Antifungal compositions and methods of use thereof

Abstract

The present disclosure provides antifungal compositions and methods of using the same. In particular, the compositions comprise (E)-3-methyl-N '-(1-(naphthalen-2-yl) ethylidene) benzoyl hydrazine, which enhances or enhances the activity of certain fungicides.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of the earlier filing date of U.S. Provisional Patent Application No. 63 / 419,568, filed on October 26, 2022, which is hereby incorporated by reference in its entirety. Technical field

[0003] The present disclosure relates to compositions and methods for treating crops susceptible to fungal pathogens. Background art

[0004] Crops worldwide are troubled by fungal pathogens. Fungi have developed a series of mechanisms to survive under fungicides, such as by sequestering, exporting, or detoxifying fungicides. There is a need for formulations that enhance the efficacy of fungicides by blocking certain resistance mechanisms. Summary of the invention

[0005] Disclosed herein are methods and compositions for supporting crop viability and yield, for example, by protecting crops from fungal pathogens. In one embodiment, disclosed herein is a method of enhancing the efficacy of a fungicide by treating a crop with a combination of an adenosine triphosphate diphosphatase inhibitor having the formula of Compound 1:

[0006]

[0007] (E)-3 - methyl - N'-(1-(naphthalen - 2 - yl)ethylidene)benzohydrazide.

[0008] and a specific fungicide. In one embodiment, treating the crop with the adenosine triphosphate diphosphatase inhibitor acts synergistically with the fungicide.

[0009] The foregoing and other objects, features, and advantages of the present invention will become more apparent from the following detailed description with reference to the accompanying drawings. Brief description of the drawings

[0010] Figure 1 Shows the severity of Asian soybean rust in soybeans treated with azoxystrobin, chlorothalonil, tebuconazole, or a combination of azoxystrobin and tebuconazole, with and without the enhancer compound (TX 15) of the present invention, compared to untreated crops (UTC), at 1, 7, 9, 14, and 16 days after application (DAA).

[0011] Figure 2 Shows the intensity of soybean frogeye leaf spot infection in soybeans treated with azoxystrobin, chlorothalonil, tebuconazole, or a combination of azoxystrobin and tebuconazole, with and without the enhancer compound (TX15) of the present invention, compared to untreated crops (UTC), at 4, 11, and 18 days after application (two trials) (DAA).

[0012] Figure 3 Shows the percentage of foliar infection of wheat yellow rust in untreated crops (UTC) and in prophylactic applications with and without the enhancer compound (TX15) of the present invention (azoxystrobin), folpet, (prothioconazole), (fluxapyroxad and pyraclostrobin), A20944 (prothioconazole and fluxametamide), ERA (prothioconazole and bixafen), A21857 ( fluxametamide), (pyriminostrobin) in wheat.

[0013] Figure 4 Shows the time course of the percentage of foliar infection of wheat yellow rust in untreated crops and in wheat with prophylactic application of prothioconazole or a combination of prothioconazole and the enhancer compound (TX15) of the present invention.

[0014] Figure 5 Shows the percentage of foliar infection of wheat Septoria nodorum in untreated crops (UTC) and in prophylactic applications with and without the enhancer compound (TX15) of the present invention (azoxystrobin), folpet, (prothioconazole), (fluxapyroxad and pyraclostrobin), A20944 (prothioconazole and fluxametamide), ERA (prothioconazole and bixafen), A21857 ( fluxametamide), (pyriminostrobin) in wheat.

[0015] Figure 6 Shows the percentage of foliar infection of wheat Septoria nodorum in four winter wheat crops treated with a standard fungicide and with a standard fungicide and the enhancer compound (TX15) of the present invention.

[0016] Figure 7 Shows the severity of downy mildew infecting grape crops evaluated on ears and leaves in untreated crops (UTC) and in crops treated with cyazofamid, or cyazofamid and the enhancer compound (TX15) of the present invention.

[0017] Figure 8 Shows untreated grape crops (UTC) and QUADRIS used alone or in combination with the enhancer compound (TX15) of the present invention Percentage of infection of grape crops treated with (azoxystrobin and difenoconazole).

[0018] Figure 9 Shows the percentage of winter wheat treated with metconazole and with a combination of metconazole and the enhancer compound (TX 15) of the present invention and untreated crops infected with Zymoseptoria tritici. Detailed Description

[0019] I. Terms

[0020] The following explanations of terms and methods are provided to better describe the present disclosure and to guide one of ordinary skill in the art in practicing the present disclosure. Unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" are meant to include one or more than one. Unless the context clearly dictates otherwise, the term "or" means a single element of the recited alternative elements or a combination of two or more elements. As used herein, "comprising" means "including". Thus, "comprising A or B" means "including A, B, or A and B", without excluding additional elements. All references (including patents and patent applications) cited herein are incorporated by reference in their entirety unless otherwise stated.

[0021] Unless otherwise stated, all numerical values expressing quantities of components, molecular weights, percentages, temperatures, times, etc. used in the specification or claims should be understood to be modified by the term "about". Thus, unless otherwise implied or stated explicitly, the numerical parameters shown are approximations, which may depend on the desired characteristics sought and / or the detection limits under standard test conditions / methods. When distinguishing an embodiment directly and explicitly from the prior art being discussed, the embodiment numerical value is not an approximation unless the word "about" is explicitly recited.

[0022] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0023] "Applying" means any suitable mode of application for controlling pathogens such as fungal pathogens, including treating existing crops, agricultural products, seeds, soil, or combinations thereof. As used herein, applying to a crop is expected to mean applying by treating existing crops, agricultural products, seeds, soil, or combinations thereof to benefit the crop.

[0024] "Combined with..." means administering the compounds simultaneously in a single application, or sequentially in two or more different applications that may be separated in time, location, or method.

[0025] "Control" with respect to a fungal pathogen means blocking, inhibiting, and / or eradicating the pathogen and / or preventing the pathogen from damaging the crop. In one embodiment, control means reducing one or more fungi to undetectable levels, or reducing or inhibiting the fungal pathogen to an acceptable level determined by one of ordinary skill in the art (e.g., a crop grower). The determination of an acceptable level of fungal pathogen reduction is based on a number of factors, including the crop, the pathogen, the severity of the pathogen, use restrictions, economic thresholds, and other factors known to one of ordinary skill in the art.

[0026] As used herein, the terms "enhancer" and "synergist" refer to one or more compounds that enhance the effect of a fungicide as disclosed herein. Without being bound by theory, the enhancer compounds of the invention disclosed herein may act by blocking one or more pathways of a fungal pathogen to avoid toxicity, such as by detoxifying, sequestering, or transporting the fungicide. In certain embodiments, the enhancer compounds of the invention inhibit the enzymatic activity of ATP diphosphatase, which results in an enhanced, potentiated, or synergized fungicidal effect. For example, when an enhancer or synergist is used in combination with a fungicide, the combination of the enhancer and the fungicide enhances the fungicidal effect of the fungicide and / or renders fungi resistant to the fungicide sensitive to the fungicide due to the activity of the enhancer. Most commonly, the enhancer compounds of the invention do not directly inhibit the growth of fungi and do not have an adverse effect on the crop that is (or may be) infected by the pathogen.

[0027] As used herein, the term "botanically acceptable" means that a composition, diluent, excipient, and / or carrier is generally suitable for use with any part of a plant (including but not limited to seeds, seedlings, plant cells, plants, or flowers) during any part of the plant life cycle. The composition can be prepared according to procedures, methods, and formulations known to those skilled in the agricultural arts. In accordance with the teachings of the present disclosure, those skilled in the agricultural and / or chemical arts can readily prepare the desired composition. Most commonly, the compounds of the present invention can be formulated for storage and / or application in the form of an aqueous or non-aqueous suspension or emulsion, either pure or prepared from a concentrated formulation of the composition. Alternatively, the compounds of the present invention can be formulated for use in an aerosol generating device for application to agricultural products stored in a sealed chamber - a method of application known as atomization. Water-soluble, water-suspendable, or emulsifiable formulations containing the compounds disclosed herein can also be converted into or formulated as solids (e.g., wettable powders), which are then diluted into the final formulation. In certain formulations, the compositions of the present disclosure can also be provided in a growth medium such as an in vitro medium for culturing plants or other types of cells, a laboratory plant growth medium, soil, or for spraying on seeds, seedlings, roots, stems, stalks, leaves, flowers, or entire plants.

[0028] As used herein, the term "treatment" means a method for applying or administering an effective amount of the disclosed compound or its formulation to a field and / or a target area of a plant. The treatment methods can be, but are not limited to, aerosol spraying, pressure spraying, direct watering, chemigation, atomization, and dipping. The target areas of a plant can include, but are not limited to, the leaves, roots, stems, buds, flowers, fruits, seeds, and bulbs of the plant, including bulbs, corms, rhizomes, tubers, taproots, and rootstocks. The treatment can include methods in which one area of a plant (e.g., the root zone or the leaf surface) is treated and another area of the plant is protected (e.g., treating the leaf surface when the disclosed compound is applied to the root zone, or treating new growth when the disclosed compound is applied to the leaf surface).

[0029] II. Booster Compounds

[0030] Compositions are described herein that contain booster compounds having the following structures:

[0031]

[0032] (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide (also referred to herein as Compound 1). This compound is referred to herein by its chemical structure and name; however, as will be apparent to one of ordinary skill in the art upon consideration of the structure of the enhancer compound, the compound may also be its Z isomer. The existence of tautomers of the exemplified enhancer compound will also be apparent to those skilled in the art. All such isomers and tautomers of the enhancer compound are contemplated herein.

[0033] This compound is referred to herein as an enhancer, synergist, or ATP diphosphatase inhibitor by its function. As understood by one of ordinary skill in the art, the terms enhancer compound, synergist compound, and ATP diphosphatase inhibitor all refer to (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide, its (Z)-isomer, and its tautomers.

[0034] Without being bound by any particular theory, it is believed that the enhancer compound acts by blocking one or more pathways by which fungal pathogens avoid toxicity, such as by detoxifying, sequestering, or transporting the fungicide. In one aspect, the compounds of the present invention inhibit enzymatic ATP diphosphatase activity, which results in the fungicidal action being enhanced, potentiated, or synergized. For example, when an enhancer or synergist is used in combination with a fungicide, the combination of the enhancer and the fungicide enhances the fungicidal effect of the fungicide and / or renders fungi resistant to the fungicide sensitive due to the activity of the enhancer. Most commonly, the enhancers of the present invention do not directly inhibit fungi and do not have an adverse effect on seeds, crops, or crop products that are (or may be) infected with fungi.

[0035] III. COMBINATION TREATMENT

[0036] In one embodiment, the ATP diphosphatase inhibitors disclosed herein can be used to enhance the fungicidal action of a variety of fungicides. The inventors have found that certain fungicides are enhanced by the enhancer compound, while other fungicides are not enhanced by the enhancer compound. Therefore, the fungicides to be used in combination with the specific enhancer compounds described herein must be carefully selected. In one embodiment, treatment with a combination of a selected fungicide and an enhancer compound provides synergistic fungicidal activity against phytopathogenic fungi. As Figures 1 - 8 shown, the combination of the enhancer compounds of the present invention with exemplary fungicides significantly reduces fungal growth. In certain examples, the enhancer compounds of the present invention differentially enhance the efficacy of certain fungicides. Certain fungicides are not enhanced by the enhancer compounds of the present invention.

[0037] According to the methods and compositions of the present invention, the fungicides whose efficacy is restored or enhanced by the enhancer compounds of the present invention include azoxystrobin, difenoconazole, chlorothalonil, tebuconazole, folpet, prothioconazole, fluxapyroxad, metconazole, cyflufenamid, benzovindiflupyr, pyrimethanil, cyazofamid, pyraclostrobin, and combinations thereof.

[0038] In one embodiment, a method for inhibiting fungal infections in at-risk seeds or plants is disclosed, the method comprising contacting the seeds or plants with a fungicide selected from: azoxystrobin, difenoconazole, chlorothalonil, tebuconazole, folpet, prothioconazole, fluxapyroxad, metconazole, cyflufenamid, benzovindiflupyr, pyrimethanil, cyazofamid, pyraclostrobin, or combinations thereof.

[0039] In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes pyrimethanil.

[0040] In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes fluxapyroxad. In one such embodiment, in addition to fluxapyroxad, the fungicide further includes prothioconazole.

[0041] In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes benzovindiflupyr. In one such embodiment, in addition to benzovindiflupyr, the fungicide further includes prothioconazole.

[0042] In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes fluxapyroxad. In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes cyflufenamid. In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes fluxapyroxad and cyflufenamid.

[0043] In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes methoxyacrylates, such as azoxystrobin, pyraclostrobin, or both. In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes a fungicide selected from azoxystrobin, pyraclostrobin, or combinations thereof. In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes azoxystrobin. In one embodiment, the fungicide enhanced by the enhancer compound of the present invention includes pyraclostrobin, and in one such embodiment, the fungicide includes pyraclostrobin and cyflufenamid.

[0044] In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include azoxystrobin, fluxapyroxad, fluxametamide, or combinations thereof. In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include azoxystrobin, fluxametamide, or both. In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include azoxystrobin and fluxametamide.

[0045] In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include difenoconazole, cyflufenamid, prothioconazole, or both. In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include cyflufenamid, prothioconazole, or both. In one embodiment, the fungicide enhanced by the enhancer compounds of the present invention is cyflufenamid. In one embodiment, the fungicide enhanced by the enhancer compounds of the present invention is prothioconazole. In one embodiment, the fungicide enhanced by the enhancer compounds of the present invention is difenoconazole.

[0046] In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include fluxapyroxad. In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include cyflufenamid and fluxapyroxad.

[0047] In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include folpet.

[0048] In one embodiment, the fungicides enhanced by the enhancer compounds of the present invention include triazole carboxamides such as ethaboxam.

[0049] In one embodiment, the present disclosure provides compositions and methods for treating plants or plant seeds infected with or at risk of being infected with fungal pathogens. In one embodiment, the compositions of the present disclosure comprise a fungicide such as one or more of the above fungicides, an enhancer compound, and a botanically acceptable carrier. In another embodiment, the fungicide and the enhancer compound are applied in separate compositions.

[0050] In additional embodiments, agricultural or horticultural fungicides are used in combination with other compounds in addition to the disclosed enhancer compounds. Such other compounds may be applied in the same or separate compositions as the fungicide and / or formulation. Examples of other components include known carriers for formulation. Other examples thereof include conventionally known herbicides, insecticide / acaricides, nematicides, molluscicides, soil insecticides, plant protectants, synergists, fertilizers, and soil conditioners. In one embodiment, the inclusion of such other components results in a further enhancement of crop growth, and in some embodiments, a synergistic effect on crop growth.

[0051] IV. Target Crops and Their Pathogens

[0052] The present disclosure provides formulations and methods for treating fungal pathogens of crops, products, seeds, and soil. In one embodiment, the enhancer compounds of the present invention are applied in combination with agricultural fungicides such as those described in Part III above. Crops that can be treated as known to those of ordinary skill in the agricultural art include crops infected with fungal pathogens. By way of example, such agricultural and horticultural crops that can be treated according to the present disclosure include plants, whether genetically modified or not, including their harvested products, such as: grains; vegetables; root crops; potatoes; trees such as fruit trees, e.g., banana trees, tea trees, coffee trees, or cocoa trees; grasses; turfgrasses; or cotton.

[0053] The agricultural or horticultural enhancer and fungicide combinations disclosed herein can be applied to each part of the plant, such as leaves, stems, patterns, flowers, flower buds, fruits, seeds, seedlings, roots, tubers, taproots, buds, or cuttings. The agricultural or horticultural enhancer according to the present disclosure can also be applied to improved varieties / varieties, cultivars, and mutants, hybrids, and genetically modified embodiments of these plants.

[0054] The agricultural or horticultural treatments described herein can be used for seed treatment, foliar application, soil application, or water application to control various diseases occurring in agricultural or horticultural crops (including flowers, turf, and forage).

[0055] The enhancer compounds of the present invention are particularly useful for enhancing the action of fungicides against plant fungal pathogens. Examples of pathogens treated according to the methods and compositions of the present invention include, but are not limited to, Botrytis cinerea, Colletotrichum graminicola, Fusarium oxysporum, Sclerotiana sclerotiorum, Verticillium dahlia, Mycospharella gramincola, and Sphacelotheca reliana.

[0056] Botrytis cinerea is an airborne plant pathogen with a necrotrophic lifestyle that attacks over 200 crop hosts worldwide. It mainly attacks dicotyledonous plant species (including important protein, oil, fiber, and horticultural crops, grapes, and strawberries), and Botrytis also causes secondary soft rot of fruits and vegetables during storage, transportation, and in the market. Many types of fungicides cannot control Botrytis cinerea due to its genetic plasticity.

[0057] The genus Colletotrichum includes approximately 600 species that attack more than 3,200 monocotyledonous and dicotyledonous plant species. Colletotrichum graminicola mainly infects maize (Zea mays), causing losses of approximately $1 billion per year in the United States alone (Connell et al., 2012).

[0058] Another pathogen that can be treated according to the methods and compositions of the present invention is banana wilt caused by the soil-borne fungus Fusarium oxysporum f.sp. cubense, which is a major threat to banana production worldwide. Currently, there are no fungicides available to effectively control the disease after the plant is infected (Peng J et al., 2014).

[0059] The ascomycete Sclerotinia sclerotiorum is known to attack more than 400 host species and is considered one of the most prolific plant pathogens. Sclerotinia sclerotiorum is another pathogen that can be treated according to the methods and compositions of the present invention to improve crop health and yield. Most infected crop species are dicotyledons, as well as some agriculturally important monocotyledons. Some important crops infected by Sclerotinia sclerotiorum include legumes (soybeans), most vegetables, stone fruits, and tobacco.

[0060] The ascomycete Verticillium dahliae is a soil-borne fungal plant pathogen that causes vascular wilt in a wide range of dicotyledonous host species. Verticillium dahliae can cause severe yield and quality losses in cotton and other important crops such as vegetables, fibers, fruits, nut trees, forest trees, and ornamental plants.

[0061] The ascomycete fungus Septoria tritici blotch (anamorph: Septoria tritici) is one of the most important foliar diseases of wheat leaves and occurs wherever wheat is grown. Yield losses caused by this disease range from 25% to 50%, and are particularly high in Europe, the Mediterranean region, and East Africa. Infection by Septoria tritici is initiated by airborne ascospores produced on crop residues from the previous season. Primary infection usually occurs after emergence in spring or autumn. The mature disease is characterized by necrotic lesions on the leaves and stems of infected plants.

[0062] The basidiomycete fungus Sphacelotheca reiliana systemically infects maize (Zea mays), causing smut. Yield losses caused by the disease are variable and depend directly on the incidence of the disease. The fungus overwinters in crop debris or soil in the form of diploid teliospores. The flower structure is transformed into a sorus containing a large amount of powdery teliospores, similar to the mature gall of common smut.

[0063] Examples of crops treated with the methods and compositions disclosed herein and plant diseases (pathogens) controlled include, but are not limited to:

[0064] Beets: Cercospora leaf spot (Cercospora beticola), black root rot (Aphanomyces cochlioides), root rot (Thanatephorus cucumeris), leaf rot (Thanatephorus cucumeris), etc.

[0065] Peanuts: Brown leaf spot (Mycosphaerella arachidis), leaf mold (Ascochyta sp.), rust (Puccinia arachidis), damping-off (Pythium debaryanum), rust spot (Alternaria alternata), stem rot (Sclerotium rolfsii), black rust (Mycosphaerella berkeleyi), etc.

[0066] Cucumbers: Powdery mildew (Sphaerotheca fuliginea), downy mildew (Pseudoperonospora cubensis), gummy stem blight (Mycosphaerella melonis), fusarium wilt (Fusarium oxysporum), sclerotinia rot (Sclerotinia sclerotiorum), gray mold (Botrytis cinerea), anthracnose (Colletotrichum orbiculare), angular leaf spot (Cladosporium cucumerinum), brown spot (Corynespora cassiicola), damping-off (Pythium debaryanum, Rhizoctonia solani Kuhn), Phomopsis root rot of cucumber (Phomopsis sp., Pseudomonas syringae pv. Lechrymans), etc.

[0067] Tomato: Botrytis cinerea (Botrytis cinerea), leaf mold (Cladosporium fulvum), late blight (Phytophthora infestans), Verticillium wilt (Verticillium albo-atrum, Verticillium dahliae), powdery mildew (Oidium neolycopersici), early blight (Alternaria solani), leaf mold (Pseudocercospora fuligena), etc.

[0068] Eggplant: Botrytis cinerea (Botrytis cinerea), black rot (Corynespora melongenae), powdery mildew (Erysiphe cichoracearum), leaf mold (Mycovellosiella nattrassii), sclerotinia rot (Sclerotinia sclerotiorum), Verticillium wilt (Verticillium dahliae), brown spot (Phomopsis vexans), etc.

[0069] Strawberry: Botrytis cinerea (Botrytis cinerea), powdery mildew (Sphaerotheca humuli), anthracnose (Colletotrichum acutatum, Colletotrichum fragariae), Phytophthora rot (Phytophthora cactorum), soft rot (Rhizopus stolonifer), Fusarium wilt (Fusarium oxysporum), Verticillium wilt (Verticillium dahliae), etc.

[0070] Onion: neck rot (Botrytis allii), Botrytis cinerea (Botrytis cinerea), leaf blight (Botrytis squamosa), downy mildew (Peronospora destructor), Phytophthora porn disease (Phytophthora porn), etc.

[0071] Cabbage: Clubroot (Plasmodiophora brassicae), Soft rot (Erwinia carotovora), Black rot (Xanthomonas campestris pv. campestris, Pseudomonas syringae pv. Maculicola), P. s. pv. alisalensis, Downy mildew (Peronospora parasitica), Sclerotinia rot (Sclerotinia sclerotiorum), Black spot (Alternaria brassicicola), Botrytis cinerea rot (Botrytis cinerea), etc.

[0072] Common bean: Sclerotinia rot (Sclerotinia sclerotiorum), Botrytis cinerea rot (Botrytis cinerea), Anthracnose (Colletotrichum lindemuthianum), Angular leaf spot (Phaeoisariopsis griseola), etc.

[0073] Apple: Powdery mildew (Podosphaera leucotricha), Scab (Venturia inaequalis), Brown rot (Monilinia mali), Black spot (Mycosphaerella pomi), Canker (Valsa mali), Alternaria blotch (Alternaria mali), Rust (Gymnosporangium yamadae), Ring rot (Botryosphaeria berengeriana), Anthracnose (Glomerella cingulata, Colletotrichum acutatum), Leaf rot (Diplocarpon mali), Flyspeck (Zygophiala jamaicensis), Sooty blotch (Gloeodes pomigena), Violet root rot (Helicobasidium mompa), Botrytis cinerea rot (Botrytis cinerea), etc.

[0074] Japanese apricot: Scab (Cladosporium carpophilum), Botrytis cinerea rot (Botrytis cinerea), Brown rot (Monilinia mumecola), etc.

[0075] Persimmons: Powdery mildew (Phyllactinia kakicola), anthracnose (Gloeosporium kaki), angular leaf spot (Cercospora kaki), etc.

[0076] Peaches: Brown rot (Monilinia fructicola), scab (Cladosporium carpophilum), Phomopsis rot (Phomopsis sp.), bacterial leaf spot (Xanthomonas campestris pv. pruni), etc.

[0077] Apricots: Brown rot (Monilinia taxa), spot blotch (Stigminacarpophila), scab (Cladosporium carpophilum), red leaf spot (Polystigma rubrum), target spot (Alternaria alternata), anthracnose (Colletotrichum gloeospoides), etc.

[0078] Yellow peaches: Brown rot (Monilinia fructicola), anthracnose (Colletotrichum acutatum), black spot (Alternaria sp.), sclerotinia of young fruits (Monilinia kusanoi), etc.

[0079] Grapes: Gray mold (Botrytis cinerea), powdery mildew (Uncinula necator), ripe rot (Glomerella cingulata, Colletotrichum acutatum), downy mildew (Plasmopara viticola), anthracnose (Elsinoe ampelina), brown leaf spot (Pseudocercospora vitis), black rot (Guignardia bidwellii), white rot (Coniella castaneicola), rust (Phakopsora ampelopsidis), etc.

[0080] Pear: Venturia nashicola (black spot), Gymnosporangium asiaticum (rust), Alternaria kikuchiana (black spot), Botryosphaeria berengeriana (ring rot), Phyllactinia mali (powdery mildew), Phomopsis fukushii (spruce rot), Stemphylium vesicarium (brown spot), Glomerella cingulata (anthracnose), etc.

[0081] Tea: Pestalotiopsis longiseta and Pestalotiopsis theae (target spot), Colletotrichum theae-sinensis (anthracnose), Exobasidium reticulatum (net blight), etc.

[0082] Citrus fruits: Elsinoe fawcettii (black spot), Penicillium italicum (blue mold), Penicillium digitatum (common green mold), Botrytis cinerea (gray mold), Diaporthe citriXanthomonas campestrispv.Citri (black rot), Oidium sp. (powdery mildew), etc.

[0083] Wheat: Powdery mildew (Blumeria graminis f.sp.tritici), Red mold (Gibberella zeae), Red rust (Puccinia recondita), Brown snow mold (Pythium iwayamai), Pink snow mold (Monographella nivalis), Eyespot (Pseudocercosporella herpotrichoides), Leaf scorch (Septoria tritici), Glume blotch (Leptosphaeria nodorum), Spot blotch snow blight (Typhula incarnata), Sclerotial snow blight (Myriosclerotinia borealis), Damping-off (Gaeumannomyces graminis), Ergot (Claviceps purpurea), Bunt (Tilletia caries), Loose smut (Ustilago nuda), etc.

[0084] Barley: Leaf spot (Pyrenophora graminea), Net blotch (Pyrenophora teres), Leaf spot (Rhynchosporium secalis), Loose smut (Ustilago tritici, U. nuda), etc.

[0085] Rice: Blast (Pyricularia oryzae), Sheath rot (Rhizoctonia solani), Bakanae disease (Gibberella fujikuroi), Brown spot (Cochliobolus miyabeanus), Damping-off (Pythium graminicola), Bacterial leaf blight (Xanthomonas oryzae), Bacterial seedling blight (Burkholderia plantarii), Brown stripe (Acidovorax avenae), Bacterial grain rot (Burkholderia glumae), Cercospora leaf spot (Cercospora oryzae), False smut (Ustilaginoidea virens), Rice brown spot (Alternaria, Curvularia intermedia), Discoloration of rice grains (Alternaria padwickii), Powdering of rice grains (Epicoccum purpurascens), etc.

[0086] Tobacco: Sclerotinia rot (Sclerotinia sclerotiorum), Powdery mildew (Erysiphe cichoracearum), Phytophthora rot (Phytophthora nicotianae), etc.

[0087] Tulip: Botrytis blight (Botrytis cinerea), etc.

[0088] Sunflower: Downy mildew (Plasmopara halstedii), Sclerotinia rot (Sclerotinia sclerotiorum), etc.

[0089] Evergreen grass: Sclerotinia snow blight (Sclerotinia borealis), Large patch (Rhizoctonia solani), Brown patch (Rhizoctonia solani), Dollar spot (Sclerotinia homoeocarpa), Blast (Pyricularia sp.), Pythium root rot (Pythium aphanidermatum), Anthracnose (Colletotrichum graminicola), etc.

[0090] Orchard grass: Powdery mildew (Erysiphe graminis), etc.

[0091] Soybeans: Purple spot (Cercospora kikuchii), downy mildew (Peronospora manshurica), Phytophthora rot (Phytophthora sojae), rust (Phakopsora pachyrhizi), sclerotinia rot (Sclerotinia sclerotiorum), anthracnose (Colletotrichum truncatum), gray mold (Botrytis cinerea), citrus scab (Elsinoe glycines), black rot (Diaporthe phaseolorum var. sojae), etc.

[0092] Potatoes: Phytophthora rot (Phytophthora infestans), early blight (Alternaria solani), scurf (Rhizoctonia solani), Verticillium wilt (Verticillium albo - atrum, Verticillium dahliae, Verticillium nigrescens, etc.

[0093] Bananas: Panama disease (Fusarium oxysporum), banana leaf spot (Mycosphaerella fijiensis, M. musicola), etc.

[0094] Rapeseed: Sclerotinia rot (Sclerotinia sclerotiorum), root rot (Phoma lingam), black leaf spot (Alternaria brassicae), etc.

[0095] Coffee: Rust (Hemileia vastatrix), anthracnose (Colletotrichum coffeanum), leaf spot (Cercospora coffeicola), etc.

[0096] Sugarcane: Brown rust (Puccinia melanocephala), etc.

[0097] Maize: Banded leaf spot (Gloeocercospora sorghi), rust (Puccinia sorghi), southern rust (Puccinia polysora), smut (Ustilago maydis), brown spot (Cochliobolus heterostrophus), northern leaf blight (Setosphaeria turcica), etc.

[0098] Cotton: Seedling blight (Pythium sp.), rust (Phakopsora gossypii), sour rot (Mycosphaerella areola), anthracnose (Glomerella gossypii), etc.

[0099] V. Formulations

[0100] The present disclosure provides a potentiator compound and its formulation for enhancing the efficacy of a fungicide to effectively limit the growth of pathogenic fungi affecting crops, agricultural products, seeds, and / or soil. In certain non-limiting embodiments, the apyrase inhibitor can be provided in an amount of from about 0.01 to about 80% weight / weight in the final composition, or from about 25% to about 55% in the final composition, such as from about 30% to about 50%, from about 35% to about 45%, such as about 0.01, 0.05, 0.1, 0.5, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 4.0, 5.0, 7.5, 10, 20, 30, 40, 50, 55, 60, or 80% weight / weight. In one embodiment, the apyrase inhibitor is provided in liquid form in an amount of from about 0.01 to about 50% in the final diluted composition, such as from about 15% to about 50%, from about 20% to about 45%, from about 25% to about 40%, such as about 0.01, 0.05, 0.1, 0.5, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 4.0, 5.0, 7.5, 10, 15, 20, 30, 40, or 50% volume / volume. Those skilled in the art will recognize that formulations of pesticides, apyrase inhibitors, or combinations thereof can be provided in the form of concentrates that can be diluted prior to use, or can be provided in a diluted form ready for treatment.

[0101] The potentiator, pesticide, and combinations thereof are not particularly limited by the dosage form. Examples of dosage forms include wettable powders, emulsions, emulsifiable concentrates, oil-dispersible liquids, powders, granules, water-soluble agents, suspensions, granular wettable powders, and tablets. The method for preparing the formulation is not particularly limited, and conventional known methods can be employed according to the dosage form.

[0102] Several formulation examples are described below. The formulation recipes shown below are only examples and can be modified within the scope not departing from the essence of the present disclosure. For example, additional active and inert components can be added to the following formulations. Unless otherwise specified, "parts" means "parts by mass".

[0103] Formulation Example 1

[0104] Wettable powder

[0105] 40 parts of the enhancer compound disclosed herein, 53 parts of diatomaceous earth, 4 parts of ethoxylated higher alcohol sulfate combined with a suitable solid carrier such as magnesium sulfate, and 3 parts of alkylnaphthalenesulfonate are mixed uniformly and then finely ground to obtain a wettable powder containing 40 parts by mass of the enhancer.

[0106] Formulation Example 2

[0107] Aqueous suspension concentrate

[0108] 2.5 g of the enhancer compound, 0.5 g of the dispersant Tamol SN, 1 g of propylene glycol, 0.006 g (10 mM) of boric acid powder buffer, 5 g of water, optionally 0.05 g of the low molecular weight surfactant Surfonic L24-7, and optionally 0.01 g of the defoamer SAG are placed in a 100 mL glass beaker. 1572.30 g of glass beads with a diameter of 2 mm are added, and the suspension is ground with a mechanical stirrer to a median diameter of less than 1.5 microns as measured on a Malvern Mastersizer 3000. 0.5 g of a pre-gel containing 2% xanthan gum polysaccharide and 2% biocide Acticide B20 is added to the suspension concentrate, and the mechanical stirrer is run for another 10 minutes. The pH is adjusted to 9.0 using 2% phosphoric acid or 1 M sodium hydroxide as needed. Water is added as needed to bring the final concentration of Compound B to 25 wt%. The suspension concentrate is collected by sieving out the glass beads.

[0109] Formulation Example 3

[0110] Aqueous suspension concentrate

[0111] An aqueous suspension concentrate is prepared with the following composition: 30 wt% of Compound 1, 2.5 wt% of a triphenylvinylphenol polyoxyethylene ether surfactant, 2.0 wt% of an ethylene oxide-propylene oxide block copolymer dispersant, 5.0 wt% of a propylene glycol antifreeze protectant, 0.1 wt% of a silicone oil defoamer, 52.4% of distilled water, and 8.0 wt% of a viscosity modifier gel containing 2.0% xanthan gum and 1.0% biocide aqueous solution is added after 2 hours of grinding. Aliquots of the suspension are adjusted to pH 8 with 10 wt% sulfuric acid, pH 10 borate buffer, and 10 wt% sodium hydroxide, respectively.

[0112] VI. Method for Evaluating Activity

[0113] The compounds disclosed by the present invention exhibit activities against a variety of pathogens. Their activities are partially evaluated according to the following assays:

[0114] Method 1: In vitro ATP diphosphatase assay:

[0115] The ATP diphosphatase inhibitory activity was evaluated using an in vitro assay. The method of Windsor, BioTechniques 33:1024 - 1030 (November 2002) was used as follows:

[0116] Screening of ATP diphosphatase inhibitors—

[0117] A 96 - well plate was used for this assay: (Greiner bio - one: REF - 655901—96 wells, PS, F - bottom, transparent, non - binding)

[0118] Buffers:

[0119] Reaction buffer: 60 mM Hepes; 3 mM MgCl 2 , 3 mM CaCl 2 and 3 mM ATP (pH 6.5)

[0120] Development buffer A: 2% aqueous ammonium molybdate

[0121] Development buffer B: Aqueous solution of 11% ascorbic acid in 37.5% TCA

[0122] Termination buffer C: 2% aqueous acetic acid in 2% sodium citrate

[0123] · Add 100 μl of reaction buffer to each well.

[0124] · Add 10 μl of DMSO (control) or inhibitor / one compound or multiple compounds such as N1915 or vanadate to each well. (Use an inhibitor concentration of 1 mM; 2 mM vanadate, 1 mM N1915)

[0125] · Add 10 μl of ATP diphosphatase (concentration based on optimization—dilute 1 U / μl enzyme to different concentrations such as 0.1 U, 0.05 U, 0.0025, 0.001 U, 0.0005 U—to find a good range)

[0126] · Incubate the plate at room temperature for 1 hour

[0127] · Mix development buffer A and B in a ratio of 1:1.5 (before use).

[0128] · Add 50 μl of the A:B mixture to each well (incubate for 2 minutes)

[0129] · Add 50 ul of C to each well

[0130] · Measure / Read the absorbance of the plate at 630 nm

[0131] Compound 1 inhibits about 60% of the ATP diphosphatase in this assay.

[0132] Method 2: Greenhouse crop test

[0133] In this method, the ability of compound 1 to enhance the activity against plant pathogenic fungi Septoria tritici on wheat, Botrytis cinerea on tomato, Phakopsora pachyrhizi on soybean and Puccinia recondita on wheat in combination with one of four fungicides Amistar (azoxystrobin), Imtrex (fluxapyroxad), Proline (prothioconazole) or Balaya (fluopicolide and pyraclostrobin) in a controlled greenhouse environment was evaluated. In these studies, soybean cultivar Siverka, tomato (Money maker) and wheat plants (JBDiego) were used. Seeds were sown to a depth of 1 - 2 cm in 9 cm diameter pots using Petersfield potting compost (75% medium grade peat, 12% screened sterilized loam, 3% medium grade vermiculite, 10% coarse sand (5 mm screened, lime free), 1.5 kg PG mixture / m3, lime to pH 5.5 - 6.0 and wetting agent (Vitax Ultrawet 200 ml / m3) and germinated / grown at 23 °C under 16 h day / 8 h night lighting regime. Plants were treated two to three weeks after sowing when they were at the BBCH 11 growth stage (when the first pair of true leaves (single leaves) had unfolded). Using a track sprayer, plants were treated with a mixture of commercial fungicide and test compound using a water volume of 200 L / ha. Twenty-four hours after treatment, plants were inoculated with the appropriate fungus (pathogen). The fungal pathogens used were Botrytis cinerea (grey mould on tomato plants), Septoria tritici (septoria leaf spot on wheat plants), Puccinia triticina (brown rust on wheat plants) and Phakopsora pachyrhizi (Asian soybean rust on soybean plants). Each combination of fungicide, pathogen and test compound was used with four replicates. After disease symptoms had fully developed between seven and twenty days (depending on the pathogen), the percent disease control of each plant was evaluated. Appropriate controls were used for all experiments, including 'inoculation checks' where plants were inoculated with the specific pathogen of the plant to evaluate disease levels. Additionally, each commercial fungicide was tested separately as part of each treatment, which served as a benchmark for evaluating the combination of compound 1 with the fungicide. The exemplary combinations showed enhanced disease control compared to disease control observed with the fungicide alone. That is, the compounds of the present invention, while not fungicidal per se, enhance the activity of the fungicide.

[0134] In these studies, the fungicides were applied at the following rates

[0135]

[0136] Compound 1 was applied at 15 ppm or 30 ppm.

[0137] At 15 ppm, the results showed additional disease control benefits as shown in the table below

[0138] Amistar Imtrex Proline Balaya Septoria tritici -- 19.9％ 5.8％ -- Botrytis cinerea 19.1％％ -- -- -- Phakopsora pachyrhizi 11.4％ 6.3％ 98.0％％ 26.3％ Puccinia horiana 11.6％ 65.4％ -- 86.4％

[0139] At 30 ppm, the results showed additional disease control benefits as shown in the table below

[0140] Amistar Imtrex Proline Balaya Septoria tritici 10.6％ --％ 15.0％ -- Botrytis cinerea 35.8％ 10.6 12.4％ -- Phakopsora pachyrhizi 13.0％ 19.7％ 96.0％％ 24.5％ Puccinia horiana 36.5％ 82.4％ -- 87.0％

[0141] In the table above, the symbol "--" indicates that no results were obtained or no activity was observed. In some tests, the lack of activity was due to the application rate of the fungicide being too high to observe any activity over the control. The results in the table above indicate that Compound 1 showed significant synergistic effects against Septoria tritici, Botrytis cinerea, and Phakopsora pachyrhizi in combination with Amistar, Imtrex, and Proline. The combination of the compound with Balaya showed significant synergistic effects against Phakopsora pachyrhizi and Puccinia brownii. The combination of Compound 1 with Amistar and Imtrex showed significant synergistic effects against Puccinia brownii.

[0142] Method 3: Greenhouse crop test of Compound 1 with metconazole

[0143] The 2019 field isolate of Septoria tritici was cultured on potato dextrose agar (PDA) at 20 °C for 6 days. The potato dextrose agar was modified with penicillin and streptomycin to eliminate possible bacterial contamination. This allowed for the comparison of fungicide activity against the current strain carrying recent insensitivity (resistance) mutations to the pathogen.

[0144] A spore suspension was prepared by immersing the plate in sterile distilled water and gently scraping. The spore suspension was adjusted to 10 6 conidia mL -1 by counting with a hemocytometer and appropriate dilution, and then finally resuspended in potato dextrose broth modified with 1.5 g L -1 gelatin and 0.5 g L -1 sodium oleate.

[0145] Winter wheat cv Trinity, sensitive to Septoria tritici, was planted in Levington M3 compost. Seeds (12 - 15 per pot) were planted in each 9 cm pot and grown to growth stage 12. The plants were placed in a greenhouse heated to 20 °C during the day, ventilated to 22 °C, and heated at night to maintain 15 °C. By applying at 10 6 spores ml-1 Spray the spore suspension and inoculate the plants with Septoria tritici. Use three replicate pots for each treatment. Place the plants in a sealed, transparent growth chamber for 72 hours to maintain high relative humidity and ensure that free water remains on the leaves. Provide shade to ensure that the plants do not overheat inside the growth chamber. Apply a prophylactic fungicide spray 1 day before inoculation. Treatments are randomly assigned in the greenhouse. Use a calibrated, pressurized hand-held sprayer to apply all fungicides at an equivalent rate of 200 L of water per hectare. This is achieved by placing the plants to be treated in an area of 0.5 m 2 and applying 10 mL of fungicide spray. The results are as Figure 9 shown in the figure, which shows the synergistic effect of combining compound 1 (represented as TX15 in Figure 9 ) with metconazole in treating winter wheat infected with Septoria tritici.

[0146] In view of the many possible embodiments in which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are merely preferred examples of the invention and should not be regarded as limiting the scope of the invention. On the contrary, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

1. A method for inhibiting fungal infections in at-risk seeds or plants, the method comprising contacting the seeds or plants with: a fungicide comprising azoxystrobin, difenoconazole, chlorothalonil, tebuconazole, folpet, prothioconazole, fluxapyroxad, metconazole, cyflufenamid, fluxametamide, benzovindiflupyr, pyrimethanil, cyazofamid, pyraclostrobin or a combination thereof; and an apyrase inhibitor (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide.

2. The method according to claim 1, wherein the fungicide comprises metconazole.

3. The method according to claim 1, wherein the fungicide comprises cyflufenamid.

4. The method according to claim 1, wherein the fungicide comprises fluxametamide.

5. The method according to claim 1, wherein the fungicide comprises benzovindiflupyr.

6. The method according to claim 1, wherein the fungicide comprises fluxapyroxad.

7. The method according to claim 4, the method further comprising contacting the seeds or plants with azoxystrobin.

8. The method according to claim 1, wherein the fungicide comprises prothioconazole.

9. The method according to claim 1 or claim 6, wherein the fungicide comprises cyflufenamid.

10. The method according to claim 1, wherein the fungicide comprises pyrimethanil.

11. The method according to claim 1, wherein the fungicide comprises difenoconazole.

12. The method according to claim 11, wherein the fungicide further comprises azoxystrobin.

13. The method according to claim 1, wherein the fungicide is selected from azoxystrobin, pyraclostrobin or a combination thereof.

14. The method according to claim 1, wherein the fungicide comprises folpet.

15. The method according to claim 1, wherein the fungicide comprises chlorothalonil.

16. The method according to claim 1 or claim 9, wherein the fungicide comprises pyraclostrobin.

17. The method according to claim 1, wherein the fungicide comprises cyazofamid.

18. A method for inhibiting fungal infections in at-risk seeds or plants, the method comprising contacting the seeds or plants with: azoxystrobin, difenoconazole, chlorothalonil, tebuconazole, folpet, prothioconazole, fluxapyroxad, metconazole, cyflufenamid, fluxametamide, benzovindiflupyr, pyrimethanil, cyazofamid, pyraclostrobin; and an apyrase inhibitor (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide, wherein the fungal infections comprise Phakopsora pachyrhizi, Cercospora sojina, Puccinia striiformis, downy mildew pathogens or a combination thereof.

19. The method according to claim 1 or claim 18, wherein the combination of the adenosine triphosphate diphosphatase inhibitor and the fungicide has a synergistic effect against fungal infections.

20. A synergistically effective antifungal composition, the synergistically effective antifungal composition comprising: a fungicide selected from the group consisting of fungicides including the following: azoxystrobin, difenoconazole, chlorothalonil, tebuconazole, folpet, prothioconazole, fluxapyroxad, metconazole, trifloxystrobin, fluxametamide, benzovindiflupyr, pyrimethanil, cyazofamid, pyraclostrobin, or combinations thereof; and an adenosine triphosphate adenosine triphosphate adenosine triphosphatase inhibitor (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide.

21. The synergistically effective antifungal composition according to claim 20, wherein the fungicide comprises a compound selected from the group consisting of fluxametamide, benzovindiflupyr, fluxapyroxad, azoxystrobin, folpet, prothioconazole, trifloxystrobin, pyrimethanil, difenoconazole, and combinations thereof.

22. The synergistically effective antifungal composition according to claim 20, wherein the fungicide comprises azoxystrobin.

23. The synergistically effective antifungal composition according to claim 20, wherein the composition is synergistically effective against Phakopsora pachyrhizi, Cercospora sojina, Puccinia striformis, downy mildew pathogens, or combinations thereof.

24. A method for inhibiting the infection of Septoria tritici, Botrytis cinerea, Phakopsora pachyrhizi, or combinations thereof in at-risk seeds or plants, the method comprising contacting the seeds or plants with the following: azoxystrobin, fluxapyroxad, prothioconazole, or combinations thereof; and (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide.

25. A method for inhibiting the infection of Phakopsora pachyrhizi, brown rust pathogen, or both in at-risk seeds or plants, the method comprising contacting the seeds or plants with the following: trifloxystrobin, pyraclostrobin; and (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide.

26. A method for inhibiting the infection of brown rust pathogen in at-risk seeds or plants, the method comprising contacting the seeds or plants with the following: azoxystrobin, fluxapyroxad, or both; and (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide.

27. A method for inhibiting the infection of Phakopsora pachyrhizi in at-risk seeds or plants, the method comprising contacting the seeds or plants with the following: (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and a fungicide comprising azoxystrobin and tebuconazole.

28. The method according to claim 27, wherein the fungicide further comprises chlorothalonil.

29. A method for inhibiting infection of soybean Septoria brown spot pathogen in at-risk seeds or plants, the method comprising contacting the seeds or plants with: (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and a fungicide comprising azoxystrobin and tebuconazole.

30. The method according to claim 29, wherein the fungicide further comprises chlorothalonil.

31. A method for inhibiting infection of yellow rust pathogen in at-risk seeds or plants, the method comprising contacting the seeds or plants with: (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and a fungicide comprising azoxystrobin, folpet, prothioconazole, fluxapyroxad, fluopyram, sedaxane, benzovindiflupyr, pyrimethanil, or a combination thereof.

32. The method according to claim 31, wherein the fungicide comprises prothioconazole.

33. A method for inhibiting infection of Septoria musiva in at-risk seeds or plants, the method comprising contacting the seeds or plants with: (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and a fungicide comprising azoxystrobin, folpet, prothioconazole, fluxapyroxad, fluopyram, sedaxane, benzovindiflupyr, pyrimethanil, or a combination thereof.

34. A method for inhibiting infection of downy mildew pathogen in at-risk seeds or plants, the method comprising contacting the seeds or plants with: (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and a fungicide comprising cyazofamid.

35. A method for inhibiting infection of downy mildew pathogen in at-risk seeds or plants, the method comprising contacting the seeds or plants with: (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and a fungicide comprising azoxystrobin, difenoconazole, or both.

36. A method for inhibiting infection of Septoria tritici in wheat, the method comprising contacting the seeds or plants with: (E)-3-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzohydrazide; and a fungicide comprising metconazole.

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