CN115043829B

CN115043829B - Indole compound and preparation method and application thereof

Info

Publication number: CN115043829B
Application number: CN202210162939.2A
Authority: CN
Inventors: 王彩霞; 徐翠莲; 杨囯玉; 赵士举; 赵仲麟; 李旭; 赵金芳; 孟凡冲
Original assignee: Henan Agricultural University
Current assignee: Henan Agricultural University
Priority date: 2022-02-22
Filing date: 2022-02-22
Publication date: 2023-07-25
Anticipated expiration: 2042-02-22
Also published as: CN115043829A

Abstract

The invention belongs to the technical field of pesticides, and particularly relates to an indole compound, a preparation method and an application thereof.

Description

Indole compound and preparation method and application thereof

Technical Field

The invention belongs to the technical field of pesticides, and particularly relates to an indole compound, and a preparation method and application thereof.

Background

Crop diseases caused by fungi have become one of the most interesting problems in the field of whole-sphere agriculture. The fungal diseases not only directly cause the reduction of crop yield and quality, but also can secrete and produce various toxins and metabolites harmful to human beings and animals in the process of infecting crops by part of pathogenic fungi, thus greatly threatening the safety of agricultural products. It has been estimated by experts that fungal diseases have reduced the yield of 5 large grain crops, corn, rice, wheat, potato and soybean, by 1.25 million tons per year worldwide; among them, the damage of these diseases to corn, wheat and rice alone brings about economic loss of 600 million dollars per year to global agriculture, and if in extreme cases the above 5-grain crops are simultaneously in a fungal disease pandemic in one year, the global grain yield reduction in the current year may be as high as 9 million tons, which would lead to 42 million hungry people and global familiarity.

Fusarium oxysporum (Fusarium oxysporum) is a facultative parasitic fungus, has a wide host range, and can cause wilt of more than 100 plants such as leguminous plants, melons, cotton (Gossypium hirsutum) and the like. The disease can occur in the whole plant breeding period, so that the yield of field crops is reduced by 20% -30%, 50% -60% and even absolute yield can be achieved when the disease is serious, serious disasters are brought to agriculture, and serious economic loss is caused. Fusarium graminearum (F.graminearum) is one of the important pathogenic bacteria of gramineous crops, and can cause wheat, barley, rice, oat, and Fusarium head blight or "ear scab" disease (FHB) and corn stem rot and ear rot, also known as scab. Meanwhile, fusarium graminearum produces mycotoxins such as Trichothecenes (Trichothecenes) and zearalenone (zearalenone) which are harmful to human bodies and animals in the infection process, so that the cereal grains are unsuitable as food or feed after being infected. Fusarium moniliforme (F.moniliforme) is a toxigenic mould that can infect more than ten plants of the family. The fungus is easy to occur in crops and products in a growing period and a storage period, and is one of animal and plant pathogenic fungi with serious harm worldwide. The pathogenic fungi not only can cause the root rot, the stem rot, the spike rot and the like to be caused by the infection of the stem rot germ of crops to cause direct yield reduction, but also can reduce the germination rate of the seed with bacteria and the survival rate of the seedling, thereby causing further loss. In addition, fusarium moniliforme can also produce a large amount of mycotoxin fusarium moniliforme, and the toxin can cause plant diseases, pollute food and feed, cause poisoning and even death of people and animals, and form serious threat to the life health of people and animals. Although new bacteriostats are being developed at present, overuse of antifungal agents increases the resistance of fungi to bactericides.

The new agricultural chemical in China is to enhance the competitiveness, is innovative in the original structure, is different from the existing variety in the action mechanism, is more efficient in effect and is more selective, so that the discovery of the lead compound with high activity and an entirely new structure is one of key links, and the new lead antifungal compound is an urgent and difficult task faced by agricultural chemical researchers.

Disclosure of Invention

Aiming at the defects existing in the prior art, the invention provides an indole compound, and a preparation method and application thereof; according to the invention, chemical discipline principles and experimental technology are adopted, and a series of compounds containing indole rings, 1,3, 4-thiadiazole and thioether group skeletons are designed and synthesized according to a drug design active group splicing principle, the inhibition activity of the compounds on plant fungi is tested, the structure-activity relationship of the compounds is analyzed, novel and efficient compounds with broad-spectrum bactericidal effect are screened, and novel active compounds with novel frameworks are provided for developing green pesticides.

In order to achieve the above purpose, the technical scheme of the invention is as follows:

an indole compound has a structural formula shown in formula (I):

wherein R is selected from benzyl, picolyl, halogenated benzyl, nitrobenzyl, methoxybenzyl, CF ₃ One of phenylmethyl, benzimidazolylmethyl, allyl, halothiazolylmethyl, vinylphenylmethyl.

The invention also discloses a preparation method of the indole compound, which comprises the following steps:

(1) Preparing 2-amino-5-S-alkyl-1, 3, 4-thiadiazole compounds;

(2) Preparation of indole compounds:

dissolving 2-amino-5-S-alkyl-1, 3, 4-thiadiazole compound in a solvent, then dropwise adding anhydrous ethanol solution of 3-indole formaldehyde while stirring, continuously heating and refluxing for 6-8h, cooling to separate out solid, filtering to obtain a crude product, and recrystallizing to obtain indole compound pure product.

The invention also protects the application of the indole compounds in preparing plant bactericides, wherein the bactericides are used for inhibiting plant pathogenic fungi.

Compared with the prior art, the invention has the beneficial effects that:

1. the invention designs and synthesizes the structural compound with high fungal activity inhibition, tests the antibacterial rate of the structural compound, and provides a new lead compound for the creation of green pesticides.

2. The indole compound based on indole, 1,3, 4-thiadiazole, thioether and Schiff base compounds is synthesized for the first time, and the sterilization advantages of indole, 1,3, 4-thiadiazole, thioether and Schiff base compounds are achieved.

The heterocyclic compound has good systemic conduction performance and characteristics of various structures and easy modification in plants, and is an important object of current new pesticide research. Indole is a condensed heterocyclic compound containing a benzene ring and pyrrole, and indole derivatives are present in almost all plants and animals. A unique feature of the indole ring is that it can be used for multiple receptors, exhibiting a range of biological activities. Indole and its analogues have good antibacterial and antiviral effects, have good activities such as regulating plant growth, have important effects in pesticide synthesis and pharmaceutical synthesis, and have been widely used. Such as 3-dimethylamino indole (donut's bamboo reed base), is a plant source pesticide, and can be used as pesticide; indole acetic acid, indole-3-butyric acid is an important plant regulator; indoleacetonitrile is used as a plant growth hormone.

The 1,3, 4-thiadiazole is a five-membered aromatic heterocycle containing one sulfur atom and two nitrogen atoms, and has a "-N=C-S" structure, so that the 1,3, 4-thiadiazole can be used as an active center to chelate certain metal ions in organisms and can be used as a hydrogen bond receptor, has better tissue cell permeability, can better exert drug effects, and becomes a focus of attention in the current new pesticide research. The 1,3, 4-thiadiazole compound has stronger pharmacological activity, and has important application in medicineIncluding bacteriostasis, tumor suppression, inflammation suppression and the like; because the plant material has good systemic conduction performance in plants, the plant material has biological activities such as bacteriostasis, weeding, disinsection and the like in the aspect of pesticides. The 1,3, 4-thiadiazole ring as an important heterocyclic group is often considered to be introduced into the structural design of new drug lead compounds such as bacteriostats, pesticides, herbicides and the like so as to enhance the biological activity of the new compounds. Commercial 1,3, 4-thiadiazole-containing bactericides have been developed for controlling bacterial leaf blight of rice, having phyllostachys bis (N, N-methyl-bi- (2-amino-5-mercapto-1, 3, 4-thiazole), flufenazamide (Fluthiamide), flufenacet (fluthiacetmethyl) as herbicides, having sulfur atoms (donor atoms) introduced into molecules having heterocyclic compounds can significantly increase the affinity of receptors with ligands to form complexes, which is advantageous for improving the biological activity, sulfide compounds have a broad spectrum of biological activity, aromatic heterocyclic sulfide compounds have excellent biological activity, 1,3, 4-thiadiazole sulfide is also an important pharmacophore, schiff base has an antifungal, antitumor, antiviral effect due to the inclusion of imino groups (CH=N), a mixed molecule of two or more existing pharmacophores has attractive effects due to its various mechanisms, in recent years, many reports on synthesis and biological activity tests of indole and thiadiazole compounds are about, but research on Schiff bases containing 1,3, 4-thiadiazole, indole and thioether frameworks as fungi inhibition is not reported, in order to obtain pesticide lead compounds with higher antibacterial activity, a series of indole compounds are synthesized by constructing sulfide-containing 1,3, 4-thiadiazole and indole on a molecular framework through imine bonds, synthesis conditions are optimized, and the method is established, namely, infrared spectrum and nuclear magnetic resonance hydrogen spectrum are utilized ¹ HNMR) and carbon spectrum ¹³ C NMR), high Resolution Mass Spectrometry (HRMS) characterizes the structure of the compound.

1. The indole compounds prepared by the invention have activity inhibition effects on plant fungi such as fusarium graminearum, fusarium moniliforme, fusarium oxysporum, phytophthora nicotianae and the like.

Drawings

FIG. 1 is a flow chart showing the test of indole compounds according to examples 1 to 20 of the present invention;

FIG. 2 is an infrared spectrum of indole compound 1 prepared in example 1 of the present invention;

FIG. 3 shows the hydrogen spectrum of indole compound 1 prepared in example 1 of the present invention ¹ H-NMR) map;

FIG. 4 shows the carbon spectrum of indole compound 1 prepared in example 1 of the present invention ¹³ C-NMR) map;

FIG. 5 is a High Resolution Mass Spectrum (HRMS) of indole compound 1 prepared in example 1 of the present invention;

FIG. 6 is an infrared spectrum of indole compound 2 prepared in example 2 of the present invention;

FIG. 7 shows the hydrogen spectrum of indole compound 2 prepared in example 2 of the present invention ¹ H-NMR) map;

FIG. 8 shows the carbon spectrum of indole compound 2 prepared in example 2 of the present invention ¹³ C-NMR) map;

FIG. 9 is a High Resolution Mass Spectrum (HRMS) of indole compound 2 as prepared in example 2 of the present invention;

FIG. 10 is an infrared spectrum of indole compound 8 prepared in example 8 of the present invention;

FIG. 11 shows the hydrogen spectrum of indole compound 8 prepared in example 8 of the present invention ¹ H-NMR) map;

FIG. 12 shows the carbon spectrum of indole compound 8 prepared in example 8 of the present invention ¹³ C-NMR) map;

FIG. 13 is a High Resolution Mass Spectrum (HRMS) of indole compound 8 as prepared in example 8 of the present invention;

FIG. 14 is an infrared spectrum of indole compound 10 prepared in example 10 of the present invention;

FIG. 15 shows the hydrogen spectrum of indole compound 10 prepared in example 10 of the present invention ¹ H-NMR) map;

FIG. 16 shows a carbon spectrum of an indole compound 10 prepared in example 10 of the present invention ¹³ C-NMR) map;

FIG. 17 is a High Resolution Mass Spectrum (HRMS) of indole compound 10 of example 10 of the present invention;

FIG. 18 is an infrared spectrum of indole compound 12 prepared in example 12 of the present invention;

FIG. 19 shows a 12 hydrogen spectrum of an indole compound prepared in example 12 of the present invention ¹ H-NMR) map;

FIG. 20 shows a 12 carbon spectrum of an indole compound prepared in example 12 of the present invention ¹³ C-NMR) map;

FIG. 21 is a High Resolution Mass Spectrum (HRMS) of indole compound 12 of example 12 of the present invention;

FIG. 22 is a graph showing the activity of Compound 10 and Compound 17 of the present invention against Fusarium graminearum, respectively; wherein a is a blank control, b1, b2 and b3 are respectively inhibitory activity physical patterns of the compound 10 on fusarium graminearum in parallel under the same test conditions; c1, c2 and c3 are respectively active substance diagrams of the compound 17 for inhibiting fusarium graminearum in parallel under the same test conditions;

FIG. 23 is a graph showing the activity of Compound 10 and Compound 15 of the present invention against Fusarium moniliforme, respectively; wherein a is a blank control, b1, b2 and b3 are respectively inhibitory activity physical patterns of the compound 10 on Fusarium moniliforme in parallel under the same test condition; c1, c2 and c3 are respectively inhibitory activity physical figures of the compound 15 on fusarium moniliforme in parallel under the same test conditions;

FIG. 24 is a graph showing the activity of Compound 10 and Compound 15, respectively, against Fusarium oxysporum; wherein a is a blank control, b1, b2 and b3 are respectively inhibitory activity physical patterns of the compound 10 on fusarium oxysporum in parallel under the same test conditions; c1, c2 and c3 are respectively active substance diagrams of the compound 15 for inhibiting fusarium oxysporum in parallel under the same test conditions;

FIG. 25 is a graph showing the activity of Compound 10 and Compound 14, respectively, against Phytophthora nicotianae; wherein a is a blank control, b1, b2 and b3 are respectively inhibitory activity physical graphs of the compound 10 on the phytophthora nicotianae in parallel under the same test conditions, and c1, c2 and c3 are respectively inhibitory activity physical graphs of the compound 14 on the phytophthora nicotianae in parallel under the same test conditions.

Detailed Description

The following detailed description of specific embodiments of the invention is, but it should be understood that the invention is not limited to specific embodiments.

Example 1:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 20mL of absolute ethyl alcohol is added to dissolve the 3-indolecarboxaldehyde completely, then a solution of an intermediate 2 (2-amino-5-S-benzyl-1, 3, 4-thiadiazole, 0.67g,3 mmol) in ethanol (20 mL) is slowly dripped into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent), heating and refluxing are carried out for 5 hours, a large amount of yellow solid is separated out, heating is stopped, cooling is carried out, decompression filtration is carried out, a crude product is obtained, then a mixed solution of DMF and absolute ethyl alcohol is used as a solvent (1:1) is recrystallized, orange-yellow needle-like crystals are obtained, and the crystals are dried, 0.75g of pure product is obtained, the yield is 72%, and the measured melting point is m.p.199.2-200.5 ℃.

Example 2:

0.57g (3.9 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol is added to dissolve the 3-indolecarboxaldehyde completely, then a solution of intermediate 2 (2-amino-5-S- (2-picolyl) -1,3, 4-thiadiazole, 0.68g,3 mmol) in ethanol (25 mL) is slowly dropped into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent) simultaneously, heating reflux is carried out for 6h, a large amount of yellow solid is separated out, heating is stopped, cooling to room temperature is carried out, decompression filtration is carried out, a crude product is obtained, then DMF and absolute ethyl alcohol mixed solution is used as a solvent (1:1) is used for recrystallization, yellow needle-like crystals are obtained, and 0.74g of pure product is obtained after drying, the yield is 70%, m.p.209-210 ℃.

Example 3:

0.57g (3.9 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol is added to dissolve the 3.9mmol completely, then a solution of intermediate 2 (2-amino-5-S- (3-picolyl) -1,3, 4-thiadiazole, 0.68g,3 mmol) in ethanol (25 mL) is slowly dropped into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to simultaneously track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent), heating reflux is carried out for 6h until the reaction is completed, heating is stopped, a large amount of yellow solid is separated out after cooling, the solution is decompressed and filtered, a crude product is obtained, and recrystallized by using a mixed solvent of DMF and absolute ethyl alcohol (1:1), and the solution is dried, so that dark yellow needle-like crystals are obtained, 0.99g, the yield is 94%, m.p.206.2-207.5 ℃.

Example 4:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol is added to dissolve the 3.6mmol completely, then a solution of an intermediate 2 (2-amino-5-S- (2, 4, 5-trifluorobenzyl) -1,3, 4-thiadiazole, 0.83g,3 mmol) in ethanol (25 mL) is slowly dropped into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent) at the same time, heating reflux is carried out for 6.5 hours until the reaction is completed, heating is stopped, a large amount of solids are separated out after cooling, the cooling is carried out, the reduced pressure filtration is carried out, a crude product is obtained, the crude product is recrystallized by using absolute ethyl alcohol, and the crude product is dried, so that 0.88g of bright yellow needle-like crystals is obtained, the yield is 73%, and m.p.205.3-206.2 ℃.

Example 5:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 20mL of absolute ethyl alcohol is added to dissolve the 3-indolecarboxaldehyde completely, then a solution of an intermediate 2 (2-amino-5-S- (4-chlorobenzoyl) -1,3, 4-thiadiazole, 0.77g,3 mmol) in ethanol (20 mL) is slowly dropped into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to simultaneously track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent), heating reflux is carried out for 5.5h until the reaction is completed, heating is stopped, solid precipitation is carried out after cooling, and decompression filtration is carried out, thus obtaining a crude product, and 0.78g of beige needle-like crystals is obtained after recrystallization by using a mixed solvent of DMF and absolute ethyl alcohol (1:1), the yield is 68%, m.p.201.5-202.4 ℃.

Example 6:

weighing 0.52g (3.6 mmol) of 3-indolecarboxaldehyde in a 100mL round bottom flask, adding 20mL of absolute ethyl alcohol to completely dissolve the 3-indolecarboxaldehyde, then dropwise adding a solution of an intermediate 2 (2-amino-5-S- (2-benzimidazolemethyl) -1,3, 4-thiadiazole, 0.79g and 3 mmol) in ethanol (20 mL) into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, adding a few drops of acetic acid as a catalyst, adopting TLC and HPLC to simultaneously track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent), heating and refluxing for 6.5h until the reaction is completed, stopping heating, cooling, precipitating solids, and filtering under reduced pressure to obtain a crude product; recrystallizing with mixed solvent of DMF and absolute ethanol (1:1), and drying to obtain reddish brown needle crystals 0.76g, 65% yield, m.p.244.5-245.8 ℃.

Example 7:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 20mL of 1, 4-dioxane is added to dissolve the 3-indolecarboxaldehyde completely, then a solution of intermediate 2 (2-amino-5-S-allyl-1, 3, 4-thiadiazole, 0.57g,3 mmol) in 1, 4-dioxane (18 mL) is slowly dropped into the round bottom flask by using a constant pressure dropping funnel under stirring, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent), heating reflux is carried out for 5.5h, the reaction is completed, heating is stopped, cooling is carried out, a large amount of solids are separated out, the filtration is carried out under reduced pressure, a crude product is obtained, then absolute ethyl alcohol is recrystallized, dark red solid powder is obtained, and the powder is dried, thus obtaining 0.61g of pure product, the yield is 68%, and m.p.192-193 ℃.

Example 8:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 20mL of absolute ethyl alcohol is added to dissolve the 3-indolecarboxaldehyde completely, then 0.84g,3mmol of 1, 4-dioxane (18 mL) of intermediate 2 (2-amino-5-S- (2-chloro-4-thiazolomethyl) -1,3, 4-thiadiazole) is slowly dropped into the round bottom flask by using a constant pressure dropping funnel under stirring, a few drops of acetic acid are added as a catalyst, and the reaction process is simultaneously tracked by TLC and HPLC (TLC uses ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 6.5h until the reaction is completed, stopping heating, cooling to precipitate a large amount of solid, decompressing and filtering to obtain a crude product, then recrystallizing with absolute ethanol to obtain yellow solid powder, drying to obtain 0.72g of pure product, wherein the yield is 62%, and m.p.168.0-169.2 ℃.

Example 9:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 20mL of absolute ethyl alcohol is added to dissolve the 3-indolecarboxaldehyde completely, then a solution of an intermediate 2 (2-amino-5-S- (2, 4-dichlorobenzyl) -1,3, 4-thiadiazole, 0.87g,3 mmol) in ethanol (20 mL) is slowly dripped into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent) at the same time, heating reflux is carried out for 7h until the reaction is completed, heating is stopped, cooling is carried out, solid precipitation is carried out, decompression filtration is carried out, a crude product is obtained, DMF and absolute ethyl alcohol is mixed (1:1) as a solvent for recrystallization, and drying is carried out, thus obtaining yellow powder of 0.81g, the yield is 65%, m.p.182.6-183.4 ℃.

Example 10:

0.58g (4.2 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 25mL of absolute ethanol was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (4-nitrophenyl) -1,3, 4-thiadiazole) 0.85g,3 mmol) in 1, 4-dioxane (21 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, and a catalytic amount of glacial acetic acid was added, followed by simultaneous tracking of the reaction process by TLC and HPLC (TLC with ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 7h until the reaction is completed, stopping heating, cooling, precipitating a large amount of solid, decompressing and filtering to obtain a crude product, then recrystallizing with a mixed solution of DMF and absolute ethanol as a solvent (1:1) to obtain brown solid powder, and drying to obtain 0.78g of pure product with the yield of 71%, m.p.194.6-195.5 ℃.

Example 11:

0.57g (3.9 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (2, 6-difluorobenzyl) -1,3, 4-thiadiazole) in absolute ethyl alcohol (20 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, a catalytic amount of glacial acetic acid was added, and the reaction process was simultaneously followed by TLC and HPLC (TLC was performed using ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 6.5h until the reaction is completed, stopping heating, and cooling to precipitate a solid; filtering under reduced pressure to obtain crude product; recrystallizing with mixed solvent of DMF and absolute ethanol (1:1), and drying to obtain pale yellow solid powder 0.76g, yield 64%, m.p. 177.0-177.8deg.C.

Example 12:

0.57g (3.9 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (vinylbenzyl) -1,3, 4-thiadiazole) in absolute ethyl alcohol (20 mL) was gradually added dropwise to the round bottom flask with stirring using a constant pressure dropping funnel, followed by adding a catalyst amount of glacial acetic acid, and the reaction process was simultaneously followed by TLC and HPLC (TLC was performed with ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 7.5h until the reaction is completed, stopping heating, and cooling to precipitate a solid; the crude product was obtained by filtration under reduced pressure, recrystallized from a mixed solvent of DMF and absolute ethanol (1:1) and dried to give 0.77g of yellow solid powder with a yield of 69%, m.p.217.0-218.1 ℃.

Example 13:

0.57g (3.9 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol is added to dissolve the 3-indolecarboxaldehyde in the whole, then a solution of an intermediate 2 (2-amino-5-S- (4-picolyl) -1,3, 4-thiadiazole, 0.68g,3 mmol) in ethanol (25 mL) is slowly dropped into the round bottom flask by using a constant pressure dropping funnel under the stirring condition, a few drops of acetic acid are added as a catalyst, TLC and HPLC are adopted to simultaneously track the reaction process (TLC uses ethyl acetate: dichloromethane=1:5 as a developing agent), heating and refluxing are carried out for 7h until the reaction is completed, heating is stopped, yellow solid is separated out after cooling, the solution is decompressed and filtered, a crude product is obtained, the crude product is recrystallized by using a mixed solvent of DMF and absolute ethyl alcohol (1:1), and dried, so that orange solid powder of 0.0.68g and the yield 65% and m.p.183.2-183.6 ℃ is obtained.

Example 14:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 25mL of 1, 4-dioxane was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (2-fluoro-3-bromobenzyl) -1,3, 4-thiadiazole) 0.95g,3 mmol) in 1, 4-dioxane (25 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, and a catalytic amount of glacial acetic acid was added, followed by simultaneous tracking of the reaction process using TLC and HPLC (TLC with ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 7h until the reaction is completed, stopping heating, and cooling until solid is separated out; filtering under reduced pressure to obtain crude product; recrystallizing with mixed solvent of DMF and absolute ethanol (1:1), and drying to obtain yellow solid powder 1.01g, yield 76%, m.p.198.0-199.3 ℃.

Example 15:

0.52g (3.6 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 25mL of 1, 4-dioxane was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (3-methoxybenzyl) -1,3, 4-thiadiazole) 0.76g,3 mmol) of 1, 4-dioxane (23 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, and a catalytic amount of glacial acetic acid was added to follow the reaction process simultaneously using TLC and HPLC (TLC was performed using ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 7.5h until the reaction is completed, stopping heating, and cooling to precipitate a solid; filtering under reduced pressure to obtain crude product; recrystallizing with mixed solvent of DMF and absolute ethanol (1:1), and drying to obtain yellow solid powder 0.83g, 73% yield, m.p. 194.2-195.4deg.C.

Example 16:

0.61g (4.2 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 20mL of 1, 4-dioxane was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (3-trifluoromethylbenzyl) -1,3, 4-thiadiazole) 0.87g,3 mmol) in 1, 4-dioxane (23 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, and a catalytic amount of glacial acetic acid was added, followed by simultaneous tracking of the reaction process using TLC and HPLC (TLC with ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 6.5h until the reaction is completed, stopping heating, and cooling to precipitate a solid; filtering under reduced pressure to obtain crude product; recrystallizing with absolute ethanol, and drying to obtain yellow solid powder 0.85g with yield 68%, m.p.201.3-202.2 ℃.

Example 17:

0.61g (4.2 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (3, 5-bistrifluoromethylbenzyl) -1,3, 4-thiadiazole) in absolute ethyl alcohol (25 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, and a catalytic amount of glacial acetic acid was added to follow the reaction course simultaneously by TLC and HPLC (TLC was performed using ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 6.5h until the reaction is completed, stopping heating, and cooling to precipitate a solid; filtering under reduced pressure to obtain crude product; recrystallizing with absolute ethanol, and drying to obtain yellow solid powder 1.05g with yield of 72%, m.p.201.3-202.2 ℃.

Example 18:

0.58g (4.2 mmol) of 3-indolecarboxaldehyde is weighed into a 100mL round bottom flask, 25mL of absolute ethyl alcohol is added to dissolve the 3-indolecarboxaldehyde completely, then 0.82g,3mmol of 1, 4-dioxane (23 mL) of intermediate 2 (2-amino-5-S- (2-fluoro-6-chloromethyl) -1,3, 4-thiadiazole) is slowly dropped into the round bottom flask with a constant pressure dropping funnel under stirring, a catalytic amount of glacial acetic acid is added, and the reaction process is simultaneously tracked by TLC and HPLC (TLC uses ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 8 hours until the reaction is completed, stopping heating, cooling, precipitating a large amount of solid, decompressing and filtering to obtain a crude product, then recrystallizing with a mixed solution of DMF and absolute ethanol as a solvent (1:1) to obtain yellow solid powder, and drying to obtain 0.76g of pure product with the yield of 63%, m.p.194.6-195.5 ℃.

Example 19:

0.61g (4.2 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 20mL of 1, 4-dioxane was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (3-trifluoromethylbenzyl) -1,3, 4-thiadiazole) 0.87g,3 mmol) in 1, 4-dioxane (23 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, and a catalytic amount of glacial acetic acid was added, followed by simultaneous tracking of the reaction process using TLC and HPLC (TLC with ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 7h until the reaction is completed, stopping heating, and cooling until solid is separated out; filtering under reduced pressure to obtain crude product; recrystallizing with absolute ethanol, and drying to obtain yellow solid powder 0.81g with yield of 65%, m.p. 198.1-199.0deg.C.

Implementation of the embodimentsExample 20:

0.61g (4.2 mmol) of 3-indolecarboxaldehyde was weighed into a 100mL round bottom flask, 20mL of 1, 4-dioxane was added to dissolve it completely, and then a solution of intermediate 2 (2-amino-5-S- (2-trifluoromethylbenzyl) -1,3, 4-thiadiazole) 0.87g,3 mmol) in 1, 4-dioxane (23 mL) was slowly dropped into the round bottom flask with stirring using a constant pressure dropping funnel, and a catalytic amount of glacial acetic acid was added, followed by simultaneous tracking of the reaction process by TLC and HPLC (TLC with ethyl acetate: dichloromethane=1:5 as developing agent), heating and refluxing for 7h until the reaction is completed, stopping heating, and cooling until solid is separated out; filtering under reduced pressure to obtain crude product; recrystallizing with absolute ethanol, and drying to obtain yellow solid powder 0.79g, yield 63%, m.p. 194.7-195.6deg.C.

Characterization of the structure of the compounds prepared in examples 1-20: by infra-red (IR) and nuclear magnetic resonance ¹ H-NMR ¹³ The structure of the target compound was confirmed by C-NMR spectrum and High Resolution Mass Spectrum (HRMS), and the results are shown in FIGS. 2 to 21.

The compounds of examples 1-20 were tested for their phytopathogenic fungi inhibiting activity by the following methods:

testing the inhibitory activity of the compounds 1-20 on experimental fungi by adopting a hypha growth method; the synthesized compounds 1-20 are respectively dissolved in 20% acetone aqueous solution, and the solution of each compound is added into sterilized potato dextrose solution to make the final concentration of the compound be 500 mug/mL; after the mixture was cooled, the mycelia (6.5 mm) of the fungi were transferred to a test plate, cultured at 25℃for 3 to 7 days, and when the mycelia of the fungi reached the edge of a dish (blank, no sample was added), the colony diameter was measured by the crisscross method, the inhibition rate was calculated according to the following formula, the test was set in parallel for 3 times, and the average value was taken, and the plant pathogenic fungi inhibition activity results were shown in Table 1:

table 1 results of the inhibitory Activity of Compounds 1 to 20 against plant pathogenic fungi Table

From the primary antibacterial activity test results, it can be seen that: the target compounds had various degrees of inhibition of the test fungi at a concentration of 500. Mu.g/mL. Wherein the inhibition rate of the compounds 1, 2,6, 8, 10, 11, 12, 14, 15, 16 and 17 on fusarium oxysporum is higher than that of the control drug triazolone 1 (the concentration is 50 mug/mL, the inhibition rate is 45.6%), the inhibition activity of the compounds is better than or equal to that of the control drug triazolone, and the highest inhibition rate of the compound 10 reaches 94.7%. Under the same concentration condition, the inhibition rate of the compounds 9, 10, 13, 14, 15, 16 and 18 on fusarium graminearum is higher than that of a control drug triazolone (the concentration is 50 mug/mL, the inhibition rate is 47.6%), and the inhibition activity of the compound is better than or equal to that of the control drug triazolone, wherein the highest inhibition rate of the compound 10 reaches 97.5%. And for Fusarium moniliforme, under the condition of the concentration of 500 mug/mL, the antibacterial activity of the compound 10 is better than that of the control medicine triazolone, the inhibition rate is 89.2 percent and higher than that of the triazolone (the concentration of 50 mug/mL, and the inhibition rate is 81.1 percent). The inhibition activity of the compounds 8, 10, 14 and 16 on phytophthora nicotianae is superior to or equal to that of the control drug triazolone 2 (the concentration is 50 mug/mL, the inhibition rate is 50.4%), the inhibition rate is higher than that of the triazolone, and the inhibition rate of the compound 10 is the highest (72.1%). From the compound, some compounds have better inhibition activity on two or more fungi, such as compounds 8, 9, 10, 14, 15, 16 and the like, wherein the inhibition activity of compound 10 on four fungi is better than triazolone (concentration 50 mug/mL), the inhibition rate on experimental fungi is the highest in all compounds, and the inhibition rate on fusarium graminearum (97.5%) is more than twice that of the control drug triazolone (47.6%/50 mug). From the structural-activity relation, the compound 10 with the nitro group attached to the benzene ring has the best antibacterial activity, which indicates that the activating effect of the nitro group is the strongest, and other groups have different degrees of influence on the antibacterial activity of the compound.

FIGS. 22-25 are physical graphs showing the experimental results of the inhibition activity of a selected portion of the compounds against experimental fungi, wherein the data in the table are the inhibition rates of the compounds against experimental fungi calculated from the results of the picture test. The results in FIGS. 22-25 show that compound 10 has better inhibition effect on 4 fungi, especially Fusarium graminearum, and that compounds 14, 15 and 17 have better inhibition activity on different experimental fungi. The method lays a good foundation for the next selection of new pesticide lead compounds.

It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims

1. An indole compound is characterized in that the structural formula is shown as the formula (I):

wherein R is selected from benzyl, picolyl, halogenated benzyl, nitrobenzyl, methoxybenzyl, CF ₃ Phenylmethyl, benzimidazolylmethyl, allyl, halothiazolylmethyl, vinylphenylmethylOne of them.

2. An indole compound according to claim 1 wherein R is selected from

One of them.

3. A process for the preparation of an indole compound according to claim 1, comprising the steps of:

(1) Preparing 2-amino-5-S-alkyl-1, 3, 4-thiadiazole compounds;

(2) Preparation of indole compounds:

4. The method for preparing indole compounds according to claim 3, wherein the 2-amino-5-S-hydrocarbyl-1, 3, 4-thiadiazole compound of step (1) is prepared according to the following steps:

dissolving thiosemicarbazide and carbon disulfide in N, N' -dimethylformamide, and heating and refluxing for 8-10 hours to prepare 2-amino-5-mercapto-1,3, 4-thiadiazole;

wherein, the molar ratio of thiosemicarbazide to carbon disulfide is 1:1.5;

completely dissolving 2-amino-5-mercapto-1,3, 4-thiadiazole and sodium hydroxide in deionized water, then dropwise adding a methanol solution of a halogenated hydrocarbon compound into the solution, stirring the solution at room temperature overnight, and recrystallizing the solution with absolute ethyl alcohol to obtain a 2-amino-5-S-alkyl-1, 3, 4-thiadiazole compound;

wherein the halohydrocarbon compound is selected from arylmethyl halohydrocarbon, heteroarylmethyl halohydrocarbon or allyl halohydrocarbon, and the ratio of the amount of 2-amino-5-mercapto-1,3, 4-thiadiazole, sodium hydroxide and halohydrocarbon compound is 1:1:1.

5. The process for preparing indole compounds according to claim 3, wherein the solvent in step (2) is selected from ethanol or 1, 4-dioxane.

6. The method for preparing indole compounds according to claim 3, wherein the molar ratio of 3-indole carbaldehyde to 2-amino-5-S-hydrocarbyl-1, 3, 4-thiadiazole compounds in step (2) is 1.2 to 1.4:1.

7. use of an indole compound according to claim 1 for the preparation of a plant fungicide.

8. Use of an indole compound according to claim 7 for the preparation of a plant fungicide, characterised in that the fungicide is for the inhibition of phytopathogenic fungi.

9. The use according to claim 8, wherein the plant pathogenic fungus is one or more of fusarium graminearum (Fusarium graminearum), fusarium moniliforme (Fusarium moniliforme), fusarium oxysporum (Fusarium oxysporum), phytophthora nicotianae (Phytophthora parasitica var. Nicote).