Rice bakaenii disease (RBD) is a widespread and devastating disease mainly caused by Fusarium fujikuroi. Pydiflumetofen (Pyd) is a novel succinate dehydrogenase inhibitor (SDHI) with strong inhibitory activity against F. fujikuroi, but the mechanism of resistance to Pyd has not been well studied for this pathogen. Through fungicide adaption, a total of 12 Pyd-resistant mutants were obtained and the resistance level could be divided into three categories of high resistance (HR), moderate resistance (MR), and low resistance (LR) with resistance factors (RF) of 184.04-672.90, 12.63-42.49, and <10, respectively. Seven genotypes of point mutations in FfSdh genes (FfSdhBH248L, FfSdhBH248D, FfSdhBH248Y, FfSdhC2A83V, FfSdhC2H144Y, FfSdhDS106F, and FfSdhDE166K) were found in these mutants, among which genotype FfSdhBH248L and FfSdhC2A83V mutants showed HR, genotype FfSdhBH248D, FfSdhBH248Y, FfSdhC2H144Y, and FfSdhDE166K mutants showed MR, and genotype FfSdhDS106F mutants showed LR. Moreover, all the substitutions of amino acid point mutations including FfSdhBH248L/D/Y, FfSdhC2A83V,H144Y, and FfSdhDS106F,E166K conferring resistance to Pyd in F. fujikuroi were verified by protoplast transformation. Additionally, a positive cross-resistance was detected between Pyd and another SDHI fungicide penflufen, while no cross-resistance was detected between Pyd and phenamacril, prochloraz, azoxystrobin, carbendazim, or fludioxonil. Although pathogenicity of the mutants was increased compared with that of the wild-type parental strains, the mycelial growth rate and spore production levels of the resistant mutants were significantly decreased (P < 0.05), indicating significant fitness cost of resistance to Pyd in F. fujikuroi. Taken together, the risk of resistance to Pyd in F. fujikuroi might be moderate, and appropriate precautions against resistance development in natural populations should be taken into account when Pyd is used for the control of RBD.

Study on Mechanisms of Resistance to SDHI Fungicide Pydiflumetofen in Fusarium fujikuroi.

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. 

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

The conformational restriction switch concept has been adopted as a major tool for structural optimization of pharmaceuticals in order to expand the chemical structure scope and improve therapeutic activity against specific proteins. Several of the 1-aminocyclobutanecarboxylic acid derivatives produced in this way exhibited satisfactory antifungal activity in vitro compared with positive control boscalid. In vitro antifungal tests revealed that compound A21 had comparable, even higher antifungal activity against Rhizoctonia solani (R.s., EC50 = 0.03 mg/L) and Botrytis cinerea (B.c., EC50 = 0.04 mg/L) than fluxapyroxad (R.s., EC50 = 0.02 mg/L; B.c., EC50 = 0.20 mg/L) and boscalid (R.s., EC50 = 0.29 mg/L; B.c., EC50 = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activity against porcine SDH, its IC50 value was 3.73 μM, which has considerable potency compared with fluxapyroxad (IC50 = 3.76 μM). The mode of action was determined using SEM and membrane potential research. The effects of the substituent steric hindrance, electrostatic property, hydrophobicity, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable models of comparative molecular field analysis and comparative molecular similarity index analysis. Furthermore, density functional theory simulations, molecule electrostatic potential, and molecular docking were also used to study the probable binding mode of target compounds with flexible fragments. The results showed that the scaffold of 1-aminocyclobutanecarboxylic acid derivatives could be used as lead for discovering new succinate dehydrogenase inhibitors.

Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors.

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. 

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

Abstract As the world's population continues to grow and demand for food increases, the agricultural industry faces the challenge of producing higher yields while ensuring the safety and quality of harvests, operators, and consumers. The emergence of resistance, pest shifts, and stricter regulatory requirements also urgently calls for further advances in crop protection and the discovery of new innovative products for sustainable crop protection. This study reviews recent highlights in innovation as presented at the 15th IUPAC International Congress of Crop Protection Chemistry held in New Delhi, in 2023. The following new products are discussed: the insecticides Indazapyroxamet, Dimpropyridaz and Fenmezoditiaz, the fungicides Mefentrifluconazole and Pyridachlomethyl, the nematicide Cyclobutrifluram, the herbicides Rimisoxafen, Dimesulfazet, and Epyrifenacil as well as the abiotic stress management product Anisiflupurin. In addition, the latest innovative research areas and discovery highlights in all areas of crop protection will be presented, including insecticidal alkyl sulfones and 1,3,4‐trisubstituted pyrazoles, fungicidal picolinamides, herbicidal ketoenols, and trifluoromethylpyrazoles, as well as the latest advances in crop enhancement and green pest control research. © 2024 The Author(s). Pest Management Science published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry. 

Recent innovations in crop protection research

Fusarium fujikuroi is one of the dominant phytopathogenic fungi causing rice bakanae disease worldwide. Cyclobutrifluram is a novel succinate dehydrogenase inhibitor (SDHI), which shows strong inhibitory activity against F. fujikuroi. The baseline sensitivity of 112 F. fujikuroi to cyclobutrifluram was determinated with a mean EC50 value of 0.025 μg/mL. A total of 17 resistant mutants were obtained by fungicide adaptation and displayed equal or slightly weaker fitness than parental isolates, which suggests that the resistance risk of F. fujikuroi to cyclobutrifluram is medium. A positive cross-resistance was detected between cyclobutrifluram and fluopyram. The amino acid substitutions H248L/Y of FfSdhB and G80R or A83V of FfSdhC2 conferred cyclobutrifluram resistance in F. fujikuroi, which was validated by molecular docking and protoplast transformation. The results indicate that the affinity between cyclobutrifluram and FfSdhs obviously decreased after point mutations, causing the resistance of F. fujikuroi.

Multiple Mutations in SDHB and SDHC2 Subunits Confer Resistance to the Succinate Dehydrogenase Inhibitor Cyclobutrifluram in Fusarium fujikuroi.

Cyclobutrifluram is a novel succinate dehydrogenase inhibitor (SDHI) developed by Syngenta and helps to inhibit Fusarium pseudograminearum. Here, the potential for cyclobutrifluram resistance in F. pseudograminearum and the resistance mechanism involved were evaluated. Baseline sensitivity of F. pseudograminearum to cyclobutrifluram was determined with a mean EC50 value of 0.0248 μg/mL. Fungicide adaption generated five resistant mutants, which possess a comparable or a slightly impaired fitness compared to corresponding parental isolates. This indicates that the resistance risk of F. pseudograminearum to cyclobutrifluram might be moderate. Cyclobutrifluram-resistant isolates also demonstrated resistance to pydiflumetofen but sensitivity to carbendazim, phenamacril, tebuconazole, fludioxonil, or pyraclostrobin. Additionally, point mutations H248Y in FpSdhB and A83V or R86K in FpSdhC1 were found in cyclobutrifluram-resistant F. pseudograminearum mutants. Molecular docking and overexpression transformation assay revealed that FpSdhBH248Y and FpSdhC1A83V or FpSdhC1R86K confer the resistance of F. pseudograminearum to cyclobutrifluram.

Resistance Risk and Resistance-Related Point Mutation in SdhB and SdhC1 of Cyclobutrifluram in Fusarium pseudograminearum.

BACKGROUND
Fusarium pseudograminearum is one of the dominant pathogens of Fusarium crown rot (FCR) worldwide. Unfortunately, no fungicides have yet been registered for the control of FCR in wheat in China. Pydiflumetofen, a new-generation succinate dehydrogenase inhibitor, exhibits excellent inhibitory activity to Fusarium spp. A resistance risk assessment of F. pseudograminearum to pydiflumetofen and the resistance mechanism involved have not yet been investigated.


RESULTS
The mean EC50 value of 103 F. pseudograminearum isolates to pydiflumetofen was 0.0162 μg mL-1 , and the sensitivity exhibited a unimodal distribution. Four resistant mutants were generated by fungicide adaption, which possessed similar or impaired fitness compared to corresponding parental isolates based on the results of mycelial growth, conidiation, conidium germination rate, and virulence determination. Pydiflumetofen showed strong positive cross-resistance with cyclobutrifluram and fluopyram but no cross-resistance with carbendazim, phenamacril, tebuconazole, fludioxonil, or pyraclostrobin. Sequence alignment revealed that pydiflumetofen-resistant F. pseudograminearum mutants had two single-point mutations of A83V or R86K in FpSdhC1 . Molecular docking further confirmed that point mutation of A83V or R86K in FpSdhC1 could confer resistance of F. pseudograminearum to pydiflumetofen.


CONCLUSION
F. pseudograminearum shows an overall moderate risk of developing resistance to pydiflumetofen, and point mutation FpSdhC1 A83V or FpSdhC1 R86K could confer pydiflumetofen resistance in F. pseudograminearum. This study provided vital data for monitoring the emergence of resistance and developing resistance management strategies for pydiflumetofen. This article is protected by copyright. All rights reserved.

Resistant risk and resistance-related point mutation in SdhC1 of pydiflumetofen in Fusarium pseudograminearum.

BACKGROUND
Wheat Fusarium crown rot (FCR) stands as a pernicious affliction primarily instigated by Fusarium pseudograminearum, a pathogenic agent known to produce mycotoxins, including deoxynivalenol (DON). Cyclobutrifluram, a novel succinate dehydrogenase inhibitor (SDHI) devised by Syngenta, carries with it immense potential to control both nematodes and Fusarium diseases. However, its efficacy in combating Fusarium species, its abilities in preventing and reversing the detrimental effects of FCR, and its impact on the production of DON by F. pseudograminearum are yet to be fully ascertained.


RESULTS
Cyclobutrifluram exhibited substantial inhibitory activity against Fusarium species, with EC50 values ranging from 0.0021-0.0647 μg mL-1 . It demonstrated significant inhibitory activity to three developmental stages of F. pseudograminearum, F. graminearum and F. asiaticum. Furthermore, cyclobutrifluram showed both protective and curative activities against FCR and was rapidly absorbed by roots and transported to wheat stems and leaves. Cyclobutrifluram could also decrease the DON production of F. pseudograminearum.


CONCLUSION
The present investigation has revealed the tremendous potential of cyclobutrifluram as a formidable contender in the realm of fungicides, particularly in its ability to effectively combat FCR and other Fusarium-related ailments. This novel compound showcases exceptional pathogen-fighting capabilities, coupled with remarkable systemic translocation properties, and a commendable aptitude for reducing the production of DON. This article is protected by copyright. All rights reserved.

Inhibitory activity to Fusarium spp. and control potential for wheat Fusarium crown rot of a novel succinate dehydrogenase inhibitor cyclobutrifluram.

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Multiple Mutations in SDHB and SDHC2 Subunits Confer Resistance to the Succinate Dehydrogenase Inhibitor Cyclobutrifluram in Fusarium fujikuroi.

Resistance Risk and Resistance-Related Point Mutation in SdhB and SdhC1 of Cyclobutrifluram in Fusarium pseudograminearum.

Resistant risk and resistance-related point mutation in SdhC1 of pydiflumetofen in Fusarium pseudograminearum.

Inhibitory activity to Fusarium spp. and control potential for wheat Fusarium crown rot of a novel succinate dehydrogenase inhibitor cyclobutrifluram.