An indole derivative containing benzothiazole and pyridine, and a preparation method and application thereof

Abstract

The application discloses an indole derivative containing benzothiazole and pyridine as well as a preparation method and application thereof, and belongs to the technical field of pesticide synthesis. The application introduces benzothiazole and pyridine groups with excellent activity into the structure of indole, and synthesizes a series of indole derivatives containing benzothiazole and pyridine. Through inhibition of plant pathogenic bacteria activity test on the synthesized indole derivatives containing benzothiazole and pyridine, it is found that the synthesized indole derivatives containing benzothiazole and pyridine can effectively inhibit plant pathogenic fungi, especially pepper phytophthora blight.

Description

Technical Field

[0001] This invention belongs to the field of pesticide synthesis technology, specifically relating to an indole derivative containing benzothiazole and pyridine, its preparation method, and its application. Background Technology

[0002] Plant fungal diseases pose a significant threat to global agriculture and ecosystems, with profound ecological and economic impacts. Due to the parasitic interactions between plant pathogens and host plants, these diseases often exhibit devastating effects. Fungal pathogens such as corn rust, powdery mildew, and Phytophthora can infect important economic crops, leading to significant yield reductions, deterioration of crop quality, and huge economic losses for farmers. It is estimated that global crop yield reductions due to plant diseases reach 20%–40% annually, highlighting the urgent need to develop effective and sustainable strategies for controlling fungal pathogens. However, traditional synthetic pesticides have significant limitations, including excessive residue accumulation, increased risk of poisoning in humans and animals, the emergence of pesticide-resistant pest strains, sharp decline in natural enemy populations, and disruption of ecological balance. Therefore, the research community has focused considerable attention on the development of environmentally friendly biopesticides based on structurally modified natural products. These products offer advantages such as low mammalian toxicity, high target specificity, low environmental residue, and low likelihood of inducing resistance.

[0003] Indole, a dominant nitrogen-containing heterocyclic skeleton, is widely found in alkaloids, plant and animal hormones, and microbial metabolites. As a key pharmacophore, indole derivatives exhibit diverse biological activities, including antibacterial, antiviral, antitumor, anti-inflammatory, and protein kinase inhibitory properties. Due to their broad-spectrum biological activity and therapeutic potential, indole compounds have been extensively isolated from natural sources or chemically synthesized, and are widely used in pharmaceuticals, agrochemicals, fragrances, and dyes.

[0004] Benzothiazole, with its electron-rich heterocyclic skeleton, is an important intermediate in the synthesis of pharmaceuticals and agrochemicals. This structural unit exhibits broad-spectrum biological activity, encompassing multiple effects including antifungal, antiviral, insecticidal, antitumor, and anti-inflammatory properties. Numerous highly effective agents have been developed based on this skeleton, such as the antiviral drug flufenoxuron. Therefore, benzothiazole derivatives remain a key research focus in new drug development. Furthermore, piperidine structural units are also present in various commercially available fungicides, including pyraclostrobin, flufenoxuron-methyl, and benzyl sulfide, which are widely used in the control of plant diseases in agricultural production.

[0005] In summary, no studies have been found on the synthesis of indole derivatives containing benzothiazole and piperidine by introducing piperidine and benzothiazole into the indole structure, nor have any studies on the use of indole derivatives containing benzothiazole and piperidine for agricultural activity research been found. Summary of the Invention

[0006] The purpose of this invention is to provide an indole derivative containing benzothiazole and piperidine, its preparation method, and its application. The provided indole derivative containing benzothiazole and piperidine can be used to inhibit plant pathogenic fungi, especially *Phytophthora capsici*.

[0007] To achieve the above objectives, the present invention provides the following technical solution: One of the technical solutions of this invention is to provide an indole derivative containing benzothiazole and piperidine, with the following structure: , In the above formula, R1 and R2 are independently selected from H, one or more halogens, one or more nitro groups, a C1-C6 alkyl group, a C1-C6 substituted alkyl group, and a C1-C6 alkoxy group.

[0008] Preferably, the halogen is F, Cl, or Br.

[0009] The second technical solution of the present invention provides a method for preparing an indole derivative containing benzothiazole and piperidine, comprising the following steps: (1) Using substituted 2-aminobenzothiazole and 1-Boc-4-piperidinecarboxylic acid as raw materials, HATU and DIPEA were added as catalysts and the reaction was carried out at room temperature. After the reaction was completed, the product was poured into water to precipitate and filtered to obtain intermediate a. The structural formula of the substituted 2-aminobenzothiazole is: ; (2) Using intermediate a as raw material, remove BOC protection to obtain intermediate b; The structural formula of intermediate a is: ; (3) Using substituted indole and epibromopropane as raw materials, and NaH as a catalyst, the reaction was carried out under heat. After the reaction was completed, the mixture was extracted with ethyl acetate and concentrated to obtain intermediate c; The structural formula of the substituted indole is: ; (4) Using intermediates b and c as raw materials and potassium carbonate as catalyst, the reaction was carried out under reflux. After the reaction was completed, the product was extracted with dichloromethane, concentrated and purified to obtain the indole derivative containing benzothiazole and pyridine. The structural formula of intermediate b is as follows: The structure of intermediate c is .

[0010] Preferably, the molar ratio of the substituted 2-aminobenzothiazole, 1-Boc-4-piperidinecarboxylic acid, HATU and DIPEA in step (1) is 1:(1~3):(1~2):(1~2); and the heating reaction time is 10~12 h.

[0011] Preferably, the step of removing BOC protection in step (2) includes: dissolving intermediate a in acetonitrile, heating to 70~80℃, adding trifluoroacetic acid in a molar ratio of 1:(5~10) dropwise, heating under reflux for 2 h to remove BOC protection.

[0012] Preferably, step (2) further includes a separation step after removing BOC protection. The separation step specifically involves: after removing BOC protection, repeatedly adding acetonitrile to the reaction system and concentrating under reduced pressure to remove excess trifluoroacetic acid, and finally adding ethanol for recrystallization.

[0013] Preferably, the molar ratio of the substituted indole, epoxybromopropane and NaH in step (3) is 1:2:2; the heating temperature is 45 °C and the heating time is 1~2 h.

[0014] Preferably, the molar ratio of intermediate b, intermediate c and K2CO3 in step (4) is 1:(1~2):(2~3).

[0015] Preferably, the purification step in step (4) specifically includes: silica gel column chromatography (dichloromethane:methanol = 35:1, v / v) purification.

[0016] The third technical solution of the present invention provides the application of the above-mentioned indole derivative containing benzothiazole and piperidine in the preparation of drugs that inhibit plant pathogenic fungi.

[0017] Preferably, the plant pathogenic fungus includes *Rhizoctonia solani*, the causal agent of rice sheath blight. Rs Phytophthora capsici, the pathogen of which is the fungus Phytophthora capsici Pc Sclerotinia sclerotiorum var. sclerotiorum Ss Kiwifruit stem spot pathogen Ps Grape cavitation bacteria Bd Fusarium oxysporum Fo Fusarium wilt of cucumber Foc Black spot disease of Chinese cabbage Ab One or more of them.

[0018] The beneficial technical effects of the present invention are as follows: This invention provides an indole derivative containing benzothiazole and piperidine, its preparation method, and its application. This invention introduces benzothiazole and piperidine groups with excellent activity into the structure of indole, synthesizing a series of indole derivatives containing benzothiazole and piperidine. Through testing the inhibitory activity of the synthesized indole derivatives containing benzothiazole and piperidine against plant pathogenic fungi, it was found that the indole derivatives containing benzothiazole and piperidine synthesized in this invention can effectively inhibit plant pathogenic fungi, especially Phytophthora capsici. Detailed Implementation

[0019] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0020] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, are also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0021] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention.

[0022] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0023] One of the technical objectives of this invention is to provide an indole derivative containing benzothiazole and piperidine, with the following structure: , In the above formula, R1 and R2 are independently selected from H, one or more halogens, one or more nitro groups, a C1-C6 alkyl group, a C1-C6 substituted alkyl group, and a C1-C6 alkoxy group.

[0024] Preferably, the halogen is F, Cl, or Br.

[0025] The second technical objective of this invention is to provide a method for preparing the above-mentioned indole derivative containing benzothiazole and piperidine, the steps of which include: (1) Using substituted 2-aminobenzothiazole and 1-Boc-4-piperidinecarboxylic acid as raw materials and DMF as solvent, the reaction was carried out overnight at room temperature under the action of catalysts HATU and DIPEA. The reaction solution was poured into water, and the precipitated solid was filtered and dried to obtain intermediate a.

[0026] The reaction formula is as follows: , The molar ratio of the substituted 2-aminobenzothiazole, 1-Boc-4-piperidinecarboxylic acid, HATU and DIPEA is 1:(1~3):(1~2):(1~2).

[0027] (2) Using intermediate a as raw material and acetonitrile as solvent, trifluoroacetic acid was added dropwise under the condition of heating to 40~80 ℃ and reacted for 1~4 h to remove BOC protection. The solvent was removed by vacuum evaporation and recrystallization with ethanol to obtain intermediate b.

[0028] The reaction formula is as follows: , The molar ratio of intermediate a to trifluoroacetic acid is 1:(5~10).

[0029] (3) Using substituted indole as a raw material, DMF as a solvent, and NaH as a catalyst, epoxybromopropane was added after stirring for 20 minutes. The reaction was refluxed at 45 °C for 2-4 h. After the reaction was completed, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an oily intermediate c.

[0030] The reaction formula is as follows: , The molar ratio of the substituted indole, epoxybromopropane and NaH is 1:(1~3):(1~3).

[0031] (4) Using intermediates b and c as raw materials and potassium carbonate as catalyst, indole derivatives containing benzothiazole and piperidine were prepared by reflux in a solvent.

[0032] The reaction formula is as follows: , In some embodiments, the solvent is isopropanol; the reflux reaction time is 1-2 h; after the reaction is completed, the reaction system is dispersed in water, and then extracted, dried, subjected to vacuum rotary evaporation, and column chromatography, wherein the column chromatography eluent is a mixture of dichloromethane and methanol in a volume ratio of 35:1.

[0033] The molar ratio of intermediate b, intermediate c and potassium carbonate is 1:(1~2):(2~4).

[0034] The third technical objective of this invention is to provide the application of the above-mentioned indole derivative containing benzothiazole and piperidine in the preparation of drugs for inhibiting plant pathogenic fungi.

[0035] To achieve the above-mentioned technical objectives, the present invention provides the following embodiments.

[0036] Example 1

[0037] N -(benzo[d]thiazo-2-yl)-1-[2-hydroxy-3-(1 H[-indol-1-yl)propyl]piperidine-4-carboxamide (compound number H1), the steps are as follows: (1) Synthesis of tert-butyl-4-((benzo[d]thiazol-2-yl)carbamoyl)piperidine-1-carboxylic acid ester: 2-aminobenzothiazolium (1.0 g, 5.42 mmol) and HATU (2.47 g, 6.50 mmol) were dissolved in DMF in a 250 mL round-bottom flask, and DIPEA (1.13 mL, 6.50 mmol) was added dropwise. After stirring for 30 minutes, 1-Boc-4-piperidinecarboxylic acid (2.24 g, 9.75 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction solution was poured into water, and the precipitated solid was filtered and dried to obtain a brown solid with a yield of 82.3%.

[0038] (2) N Synthesis of -(benzo[d]thiazolyl)piperidine-4-carboxamide: The product from step (1) (2.0 g, 5.53 mmol) was dissolved in 50 mL of acetonitrile in a 100 mL round-bottom flask, and trifluoroacetic acid (2.06 mL, 27.67 mmol) was added dropwise. The mixture was heated under reflux for 2 hours. The solvent was removed by vacuum distillation, and the product was recrystallized from ethanol to give a brown solid in 75.2% yield.

[0039] (3) 1-(2-epoxypropyl)-1 H Preparation of indole: Indole (2.0 g, 17.07 mmol) and 50 mL DMF were added to a 100 mL round-bottom flask. NaH (1.37 g, 37.14 mmol) was slowly added, and the mixture was stirred for 30 minutes. Then, epichlorohydrin (2.8 mL, 34.14 mmol) was added. The mixture was refluxed at 45 °C for 2–4 hours. After the reaction was complete, 90 mL of distilled water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine (3 times), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily substance with a yield of 67.5%.

[0040] (4) N -(benzo[d]thiazo-2-yl)-1-[2-hydroxy-3-(1 H Synthesis of [-indol-1-yl)propyl]piperidine-4-carboxamide: N -(benzo[d]thiazolyl)piperidine-4-carboxamide (0.6 g, 2.38 mmol), 1-(2-epoxypropyl)-1 HIndole (1.0 g, 3.57 mmol), K₂CO₃ (0.9 g, 7.14 mmol), and 50 mL of acetonitrile were added to a 100 mL round-bottom flask, and the mixture was heated under reflux for 1–2 h. The reaction progress was monitored by thin-layer chromatography (TLC, dichloromethane:methanol = 15:1, v / v) until the starting material disappeared. The reaction solution was extracted with dichloromethane (3 × 30 mL), and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 35:1, v / v) to give a white solid in 40% yield.

[0041] Example 2

[0042] N -(benzo[d]thiazo-2-yl)-1-[3-(5-bromo-1-yl) H Synthesis of [-indole-1-yl]-2-hydroxypropyl]piperidine-4-carboxamide (compound number H2) was performed in the same manner as in Example 1, except that indole in step (3) was replaced with 5-bromoindole in a molar ratio of 1:2.1:2.2. Yield: 44%.

[0043] Example 3

[0044] N -(benzo[d]thiazo-2-yl)-1-[3-(5-chloro-1-yl] H Synthesis of [-indole-1-yl)-2-hydroxypropyl]piperidine-4-carboxamide (compound number H3) was performed in the same manner as in Example 1, except that indole in step (3) was replaced with 5-chloroindole in a molar ratio of 1:2.3:2. Yield: 31%.

[0045] Example 4

[0046] N -(benzo[d]thiazolyl-2-yl)-1-[2-hydroxy-3-(5-methoxy-1-yl] H Synthesis of [-indole-1-yl]propyl]piperidine-4-carboxamide (compound number H4): The steps were the same as in Example 1, except that indole in step (3) was replaced with 5-methoxyindole in a molar ratio of 1:2.5:2.3. Yield: 35%.

[0047] Example 5

[0048] N -(benzo[d]thiazo-2-yl)-1-[3-(4-fluoro-1-yl) H Synthesis of [-indole-1-yl]-2-hydroxypropyl]piperidine-4-carboxamide (compound number H5): The steps were the same as in Example 1, except that indole in step (3) was replaced with 6-fluoroindole in a molar ratio of 1:2.3:2.6. Yield: 43%.

[0049] Example 6

[0050] 1-[2-hydroxy-3-(1 H [-indole-1-yl)propyl]- N The synthesis of -(5-methoxybenzo[d]thiazol-2-yl)piperidine-4-carboxamide (compound number H6) was performed according to the same procedure as in Example 1, except that 2-aminobenzothiazolium in step (1) was replaced with 5-methoxybenzo[d]thiazol-2-amine in a molar ratio of 1:1.8:1.5:1.3. Yield: 39%.

[0051] Example 7

[0052] 1-[3-(5-bromo-1-] H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of -(5-methoxybenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H7) was performed in the same manner as in Example 6, except that the indole from step (3) was replaced with 5-bromoindole in a molar ratio of 1:1.3:1.4. Yield: 30%.

[0053] Example 8

[0054] 1-[3-(5-chloro-1-] H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of -(5-methoxybenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H8) was performed in the same manner as in Example 6, except that the indole in step (3) was replaced with 5-chloroindole in a molar ratio of 1:1.5:1.5. Yield: 44%.

[0055] Example 9

[0056] 1-[3-(5-methoxy-1 H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of -(5-methoxybenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H9) was performed in the same manner as in Example 6, except that the indole in step (3) was replaced with 5-methoxyindole in a molar ratio of 1:1.6:1.4. Yield: 41%.

[0057] Example 10

[0058] 1-[3-(6-fluoro-1-] H [-indole-1-yl)-2-hydroxypropyl]- NThe synthesis of -(5-methoxybenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H9) was performed in the same manner as in Example 6, except that the indole in step (3) was replaced with 6-fluoroindole in a molar ratio of 1:1.7:1.6. Yield: 37%.

[0059] Example 11

[0060] 1-[2-hydroxy-3-(1 H [-indole-1-yl)propyl]- N The synthesis of (4-methylbenzo[d]thiazol-2-yl)piperidine-4-carboxamide (compound number H11) was performed according to the same procedure as in Example 1, except that 2-aminobenzothiazolium in step (1) was replaced with 4-methylbenzo[d]thiazol-2-amine in a molar ratio of 1:1.8:1.2:1.3. Yield: 30%.

[0061] Example 12

[0062] 1-[3-(5-bromo-1-] H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of (4-methylbenzo[d]thiazo-2-yl)piperidine-4-carboxamide (compound number H12) was performed in the same manner as in Example 11, except that indole in step (3) was replaced with 5-bromoindole in a molar ratio of 1:2.1:3. Yield: 40%.

[0063] Example 13

[0064] 1-[3-(5-chloro-1-] H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of (4-methylbenzo[d]thiazo-2-yl)piperidine-4-carboxamide (compound number H13) was performed in the same manner as in Example 11, except that indole in step (3) was replaced with 5-chloroindole in a molar ratio of 1:2.3:2.3. Yield: 34%.

[0065] Example 14

[0066] 1-[3-(5-methoxy-1 H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of 4-(4-methylbenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H14) was performed in the same manner as in Example 11, except that indole in step (3) was replaced with 5-methoxyindole in a molar ratio of 1:2.5:2.3. Yield: 50%.

[0067] Example 15

[0068] 1-[3-(6-fluoro-1-]H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of (4-methylbenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H15) was performed in the same manner as in Example 11, except that indole in step (3) was replaced with 6-fluoroindole in a molar ratio of 1:2:2.3. Yield: 50%.

[0069] Example 16

[0070] N -(5-chlorobenzo[d]thiazolyl-2-yl)-1-[2-hydroxy-hydroxy-3-(1 H Synthesis of [-indol-1-yl]propyl]piperidine-4-carboxamide (compound number H16): The steps were the same as in Example 1, except that 2-aminobenzothiazole in step (1) was replaced with 5-chloro[d]thiazole-2-amine in a molar ratio of 1:2:3. Yield: 38%.

[0071] Example 17

[0072] 1-[3-(5-bromo-1-] H [-indole-1-yl)-2-hydroxypropyl]- N Synthesis of (5-chlorobenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H17): The procedure was the same as in Example 16, except that indole in step (3) was replaced with 5-bromoindole in a molar ratio of 1:2:2. Yield: 24%.

[0073] Example 18

[0074] 1-[3-(5-chloro-1-] H [-indole-1-yl)-2-hydroxypropyl]- N Synthesis of (5-chlorobenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H18), the steps were the same as in Example 16, except that indole in step (3) was replaced with an equimolar amount of 5-chloroindole. Yield: 24%.

[0075] Example 19

[0076] 1-[3-(5-methoxy-1 H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of (5-chlorobenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H19) was performed in the same manner as in Example 16, except that indole in step (3) was replaced with 5-methoxyindole in a molar ratio of 1:2.2:2.2. Yield: 32%.

[0077] Example 20

[0078] 1-[3-(6-fluoro-1-] H [-indole-1-yl)-2-hydroxypropyl]- N Synthesis of (5-chlorobenzo[d]thiazolyl)piperidine-4-carboxamide (compound number H20): The procedure was the same as in Example 16, except that indole in step (3) was replaced with 6-fluoroindole in a molar ratio of 1:2:2.1. Yield: 30%.

[0079] Example 21

[0080] 1-[3-(5-bromo-1-] H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of (5-fluorobenzo[d]thiazol-2-yl)piperidine-4-carboxamide (compound number H21) was performed in the same manner as in Example 2, except that 2-aminobenzothiazolium in step (1) was replaced with 4-methylbenzo[d]thiazol-2-amine in a molar ratio of 1:2:1.3:1.2. Yield: 40%.

[0081] Example 22

[0082] 1-[3-(5-bromo-1-] H [-indole-1-yl)-2-hydroxypropyl]- N The synthesis of (5-fluorobenzo[d]thiazol-2-yl)piperidine-4-carboxamide (compound number H21) was performed according to the same procedure as in Example 2, except that 2-aminobenzothiazolium in step (1) was replaced with 4-methylbenzo[d]thiazol-2-amine in a molar ratio of 1:2.1:1.5:1.3. Yield: 34%.

[0083] Table 1. Physicochemical properties and mass spectrometry data of the target compounds compound Yield (%) Properties Melting point (°C) HRMS, m / z (calcd.) H1 40 % White solid 140-142 <![CDATA[436.18492(436.18436)[M+H] + ]]> H2 31% White solid 186-188 <![CDATA[513.09544(513.09491)[M+H] + ]]> H3 36 % White solid 178-179 <![CDATA[469.14595(469.14536)[M+H] + ]]> H4 35% White solid 156-157 <![CDATA[465.19549(465.17401)[M+H] + ]]> H5 43 % White solid 95-96 <![CDATA[453.17550(453.17401)[M+H] + ]]> H6 39 % White solid 166-168 <![CDATA[465.19549(465.19461)[M+H] + <!-- 7 -->]]> H7 30 % White solid 139-141 <![CDATA[543.10600(543.10529)[M+H] + ]]> H8 44 % White solid 124-126 <![CDATA[499.15652(499.15576)[M+H] + ]]> H9 41 % White solid 142-144 <![CDATA[495.20605(495.20523)[M+H] + ]]> H10 37 % White solid 139-142 <![CDATA[483.18607(483.18527)[M+H] + ]]> H11 30 % White solid 138-139 <![CDATA[449.20057(449.20001)[M+H] + ]]> H12 40 % White solid 99-101 <![CDATA[527.11109(527.10980)[M+H] + ]]> H13 34 % White solid 97-99 <![CDATA[483.16160(483.15979)[M+H] + ]]> H14 50 % White solid 148-150 <![CDATA[479.21114(479.21051)[M+H] + ]]> H15 35 % White solid 147-150 <![CDATA[467.19115(467.19049)[M+H] + ]]> H16 38 % White solid 107-109 <![CDATA[469.14595( 469.14551)[M+H] + ]]> H17 24 % White solid 103-105 <![CDATA[547.05646(547.05591)[M+H] + ]]> H18 32 % White solid 114-116 <![CDATA[503.10698(503.10641)[M+H] + ]]> H19 27 % White solid 121-123 <![CDATA[499.15652( 499.15598)[M+H] + ]]> H20 30 % White solid 122-124 <![CDATA[487.13653(487.13580)[M+H] + ]]> H21 40 % White solid 123-125 531.08601(531.08368)[M+H]+ H22 34 % White solid 145-146 494.18565(494.18326)[M+H]+ Table 2. NMR spectral data of the target compound

[0084]

[0085]

[0086]

[0087]

[0088] Experimental Example 1 Anti-plant pathogenic fungal activity test Test method: The mycelial growth rate method was used to investigate the pathogenic fungi of eight plant pathogens (including rice sheath blight fungus). Rs Phytophthora capsici, the pathogen of which is the fungus Phytophthora capsici Pc Sclerotinia sclerotiorum var. sclerotiorum Ss Kiwifruit stem spot pathogen Ps Grape cavitation bacteria Bd Fusarium oxysporum Fo Fusarium wilt of cucumber Foc Black spot disease of Chinese cabbage Ab In vitro activity evaluation was performed, using the commercial drug azoxystrobin as a positive control. The specific steps are as follows: (1) Preparation steps of the culture medium: When preparing potato dextrose agar (PDA) medium, first weigh 27.0 g of PDA medium, then place it in 1000 mL of deionized water and heat to boiling until completely dissolved. Next, while still hot, quickly measure 19.8 mL of the medium and carefully pour it into a 50 mL Erlenmeyer flask. To ensure airtightness while maintaining permeability, use a breathable sealing film to tightly seal the flask opening. Finally, place the Erlenmeyer flask in an autoclave and set the temperature to 121 ℃ for 20 min for thorough sterilization, ready for subsequent use.

[0089] (2) Antifungal activity test procedure: First, weigh 2.5 mg of the test compound and dissolve it in 250 μL of DMSO. Next, in a sterile laminar flow hood, accurately transfer 200 μL of the solution using a pipette and add it to sterilized PDA medium. After mixing thoroughly, evenly distribute the mixture into three sterile culture dishes and allow it to cool before use.

[0090] (3) Using a punch, pre-activated fungal cultures were prepared into 5 mm diameter mycelial cakes, which were then placed upside down in the center of the cooled culture medium. To ensure sterility, the culture dishes were completely sealed with sealing film to effectively prevent the intrusion of external contaminants. PDA medium containing the same concentration of DMSO was used as a blank control. When the mycelium covered 3 / 4 of the culture dish, the diameter of the mycelium was measured using the cross-sectional method. Each test compound was tested in triplicate, and the fungal inhibition rate was calculated according to formula (3-2): Inhibition rate I% = (CT) / (C-5) × 100 (3-2) C: Mycelial growth diameter in blank control (unit: mm) T: Diameter of mycelial growth after treatment with the chemical (unit: mm) 5: Diameter of the mushroom cake (unit: mm).

[0091] EC 50Determination of inhibitory activity: Based on the results of the preliminary screening test, compounds with inhibition rates superior to the control agent were selected to further investigate their activity against fungi with good inhibitory effects. Following the experimental method described in the preliminary screening, test concentration gradients of 50, 25, 12.5, 6.25, and 3.125 µg / mL were set up for testing. The growth of fungal hyphae at each concentration was recorded in detail. Subsequently, based on the collected data, the inhibition rate of fungal hyphae growth was calculated at each of the five different concentration gradients. To more accurately measure the effects of the target compound and the control agent, an Excel spreadsheet was used to construct a linear regression equation between the logarithm of concentration and the inhibition rate. After calculation, the EC50 values ​​of the target compound with better activity and the control agent were obtained. 50 value.

[0092] Table 3. In vitro antibacterial activity of H1-H22 (100 μg / mL)

[0093] Table 3 shows that all target compounds exhibited inhibitory activity against eight plant fungi at a concentration of 100 μg / mL. Among them, H11, H14, and H15 showed inhibitory activity against... Fo The inhibition rate was 100%, which was better than that of azoxystrobin (61.4%).

[0094] Table 4. EC50 of certain compounds against certain fungi 50 Test results.

[0095] Compds. Pathogeas Regression equation Correlation coefficient(r) <![CDATA[EC 50 (µg / mL)]]> H2 y = 2.0750x + 2.6677 0.9796 13.31 H12 y = 2.2857x + 2.6439 0.9924 10.73 H13 y = 2.1050x + 2.7893 0.9689 11.23 H17 y = 2.3009x + 2.4406 0.9881 12.95 H18 y = 2.2768x + 2.4934 0.9923 12.62 Az y = 0.7808x + 3.8898 0.9714 26.42 H12 y = 1.5122x + 3.1784 0.9800 16.02 H13 y = 2.1893x + 2.3028 0.9813 17.06 H15 y = 1.8743x + 2.6897 0.9836 17.08 Az y = 1.4325x + 2.5749 0.9811 49.31 H2 y = 2.1323x + 2.5770 0.9924 13.69 H8 y = 2.0619x + 2.6399 0.9896 13.95 H12 y = 1.3363x + 3.7518 0.9984 8.59 H13 y = 1.5548x + 3.5345 0.9905 8.76 H21 y = 1.7270x + 3.3174 0.9957 9.43 H22 y = 1.7433x + 3.0555 0.9977 13.04 Az y = 1.4966x + 1.9375 0.9813 111.27

[0096] Table 4 shows the results of compound H12 against *Phytophthora capsici* (the causal agent of *Phytophthora capsici*). Pc The half-maximal effective concentration (EC) 50 The antifungal activity of the drug with the lowest concentration (8.59 μg / mL) was significantly superior to that of the positive control drug azoxystrobin (Az; EC). 50 =111.27 μg / mL).

[0097] The above experimental activity data show that indole derivatives containing benzothiazole and piperidine have a good inhibitory effect on plant pathogenic fungi, especially Phytophthora capsici, and can be used as potential anti-plant pathogen drugs with good application prospects.

[0098] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. An indole derivative containing benzothiazole and pyridine, characterized in that, The structure is shown in the following formula: ， In the above formula, R1 and R2 are independently selected from H, one or more halogens, one or more nitro groups, a C1-C6 alkyl group, a C1-C6 substituted alkyl group, or a C1-C6 alkoxy group.

2. The method for preparing the indole derivative containing benzothiazole and pyridine according to claim 1, characterized in that step... include: (1) Using substituted 2-aminobenzothiazole and 1-Boc-4-piperidinecarboxylic acid as raw materials, HATU and DIPEA were added as catalysts, and the reaction was carried out at room temperature. After the reaction was completed, the product was poured into water to precipitate, filtered, and intermediate a was obtained; the structural formula of the substituted 2-aminobenzothiazole is: ; (2) Using intermediate a as raw material, remove BOC protection to obtain intermediate b; The structural formula of intermediate a is: ; (3) Using substituted indole and epibromopropane as raw materials, and NaH as a catalyst, the reaction was carried out under heat. After the reaction was completed, the mixture was extracted with ethyl acetate and concentrated to obtain intermediate c; The structural formula of the substituted indole is: ; Using intermediates b and c as raw materials and potassium carbonate as a catalyst, the reaction was carried out under reflux. After completion, the mixture was extracted with dichloromethane, concentrated, and purified to obtain the indole derivative containing benzothiazole and pyridine. The structural formula of intermediate b is as follows: The structure of intermediate c is .

3. The preparation method according to claim 2, characterized in that, The molar ratio of the substituted 2-aminobenzothiazole, 1-Boc-4-piperidinecarboxylic acid, HATU and DIPEA in step (1) is 1:(1~3):(1~2):(1~2); the heating reaction time is 10~12 h.

4. The preparation method according to claim 2, characterized in that, The step of removing BOC protection described in step (2) includes: dissolving intermediate A in acetonitrile, heating to 70-80°C, and adding dropwise an additive with a molar ratio of 1:

1. 5-10% trifluoroacetic acid was heated under reflux for 2 hours to remove BOC protection.

5. The preparation method according to claim 2, characterized in that, After removing BOC protection in step (2), a separation step is also included. The separation step is as follows: after removing BOC protection, the reaction system is repeatedly added to acetonitrile and concentrated under reduced pressure to remove excess trifluoroacetic acid. Finally, ethanol is added for recrystallization.

6. The preparation method according to claim 2, characterized in that, In step (3), the molar ratio of substituted indole, epichlorohydrin and NaH is 1:(1~2):(1~2); the heating temperature is 45 ℃ and the heating time is 1~2 h.

7. The preparation method according to claim 2, characterized in that, The molar ratio of intermediate b, intermediate c and K2CO3 in step (4) is 1:(1~2):(2~4).

8. The preparation method according to claim 2, characterized in that, The purification step described in step (4) is specifically: silica gel column chromatography (dichloromethane:methanol = 35:1, v / v) purification.

9. The use of the indole derivative containing benzothiazole and pyridine according to claim 1 in the preparation of a drug for inhibiting plant pathogenic fungi.

10. The application according to claim 9, characterized in that, The plant pathogenic fungi include rice sheath blight fungus. Rs Phytophthora capsici, the pathogen of the pepper blight Pc Sclerotinia sclerotiorum var. sclerotiorum, the causal agent of rapeseed disease Ss Kiwifruit stem spot pathogen Ps Grape cavitation bacteria Bd Fusarium oxysporum Fo Cucumber wilt pathogen Foc and black spot disease of Chinese cabbage Ab .

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