CN111574507B

CN111574507B - Compound containing natural butenolide skeleton, preparation and application thereof

Info

Publication number: CN111574507B
Application number: CN202010585616.5A
Authority: CN
Inventors: 段红霞; 朱凯; 杨朝凯; 路星星; 李慧琳; 韩清; 凌云; 李想
Original assignee: China Agricultural University
Current assignee: China Agricultural University
Priority date: 2020-06-24
Filing date: 2020-06-24
Publication date: 2021-08-10
Anticipated expiration: 2040-06-24
Also published as: CN111574507A

Abstract

本发明公开了一种具有天然丁烯内酯骨架结构的新颖化合物、制备及其应用，其结构式如式I‑1或式I‑2所示，

式I‑1中：R₁为氢、卤素；R₂为氢、卤素、硝基、二甲基氨基、C1～C5直链或支链烷基；式I‑2中：R₁为氢；R₂为氢、卤素、硝基、C1～C5直链或支链烷基。本发明提供的化合物作为农用杀虫剂具有活性高，结构简单，易于合成；作为植物病原真菌抑制剂表现出良好的抑制真菌活性和多重的抑菌谱。The invention discloses a novel compound having a natural butenolide skeleton structure, preparation and application thereof. Its structural formula is shown in formula I-1 or formula I-2,

In formula I-1: R ₁ is hydrogen, halogen; R ₂ is hydrogen, halogen, nitro, dimethylamino, C1～C5 straight-chain or branched alkyl; In formula I-2: R ₁ is hydrogen; R ₂ is hydrogen, halogen, nitro, C1-C5 straight-chain or branched-chain alkyl. The compounds provided by the invention have high activity as agricultural insecticides, simple structure and easy synthesis; as phytopathogenic fungi inhibitors, the compounds exhibit good fungistatic activity and multiple antibacterial spectrums.

Description

Compound containing natural butenolide skeleton, preparation and application thereof

Technical Field

The invention belongs to the technical field of agricultural pest control, and particularly relates to preparation of an agricultural pest control agent and a plurality of plant pathogenic fungi control agents of a novel butenolide skeleton compound and application of the agricultural pest control agent and the control agents in the field of agricultural pest control.

Background

Chemical pesticides hold an important place in the field of crop pest control. However, with the frequent use of chemical pesticides, negative effects such as: the pest resistance to drugs, environmental pollution and biosafety to human and livestock, natural enemies or non-target organisms and the like, and the method has attracted extensive attention. With the continuous progress of science and technology and the deepening of people's understanding of nature, the use of natural products and synthetic organic chemicals as pesticides or bactericides to resist the invasion of diseases and pests to crops has become one of the main means of plant pest defense at present. Therefore, research and development of novel efficient and environment-friendly green pesticides for quality and safety guarantee of modern agricultural products are urgently needed.

Nicotinic insecticides account for a major share of today's agricultural insecticide market. However, with the large-scale use of the nicotine compound, toxic effects on non-target pollination insect bees are caused, so that a plurality of nicotine varieties are forbidden to different degrees in the countries such as the United states, European Union and the like. Thus, in recent years, scientists and pharmaceutical companies have been working on developing new classes of insecticides that are highly effective and safe for non-target organisms. Such as: in 2008, the university of eastern China successfully developed neonicotinoid insecticides meperidine and cycloxaprid, and the university of China agriculture created the neonicotinoid insecticide pentapyrindin, which is not only effective to target pests, but also appears to be safe to bees; in 2010, Sulfoxide imine insecticide sulfoximine is developed by Yinong Dorstalli; in 2015, Bayer company was inspired by stemonine head structure, and developed a new skeleton pesticide fluropyrone with butenolide fragment as core fragment, which is effective in preventing and treating various aphids and low in bee venom; in 2017, Flupyrimin, a novel insecticide with a unique pharmacophore, was developed by mitsubishi corporation. Therefore, aiming at the serious problem that the nicotine pesticide is forbidden due to the safety to bees, the novel nicotine substitute which is novel in structure and safe to non-targets is greatly developed. Particularly, on the basis of a novel structure of a functional natural product, a multi-drug effect fragment transition strategy is combined, the characteristics of the existing pesticide product are broken through, and the key problem which is urgently needed to be solved is to develop a novel nicotine pesticide substitute which is simple in structure, easy to synthesize and low in economic cost and is used for preventing and controlling pests in modern agriculture.

Pathogenic fungi develop their parasitism and pathogenicity during long-term evolution and complex interactions with plants. Therefore, a large number of bactericide varieties are used in modern agricultural disease control, especially in agricultural products such as vegetables and fruits, but with the large-scale use of more and more bactericides on crops, plant pathogenic fungi are easy to generate drug resistance, the control effect can be achieved only by inducing the application of more medicaments, and the effective service life of the newly developed bactericide is greatly shortened. Therefore, the development of fungicide varieties with novel structures has always been a major research topic in the field of agricultural disease control. The natural product has the advantages of structural diversity and novel skeleton, and can be domesticated and interacted with various organisms continuously in nature for a long time, so that the natural product becomes a rich treasury for drug screening and new drug discovery. Therefore, based on the characteristics of a new skeleton structure of a natural product, by means of a multi-fragment transition fusion strategy, the method is beneficial to screening and discovering a novel guide structure effective to various plant pathogenic fungi, and has important significance for disease control of modern crops.

Disclosure of Invention

Based on the previous research results, the technical problem to be solved by the invention is to provide preparation and application of a novel compound containing a butenolide skeleton and multiple pharmacophores, and the butenolide compound provided by the invention has high activity, good broad spectrum, simple structure and easy synthesis as an aphid insecticide and multiple plant pathogenic fungi inhibitors, and shows excellent insecticidal capacity and antibacterial effect.

Compared with the prior art, the invention provides the preparation and application of the compounds with the formula I-1 and the formula I-2 as aphid insecticides and various plant pathogenic fungi inhibitors, and biological activity experimental research shows that the compounds with the structure of the formula I-1 and the formula I-2 have excellent lethal effect on soybean aphids and low bee venom; meanwhile, the compound has good inhibitory activity on various plant pathogenic fungi, and the compound has the advantages of easily available raw materials and simple synthesis, and can be used for industrial development.

According to the first aspect of the invention, a butenolide skeleton compound containing a pyridine ring or a pepper ring or a pharmaceutically acceptable salt thereof is provided, and the structural formula of the butenolide skeleton compound is shown as a formula I-1 or a formula I-2.

In the formula: r₁Is hydrogen, halogen, nitro or cyano, or substituted or unsubstituted hydroxyl, amino, carboxyl, ester group, sulfhydryl, amido, carbamido, C1-C5 straight chain or branched chain alkyl, C1-C5 alkoxy.

R₂The aryl group is hydrogen, halogen, nitro or cyano, or substituted or unsubstituted hydroxyl, amino, carboxyl, ester, sulfhydryl, amido, carbamido, phenyl, aryl or heteroaryl, or substituted or unsubstituted C1-C5 straight chain or branched chain alkyl, or substituted or unsubstituted C1-C5 alkoxy, or substituted or unsubstituted C6-C30 aryl, condensed ring or condensed heterocyclic ring.

According to a second aspect of the present invention, there is provided a process for producing a pyridine ring-containing butenolide compound (formula I-1):

taking potassium methylpropionate (1) and ethyl chloroacetate (2) as raw materials, obtaining 2-methoxy-2-oxyethyl methyl malonate (3) at room temperature, then heating and cyclizing to obtain 4- (methoxycarbonyl) -5-oxo-2, 5-dihydrofuran-3-sodium oleate (4), reacting 5- (aminomethyl) -substituted pyridine (5) and substituted cinnamaldehyde (6) at room temperature under the condition of ethanol, and then reducing to obtain (1E, 2E) -N- ((6-chloropyridin-3-yl) methyl) -3-phenylpropan-2-ene-1-imine (7). Finally, 4- (methoxycarbonyl) -5-oxo-2, 5-dihydrofuran-3-oleate (4) reacts with (1E, 2E) -N- ((6-chloropyridin-3-yl) methyl) -3-phenylpropan-2-en-1-imine (7) to obtain a target compound I-1;

the synthetic route of the formula I-1:

according to a third aspect of the invention, a preparation method of the piperonyl-containing butenolide compound (formula I-2) is provided:

taking potassium methylpropionate (1) and ethyl chloroacetate (2) as raw materials, obtaining 2-methoxy-2-oxyethyl methyl malonate (3) at room temperature, then heating and cyclizing to obtain 4- (methoxycarbonyl) -5-oxo-2, 5-dihydrofuran-3-sodium oleate (4), reacting benzo [1,3] dioxa-5-ylmethylamine (8) and substituted cinnamaldehyde (6) at room temperature under the condition of ethanol, and then reducing to obtain (E) -N- (benzo [1,3] dioxa-5-ylmethyl) -3-phenylprop-2-ene-1-amine (9). Finally reacting sodium 4- (methoxycarbonyl) -5-oxo-2, 5-dihydrofuran-3-oleate (4) with (E) -N- (benzo [1,3] dioxa-5-ylmethyl) -3-phenylprop-2-en-1-amine (9) to obtain the target compound I-2;

synthetic route of formula I-2:

the invention further provides an application of the butenolide skeleton compound containing pyridine ring or pepper ring shown in the formula I-1 and the formula I-2 or the pharmaceutically acceptable salt thereof in any one of the following 1) to 4):

1) killing insects;

2) preparing an insecticide;

the invention provides an aphid insecticide with low bee venom, and the active ingredient of the aphid insecticide is the compound containing butenolide skeleton or the pharmaceutically acceptable salt thereof.

3) Sterilizing;

4) preparing one or more plant pathogenic fungi inhibitors;

the invention provides a plant pathogenic fungi inhibitor, which is mainly applied to the prevention and treatment of rice sheath blight pathogenic fungi, wheat scab pathogenic fungi, apple rot pathogenic fungi, tomato gray mold pathogenic fungi and rape sclerotium pathogenic fungi, and the active component of the plant pathogenic fungi inhibitor is the compound containing butenolide skeleton or the pharmaceutically acceptable salt thereof.

The invention also provides a pesticide or a bactericide, and the active component of the pesticide or the bactericide is the compound containing the butenolide skeleton or the pharmaceutically acceptable salt thereof. The dosage form of the pesticide or the bactericide is a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, wettable powder, suspending agent, powder, soluble powder, aqueous solution, water dispersible powder, smoke agent, granules and seed coating agent.

The invention has the following advantages:

compared with the prior art, the invention provides the application of screening on the basis of a natural active fragment butenolide skeleton in preventing and treating aphids and inhibiting various plant pathogenic fungi. According to a natural butenolide molecular skeleton structure, a skeleton transition thought in a computer-aided drug design method is combined, 17 novel butenolide skeleton-containing compounds are designed and synthesized through a multi-drug effect fragment splicing fusion strategy, and through the evaluation of aphid killing activity of soybean aphids, the compounds are found to generally show lethal effect on the soybean aphids, and part of the compounds have excellent activity, and the compounds are found to be low in bee venom through bee contact toxicity experiments. The activity test of inhibiting various plant pathogenic fungi finds that the butenolide compound has a good inhibiting effect on various plant pathogenic fungi, particularly has an excellent inhibiting effect on apple rot pathogenic fungi, and is worthy of deep research. The compound provided by the invention has the characteristics of novel skeleton, simple structure, easiness in synthesis, good insecticidal effect, low bee venom, excellent and broad-spectrum antibacterial activity and the like, and has good agricultural and medicinal research value.

Drawings

FIG. 1 shows the NMR spectrum of compound I-1-01.

FIG. 2 is the NMR spectrum of compound I-2-01.

Detailed Description

The invention is further described with reference to the following examples, but the scope of the invention is not limited thereto. The experimental procedures used in the following examples are conventional unless otherwise specified. The raw materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Example 1: preparation of pyridine ring-containing butenolide compound I-1-01

Raw material 1(0.13mol) was dissolved in 125mL of Dimethylformamide (DMF), and then raw material 2(0.12mol) was added dropwise to the above mixture and stirred at 35 ℃ for 8 h. After the reaction was completed, the solvent was decompressed. Water (45mL) was added and the mixture was extracted three times with 30mL of toluene. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 2-methoxy-2-oxyethylmethylmalonate 3. 0.1mol of intermediate 3 was dissolved in 50ml of pure methanol and the reaction mixture was heated to 40 ℃. And (3) dropwise adding a 30% sodium methoxide solution, refluxing for 3 hours, and separating a certain amount of white solid. After the reaction was completed, the mixture was cooled to 0 ℃, and the precipitate was collected by filtration, washed with methanol, and dried to obtain 4- (methoxycarbonyl) -5-oxo-2, 5-dihydrofuran-3-oleate 4 in a yield of 89%.

Starting material 6(2.1mmol) and starting material 5(1.8mmol) were dissolved in 20ml of absolute ethanol and stirred overnight. After that 4.4mmol of sodium borohydride were added in portions. The reaction was monitored by thin layer chromatography. When the imine disappeared, the solvent was removed under vacuum, then 45mL of water was added to the residue, and extracted three times with 15mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give (1E, 2E) -N- ((6-chloropyridin-3-yl) methyl) -3-phenylprop-2-en-1-imine 7 in 68% yield.

1.6mmol of 4 as starting material, 1.5mmol of 7 as starting material, 2.9mmol of potassium hydrogen sulfate and 10mL of butyronitrile were added to a 50mL flask and stirred at 90 ℃ and the progress of the reaction was monitored by thin layer chromatography. After complete consumption of starting material 7, the reaction mixture was cooled to room temperature, poured into 50mL of water and extracted three times with 15mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, and then eluted with ethyl acetate/petroleum ether (volume ratio 1: 1) to give the objective compound I-1-01 in 67% yield.

Structural characterization data:

¹H NMR(300MHz,DMSO-d₆)δ8.39(d,J＝2.4Hz,1H),7.81(dd,J＝8.3,2.5Hz,1H),7.54–7.18(m,6H),6.56(d,J＝15.9Hz,1H),6.30(s,1H),4.99(s,2H),4.81(s,1H),4.52(s,2H),3.99(d,J＝5.9Hz,2H)；HRMS(ESI)m/z calcd for C₁₉H₁₇ClN₂O₂[M+H]⁺:341.1051；found:341.1051.

other butenolide series compounds containing pyridine ring with the general formula of (I-1) can be prepared by the method.

Example 2: preparation of butenolide compound I-2-01 containing piperonyl

Starting material 6(2.1mmol) and starting material 8(1.8mmol) were dissolved in 20ml of absolute ethanol and stirred overnight. After that 4.4mmol of sodium borohydride were added in portions. The reaction was monitored by thin layer chromatography. When the imine disappeared, the solvent was removed under vacuum, then 45mL of water was added to the residue, and extracted three times with 15mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give (E) -N- (benzo [1,3] dioxa-5-ylmethyl) -3-phenylprop-2-en-1-amine 9 in 78% yield.

1.6mmol of 4 as starting material, 1.5mmol of 9 as starting material, 2.9mmol of potassium hydrogen sulfate and 10mL of butyronitrile were added to a 50mL flask and stirred at 90 ℃ and the progress of the reaction was monitored by thin layer chromatography. After complete consumption of starting material 9, the reaction mixture was cooled to room temperature, poured into 50mL of water and extracted three times with 15mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, and then eluted with ethyl acetate/petroleum ether (volume ratio 1: 1) to give the objective compound I-2-01 in 70% yield.

Structural characterization data:

¹H NMR(300MHz,DMSO-d₆)δ7.42(d,J＝7.4Hz,2H),7.32(t,J＝7.3Hz,2H),7.24(dd,J＝8.3,5.9Hz,1H),6.92–6.86(m,2H),6.79(dd,J＝8.0,1.5Hz,1H),6.54(d,J＝15.9Hz,1H),6.28(s,1H),5.99(s,2H),4.94(s,2H),4.75(s,1H),4.35(s,2H),3.93(d,J＝5.8Hz,2H).；HRMS(ESI)m/z calcd for C₂₁H₁₉NO₄[M+H]⁺:350.1390；found:350.1387.

other butenolide compounds containing piperonyl rings with the general formula of (I-2) can be prepared by the method.

Example 3: soybean aphid killing activity determination method of compound with butenolide framework structure

Weighing 2g of agar powder and 98g of water, heating in a microwave oven for 15 seconds, taking out, heating for several times to prepare a transparent agar solution, pouring the transparent agar solution into a 12-hole plate, and naturally drying for later use. 6mg of sample is weighed in a 1.5mL centrifuge tube, dissolved in 0.6mL DMSO, injected into a 50mL small beaker by a 0.5mL pipette, and added with 9.5mL Triton X-100(5 ‰) aqueous solution to prepare 500mg/L solution. Soybean leaves not exposed to any chemicals and insects were cultivated indoors, and after punching leaves of appropriate size with punches of 15mm in diameter, respectively, and dipping them in a diluted chemical-containing solution for 15 seconds, the leaves were naturally dried to evaporate the solvent and placed in a 12-well plate, the back of the leaves was turned upside down, and 20 soybean aphids of appropriate age were placed in each well and sealed with ventilated filter paper. More than 20 soybean aphids per dose were treated and the experiment was repeated 3 times. The aphids are placed in a climatic chamber with the temperature of (25 +/-1) DEG C, and the death number of the aphids is checked after 48 hours. Commercial agents imidacloprid, pymetrozine and fluropyrone are used as positive controls, and 0.5mL of DMSO and 9.5mL of Triton water solution are added as solvent blank controls.

The death judgment criteria were: the dead one is the dead one when the body is touched slightly

Corrected mortality (%) - (treatment-blank mortality)/(1-blank mortality) × 100%

TABLE 1 lethality of butenolide compounds containing pyridine ring to Aphis glycines at a concentration of 500. mu.g/mL (48h)

TABLE 2 mortality of Periploca glycines with the piperonyl cyclobutene lactones at a concentration of 500. mu.g/mL (48h)

As shown in tables 1 and 2, each of the compounds having a butenolide skeleton exhibited insecticidal activity against soybean aphids, and some of the compounds exhibited excellent lethal effect against soybean aphids. Therefore, the compound containing the butenolide skeleton has a simple structure, is easy to synthesize, and can be used as an aphid regulator candidate for further research.

Example 4: bee toxicity test for compounds having butenolide backbone structure

The compounds I-1-07 and I-1-12 with good insecticidal activity on soybean aphids are selected to carry out bee acute contact toxicity test, and the toxicity on bees is researched. Adult Italian worker bees (Apis mellifera L) are provided by the bee research institute of Chinese academy of agricultural sciences, healthy and active adult worker bees with consistent sizes are selected and fed into test bee cages for later use, and the test is carried out under the conditions of the temperature of 25.0-25.2 ℃, the relative humidity of 56.8-58.6% and low light level. Four concentrations of 100000mg/L, 10000mg/L, 1000mg/L and 100mg/L are respectively set for samples I-1-07 and I-1-12 to carry out bee venom experimental test, 5 microliter of acetone and 5 microliter of DMSO mixed solution are used as solvent control, 3 repetitions are set for the experimental group and the control group, and 10 bees are repeatedly used for each repetition. A test sample to be tested was weighed at 10mg, and 5. mu.L of acetone and 5. mu.L of DMSO as solvents were added to prepare a test solution having the above-mentioned specific concentration. Before the test, the bees in the test cages were first placed in a desiccator for anaesthesia (CO-infusion)₂Anaesthetizing for 3min), dripping sample liquid medicine with different concentrations onto the middle chest back plate of bee with 1.00 μ L continuous distributor, transferring the bee into bee cage after the liquid medicine is dried, and placing the bee in normal physiological state in culture paperAnd (3) putting the plastic cup with the hole in the culture dish on the culture dish, and putting the injector filled with 2mL of honey water in the hole at the bottom end of the plastic cup to normally feed the bees for testing insects under the low-light condition. The results were checked at 24h, 48h and the number of deaths recorded.

The death criteria was touching the bee body without any response.

TABLE 3 acute contact toxicity of highly insecticidally active butenolide compounds I-1-07 and I-1-12 to Italian bees

^*Bee toxicity grade: virulent strain, LD₅₀Less than or equal to 0.001 mu g/bee; high toxicity, 0.001 μ g/bee<LD₅₀Less than or equal to 2.0 mu g/bee; poisoning, 2.0 μ g/bee<LD₅₀Less than or equal to 11.0 mu g/bee; low toxicity, LD₅₀>11.0μg/bee.

^a: correcting mortality as negative

As shown in Table 3, the compounds containing butenolide frameworks have the contact toxicity to bees which is 2-3 orders of magnitude lower than that of commercial imidacloprid, and the compounds are characterized by low bee toxicity. The novel compound containing the butenolide skeleton not only shows good aphid killing activity, but also is safe to non-target bees, and can be used as a novel aphid regulator candidate for deep development.

Example 5: test for phytopathogenic fungus inhibitory Activity of Compounds having butenolide skeleton Structure

And testing the activity of the synthesized compound for inhibiting the pathogenic fungi by adopting a hyphal growth rate method. Respectively dissolving the drug to be detected and the control medicament in DMSO solvent to prepare a sample medicament with the concentration of 10000 mug/mL for later use.

In an aseptic operation table, 1mL of standby sample medicament is uniformly mixed with 199mL of PDA culture medium to prepare a medicament-containing sample culture medium with the concentration of 50 mug/mL. The strain is introduced into a culture dish with the diameter of 90cm, each dish is about 15mL, after the strain is cooled and solidified, the strain is inoculated to an activated fungus cake of the selected pathogenic fungus, the strain is placed in a manual incubator at 25 ℃ for culture, DMSO is selected as a solvent control, sterile water is used as a blank control, and a commercial drug pyraclostrobin is used as a positive control drug. Each sample was assayed in duplicate. And (4) investigating the growth condition of pathogenic bacteria hyphae according to the growth condition of the colonies in the blank control culture dish, measuring the diameter of the colonies of each treatment group by a cross method after the blank control colonies fully grow, and taking the average value of the diameters. And calculating the hypha growth inhibition rate of each medicament treatment on various pathogenic bacteria according to the ratio of the difference value of the blank control colony growth area and the medicament treatment colony growth area to the blank control colony growth area.

The bacteriostatic rate (%) - (control colony diameter-diameter of treated colony)/(control colony diameter-5) × 100%

TABLE 4 bacteriostatic activity of compounds containing natural butenolide (50. mu.g/mL) against various phytopathogenic fungi

As shown in Table 4, the compounds containing butenolide skeletons have excellent inhibitory activity against one or more plant pathogenic fungi, particularly against apple rot pathogenic fungi, and most of the compounds show excellent inhibitory activity. Therefore, the butenolide compound can be used as a candidate medicament for further research of the plant pathogenic fungi inhibitor.

The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims

1. a kind of containing natural butenolide skeleton compound or its pharmaceutically acceptable salt, its structural formula is as shown in formula I-1 or formula I-2:

In formula I-1: R ₁ is hydrogen, halogen; R ₂ is hydrogen, halogen, nitro, dimethylamino, C1-C5 straight-chain or branched-chain alkyl;

In formula I-2: R ₁ is hydrogen; R ₂ is hydrogen, halogen, nitro, C1-C5 straight-chain or branched-chain alkyl.

2. An agricultural insecticide, the active ingredient of which is the natural butenolide skeleton-containing compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. a phytopathogenic fungi inhibitor, its active ingredient is the natural butenolide skeleton compound or its pharmaceutically acceptable salt according to claim 1, and the phytopathogenic fungi is rice sheath blight pathogenic fungi , one or more of the pathogenic fungi of wheat scab, the pathogenic fungi of apple rot, the pathogenic fungi of tomato gray mold and the pathogenic fungi of Sclerotinia sclerotiorum.

4. The agricultural insecticide according to claim 2 or the phytopathogenic fungi inhibitor according to claim 3, its dosage form is a pharmacodynamically acceptable dosage form; the dosage form comprises emulsifiable concentrate, wettable powder, suspending agent , at least one of soluble powder, water, water dispersible powder, smoke, granules and seed coating.