An acylpiperidine-containing formononetin derivative, and a preparation method and application thereof

Abstract

The application discloses an acylpiperidine-containing formononetin derivative and a preparation method and application thereof, and belongs to the technical field of pesticide synthesis. An acylpiperidine group with excellent activity is introduced into the structure of formononetin, and a series of acylpiperidine-containing formononetin derivatives are synthesized. Through activity test of the synthesized acylpiperidine-containing formononetin derivatives on inhibiting plant pathogenic fungi and bacteria, it is found that the acylpiperidine-containing formononetin derivatives synthesized by the application can effectively inhibit plant pathogenic fungi and bacteria, especially pepper phytophthora blight bacteria and rice bacterial leaf blight bacteria.

Description

Technical Field

[0001] This invention belongs to the field of pesticide synthesis technology, specifically relating to a strychnine derivative containing acylpiperidine, its preparation method, and its application. Background Technology

[0002] Plant fungal and bacterial diseases cause severe reductions in crop yield and quality. Bacteria of the genus *Xanthomonas* have been reported to cause a variety of different plant diseases, such as rice bacterial blight caused by *Xanthomonas rice*, citrus canker caused by *Xanthomonas citrus*, and mango angular leaf spot caused by *Xanthomonas mangoes*. These pathogens, due to their rapid reproduction, strong transmissibility, and susceptibility to drug resistance, have become major challenges and obstacles in agricultural production worldwide, and pesticides are key to controlling these diseases. Currently, chemically synthesized antimicrobial agents are mainly used to reduce and control the severity of these diseases; however, long-term irrational use has not only led to drug resistance in pathogens but also negatively impacted human health and the environment. A sustainable strategy to combat these diseases is to find and alternate novel antimicrobial agents with low toxicity, good environmental compatibility, and unique mechanisms of action.

[0003] Plant-derived green pesticides possess advantages such as high efficiency, being environmentally friendly, harmless to humans and animals, high selectivity, and low likelihood of pests developing resistance. In today's world, where environmental protection is increasingly valued, they have attracted widespread attention from the global pesticide industry, providing development opportunities for plant-derived green pesticides. Therefore, identifying antibacterial active ingredients from plants and modifying and transforming them into effective precursors for innovative pesticides is an important approach to creating plant-derived green pesticides.

[0004] FMN (7-hydroxy-4'-methoxyisoflavone) belongs to the isoflavone class and is widely found in legumes such as Astragalus membranaceus, Spatholobus suberectus, Pueraria lobata, and Trifolium repens. Modern pharmacological studies have shown that FMN not only has antibacterial, antitumor, and anti-lipid peroxidation effects, but also scavenges oxygen free radicals and inhibits the proliferation of vascular smooth muscle cells. In 2019, Yao et al. designed and synthesized a FMN derivative and evaluated its antiproliferative activity against three gastric cancer cell lines (SGC7901, MKN45, and MGC803). The results showed that compound 5 exhibited good antiproliferative activity against SGC7901 cells, with an IC50 concentration of 5%. 50 The value is 1.07 μM has the potential for further clinical application in the treatment of gastric cancer. (JN Yao, XX Zhang, YZZhang, et al. Discovery and anticancer evaluation of a formononetinderivative against gastric cancer SGC7901 cells.) Investigational New Drugs 2019, 37 (1300-1308.). In 2021, Zuo et al. designed and synthesized a series of formononetin derivatives with substituted benzyloxy groups, and evaluated their vasodilatory activity on isolated rat mesenteric arterial rings using a linear electromyography system. The results showed that the compounds exhibited potent vasodilatory activity in potassium-induced contraction of rat mesenteric arterial rings, and also had a hypotensive effect on SHR (SJ Zuo, DL Ma, J. Li, et al. Structural modification and antihypertensive activity study of formononetin derivatives). Journal of Asian Natural Products Research 2022, 24 (839-848.). In 2025, Neha Bhardwaj et al. synthesized various gentianin ester derivatives (FMN) via acylation reactions. FMN is a natural isoflavone with broad biological activity and has become a potential lead molecule anticancer agent. The synthesized derivatives showed significantly enhanced cytotoxicity against various cancer cells, including A549, B16F10, and 4T1 (p < 0.05), and up to 200% cytotoxicity against non-cancerous L929 fibroblasts and RAW 264.7 macrophages. μ M showed no significant toxicity, indicating good biocompatibility (N. Bhardwaj, K. Kaliya, SKYadav, et al. Synthesis, characterization and biological evaluation of formononetin derivatives as anticancer agents). Medicinal Chemistry Research 2025, 34 (1974-1988). Extensive literature review revealed that research on gentiopicrin and its derivatives mainly focused on the pharmaceutical field, where they have shown significant clinical efficacy. However, there are relatively few reports and applications of gentiopicrin and its derivatives in the pesticide field.

[0005] Piperidine is a nitrogen-containing heterocyclic compound widely found in natural alkaloids. It possesses broad-spectrum biological activities, including antibacterial, antiviral, anticancer, and antioxidant effects, and exhibits advantages such as high selectivity, high activity, and low toxicity. Examples include the broad-spectrum anticonvulsant piperine, the antimalarial active ingredient styraxin B, the immunosuppressant rapamycin, and the antibiotic actinomycin. In the pharmaceutical and pesticide fields, piperidine is an important pharmacophore, and its derivatives possess a wide range of pharmacological activities such as antibacterial, anti-inflammatory, antiviral, anticancer, antimalarial, and antipsychotic effects. This makes piperidine a favored backbone in drug synthesis, and piperidine-containing building blocks are frequently used in the synthesis of small drug molecules. Acylpiperidine is an important intermediate compound commonly used in organic synthesis.

[0006] In summary, no studies have been found on the synthesis of acylpiperidine-containing strychnine derivatives by introducing acylpiperidine into the strychnine structure, nor have any studies on the use of acylpiperidine-containing strychnine derivatives in agricultural activity research been conducted. Summary of the Invention

[0007] The purpose of this invention is to provide an acylpiperidine-containing genistein derivative, its preparation method, and its applications. The provided acylpiperidine-containing genistein derivative can be used to inhibit plant pathogenic fungi and bacteria.

[0008] To achieve the above objectives, the present invention provides the following technical solution: One of the technical solutions of this invention is to provide a strychnine derivative containing acylpiperidine, the structure of which is shown in the following formula: , In the above formula, R is independently selected from H, one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, one or more C1-C6 alkoxy groups, or one or more C1-C6 substituted alkoxy groups.

[0009] One or more halogens refer to 3-F, 4-F, 3-Br, 4-Br, 2-Cl, 3-Cl, 4-Cl, and 2,4-dichloro; one or more C1-C6 alkyl groups refer to 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl, 3,5-dimethyl, 2,3,5-trimethyl, 4-ethyl, and 4-tert-butyl; one or more C1-C6 substituted alkyl groups refer to 3-trifluoromethyl and 4-trifluoromethyl; and one C1-C6 alkoxy group refers to 2-methoxy, 3-methoxy, and 4-methoxy.

[0010] The second technical solution of the present invention provides a method for preparing the above-mentioned acylpiperidine-containing strychnine derivative, the steps of which include: (1) Using gentianin and epoxybromopropane as raw materials, the reaction was carried out in a solvent under alkaline conditions. After the reaction was completed, ice water was added to precipitate the product. The product was filtered, and the residue was cleaned of impurities to obtain intermediate 1. The structural formula of the epichlorohydrin is: ; The structural formula of intermediate 1 is: ; (2) Using intermediate 1 and 1-boc-4-methylaminopiperidine as raw materials and potassium carbonate as catalyst, intermediate 2 was prepared by heating in a solvent. The structural formula of intermediate 2 is as follows: ; (3) Using intermediate 2 as raw material, remove BOC protection to obtain intermediate 3; The structural formula of the intermediate 3 is as follows: ; (4) Using intermediate c and substituted acyl chloride as raw materials and potassium carbonate as catalyst, the reaction was carried out at room temperature to obtain the benzylpiperidine-containing argentin derivative. The structural formula of the substituted acyl chloride is: Wherein R is independently selected from H, one or more halogens refer to 3-F, 4-F, 3-Br, 4-Br, 2-Cl, 3-Cl, 4-Cl, 2,4-dichloro; one or more C1-C6 alkyl groups refer to 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl, 3,5-dimethyl, 2,3,5-trimethyl, 4-ethyl, 4-tert-butyl; one or more C1-C6 substituted alkyl groups refer to 3-trifluoromethyl, 4-trifluoromethyl; one or more C1-C6 alkoxy groups refer to 2-methoxy, 3-methoxy, 4-methoxy.

[0011] Preferably, the molar ratio of gentianin and epichlorohydrin in step (1) is 11.1:(33.5~55.9); the heating reaction temperature is 60~80℃ and the time is 4~10h; the alkaline conditions are provided by anhydrous potassium carbonate; the impurity removal step includes: washing the filter residue with water and petroleum ether in sequence, then slurrying, letting it stand, filtering, and completing the washing.

[0012] More preferably, the molar ratio of styracifoliin and anhydrous potassium carbonate in step (1) is 11.1:(33.5~55.9); the solution used for pulping is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1.

[0013] Preferably, in step (2), the molar ratio of intermediate 1, 1-boc-4-methylaminopiperidine and potassium carbonate is 6.1:(12.3~18.5):(18.5~27.7); the heating reaction temperature is 80℃ and the time is 4~10h; the heating reaction is followed by a purification step.

[0014] More preferably, the purification step specifically includes: filtering the reaction system after heating, evaporating the filtrate to dryness, and performing column chromatography to complete the purification; wherein the eluent used for column chromatography is ethyl acetate.

[0015] Preferably, the step of removing BOC protection in step (3) includes: dissolving intermediate 2 in methanol, heating to 40~80℃, adding dropwise a 15~37% HCl solution, reacting for 1~4 h, and removing BOC protection.

[0016] Preferably, step (3) further includes a separation step after removing BOC protection. The separation step is as follows: after removing BOC protection, the reaction system is poured into ice water, the system is adjusted to 8-9 using 5wt% NaHCO3 solution, and then extracted with dichloromethane. The extract is evaporated to dryness to obtain intermediate 2.

[0017] Preferably, in step (4), the molar ratio of intermediate 2, substituted acyl chloride and potassium carbonate is 1.1:(2.2~4.5):(3.4~6.8); and the reaction time at room temperature is 2~4 hours.

[0018] Preferably, step (4) further includes a purification step after heating and reflux. The purification step specifically includes: pouring the reaction system after heating and reflux into water, extracting with dichloromethane, evaporating the extract to dryness, and performing column chromatography to complete the purification; wherein the eluent used for column chromatography is a mixture of dichloromethane and methanol in a volume ratio of (100~30):1.

[0019] The third technical solution of the present invention provides the application of the above-mentioned acylpiperidine-containing strychnine derivative in the preparation of drugs for inhibiting plant pathogenic bacteria.

[0020] Preferably, the plant pathogenic fungi include *Rhizoctonia solani* (r. s.), *Phytophthora capsici* (p. c.), *Sclerotinia sclerotiorum* (s. s.), *Ps* (p. s.), *B. s. d.*, *Fo* (f. s.), *Foc* (f. s.), and *Vm* (f. s. s.). The plant pathogenic bacteria include *Xoo* (x. s.), *Xac* (x. s.), *Xcm* (x. s.), and *Pcb* (x. s.).

[0021] The beneficial technical effects of the present invention are as follows: This invention provides an acylpiperidine-containing genistein derivative, its preparation method, and its application. This invention introduces an acylpiperidine group with excellent activity into the structure of genistein, synthesizing a series of acylpiperidine-containing genistein derivatives. Through tests on the inhibitory activity of the synthesized acylpiperidine-containing genistein derivatives against plant pathogenic fungi and bacteria, it was found that the acylpiperidine-containing genistein derivatives synthesized in this invention can effectively inhibit plant pathogenic fungi and bacteria. Detailed Implementation

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] One of the technical objectives of this invention is to provide a strychnine derivative containing acylpiperidine, with the structure shown in the following formula: , In the above formula, R is independently selected from H; one or more halogens refer to 3-F, 4-F, 3-Br, 4-Br, 2-Cl, 3-Cl, 4-Cl, 2,4-dichloro; one or more C1-C6 alkyl groups refer to 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl, 3,5-dimethyl, 2,3,5-trimethyl, 4-ethyl, 4-tert-butyl; one or more C1-C6 substituted alkyl groups refer to 3-trifluoromethyl, 4-trifluoromethyl; one or more C1-C6 alkoxy groups refer to 2-methoxy, 3-methoxy, 4-methoxy.

[0027] The second technical objective of this invention is to provide a method for preparing the above-mentioned acylpiperidine-containing strychnine derivative, the steps of which include: (1) Using styracin and epoxybromopropane as raw materials, the reaction was carried out in a solvent under alkaline conditions at 60°C for 4-10 hours. After the reaction was completed, the reaction system was dispersed in ice water, and then filtered, washed, and pulped to obtain intermediate 1. The reaction formula is as follows: , In some embodiments, the solvent is DMF; after the reaction is completed, the reaction solution is further dispersed with ice water to precipitate solids; after the solids are precipitated, the reaction solution is further filtered and washed; the washing is performed with water and petroleum ether respectively; the pulping is performed with petroleum ether / ethyl acetate = 3:1 (v / v); The molar ratio of gentianin to epibromopropane is 11.1:(33.5~55.9); the molar ratio of gentianin to anhydrous potassium carbonate is 11.1:(33.5~55.9). (2) Using intermediate 1 and 1-boc-4-methylaminopiperidine as raw materials and potassium carbonate as catalyst, intermediate 2 was prepared by reacting in isopropanol solvent at 80°C for 4-10 h. The reaction formula is as follows: , In some embodiments, the reaction is further performed by filtration, rotary evaporation under reduced pressure, and column chromatography; the filtration is to remove insoluble substances; and the column chromatography uses pure ethyl acetate as the eluent. The molar ratio of intermediate 1, 1-boc-4-methylaminopiperidine, and potassium carbonate is 6.1:(12.3~18.5):(18.5~27.7). (3) Using intermediate 2 as raw material and methanol as solvent, add HCl solution with a concentration of 15-37wt.% dropwise under the condition of heating to 40-80 ℃ and react for 1-4 h to remove BOC protection. Then pour the reaction system into ice water and adjust the system to alkaline with NaHCO3 aqueous solution to prepare intermediate 3. The reaction formula is as follows: , In some embodiments, the concentration of the NaHCO3 aqueous solution is 5 wt.%; the alkaline pH value is 8-9; after adjusting to alkalinity, the process further includes extraction and vacuum rotary evaporation; the extraction is performed using dichloromethane. (4) Using intermediate 3 and substituted acyl chloride as raw materials and potassium carbonate as catalyst, the acylpiperidine-containing argentin derivative was prepared by reacting in a solvent at room temperature. The reaction formula is as follows: , In some embodiments, the solvent is acetonitrile; the reflux reaction time is 1-2 hours; 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 50:1.

[0028] The molar ratio of intermediate 3, substituted acyl chloride, and potassium carbonate is 1.1:(2.2~4.6):(3.4~6.8).

[0029] The third technical objective of this invention is to provide the application of the above-mentioned acylpiperidine-containing argentin derivative in the preparation of drugs for inhibiting plant pathogenic bacteria.

[0030] To achieve the above-mentioned technical objectives, the present invention provides the following embodiments.

[0031] Example 1:

[0032] 7-(3-((1-benzoylpiperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C1), the steps are as follows: (1) Synthesis of 3-(4-methoxyphenyl)-7-(ethylene oxide-2-ylmethoxy)-4H-chromen-4-one: In a 250 mL three-necked flask, 3.0 g (11.1 mmol) of gentianin, 4.6 g (33.5 mmol) of anhydrous potassium carbonate, and 80 mL of DMF were added and the mixture was heated to 80 °C and stirred for 0.5 h. Then, 2.7 mL (33.5 mmol) of epoxybromopropane was slowly added and the mixture was reacted for 6 h. After the reaction was completed, the mixture was dispersed in 500 mL of ice water, and a large amount of solid precipitated. The solid was filtered, washed several times with water and petroleum ether, dried, and then the white solid obtained was slurried overnight with 60 mL of petroleum ether / ethyl acetate = 3:1, v / v solvent. The mixture was filtered to obtain a white solid with a yield of 84.6%.

[0033] (2) Synthesis of tert-butyl 4-((2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-oxy)propyl)(methyl)amino)piperidine-1-carboxylic acid ester: 1-boc-4-methylaminopiperidine (2.6 g, 12.3 mmol) and anhydrous K2CO3 (2.5 g, 18.5 mmol) were added to 250 mL of isopropanol solution. After stirring at room temperature for 0.5 h, 3-(4-methoxyphenyl)-7-(ethylene oxide-2-ylmethoxy)-4H-chromen-4-one (2.0 g, 6.1 mmol) was added to the system, and the mixture was heated to 80 °C and reacted for 8 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with dichloromethane, the filtrate was collected and rotary evaporated under reduced pressure, and then column chromatography with pure ethyl acetate was performed to obtain a white solid with a yield of 74.3%.

[0034] (3) Preparation of 7-(2-hydroxy-3-(methyl(4-piperidinyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: The product from step (2) was dissolved in 50 mL of methanol in a 100 mL single-necked flask, and 6 mL of 15 wt.% hydrochloric acid aqueous solution was added dropwise. The mixture was refluxed at 60 °C for 2 h. After the reaction was completed, a large amount of solvent was removed by rotary evaporation under reduced pressure. The system was then dispersed in 100 mL of water, and the pH was adjusted to 8-9 with 5 wt.% NaHCO3 solution. The mixture was extracted with dichloromethane, and the organic phase was collected. The solvent was removed by rotary evaporation under reduced pressure to obtain an oily substance with a yield of 81.3%.

[0035] (4) Synthesis of 7-(3-((1-benzoylpiperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: 3-(4-methoxyphenyl)-7-(3-(methyl(piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (0.5 g, 1.14 mmol), anhydrous K2CO3 (0.47 g, 3.42 mmol), and 20 mL of dichloromethane were added to a 50 mL round-bottom flask. After stirring at room temperature for 0.5 h, benzoyl chloride (262 μL, 2.28 mmol) was slowly added dropwise and reacted for 4 h. After the reaction was completed, the system was dispersed in 100 mL of water. Extracted three times with dichloromethane in mL of water, the organic phase was collected, dried with anhydrous Na2SO4, and the crude product was obtained by rotary evaporation under reduced pressure. The target compound was then obtained by column chromatography (dichloromethane:methanol = 50:1, v / v), with a yield of 60%.

[0036] Example 2: Synthesis of 7-(2-hydroxy-3-(methyl(1-(4-methylbenzoyl)piperidin-4-yl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C2), the steps were the same as in Example 1, except that the benzoyl chloride in step (4) was replaced with an equimolar amount of 4-methylbenzoyl chloride. Yield: 78%.

[0037] Example 3: Synthesis of 7-(2-hydroxy-3-(methyl(1-(2-methylbenzoyl)piperidin-4-yl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C3), the steps were the same as in Example 1, except that the benzoyl chloride in step (4) was replaced with an equimolar amount of 2-methylbenzoyl chloride. Yield: 49%.

[0038] Example 4: Synthesis of 7-(2-hydroxy-3-(methyl(1-(3-methylbenzoyl)piperidin-4-yl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C4), the steps were the same as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 3-methylbenzoyl chloride. Yield: 72%.

[0039] Example 5: Synthesis of 7-(3-((1-(2,4-dimethylbenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C5), the procedure was the same as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 2,4-dimethylbenzoyl chloride. Yield: 50%.

[0040] Example 6: Synthesis of 7-(3-((1-(3,5-dimethylbenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C6), the procedure was the same as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 3,5-dimethylacyl chloride. Yield: 59%.

[0041] Example 7: Synthesis of 7-(2-hydroxy-3-(methyl(1-(2,4,6-trimethylbenzylpiperidin-4-yl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C7), following the same procedure as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 2,4,6-trimethylacyl chloride. Yield: 43% Example 8: Synthesis of 7-(3-((1-(4-ethylbenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C8), the procedure was the same as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 4-ethylbenzoyl chloride. Yield: 43%.

[0042] Example 9: Synthesis of 7-(3-((1-(4-(tert-butyl)benzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C9), the procedure was the same as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 4-tert-butylbenzoyl chloride. Yield: 41%.

[0043] Example 10: Synthesis of 7-(3-((1-(2-fluorobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C10), the steps are as follows: (1) Synthesis of 3-(4-methoxyphenyl)-7-(ethylene oxide-2-ylmethoxy)-4H-chromen-4-one: In a 250 mL three-necked flask, 3.0 g (11.1 mmol), anhydrous potassium carbonate (6.18 g, 44.73 mmol), and 80 mL of DMF were added and the mixture was heated to 80 °C and stirred for 0.5 h. Then, 3.67 mL (44.73 mmol) of epoxybromopropane was slowly added and the mixture was reacted for 6 h. After the reaction was completed, the mixture was dispersed in 500 mL of ice water, and a large amount of solid precipitated. The solid was filtered, washed several times with water and petroleum ether, dried, and then the resulting white solid was slurried overnight with 60 mL of petroleum ether / ethyl acetate (3:1, v / v). The mixture was filtered to obtain a white solid with a yield of 84.6%.

[0044] (2) Synthesis of tert-butyl 4-((2-hydroxy-3-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-oxy)propyl)(methyl)amino)piperidine-1-carboxylic acid ester: 1-boc-4-methylaminopiperidine (3.96 g, 18.5 mmol) and anhydrous K2CO3 (2.5 g, 18.5 mmol) were added to 250 mL of isopropanol solution. After stirring at room temperature for 0.5 h, 3-(4-methoxyphenyl)-7-(ethylene oxide-2-ylmethoxy)-4H-chromen-4-one (2.0 g, 6.1 mmol) was added to the system, and the mixture was heated to 80 °C and reacted for 8 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with dichloromethane, the filtrate was collected and rotary evaporated under reduced pressure, and then column chromatography with pure ethyl acetate was performed to obtain a white solid with a yield of 74.3%.

[0045] (3) Preparation of 7-(2-hydroxy-3-(methyl(4-piperidinyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: The product from step (2) was dissolved in 50 mL of methanol in a 100 mL single-necked flask, and 6 mL of 20 wt.% hydrochloric acid aqueous solution was added dropwise. The mixture was refluxed at 60 °C for 2 h. After the reaction was completed, a large amount of solvent was removed under reduced pressure, and the system was dispersed in 100 mL of water. The pH was then adjusted to 8-9 with 5 wt.% NaHCO3 solution, extracted with dichloromethane, and the organic phase was collected. The solvent was removed by rotary evaporation under reduced pressure to obtain an oily substance with a yield of 81.3%.

[0046] (4) Synthesis of 7-(3-((1-benzoylpiperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one: 3-(4-methoxyphenyl)-7-(3-(methyl(piperidin-4-yl)amino)propoxy)-4H-chromen-4-one (0.5 g, 1.14 mmol), anhydrous K2CO3 (0.945 g, 6.84 mmol), and 20 mL of dichloromethane were added to a 50 mL round-bottom flask. After stirring at room temperature for 0.5 h, 2-fluorobenzoyl chloride (544 μL, 4.56 mmol) was slowly added dropwise, and the reaction was carried out for 4 h. After the reaction was completed, the system was dispersed in 100 mL of water. Extracted three times with dichloromethane in mL of water, the organic phase was collected, dried with anhydrous Na2SO4, and the crude product was obtained by rotary evaporation under reduced pressure. The target compound was then obtained by column chromatography (dichloromethane:methanol = 50:1, v / v), yield: 48%.

[0047] Example 11: Synthesis of 7-(3-((1-(4-fluorobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C11), the procedure was the same as in Example 10, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 4-fluorobenzoyl chloride. Yield: 81%.

[0048] Example 12: Synthesis of 7-(3-((1-(3-bromobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C12), the procedure was the same as in Example 10, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 3-bromobenzoyl chloride. Yield: 43%.

[0049] Example 13: Synthesis of 7-(3-((1-(4-bromobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C13), the procedure was the same as in Example 10, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 4-bromobenzoyl chloride. Yield: 51%.

[0050] Example 14: Synthesis of 7-(3-((1-(2-chlorobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C14), the procedure was the same as in Example 10, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 2-chlorobenzoyl chloride. Yield: 53%.

[0051] Example 15: Synthesis of 7-(3-((1-(3-chlorobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C15), following the same procedure as in Example 10, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 3-chlorobenzoyl chloride. Yield: 23%.

[0052] Example 16: Synthesis of 7-(3-((1-(4-chlorobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C16), the procedure was the same as in Example 10, except that benzoyl chloride in step (5) was replaced with an equimolar amount of 4-chlorobenzoyl chloride. Yield: 30%.

[0053] Example 17: Synthesis of 7-(3-((1-(2,4-dichlorobenzoyl)piperidin-4-yl)(methyl)amino)-2-hydroxypropoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C17), the procedure was the same as in Example 10, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 2,4-dichlorobenzoyl chloride. Yield: 30%.

[0054] Example 18: Synthesis of 7-(2-hydroxy-3-((1-(3-methoxybenzoyl)piperidin-4-yl)(methyl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C18), the procedure was the same as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 3-methoxybenzoyl chloride. Yield: 43%.

[0055] Example 19: Synthesis of 7-(2-hydroxy-3-(methyl(1-(3-(trifluoromethyl)benzoyl)piperidin-4-yl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C19), the procedure was the same as in Example 1, except that benzyl chloride in step (4) was replaced with an equimolar amount of 3-trifluoromethylbenzoyl chloride. Yield: 26%.

[0056] Example 20: Synthesis of 7-(2-hydroxy-3-(methyl(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)amino)propoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (compound number C20), the procedure was the same as in Example 1, except that benzoyl chloride in step (4) was replaced with an equimolar amount of 4-trifluoromethylbenzoyl chloride. Yield: 21%.

[0057] The physicochemical properties and mass spectrometry data of the acylpiperidine-containing argentinin derivatives synthesized in Examples 1-20 are shown in Table 1, and the proton nuclear magnetic resonance spectra are also shown. 1 H NMR and carbon spectroscopy 13 The C NMR data are shown in Table 2.

[0058] Table 1. Physicochemical properties and mass spectrometry analysis data of the target compounds C1 60% White solid 115-116 <![CDATA[543.24896(543.24884)[M+H] + ]]> C2 78% White solid 112-113 <![CDATA[557.26461(557.26221)[M+H] + ]]> C3 49% Yellow oily substance - <![CDATA[557.26461(557.26422)[M+H] + ]]> C4 72% Yellow oily substance - <![CDATA[557.26461(557.26410)[M+H] + ]]> C5 50% Yellow oily substance - <![CDATA[571.28026(571.27960)[M+H] + ]]> C6 59% Yellow oily substance - <![CDATA[571.28026(571.27820)[M+H] + ]]> C7 43% Yellow oily substance - <![CDATA[585.29591(585.29370)[M+H] + ]]> C8 43% Yellow oily substance - <![CDATA[571.28026(571.27826)[M+H] + ]]> C9 41% Yellow oily substance - <![CDATA[599.31156(599.30969)[M+H] + ]]> C10 48% Yellow oily substance - <![CDATA[561.23954(561.23749)[M+H] + ]]> C11 81% Yellow oily substance - <![CDATA[561.23954(561.23737)[M+H] + ]]> C12 43% White solid 90-91 <![CDATA[621.15948(621.15717)[M+H] + ]]> C13 51% White solid 104-106 <![CDATA[621.15948(621.15710)[M+H] + ]]> C14 53% Yellow oily substance - <![CDATA[577.20999(577.20801)[M+H] + ]]> C15 23% Yellow oily substance - <![CDATA[577.20999(577.20789)[M+H] + ]]> C16 30% Yellow solid 134-136 <![CDATA[577.20999(577.20801)[M+H] + ]]> C17 30% Yellow oily substance - <![CDATA[611.17102(611.16846)[M+H] + ]]> C18 43% Yellow oily substance - <![CDATA[573.25953(573.25739)[M+H] + ]]> C19 26% Yellow oily substance - <![CDATA[611.23635(611.23419)[M+H] + ]]> C20 21% Yellow oily substance - <![CDATA[611.23635(611.23450)[M+H] + ]]> Table 2. NMR spectral data of the target compound C1 <![CDATA[ 1 H NMR (500 MHz, CHLOROFORM-D)δ8.20 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.52 – 7.45 (m, 2H), 7.40 (d,J = 2.4 Hz, 5H), 7.01 (dd, J =8.9, 2.4 Hz, 1H), 6.97 – 6.95 (m,2H), 6.88 (d, J = 2.4 Hz, 1H),4.83 (s, 1H), 4.08 (s, 3H), 3.83(s, 3H), 2.77 – 2.68 (m, 1H), 2.66– 2.62 (m, 2H), 2.35 (s, 3H), 2.04– 1.24 (m, 4H), 0.90 – 0.80 (m,2H). 13 C NMR (126 MHz, CHLOROFORM-D)δ 175.99, 170.49, 163.10,159.64, 157.91, 152.24, 135.97,130.23, 129.84, 128.62, 127.93,126.98, 124.97, 124.23, 118.68,114.88, 114.04, 100.90, 70.76,65.56, 62.14, 55.43, 47.43, 41.92.]]> C2 <![CDATA[ 1 H NMR (500 MHz, CHLOROFORM-D)δ8.20 (d, J = 8.9 Hz, 1H), 7.91 (s,1H), 7.48 (d, J = 8.7 Hz, 2H),7.30 (d, J = 8.1 Hz, 2H), 7.24 –7.16 (m, 2H), 7.01 (dd, J = 8.9,2.4 Hz, 1H), 7.00 – 6.92 (m, 2H),6.87 (d, J = 2.4 Hz, 1H), 4.80 (s,1H), 4.12 – 4.03 (m, 3H), 3.83 (s,3H), 2.98 (s, 1H), 2.77 – 2.66 (m,2H), 2.68 – 2.60 (m, 2H), 2.36 (d,J = 10.0 Hz, 6H), 1.95 – 1.35 (m,4H), 1.26 (d, J = 16.7 Hz, 1H). 13 CNMR (126 MHz, CHLOROFORM-D)δ175.96, 170.68, 163.11, 159.64,157.90, 152.23, 139.99, 132.99,130.22, 129.17, 127.91, 127.12,124.95, 124.24, 118.68, 114.87,114.03, 100.91, 70.79, 65.60,62.17, 55.43, 21.50. <!-- 10 -->]]> C3 <![CDATA[ 1 H NMR (500 MHz, CHLOROFORM-D) δ8.17 – 8.08 (m, 1H), 7.85 (s, 1H),7.41 (d, J = 8.7 Hz, 2H), 7.20 (s,1H), 7.13 (q, J = 8.5 Hz, 3H),6.97 – 6.85 (m, 3H), 6.80 (s, 1H),4.02 (s, 2H), 3.76 (s, 3H), 3.01(s, 2H), 2.88 (s, 4H), 2.80 (d, J= 0.7 Hz, 2H), 2.71 – 2.57 (m,3H), 2.35 – 2.25 (m, 3H), 2.19 (s,1H), 1.99 – 1.12 (m, 4H). 13 C NMR(126 MHz, CHLOROFORM-D)δ 175.98,163.03, 162.70, 159.61, 157.89,152.26, 134.11, 130.21, 129.04,127.91, 126.04 , 125.54, 124.94,124.19, 118.66, 114.85, 114.02,100.88, 70.69, 65.53, 55.88,55.42, 46.13, 41.04, 36.63, 31.53,27.78, 19.02.]]> C4 <![CDATA[ 1 H NMR (500 MHz, CHLOROFORM-D)δ8.16 (d, J = 8.9 Hz, 1H), 7.88 (s,1H), 7.45 (d, J = 8.8 Hz, 2H),7.24 (d, J = 5.4 Hz, 1H), 7.20 –7.17 (m, 2H), 7.13 (d, J = 7.2 Hz,1H), 6.98 (dd, J = 8.9, 2.4 Hz,1H), 6.93 (d, J = 8.8 Hz, 2H),6.84 (d, J = 2.4 Hz, 1H), 4.12 –4.02 (m, 3H), 3.80 (s, 3H), 2.94(s, 1H), 2.91 (s, 2H), 2.84 (s,2H), 2.78 – 2.62 (m, 4H), 2.34 (d,J = 9.3 Hz, 6H), 1.96 – 1.49 (m,1H), 1.39 – 1.20 (m, 2H). 13 C NMR(126 MHz, CHLOROFORM-D)δ 175.99,170.69, 163.04, 162.69, 159.61,157.89, 152.26, 135.85, 130.55,130.21, 128.40, 127.90, 127.58,124.94, 124.20, 123.83, 118.65,114.88, 114.02, 100.88, 65.50,62.19, 55.42, 36.63, 31.53, 21.50. <!-- 11 -->]]> C5 <![CDATA[ 1 H NMR (500 MHz, CHLOROFORM-D)δ8.19 (dd, J = 8.9, 1.1 Hz, 1H),7.91 (s, 1H), 7.51 – 7.45 (m, 2H),7.04 (d, J = 26.3 Hz, 4H), 6.96(d, J = 8.8 Hz, 2H), 6.87 (d, J =2.4 Hz, 1H), 4.08 (s, 3H), 3.83(s, 3H), 2.94 (s, 2H), 2.87 (d, J= 0.6 Hz, 2H), 2.67 (d, J = 33.0Hz, 5H), 2.34 (s, 3H), 2.31 (s,3H), 2.22 (s, 1H), 1.91 (dd, J =46.5, 12.9 Hz, 1H), 1.78 – 1.50(m, 2H), 1.44 – 1.33 (m, 1H), 1.24(s, 1H). 13 C NMR (126 MHz,CHLOROFORM-D)δ 175.99, 170.34,163.08, 162.69, 159.63, 157.90,152.25, 134.05, 130.22, 127.92,126.71, 125.60, 124.95, 124.22,118.66, 114.87, 114.03, 100.89,70.72, 65.57, 55.78, 55.43, 46.89,46.26, 41.13, 37.69, 31.54, 27.89,21.32. <!-- 12 -->]]> C6 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.52 (d, J = 8.7 Hz, 2H), 7.16 (d,J = 2.4 Hz, 1H), 7.08 (dd, J =8.9, 2.3 Hz, 1H), 7.05 (dt, J =1.7, 0.8 Hz, 1H), 6.99 (d, J = 8.9Hz, 2H), 6.95 (dd, J = 1.7, 0.9Hz, 2H), 4.48 (s, 1H), 4.15 (dd, J= 10.1, 3.2 Hz, 1H), 4.04 (dd, J =10.1, 5.8 Hz, 1H), 3.93 (s, 1H),3.78 (s, 3H), 2.88 (s, 1H), 2.74 –2.57 (m, 3H), 2.44 (dd, J = 12.9,5.9 Hz, 1H), 2.31 (s, 1H), 2.28(s, 9H), 2.04 – 1.42 (m, 2H), 1.42– 1.15 (m, 4H). 13 C NMR (126 MHz,DMSO-D6)δ 174.69, 169.11, 163.32,162.37, 159.05, 157.47, 153.52,137.60, 136.40, 130.63, 126.97,124.24, 124.12, 123.41, 117.54,115.16, 113.66, 101.04, 71.62,67.17, 61.12, 55.79, 55.19, 20.84. <!-- 13 -->]]> C7 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.42(d, J = 5.6 Hz, 1H), 8.01 (d, J =8.9 Hz, 1H), 7.53 (dd, J = 8.8,6.8 Hz, 2H), 7.14 (t, J = 2.3 Hz,1H), 7.06 (dt, J = 8.9, 2.1 Hz,1H), 7.00 (dd, J = 8.9, 2.4 Hz,2H), 6.89 – 6.80 (m, 2H), 4.96 (s,1H), 4.56 (dd, J = 30.6, 12.9 Hz,1H), 4.12 (s, 1H), 4.04 (dd, J =10.2, 5.3 Hz, 1H), 3.90 (s, 1H),3.78 (s, 3H), 3.14 (s, 1H), 2.89(q, J = 12.2 Hz, 1H), 2.79 – 2.64(m, 1H), 2.63 – 2.52 (m, 2H), 2.38(ddd, J = 12.8, 8.7, 5.7 Hz, 1H),2.23 (dd, J = 20.5, 5.2 Hz, 6H),2.14 (s, 1H), 2.09 (s, 1H), 2.03(s, 3H), 1.80 (dd, J = 34.1, 12.8Hz, 1H), 1.57 (dd, J = 50.0, 12.6Hz, 1H), 1.38 – 1.11 (m, 3H). 13 CNMR (126 MHz, DMSO-D6)δ 174.68,167.93, 163.29, 159.05, 157.46,153.52, 137.05, 133.89, 132.83,130.13, 128.03, 127.79, 127.00,124.12, 123.40, 117.53, 113.66,101.01, 71.35, 67.22, 60.92,60.75, 55.64, 55.19, 44.92, 44.75,28.86, 28.20, 27.08, 20.68, 18.52. <!-- 14 -->]]> C8 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.42(s, 1H), 8.02 (d, J = 9.0 Hz, 1H),7.52 (d, J = 8.6 Hz, 2H), 7.26 (q,J = 8.2 Hz, 4H), 7.16 (d, J = 2.3Hz, 1H), 7.09 (dd, J = 8.7, 2.3Hz, 1H), 6.99 (d, J = 8.6 Hz, 2H),4.48 (s, 1H), 4.15 (dd, J = 10.2,3.2 Hz, 1H), 4.04 (dd, J = 10.1,5.7 Hz, 1H), 3.92 (s, 1H), 3.78(s, 3H), 2.92 (d, J = 35.8 Hz,1H), 2.62 (q, J = 7.5 Hz, 5H),2.43 (dd, J = 12.9, 5.8 Hz, 1H),2.27 (s, 3H), 1.84 – 1.52 (m, 1H),1.40 – 1.29 (m, 2H), 1.27 – 1.13(m, 6H). 13 C NMR (126 MHz, DMSO-D6)δ174.70, 169.03, 163.33, 159.05,157.49, 153.54, 145.22, 133.70,130.15, 127.74, 126.92, 124.13,123.42, 117.55, 115.19, 113.67,101.04, 71.59, 67.20, 61.09,55.20, 29.09, 28.05, 22.18, 15.49,14.04. <!-- 15 -->]]> C9 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6) δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.52 (d, J = 8.8 Hz, 2H), 7.43 (d,J = 8.4 Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 7.16 (d, J = 2.4 Hz, 1H),7.09 (dd, J = 8.9, 2.4 Hz, 1H),6.99 (d, J = 8.8 Hz, 2H), 4.98 (s,1H), 4.48 (s, 1H), 4.15 (dd, J =10.1, 3.2 Hz, 1H), 4.05 (dd, J =10.1, 5.7 Hz, 1H), 3.92 (s, 1H),3.78 (s, 3H), 3.03 – 2.87 (m, 1H),2.73 – 2.56 (m, 2H), 2.42 (dd, J =12.9, 5.7 Hz, 1H), 2.27 (s, 3H),1.86 – 1.51 (m, 2H), 1.28 (s,13H). 13 C NMR (126 MHz, DMSO-D6)δ174.69, 168.99, 163.34, 159.05,157.48, 153.53, 151.98, 133.47,130.14, 126.98, 126.68, 125.13,124.13, 123.41, 117.54, 115.21,113.66, 101.02, 71.60, 67.22,61.06, 55.19, 34.54, 31.03. <!-- 16 -->]]> C10 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.42(d, J = 2.5 Hz, 1H), 8.02 (dd, J =8.9, 2.1 Hz, 1H), 7.54 – 7.34 (m,4H), 7.32 – 7.24 (m, 2H), 7.15 (d,J = 2.2 Hz, 1H), 7.08 (dd, J =8.9, 2.3 Hz, 1H), 7.02 – 6.95 (m,2H), 5.04 (d, J = 75.9 Hz, 1H),4.53 (t, J = 12.3 Hz, 1H), 4.14(dd, J = 9.9, 3.1 Hz, 1H), 4.03(dd, J = 9.4, 3.7 Hz, 1H), 3.92(s, 1H), 3.78 (s, 3H), 2.88 (s,1H), 2.80 – 2.69 (m, 1H), 2.68 –2.56 (m, 2H), 2.43 (dd, J = 12.9,5.8 Hz, 1H), 2.27 (s, 3H), 1.88 –1.51 (m, 2H), 1.46 – 1.21 (m, 3H). 13 C NMR (126 MHz, DMSO-D6)δ174.69, 163.72, 163.31, 162.37,159.05, 158.52, 157.47, 156.58,153.53, 131.25, 130.14, 128.64,124.97, 124.49 (d, J = 18.6 Hz),124.12, 117.54, 115.77 (d, J =21.1 Hz), 115.14, 113.66, 101.04,71.59, 67.14, 60.85, 55.70 (d, J =15.0 Hz), 55.19, 54.98. 19 F NMR(471 MHz, DMSO-D6)δ -116.52. <!-- 17 -->]]> C11 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.03 (d, J = 8.9 Hz, 1H),7.55 – 7.42 (m, 4H), 7.26 (t, J =8.9 Hz, 2H), 7.16 (d, J = 2.4 Hz,1H), 7.09 (dd, J = 8.9, 2.4 Hz,1H), 6.99 (d, J = 8.8 Hz, 2H),4.49 (s, 1H), 4.15 (dd, J = 10.1,3.3 Hz, 1H), 4.05 (dd, J = 10.1,5.7 Hz, 1H), 4.01 – 3.94 (m, 1H),3.78 (s, 3H), 3.06 – 2.86 (m, 2H),2.75 – 2.64 (m, 3H), 2.50 (p, J =1.9 Hz, 3H), 2.33 (s, 3H), 1.88 –1.20 (m, 3H). 13 C NMR (126 MHz,DMSO-D6)δ 174.70, 168.03, 163.37(d, J = 26.2 Hz), 161.51, 159.05,157.47, 153.54, 132.70, 132.13 (d,J = 9.5 Hz), 130.14, 129.36 (d, J= 8.4 Hz), 127.01, 123.42, 117.58,115.48, 115.24 (d, J = 18.1 Hz),113.67, 101.07, 71.54, 66.85,61.15, 55.66, 55.19. 19 F NMR 471MHz, DMSO-D6)δ -111.24. <!-- 18 -->]]> C12 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.64 (d, J = 6.9 Hz, 1H), 7.58 (s,1H), 7.52 (d, J = 8.7 Hz, 2H),7.39 (d, J = 6.9 Hz, 2H), 7.16 (d,J = 2.4 Hz, 1H), 7.09 (dd, J =8.9, 2.4 Hz, 1H), 6.99 (d, J = 8.8Hz, 2H), 4.95 (s, 1H), 4.48 (s,1H), 4.15 (dd, J = 10.1, 3.2 Hz,1H), 4.04 (dd, J = 10.1, 5.8 Hz,1H), 3.93 (s, 1H), 3.78 (s, 3H),3.01 (d, J = 13.4 Hz, 1H), 2.76 –2.56 (m, 3H), 2.45 (s, 1H), 2.28(s, 3H), 1.85 – 1.54 (m, 2H), 1.49– 1.32 (m, 2H), 1.32 – 1.11 (m,1H). 13 C NMR (126 MHz, DMSO-D6)δ174.69, 167.14, 163.31, 162.38,159.05, 157.47, 153.53, 138.71,132.21, 130.71, 130.14, 129.37,126.99, 125.65, 124.12, 123.41,121.76, 117.54, 115.17, 113.66,101.04, 71.61, 67.16, 61.01,55.19, 46.67, 35.85. <!-- 19 -->]]> C13 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.03 (d, J = 8.9 Hz, 1H),7.66 – 7.60 (m, 2H), 7.56 – 7.49(m, 2H), 7.38 – 7.31 (m, 2H), 7.16(d, J = 2.4 Hz, 1H), 7.09 (dd, J =8.9, 2.4 Hz, 1H), 7.03 – 6.96 (m,2H), 4.94 (s, 1H), 4.47 (s, 1H),4.15 (dd, J = 10.2, 3.2 Hz, 1H),4.04 (dd, J = 10.1, 5.8 Hz, 1H),3.93 (s, 1H), 3.78 (s, 3H), 2.98(s, 1H), 2.80 – 2.51 (m, 3H), 2.43(dd, J = 13.0, 5.8 Hz, 1H), 2.27(s, 3H), 1.68 (dd, J = 80.5, 30.9Hz, 2H), 1.47 – 1.23 (m, 3H). 13 CNMR (126 MHz, DMSO-D6)δ 174.69,167.87, 163.33, 159.05, 157.47,153.53, 135.52, 131.45, 130.14,128.98, 127.00, 124.12, 123.41,122.73, 117.54, 115.16, 113.67,101.06, 71.63, 67.20, 60.98,55.79, 55.19. <!-- 20 -->]]> C14 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6) δ 8.45 –8.38 (m, 1H), 8.02 (dd, J = 8.9,4.4 Hz, 1H), 7.57 – 7.45 (m, 3H),7.47 – 7.26 (m, 3H), 7.15 (d, J =2.4 Hz, 1H), 7.08 (ddd, J = 8.6,5.4, 2.8 Hz, 1H), 7.04 – 6.95 (m,2H), 5.11 – 4.80 (m, 1H), 4.53 (s,1H), 4.14 (d, J = 8.8 Hz, 1H),4.08 – 3.98 (m, 1H), 3.92 (s, 1H),3.78 (s, 3H), 3.29 – 3.14 (m, 1H),2.88 (s, 1H), 2.81 – 2.68 (m, 1H),2.68 – 2.54 (m, 2H), 2.43 (d, J =11.5 Hz, 1H), 2.27 (s, 3H), 1.96 –1.69 (m, 1H), 1.70 – 1.49 (m, 1H),1.50 – 1.14 (m, 2H). 13 C NMR (126MHz, DMSO-D6)δ 174.69, 165.31,163.30, 162.37, 159.05, 157.46,153.52, 136.19, 136.09, 130.43,130.34, 130.13, 129.52, 129.36,129.09, 117.54, 115.12, 113.66,101.05, 67.14, 60.84, 55.19,54.98, 40.44, 35.84. <!-- 21 -->]]> C15 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.57 – 7.41 (m, 5H), 7.38 – 7.30(m, 1H), 7.16 (d, J = 2.4 Hz, 1H),7.04 – 6.95 (m, 2H), 4.48 (s, 1H),4.15 (dd, J = 10.1, 3.2 Hz, 1H),4.04 (dd, J = 10.1, 5.8 Hz, 1H),3.97 – 3.89 (m, 1H), 3.78 (s, 3H),2.94 (d, J = 56.5 Hz, 1H), 2.76 –2.57 (m, 3H), 2.45 (dd, J = 13.0,5.9 Hz, 1H), 2.29 (s, 3H), 1.70(ddd, J = 87.3, 32.0, 11.6 Hz,2H), 1.47 – 1.30 (m, 2H), 1.21 (s,2H). 13 C NMR (126 MHz, DMSO-D6)δ174.69, 167.24, 163.31, 159.05,157.47, 153.53, 138.49, 133.24,130.48, 130.14, 129.31, 126.99,126.55, 125.29, 124.12, 123.41,117.55, 115.17, 113.66, 101.04,71.61, 67.11, 61.02, 55.19, 54.98. <!-- 22 -->]]> C16 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.57 – 7.45 (m, 4H), 7.45 – 7.36(m, 2H), 7.16 (d, J = 2.4 Hz, 1H),7.09 (dd, J = 8.9, 2.4 Hz, 1H),7.04 – 6.95 (m, 2H), 4.96 (s, 1H),4.48 (s, 1H), 4.15 (dd, J = 10.1,3.2 Hz, 1H), 4.04 (dd, J = 10.1,5.8 Hz, 1H), 3.93 (s, 1H), 3.78(s, 3H), 3.05 – 2.85 (m, 1H), 2.76– 2.55 (m, 3H), 2.45 (dd, J =12.9, 5.7 Hz, 1H), 2.28 (s, 3H),1.69 (dd, J = 79.7, 27.9 Hz, 2H),1.46 – 1.15 (m, 3H). 13 C NMR (126MHz, DMSO-D6) δ 174.69, 167.82,163.31, 159.05, 157.46, 153.52,135.13, 134.04, 130.14, 128.77,128.52, 127.00, 124.12, 123.41,117.54, 115.15, 113.66, 101.05,71.61, 67.14, 61.00, 55.77, 55.18. <!-- 23 -->]]> C17 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.45 –8.38 (m, 1H), 8.02 (dd, J = 8.9,3.3 Hz, 1H), 7.77 – 7.66 (m, 1H),7.58 – 7.43 (m, 4H), 7.18 – 7.11(m, 1H), 7.12 – 7.03 (m, 1H), 7.04– 6.95 (m, 2H), 4.95 (s, 1H), 4.56– 4.45 (m, 1H), 4.18 – 4.10 (m,1H), 4.03 (ddt, J = 10.1, 6.2, 3.3Hz, 1H), 3.92 (d, J = 6.9 Hz, 1H),3.78 (s, 3H), 3.22 (t, J = 13.0Hz, 1H), 3.05 – 2.85 (m, 1H), 2.82– 2.67 (m, 1H), 2.68 – 2.53 (m,2H), 2.41 (td, J = 11.6, 4.2 Hz,1H), 2.26 (t, J = 2.4 Hz, 3H),1.87 – 1.70 (m, 1H), 1.70 – 1.49(m, 1H), 1.48 – 1.18 (m, 2H). 13 CNMR (126 MHz, DMSO-D6)δ 174.69,164.44, 163.31, 159.04, 157.46,153.52, 135.13, 135.04, 134.14,134.04, 130.32, 130.13, 129.14,129.02, 127.94, 126.99, 124.12,123.40, 117.54, 115.13, 113.66,101.05, 71.57, 67.19, 60.81,60.61, 55.70, 55.19, 40.58. <!-- 24 -->]]> C18 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.57 – 7.47 (m, 2H), 7.34 (t, J =7.8 Hz, 1H), 7.16 (d, J = 2.4 Hz,1H), 7.08 (dd, J = 8.9, 2.3 Hz,1H), 7.03 – 6.95 (m, 3H), 6.95 –6.86 (m, 2H), 4.49 (s, 1H), 4.15(dd, J = 10.1, 3.2 Hz, 1H), 4.04(dd, J = 10.1, 5.8 Hz, 1H), 3.93(dd, J = 6.2, 3.3 Hz, 1H), 3.78(d, J = 8.2 Hz, 7H), 2.92 (d, J =39.5 Hz, 1H), 2.76 – 2.56 (m, 3H),2.48 – 2.40 (m, 1H), 2.28 (s, 3H),1.87 – 1.53 (m, 2H), 1.47 – 1.32(m, 2H), 1.32 – 1.18 (m, 2H). 13 CNMR (126 MHz, DMSO-D6)δ 174.69,168.55, 163.32, 159.14, 159.05,157.47, 153.53, 137.79, 130.14,129.66, 126.99, 124.13, 123.41,118.62, 117.54, 115.17, 114.89,113.66, 112.12, 101.04, 71.62,61.08, 55.78, 55.25, 55.19, 54.98. <!-- 25 -->]]> C19 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.84 – 7.79 (m, 1H), 7.74 (s, 1H),7.72 – 7.65 (m, 2H), 7.52 (d, J =8.7 Hz, 2H), 7.16 (d, J = 2.4 Hz,1H), 7.08 (dd, J = 8.9, 2.3 Hz,1H), 7.02 – 6.95 (m, 2H), 4.96 (s,1H), 4.50 (s, 1H), 4.15 (dd, J =10.1, 3.2 Hz, 1H), 4.04 (dd, J =10.1, 5.9 Hz, 1H), 3.93 (s, 1H),3.78 (s, 3H), 3.03 (s, 1H), 2.77 –2.71 (m, 1H), 2.68 – 2.57 (m, 2H),2.49 – 2.41 (m, 1H), 2.28 (s, 3H),1.79 (dd, J = 29.8, 12.2 Hz, 1H),1.61 (dd, J = 34.6, 12.0 Hz, 1H),1.54 – 1.14 (m, 3H). 13 C NMR (126MHz, DMSO-D6)δ 174.69, 167.32,163.32, 159.05, 157.47, 153.52,137.48, 130.74, 130.14, 129.68,129.43, 129.18, 126.98, 126.06,124.12, 123.47 (d, J = 14.8 Hz),122.88, 117.54, 115.16, 113.66,101.04, 71.63, 67.16, 61.00,55.78, 55.19, 46.73, 41.17,27.58. 19 F NMR (471 MHz, DMSO-D6)δ -61.06. <!-- 26 -->]]> C20 <![CDATA[ 1 H NMR (500 MHz, DMSO-D6)δ 8.41(s, 1H), 8.02 (d, J = 8.9 Hz, 1H),7.80 (d, J = 8.1 Hz, 2H), 7.60 (d,J = 7.9 Hz, 2H), 7.57 – 7.46 (m,2H), 7.16 (d, J = 2.4 Hz, 1H),7.09 (dd, J = 8.9, 2.4 Hz, 1H),7.04 – 6.95 (m, 2H), 4.97 (s, 1H),4.51 (d, J = 12.7 Hz, 1H), 4.15(dd, J = 10.1, 3.2 Hz, 1H), 4.04(dd, J = 10.1, 5.8 Hz, 1H), 3.96 –3.89 (m, 1H), 3.78 (s, 3H), 3.00(t, J = 13.0 Hz, 1H), 2.73 (dd, J= 9.3, 5.7 Hz, 1H), 2.62 (dt, J =13.4, 9.7 Hz, 2H), 2.45 (dd, J =13.0, 5.9 Hz, 1H), 2.28 (s, 3H),1.79 (dd, J = 29.8, 12.5 Hz, 1H),1.61 (dd, J = 34.1, 12.3 Hz, 1H),1.48 – 1.32 (m, 2H), 1.30 – 1.16(m, 1H). 13 C NMR (126 MHz, DMSO-D6)δ174.69, 167.48, 163.32, 159.05,157.47, 153.52, 140.52, 130.13,129.65, 129.40, 127.53, 126.99,125.52 (d, J = 4.1 Hz), 125.09,124.12, 123.41, 122.92, 117.54,115.17, 113.66, 101.05, 71.63,67.17, 60.94, 55.80, 55.18, 46.62,41.06, 27.66. 19 F NMR (471 MHz,DMSO-D6)δ -61.06.]]> Experimental Example 1 Anti-plant pathogenic fungal activity test Test method: The mycelial growth rate method was used to evaluate the in vitro activity of seven plant fungi (Rs, *Phytophthora infestans*; Pc, *Psclerotium tumefaciens*; Ss, *Sclerotinia sclerotiorum*; Ps, *Ps, *Fusarium wilt*; Fo, *Fusarium wilt*; Foc, *Fusarium wilt*; and Vm, *Azoxystrobin*, a commercial fungicide, as a positive control. The specific steps are as follows: (1) Preparation of culture medium: According to the experimental requirements, accurately weigh the required amount of PDA at a ratio of 40.1 g potato dextrose agar (PDA) to 1000 mL of deionized water, add deionized water and heat to boiling until completely dissolved. Then dispense into Erlenmeyer flasks and seal the flask mouths with breathable sealing film. Finally, place them in an autoclave and sterilize at 121 ℃ for 20 min for later use.

[0059] (2) Activation of the strain: The sterilized PDA medium was sprayed with 75% alcohol and placed in a clean bench. After cooling appropriately, it was poured into 90 mm petri dishes. After the medium solidified, the strain to be activated was punched with a 5 mm punch. Then, the fungal cake was inoculated into the center of the petri dish using an inoculation needle. The petri dish was sealed with a wrapping film and then transferred to a 28°C constant temperature incubator for cultivation. When the strain had covered the entire petri dish, it was removed for antibacterial activity testing.

[0060] (3) Antifungal activity test: Accurately weigh 2.5 mg of the test compound and dissolve it in 250 μL of DMSO. In a clean bench, use a pipette to draw 200 μL of the solution and add it to 19.8 mL of sterilized PDA medium. After thorough mixing, prepare a medium with a compound concentration of 100 μg / mL. Pour the medium into a 60 mm petri dish and let it solidify before use. DMSO is used as a blank control, and azoxystrobin is used as a positive control. In a clean bench, use a 5 mm punch to prepare 5 mm diameter mycelial cakes from the activated fungal strain. Inoculate these mycelial cakes in the center of the medium with the hyphae facing down using an inoculation needle. Then seal the petri dish with sealing film. Then remove it and place it in a 28 ℃ constant temperature incubator for inverted culture. When the diameter of the hyphae on the surface of the blank group medium grows to 4.5-5.0 cm, measure the diameter of the hyphae in each group using the cross-cross method and record the data. Calculate the inhibition rate according to formula (3-1): I(%)=(CT) / (C-5 mm)×100% (3-1) I: Inhibition rate; C: Mycelial growth diameter in the blank control group (unit: mm); T: Mycelial growth diameter of the drug-treated group (unit: mm) (4) The results of the bioactivity test against plant pathogenic fungi are shown in Table 3.

[0061] Table 3. In vitro antibacterial activity of C1-C20 (100 μg / mL)

[0062] Table 3 shows that all target compounds exhibited inhibitory activity against the seven plant fungi at a concentration of 100 μg / mL. Among them, compounds C2, C5, C7, C13, and C20 showed 100% inhibition of Pc, superior to azoxystrobin (56.3%). Compound C8 showed 100% inhibition of Vm, significantly better than azoxystrobin (60.1%). Compounds C4-C8, C12-C13, C15-C17, and C19-C20 showed inhibition of Ps exceeding 80%, superior to azoxystrobin (62.8%). In summary, the target compounds showed significantly better inhibitory activity against three plant fungi (Ps, Pc, Vm) than against the other four (Rs, Ss, Fo, Foc).

[0063] Experimental Example 2 Antibacterial activity test against plant pathogens Test method: The in vitro activity of three Xanthomonas species (Xoo, the causal agent of rice bacterial blight; Xac, the causal agent of citrus canker; and Xcm, the causal agent of mango bacterial black spot) and one non-Xanthomonas species (Pcb, the causal agent of potato soft rot) was evaluated using the turbidimetric method, with the commercial agent thiabendazole as a positive control. The specific steps are as follows: (1) Spread the above four plant pathogenic bacteria strains evenly on NA solid medium and incubate them in a constant temperature bacterial incubator at 28 ℃ until single colonies grow. Select an appropriate amount of central single colonies and place them in NB liquid medium, and incubate them in a constant temperature shaker at 28 ℃ and 180 r / min until the logarithmic growth phase is reached for later use. 595 =0.6-0.8).

[0064] (2) Prepare 5 mL of 100 µg / mL NB culture medium containing the sample and control drugs in test tubes. Add 1% DMSO to the control group in test tubes. Take 200 µL from each test tube and measure its OD value. This value is the OD of the sterile culture medium. 595 Then, 40 µL of the test bacteria were inoculated into each test tube and cultured in a shaker at 28 °C and 180 r / min for 12–48 h. When the turbidity value was between 0.6 and 0.8, the OD value of each test tube was measured. 595 The inhibition rate of the tested compounds was calculated using the following formula, and the results are shown in Table 3.

[0065] (3) Correcting OD 595 Value = OD of bacterial culture medium 595 Value - OD of sterile culture medium 595 value Inhibition rate (%) = (OD of bacterial culture medium after correction) 595 -Correcting the OD of drug-containing culture media 595) / OD value of bacterial suspension in the control culture medium after correction × 100%.

[0066] (4) The results of the bioactivity test against plant pathogenic fungi are shown in Table 4.

[0067] Table 4. In vitro antibacterial activity of C1-C20 (100 μg / mL)

[0068] Table 4 shows that compounds C1-C8, C13, C15, and C18 all exhibited 100% inhibition rates against Xoo, which was superior to thiabendazole (74.2%). Compounds C1-C4 and C7-C8 showed 100% inhibition activity against Xac, significantly superior to thiabendazole (50.4%). Compounds C1-C3, C6, C8, C13, and C8 showed the most significant inhibitory effect against Xcm, with an inhibition rate of 100%, significantly superior to thiabendazole (72.9%). Furthermore, some compounds also showed good antibacterial activity against potato soft rot fungus (Pcb). In summary, the target compounds showed significantly better inhibitory activity against the three plant bacteria (Xoo, Xac, Xcm) than against potato soft rot fungus (Pcb). Therefore, the target compounds possess specific inhibitory activity against Xoo, Xac, and Xcm.

[0069] The above experimental activity data show that the acylpiperidine-containing gentianin derivative has a good inhibitory effect on plant pathogenic fungi and bacteria, especially Xanthomonas, and can be used as a potential anti-plant pathogen drug with good application prospects.

[0070] 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. A strychnosine derivative containing acylpiperidine, characterized in that, The structure is shown in the following formula: ， In the above formula, R is independently selected from H, one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 alkoxy groups.

2. The acetopiperidine-containing genistein derivative according to claim 1, characterized in that, The one or more halogens mentioned refer to 3-F, 4-F, 3-Br, 4-Br, 2-Cl, 3-Cl, 4-Cl, 2,4-dichloro, and 2,4-dibromo; the one or more C1-C6 alkyl groups refer to 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl, 3,5-dimethyl, 2,3,5-trimethyl, 4-ethyl, and 4-tert-butyl; the one or more C1-C6 substituted alkyl groups refer to 3-trifluoromethyl and 4-trifluoromethyl; and the one or more C1-C6 alkoxy groups refer to 2-methoxy, 3-methoxy, and 4-methoxy.

3. A method for preparing a pyrophoric acid derivative containing acylpiperidine as described in claim 1 or 2, characterized in that the step... include: (1) Using styracin and epoxybromopropane as raw materials, the reaction was carried out in a solvent under alkaline conditions. After the reaction was completed, ice water was added to precipitate the product. The product was filtered, and the residue was cleaned of impurities to obtain intermediate 1. The structural formula of the epichlorohydrin is: ; The structural formula of intermediate 1 is: ; (2) Using intermediate 1 and 1-boc-4-methylaminopiperidine as raw materials and potassium carbonate as catalyst, intermediate 2 was prepared by heating in a solvent. The structural formula of intermediate 2 is as follows: ; (3) Using intermediate 2 as raw material, remove BOC protection to obtain intermediate 3; The structural formula of the intermediate 3 is as follows: ; (4) Using intermediate 3 and substituted acyl chloride as raw materials and potassium carbonate as catalyst, the reaction was carried out at room temperature to obtain the acylpiperidine-containing argentin derivative. The structural formula of the substituted acyl chloride is: .

4. The preparation method according to claim 3, characterized in that, The molar ratio of gentianin and epichlorohydrin in step (1) is 11.1:(33.5~55.9); the heating reaction temperature is 60~80℃ and the time is 4~10h; the alkaline conditions are provided by anhydrous potassium carbonate; the impurity removal steps include: washing the filter residue with water and petroleum ether in sequence, then pulping, standing, filtering, and completing the washing; the solution used for pulping is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1~3:

1.

5. The preparation method according to claim 3, characterized in that, In step (2), the molar ratio of intermediate 1, 1-boc-4-methylaminopiperidine and potassium carbonate is 6.1:(12.3~18.5):(18.5~27.7); the heating reaction temperature is 60~80℃ and the time is 4~10 h; the heating reaction is followed by a purification step.

6. The preparation method according to claim 3, characterized in that, The step of removing BOC protection in step (3) includes: dissolving intermediate 2 in methanol, heating to 40~80℃, adding dropwise HCl solution with a mass fraction of 15~37%, reacting for 1~4 h, and removing BOC protection.

7. The preparation method according to claim 3, characterized in that... After removing BOC protection in step (3), a separation step is also included. The separation step is as follows: after removing BOC protection, the reaction system is poured into ice water, the system is adjusted to 8-9 using 5wt% NaHCO3 solution, and then extracted with dichloromethane. The extract is evaporated to dryness to obtain intermediate 2.

8. The preparation method according to claim 3, characterized in that, In step (4), the molar ratio of intermediate 3, substituted acyl chloride and potassium carbonate is 1.1:(2.2~4.5):(3.4~6.8); the reaction time at room temperature is 2~4 hours.

9. The use of the acylpiperidine-containing strychnine derivative of claim 1 or 2 in the preparation of drugs for inhibiting plant pathogenic fungi and bacteria.

10. The application according to claim 9, characterized in that, The plant pathogenic fungi include *Rhizoctonia solani* (r.), *Phytophthora indicum* (p.), *Sclerotinia sclerotiorum* (s.), *Actinidia kiwifruit* (p.), *Vitis vinifera* (b.), and *Fusarium wilt* (fo). The pathogens include: *Fusarium wilt* of cucumber (Foc); *Heterophyllum hepatum* of apple (Vm); *Bacillus thuringiensis* of rice (Xoo); *Citrus canker* of citrus (Xac); *Bacterium angularis* of mango (Xcm); and *Pcb* of potato soft rot.

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