inhibitors (DMI), and methyl benzimidazole carbamates (MBC) applied alone, and mixtures of chemistry classes that included DMI+succinate dehydrogenase inhibitor (SDHI), MBC+DMI, QoI+DMI, and QoI+DMI+SDHI. A network meta-analytic model estimated yield differences between fungicide-treated and nontreated plots, which ranged from -28 to 72 kg/ha among the fungicide treatments. Negative yield response values were estimated for the single fungicide classes MBC (-15.7 kg/ha) and QoI (-28.4 kg/ha). Yield difference as high as 72.8 kg/ha was estimated only for DMI+SDHI. Economic analyses indicated that, due to the lower yield responses, probabilities of breaking even were lower than 50% for all fungicide treatments, regardless of the fungicide cost or soybean sale price. Therefore, the low yield responses associated with foliar fungicides in low-disease environments linked to the higher risk of not offsetting the costs, suggest that growers should consider disease risk prior to making the fungicide application.

Itaconate and dimethyl itaconate upregulate IL-6 production in the LPS-induced inflammation in mice.

Itaconate is one of the most studied immunometabolites produced by myeloid cells during inflammatory response. It mediates a wide range of anti-inflammatory and immunoregulatory effects and plays a role in a number of pathological states, including autoimmunity and cancer. Itaconate and its derivatives are considered potential therapeutic agents for the treatment of inflammatory diseases. While immunoregulatory effects of itaconate have been extensively studied in vitro and using knockout mouse models, less is known about how therapeutic administration of this metabolite regulates inflammatory response in vivo. Here, we investigate the immunoregulatory properties of exogenous administration of itaconate and its derivative dimethyl itaconate in a mouse model of lipopolysaccharide-induced inflammation. The data show that administration of itaconate or dimethyl itaconate controls systemic production of multiple cytokines, including increased IL-10 production. However, only dimethyl itaconate was able to suppress systemic production of IFNγ and IL-1β. In contrast to in vitro data, administration of itaconate or dimethyl itaconate in vivo resulted in systemic upregulation of IL-6 in the blood. Electrophilic stress due to itaconate or dimethyl itaconate was not responsible for IL-6 upregulation. However, inhibition of succinate dehydrogenase with dimethyl malonate also resulted in elevated systemic levels of IL-6 and IL-10. Taken together, our study reports a novel effect of exogenous itaconate and its derivative dimethyl itaconate on the production of IL-6 in vivo, with important implications for the development of itaconate-based anti-inflammatory therapies.

3D-QSAR model-oriented optimization of Pyrazole β-Ketonitrile derivatives with diphenyl ether moiety as novel potent succinate dehydrogenase inhibitors.

Succinate dehydrogenase inhibitor (SDHI) fungicides play important roles in the control of plant fungal diseases. However, they are facing serious challenges from issues with resistance and cross-resistance, primarily attributed to their frequent application and structural similarities. There is an urgent need to design and develop SDHI fungicides with novel structures. Aiming to discover novel potent SDHI fungicides, 31 innovative pyrazole β-ketonitrile derivatives with diphenyl ether moiety were rationally designed and synthesized, which were guided by a 3D-QSAR model from our previous study. The optimal target compound A23 exhibited not only outstanding in vitro inhibitory activities against Rhizoctonia solani with a half-maximal effective concentration (EC50) value of 0.0398 μg mL-1 comparable to that for fluxapyroxad (EC50 = 0.0375 μg mL-1), but also a moderate protective efficacy in vivo against rice sheath blight. Porcine succinate dehydrogenase (SDH) enzymatic inhibitory assay revealed that A23 is a potent inhibitor of SDH, with a half-maximal inhibitory concentration of 0.0425 μm. Docking study within R. solani SDH indicated that A23 effectively binds into the ubiquinone site mainly through hydrogen-bonds, and cation-π and π-π interactions. The identified β-ketonitrile compound A23 containing diphenyl ether moiety is a potent SDH inhibitor, which might be a good lead for novel fungicide research and optimization. © 2024 Society of Chemical Industry.

The New Nematicide Cyclobutrifluram Targets the Mitochondrial Succinate Dehydrogenase Complex in Bursaphelenchus xylophilus.

Bursaphelenchus xylophilus is a dangerous quarantine pest that causes extensive damage to pine ecosystems worldwide. Cyclobutrifluram, a succinate dehydrogenase inhibitor (SDHI), is a novel nematicide introduced by Syngenta in 2013. However, the nematocidal effect of cyclobutrifluram against plant-parasitic nematodes remains underexplored. Therefore, here, we aim to address this knowledge gap by evaluating the toxicity, effects, and mode of action of cyclobutrifluram on B. xylophilus. The result shows that cyclobutrifluram is the most effective agent, with an LC50 value of 0.1078 mg·L-1. At an LC20 dose, it significantly reduced the population size to 10.40 × 103 ± 737.56-approximately 1/23 that of the control group. This notable impact may stem from the agent's ability to diminish egg-laying and hatching rates, as well as to impede the nematodes' development. In addition, it has also performed well in the prevention of pine wilt disease, significantly reducing the incidence in greenhouses and in the field. SDH consists of a transmembrane assembly composed of four protein subunits (SDHA to SDHD). Four sdh genes were characterized and proved by RNAi to regulate the spawning capacity, locomotion ability, and body size of B. xylophilus. The mortality of nematodes treated with sdhc-dsRNA significantly decreased upon cyclobutrifluram application. Molecular docking further confirmed that SDHC, a cytochrome-binding protein, is the target. In conclusion, cyclobutrifluram has a good potential for trunk injection against B. xylophilus. This study provides valuable information for the screening and application of effective agents in controlling and preventing PWD in forests.

Combined toxic effects of fluxapyroxad and multi-walled carbon nanotubes in Xenopus laevis larvae

Carbon nanomaterials rarely exist in isolation in the natural environment, and their combined effects cannot be ignored. Multi-walled carbon nanotubes (MWCNTs) have shown tremendous potential applications in diverse fields, including pollution remediation, biomedicine, energy, and smart agriculture. However, the combined toxicities of MWCNTs and pesticides on non-target organisms, particularly amphibians, are often overlooked. Fluxapyroxad (FLX), a significant succinate dehydrogenase inhibitor fungicide, has been extensively utilized for the protection of food and cash crops and control of fungi. This raises the possibility of coexistence of MWCNTs and FLX. The objective of this study was to explore the individual and combined toxic effects of FLX and MWCNTs on the early life stages of Xenopus laevis. Embryos were exposed to varying concentrations of FLX (0, 5, and 50 μg/L) either alone or in combination with MWCNTs (100 μg/L) for a duration of 17 days. The findings indicated that co-exposure to FLX and MWCNTs worsened the inhibition of growth, liver damage, and dysregulation of enzymatic activity in tadpoles. Liver transcriptomic analysis further revealed that the presence of MWCNTs exacerbated the disturbances in glucose and lipid metabolism caused by FLX. Additionally, the combined exposure groups exhibited amplified alterations in the composition and function of the gut microflora. Our study suggests that it is imperative to pay greater attention to the agricultural applications, management and ecological risks of MWCNTs in the future, considering MWCNTs may significantly enhance the toxicity of FLX.

Design, Synthesis, and Antifungal Activities of Novel Potent Fluoroalkenyl Succinate Dehydrogenase Inhibitors.

The development of new fungicide molecules is a crucial task for agricultural chemists to enhance the effectiveness of fungicides in agricultural production. In this study, a series of novel fluoroalkenyl modified succinate dehydrogenase inhibitors were synthesized and evaluated for their antifungal activities against eight fungi. The results from the in vitro antifungal assay demonstrated that compound 34 exhibited superior activity against Rhizoctonia solani with an EC50 value of 0.04 μM, outperforming commercial fluxapyroxad (EC50 = 0.18 μM) and boscalid (EC50 = 3.07 μM). Furthermore, compound 34 showed similar effects to fluxapyroxad on other pathogenic fungi such as Sclerotinia sclerotiorum (EC50 = 1.13 μM), Monilinia fructicola (EC50 = 1.61 μM), Botrytis cinerea (EC50 = 1.21 μM), and also demonstrated protective and curative efficacies in vivo on rapeseed leaves and tomato fruits. Enzyme activity experiments and protein-ligand interaction analysis by surface plasmon resonance revealed that compound 34 had a stronger inhibitory effect on succinate dehydrogenase compared to fluxapyroxad. Additionally, molecular docking and DFT calculation confirmed that the fluoroalkenyl unit in compound 34 could enhance its binding capacity with the target protein through p-π conjugation and hydrogen bond interactions.

Cercospora leaf blight and purple seed stain of soybean: A permanent challenge

AbstractCercospora leaf blight (CLB) and purple seed stain (PSS) are major diseases of soybean responsible for significant yield loss. These diseases are caused by Cercospora species, such as C. kikuchii and C. cf. flagellaris, among the main species. These pathogens overwinter in infested debris and infected seed. Due to the combination of no‐till farming, monoculture in large soybean cultivation areas and climate changes, these diseases have become serious and prevalent. At present, in addition to the practice of monoculture soybean cultivation, there is a lack of soybean varieties with genetic resistance to these diseases. As a result, the application of fungicides becomes an essential tool for effectively managing this pathosystem. However, in the main soybean‐producing countries, resistance to quinone outside inhibitors and benzimidazole fungicides has already been studied and documented. Furthermore, Cercospora spp. are believed to be naturally insensitive to succinate dehydrogenase inhibitors. Consequently, there is a growing interest in innovative and integrated tools for managing crop diseases. These new approaches include the use of biofungicides, biostimulants and plant defence inducers. Research testing new management tools in a complementary and integrated approach involves a short‐term challenge to improve CLB/PSS management in the field. This review provides comprehensive details on the taxonomy, identification and genetic diversity of the pathogen, its disease symptoms and host range. Additionally, it outlines epidemiological aspects, fungicide resistance and the latest advancements in tools and technologies, aiming to guide future research and strategies to address the escalating threat to soybean crops globally.

Various amino acid substitutions in succinate dehydrogenase complex regulating differential resistance to pydiflumetofen in Magnaporthe oryzae

Rice blast, caused by Magnaporthe oryzae, is a devastating fungal disease worldwide. Pydiflumetofen (Pyd) is a new succinate dehydrogenase inhibitor (SDHI) that exhibited anti-fungal activity against M. oryzae. However, control of rice blast by Pyd and risk of resistance to Pyd are not well studied in this pathogen. The baseline sensitivity of 109 M. oryzae strains to Pyd was determined using mycelial growth rate assay, with EC50 values ranging from 0.291 to 2.1313 μg/mL, and an average EC50 value of 1.1005 ± 0.3727 μg/mL. Totally 28 Pyd-resistant (PydR) mutants with 15 genotypes of point mutations in succinate dehydrogenase (SDH) complex were obtained, and the resistance level could be divided into three categories of very high resistance (VHR), high resistance (HR) and moderate resistance (MR) with the resistance factors (RFs) of >1000, 105.74–986.13 and 81.92–99.48, respectively. Molecular docking revealed that all 15 mutations decreased the binding-force score for the affinity between Pyd and target subunits, which further confirmed that these 15 genotypes of point mutations were responsible for the resistance to Pyd in M. oryzae. There was positive cross resistance between Pyd and other SDHIs, such as fluxapyroxad, penflufen or carboxin, while there was no cross-resistance between Pyd and carbendazim, prochloraz or azoxystrobin in M. oryzae, however, PydR mutants with SdhBP198Q, SdhCL66F or SdhCL66R genotype were still sensitive to the other 3 SDHIs, indicating lack of cross resistance. The results of fitness study revealed that the point mutations in MoSdhB/C/D genes might reduce the hyphae growth and sporulation, but could improve the pathogenicity in M. oryzae. Taken together, the risk of resistance to Pyd might be moderate to high, and it should be used as tank-mixtures with other classes of fungicides to delay resistance development when it is used for the control of rice blast in the field.

Chrysin Nanoparticles Inhibit Succinate Dehydrogenase and Ubiquinone Oxidoreductases to Treat Pancreatic Cancer

Chrysin Nanoparticles Inhibit Succinate Dehydrogenase and Ubiquinone Oxidoreductases to Treat Pancreatic Cancer

Comprehensive evaluation of penthiopyrad residues in typical fruit scenes at the enantiomeric level

Penthiopyrad (PEN) is a novel fungicide as succinate dehydrogenase inhibitor (SDHI) with chiral characteristics, and it is crucial to investigate its enantioselective residue behavior given its extensive application. This study aimed to comprehensively evaluated the storage stability, deposition, dissipation, accumulation, and dietary risk associated with PEN enantiomers and its metabolite 1-methyl-3-trifluoromethyl-1 H-pyrazole-4-carboxamide (PAM) in apple and strawberry. Two enantiomers of PEN accumulated primarily on leaves after spraying, whose concentrations were much higher than those observed in the apple and strawberry fruits, respectively. S-(+)-PEN was found to be preferentially degraded in apples (EF: 0.5113–0.5925), resulting in a relative enrichment of its antipode. Multiple sprays of PEN led to the accumulation of both of its enantiomers, with average residue accumulation value (RAaverage) of 1:2.06:1.11 for the R-(−)-PEN and 1:2.06:1.09 for the S-(+)-PEN in strawberries, respectively. The terminal residues of PAM were lower than the limit of quantification (LOQ), and that of total PEN in both fruits were below the maximum residue limit (MRL) established by China. Furthermore, the acute risk quotient (RQa) of target pesticide in apples were 0.821 %–2.105 %. The investigation provided a theoretical foundation and scientific guidance for applying PEN at the enantiomeric level in fruits.

Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury

The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.

Biological and molecular characterization of pydiflumetofen and phenamacril dual-resistant Fusarium graminearum strains.

Fusarium head blight (FHB) caused by Fusarium graminearum species complex (FGSG) remains a major challenge to cereal crops and resistance to key fungicides by the pathogen threatens control efficacy. Pydiflumetofen, a succinate dehydrogenase inhibitor, and phenamacril, a cyanoacrylate fungicide targeting myosin I, have been applied to combat this disease. Nonetheless, emergence of pydiflumetofen resistance in a subset of field isolates alongside laboratory-induced facile generation of phenamacril-resistant isolates signals a critical danger of resistance proliferation. Our study investigates the development of dual resistance to these fungicides in F. graminearum. Utilizing pydiflumetofen-resistant (PyR) and -sensitive (PyS) isolates, we obtained dual-resistant (PyRPhR) and phenamacril-resistant (PySPhR) mutants on potato sucrose agar containing phenamacril. Mutation rates for phenamacril resistance were comparable between pydiflumetofen-resistant and -sensitive isolates, implying independent pathways for resistance development. The mutants compromised in fungal growth, competitive viability and deoxynivalenol production, suggesting fitness penalties for the dual-resistant mutants. However, no cross-resistance was found with tebuconazole or fludioxonil. In addition, we characterized four critical amino acid changes (S217L, C423R, K537T, E420G) in the Myo1 that were verified to confer phenamacril resistance in F. graminearum. This research indicates the possibility of resistance development for both pydiflumetofen and phenamacril in F. graminearum and emphasizes the need for fungicide resistance management for FHB. © 2024 Society of Chemical Industry.

Synthesis, bioactivity and molecular docking of novel coumarin-quinolinamide containing monocyclic monoterpenes as potential SDH inhibitors

Succinate dehydrogenase inhibitors (SDHI) are widely used in plant antifungal agents. To break the barrier of resistance, a series of new coumarin-quinolinamide SDHI derivatives containing monocyclic monoterpenes were designed and synthesized using natural camphor or natural menthol as lead compounds, and their structures were characterized by FT-IR, 1H NMR, 13C NMR and HRMS. In vitro antifungal activity test results showed that the target compounds had inhibitory activity against most plant pathogenic fungi, especially against Rhizoctonia solani and Phytophthora nicotianae var. nicotianae, which was superior to other fungi. Among them, compounds 11t and 12t showed better inhibitory effects on Rhizoctonia solani than the commercial fungicide tricyclazole, with EC50 of 16.90 mg/L and 27.09 mg/L, respectively. Based on this, the detached leaf assay was used to further explore the in vivo therapeutic and preventive effects of compounds 11t and 12t on rice sheath blight in plants. The results of the antifungal activity test in vivo showed that compound 11t was slightly better than the positive control, while compound 12t was close to the control effect of azoxystrobin. More importantly, the more bioactive compounds 11t and 12t did not affect the germination of cowpea seeds and also did not affect the growth of normal human hepatocytes and kidney cells. Molecular docking experiments showed that the introduction of the diethylamino group could promote the formation of hydrogen bonds between the hydrogen atom on the amide bond of the target compound and residue Tyr91, and compounds 11t and 12t had smaller free energy between the amino acid residue, which would enhance the antifungal activity of the compounds. These studies proved the potential value of this series of compounds for the study of novel amide-based SDHI fungicides.

Design, Synthesis, and Antifungal Evaluation of Diverse Heterocyclic Hydrazide Derivatives as Potential Succinate Dehydrogenase Inhibitors.

Plant pathogenic fungi pose a significant threat to agricultural production, necessitating the development of new and more effective fungicides. The ring replacement strategy has emerged as a highly successful approach in molecular design. In this study, we employed the ring replacement strategy to successfully design and synthesize 32 novel hydrazide derivatives containing diverse heterocycles, such as thiazole, isoxazole, pyrazole, thiadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, thiophene, pyridine, and pyrazine. Their antifungal activities were evaluated in vitro and in vivo. Bioassay results revealed that most of the title compounds displayed remarkable antifungal activities in vitro against four tested phytopathogenic fungi, including Fusarium graminearum, Botrytis cinerea, Sclerotinia sclerotiorum, and Rhizoctonia solani. Especially, compound 5aa displayed a broad spectrum of antifungal activity against F. graminearum, B. cinerea, S. sclerotiorum, and R. solani, with the corresponding EC50 values of 0.12, 4.48, 0.33, and 0.15 μg/mL, respectively. In the antifungal growth assay, compound 5aa displayed a protection efficacy of 75.5% against Fusarium head blight (FHB) at a concentration of 200 μg/mL. In another in vivo antifungal activity evaluation, compound 5aa exhibited a noteworthy protective efficacy of 92.0% against rape Sclerotinia rot (RSR) at a concentration of 100 μg/mL, which was comparable to the positive control tebuconazole (97.5%). The existing results suggest that compound 5aa has a broad-spectrum antifungal activity. Electron microscopy observations showed that compound 5aa might cause mycelial abnormalities and organelle damage in F. graminearum. Moreover, in the in vitro enzyme assay, we found that the target compounds 5aa, 5ab, and 5ca displayed significant inhibitory effects toward succinate dehydrogenase, with the corresponding IC50 values of 1.62, 1.74, and 1.96 μM, respectively, which were superior to that of boscalid (IC50 = 2.38 μM). Additionally, molecular docking and molecular dynamics simulation results revealed that compounds 5aa, 5ab, and 5ca have the capacity to bind in the active pocket of succinate dehydrogenase (SDH), establishing hydrogen-bonding interactions with neighboring amino acid residues.

Recent Advances and Outlook of Benzopyran Derivatives in the Discovery of Agricultural Chemicals.

Scaffold structures, new mechanisms of action, and targets present enormous challenges in the discovery of novel pesticides. The discovery of new scaffolds is the basis for the continuous development of modern agrochemicals. Identification of a good scaffold such as triazole, carbamate, methoxy acrylate, pyrazolamide, pyrido-pyrimidinone mesoionic, and bisamide often leads to the development of a new series of pesticides. In addition, pesticides with the same target, including the inhibitors of succinate dehydrogenase (SDH), oxysterol-binding-protein, and p-hydroxyphenyl pyruvate dioxygenase (HPPD), may have the same or similar scaffold structure. Recent years have witnessed significant progress in the discovery of new pesticides using natural products as scaffolds or bridges. In recent years, there have been increasing reports on the application of natural benzopyran compounds in the discovery of new pesticides, especially osthole and coumarin. A systematic and comprehensive review of benzopyran active compounds in the discovery of new agricultural chemicals is helpful to promote the discussion and development of benzopyran active compounds. Therefore, this work systematically reviewed the research and application of benzopyran derivatives in the discovery of agricultural chemicals, summarized the antiviral, herbicidal, antibacterial, fungicidal, insecticidal, nematicidal and acaricidal activities of benzopyran active compounds, and discussed the structural-activity relationship and mechanism of action. In addition, some active fragments were recommended to further optimize the chemical structure of benzopyran active compounds based on reference information.

Synthesis, fungicidal activity and molecular docking of novel pyrazole-carboxamides bearing a branched alkyl ether moiety

Succinate dehydrogenase inhibitors are essential fungicides used in agriculture. To explore new pyrazole-carboxamides with high fungicidal activity, a series of N-substitutedphenyl-3-di/trifluoromethyl-1-methyl-1H-pyrazole-4-carboxamides bearing a branched alkyl ether moiety were designed and synthesized. The in vitro bioassay indicated that some target compounds displayed appreciable fungicidal activity. For example, compounds 5d and 5e showed high efficacy against S. sclerotiorum with EC50 values of 3.26 and 1.52 μg/mL respectively, and also exhibited excellent efficacy against R. solani with EC50 values of 0.27 and 0.06 μg/mL respectively, which were comparable or superior to penflufen. The further in vivo bioassay on cucumber leaves demonstrated that 5e provided strong protective activity of 94.3 % against S. sclerotiorum at 100 μg/mL, comparable to penflufen (99.1 %). Cytotoxicity assessment against human renal cell lines (239A cell) revealed that 5e had low cytotoxicity within the median effective concentrations. Docking study of 5e with succinate dehydrogenase illustrated that R-5e formed one hydrogen bond and two π-π stacking interactions with amino acid residues of target enzyme, while S-5e formed only one π-π stacking interaction with amino acid residue. This study provides a valuable reference for the design of new succinate dehydrogenase inhibitor.

Quercetin induces itaconic acid-mediated M1/M2 alveolar macrophages polarization in respiratory syncytial virus infection

BackgroundQuercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin's ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive. PurposeThis study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection. MethodsBALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism. ResultsQuercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes. ConclusionOur study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.

Advantageous properties of a new fungicide, isofetamid.

The fungicidal properties of a new fungicide, isofetamid, were examined to assess its antifungal spectrum, mode of action, and effects on the infection process of Botrytis cinerea. Additionally, we investigated its fungicidal activity against isolates of B. cinerea resistant to existing fungicides. In mycelial growth inhibition tests, isofetamid exhibited excellent fungicidal activity against ascomycetes but showed no activity against basidiomycetes and oomycetes. Respiratory enzyme assay using mitochondria revealed that isofetamid inhibited succinate dehydrogenase activity prepared from B. cinerea and other ascomycetes fungi used in the study. On the other hand, the activity of mitochondria prepared from Pythium, potato and rat were not inhibited. Isofetamid inhibited also many stages of the infection processes in B. cinerea. Furthermore, it exhibited high fungicidal activity against B. cinerea isolates that were resistant to existing fungicides.