Cyclobutrifluram (Cyclobutrifluram)

Cyclobutrifluram (cyclobutrifluram) is a nematicide and fungicide that inhibits mitochondrial succinate dehydrogenase. It is commercially known as Tymirium.

Common name (ISO): cyclobutrifluram

Synonyms: SYN549522, SYN549522A, SYN549522B (development codes); Tymirium (trademark)

Commercial product brands: Vaniva e Vaniva SC

Official chemical name (IUPAC): mixture composed of 80-100% N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide and 20-0% of the enantiomer (1R,2R)

Gross chemical formula: C17H13Cl2F3N2O

Number CAS: 1460292-16-3

Chemical class: chiral phenylcyclobutylpyridineamide

Patents: WO2013/143811 (2013); WO2015/003951 (2015); US20230371511A1 (2021)

Syngenta's development of cyclobutrifluram began in the 2000s, probably in the second half of the XNUMXs, using a pioneering methodology called "structure-based pesticide design" - an approach that uses computational molecular modeling to identify compounds with desired properties prior to chemical synthesis. This methodology allowed researchers to map specific molecular interactions between the active ingredient and its biological targets, simultaneously optimizing efficacy and safety profile.

The discovery process involved multiple structural optimization steps, starting from compounds identified through chemical library screening. The research team focused on developing specific succinate dehydrogenase inhibitors, exploring different chemical scaffolds until identifying the phenylcyclobutylpyridineamide structure as a promising one. Cyclobutrifluram represents Syngenta's 5th SDHI fungicide/nematicide, following isopyrazam, sedaxane, benzovindiflupyr and pydiflumetofen.

The official announcement of Tymirium technology took place in 2020, laying the foundation for subsequent commercial launches. The first commercial registration was obtained in 2022.

Dual action pesticide

Dual-action pesticides, such as cyclobutrifluram, can control nematodes and fungi simultaneously through a common biological target: the enzyme succinate dehydrogenase (SDH), present in the mitochondria of both organisms. Although these targets may seem distinct at first glance, the point of convergence lies in the way these pests produce energy.

Fungi and nematodes are eukaryotic organisms. This means that they have cells with a defined nucleus and mitochondria, organelles responsible for energy production. Within these mitochondria, the process of cellular respiration occurs, which depends on the functioning of key enzymes, such as succinate dehydrogenase.

SDH is an integral part of two vital systems in the cell: the citric acid cycle (or Krebs cycle) and the electron transport chain. Its function is to catalyze the conversion of succinate to fumarate, transferring electrons to ubiquinone. This reaction supports the production of ATP, the main source of cellular energy. If this enzyme fails, ATP production ceases. The cell dies.

Biochemical mode of action

The mechanism of action is based on the inhibition of the mitochondrial succinate dehydrogenase complex. Interference occurs in complex II of the respiratory chain, blocking the production of cellular ATP. This specific inhibition interrupts essential metabolic processes in susceptible nematodes and fungi. IRAC classifies nematicides with a mode of action targeting mitochondrial respiration in a specific category under development.

Symptomatic manifestation begins with reduced motility in nematodes, progressing to cessation of feeding and paralysis. In fungi, inhibition of mycelial growth and spore formation is observed. The time required for the first symptoms in nematodes varies between 24-48 hours, with complete death in 72-96 hours. Fungi show growth inhibition in 12-24 hours.

Control spectrum and selectivity

The control spectrum covers nematodes of the genera Meloidogyne, Heterodera, balloon, Pratylenchus e Rotylenchulus.

Among fungi, it stands out for its effectiveness against Fusarium spp., especially F. pseudograminearum.

Partial control is observed in Tylenchulus semipenetrans, Radopholus similis and specific strains of Fusarium oxysporum. Tolerant species include Ditylenchus spp., Aphelenchoides spp. and fungi with previous resistance to SDHIs.

Technical application recommendations

The recommended dosage varies according to the application method. Seed treatment requires 0,75-1,5 g ai/100 kg of seed. Soil application requires 150-300 g ai/ha, rising to 450 g ai/ha in high-pressure situations.

The ideal timing is pre-planting seed treatment or in-furrow application during sowing. Established crops require preventive application before critical populations are established.

Ideal climatic conditions are between 15-30°C temperature and 60-80% relative humidity. Avoid application under severe water stress or temperatures above 35°C. A soil pH between 6,0-7,5 optimizes product performance.

Compatibility and mixing strategies

Compatibility with systemic fungicides (triazoles, strobilurins), organophosphate insecticides and pyrethroids expands possibilities of use. Liquid fertilizers at pH 6,0-7,5 maintain adequate compatibility.

Common mixtures include cyclobutrifluram + metalaxyl-M for expanded control of oomycetes; cyclobutrifluram + imidacloprid for control of nematodes and early pests; and cyclobutrifluram + azoxystrobin for multiple preventive control.

Mixtures with products with extreme pH (<4,0 or >9,0), formulations with high concentrations of sulfates and copper-based products in high concentrations should be avoided. These combinations reduce efficacy or cause physical incompatibility.

Resistance and sustainable management

Resistance risk assessment in three species of Fusarium is under evaluation (doi.org/10.1016/j.toxlet.2023.04.008). There are no confirmed reports of field resistance to nematodes. Resistance management requires rotation with nematicides of different modes of action, integration with non-chemical methods and limitation of consecutive applications to 2-3 harvests.

Practical strategies include rotation with phosphorus, carbamate or biologicals, use of resistant cultivars when available, pre- and post-application population monitoring, and application only when economically necessary. These measures preserve long-term efficacy.

Agronomic efficiency and strategic positioning

Environmental factors significantly influence efficacy. Heavy rainfall 24 hours after application reduces performance. Temperatures below 10°C delay action. Soils with high adsorption capacity reduce availability. Soil pH between 6,0-7,5 optimizes results.

Advantages include dual fungicidal/nematicidal action, long persistence in the soil, low mobility reducing leaching, and compatibility with integrated management. Limitations include high cost compared to alternatives, restriction to preventive applications, reduced efficacy in soils with high organic matter, and relatively long withdrawal period.

Strategic positioning varies according to culture...

In soybeans, seed treatment is recommended in areas with a history of nematodes and in-furrow application in high-pressure regions.

For corn, standard seed treatment and foliar application are established at V4-V6 to control Fusarium spp.

Cotton requires mandatory seed treatment in infested areas and in-furrow application in sandy soils.

In wheat, seed treatment controls root rot (caused by Fusarium spp.), complemented by preventive application in areas with a history.

Vegetables require seedling treatment and application during transplantation, with restricted use due to the grace period.

Coffee uses application at the base of the plant in seedlings and preventive treatment in nurseries.

Sugarcane employs billet treatment and in-furrow application in areas with nematodes.

Fruits require pre-planting soil application and seedling treatment in specialized nurseries.

Other technical information

Studies conducted under laboratory conditions with the active ingredient and two formulations yielded no observed effect (NOEC) concentrations for earthworm reproduction (Eisenia andreii) of 71–171 mg ai/kg of dry soil, without effects on the reproduction of the soil mite (Hypoaspis aculifierUsing Brazil as a target market (soybean seed treatment and in-furrow application in fruit vegetables), our laboratory studies indicate that the risk to two species of soil invertebrates and honeybees, resulting from the use of cyclobutrifluram, whether in the planting furrow or as a seed treatment [...]. (Note: article written by Syngenta researchers) - doi.org/10.1016/j.cropro.2024.106822 -

These results indicated that the risk of resistance of Fusarium fujikuroi The resistance to cyclobutrifluram may be moderate. Sequencing analysis revealed that mutations, including H248D in FfSdhB, A83V in FfSdhC2, and S106F and E166K in FfSdhD, contributed to resistance, which was confirmed by molecular docking and homologous substitution experiments. The results suggest a high potential for cyclobutrifluram to control RBD and a moderate risk of Fusarium fujikuroi resistance to cyclobutrifluram, which are significant findings for the scientific application of cyclobutrifluram. - doi.org/10.1016/j.jia.2024.01.004 -

Cyclobutrifluram exhibited substantial inhibitory activity against species of Fusarium, with semi-maximum effective concentration values ​​ranging from 0,0021 to 0,0647 μg/mL. It demonstrated significant inhibitory activity in three stages of development of Fusarium pseudograminearum, Fusarium graminearum e Fusarium asiaticum. - doi.org/10.1002/ps.7935 -

Molecular modeling confirmed that these mutations in BcSDHB confer resistance to cyclobutrifluram in Botrytis cinereaIn conclusion, the risk of Botrytis cinerea developing resistance to cyclobutrifluram is high, and point mutations in BcSDHB (P225F, N230I, or H272R) confer resistance to cyclobutrifluram in Botrytis cinereaThis study provided important information about cyclobutrifluram resistance in Botrytis cinerea and provided valuable data for monitoring and managing this resistance in the future. - doi.org/10.1016/j.pestbp.2024.105884 -

alternaria alternata presents a moderate risk of developing resistance to cyclobutrifluram, attributed to the S73L substitution in AaSdhC or the P113T, H134N, or D145N mutations in AaSdhD, which are detectable by specific AS-PCR methods. - doi.org/10.1021/acs.jafc.4c10317 Cyclobutrifluram has been shown to be effective against selected anamorphic fungi and ascomycetes. The risk of developing resistance to cyclobutrifluram in Corynespora cassiicola It was assessed as moderate to high and primarily associated with mutations in the CcSdh genes. - doi.org/10.1007/s44154-025-00251-8 -