Osthole derivative as well as preparation method and application thereof

Abstract

The invention discloses an osthole derivative as well as a preparation method and application thereof, and relates to the technical field of pest control. The invention relates to a cnidium lactone derivative 3f, 3g of cnidium lactone derivative, and 3h of cnidium lactone derivative. According to the invention, a Schiff base reaction mechanism of coumarin in organic chemistry is taken as a theoretical basis, cnidium lactone is taken as a lead compound, 8-site methyl is oxidized into an aldehyde group (-CHO) through a selenium dioxide SeO2 and dimethyl sulfoxide DMSO system, functional groups containing halogen, thioether, sulfonic groups and the like in an imine structure are introduced, and a series of cnidium lactone derivatives are synthesized. And indoor acaricidal activity research is carried out on corresponding derivatives.

Description

Technical Field

[0001] The present invention relates to the technical field of pest control, and more particularly to an osthole derivative and a preparation method and application thereof. Background Art

[0002] The two-spotted spider mite, Tetranychus urticae, commonly known as the red spider, is a globally distributed agricultural pest mite that harms over 1,000 host plant species, including those in agriculture, horticulture, and forestry, by sucking plant sap. It primarily targets leaves, causing them to turn green and, in severe cases, scorch, reducing the quality and yield of agricultural and forestry products [1-3]. For a long time, the control of agricultural pests, particularly the two-spotted spider mite, has relied primarily on chemical pesticides. This has led to increasing resistance and increased control costs, while also causing the accidental killing of predatory insects such as mites, disrupting ecological balance, and increasing the risk of mite resurgence. Furthermore, pesticide residues are easily accumulated through the food chain, threatening human health and environmental safety. Therefore, the development of new, highly effective, low-toxic, and easily degradable green pesticides is urgent. Compounds derived from plant-derived natural products have attracted widespread attention in the pesticide field in recent years due to their advantages, such as low environmental pollution, low toxicity to non-target organisms, and the ability to delay the development of pesticide resistance in pests. Directly or indirectly utilizing these natural products to develop new pesticides for pest control can effectively avoid the hazards of large-scale use of chemical pesticides.

[0003] Osthole, a natural coumarin compound extracted from the medicinal plant Cnidium monnieri, has become a hot topic in medicinal chemistry research due to its broad spectrum of biological activities, including antibacterial and insecticidal properties. However, its natural form suffers from low water solubility, insufficient bioavailability, and weak targeting, limiting its agricultural application. Ren Zili et al. synthesized osthole derivatives containing a 1,3,4-oxadiazole-2-sulfenyl moiety, demonstrating enhanced insecticidal (mite) activity. Zhou Xurong et al. discovered that osthole ester / sulfonate derivatives can improve its antibacterial activity. Furthermore, selective chemical modification of plant-derived natural product compounds can provide a basis for the development of new insecticides. Therefore, identifying compounds with antibacterial and insecticidal (mite) activity from natural products and their derivatives has become an important approach to identifying new agricultural candidate compounds.

[0004] Osthole has certain acaricidal activity against two-spotted spider mites and has no drug resistance, but its toxicity and rapidity are relatively insufficient compared to chemical acaricides.

[0005] Therefore, it is an urgent problem for those skilled in the art to provide an easily soluble, highly insecticidal (mite) activity osthole derivative to provide new strategies and technical support for the green control of spider mites. Summary of the Invention

[0006] In view of this, the present invention provides an osthole derivative and a preparation method and application thereof.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] Osthole derivatives and pharmaceutically acceptable salts thereof have a structural formula as shown below:

[0009] Osthole derivative 3f:

[0010]

[0011] Osthole derivative 3g:

[0012]

[0013] Osthole derivatives 3h:

[0014]

[0015] The preparation method of osthole derivative 3f, the specific reaction formula is as follows:

[0016] The preparation method of 3g of osthole derivative is as follows:

[0017]

[0018] The preparation method of osthole derivative 3h, the specific reaction formula is as follows:

[0019] Furthermore, the preparation of osthole intermediate 2a is also included. The specific reaction formula is as follows:

[0020]

[0021] Application of osthole derivatives in agricultural pest control, wherein the pest is Tetranychus urticae.

[0022] It can be seen from the above technical solution that compared with the prior art, the beneficial effects of the present invention are:

[0023] The present invention takes the Schiff base reaction mechanism of coumarin in organic chemistry as its theoretical basis, uses osthole as the lead compound, oxidizes the methyl group at the 8-position to an aldehyde group (-CHO) through a selenium dioxide (SeO2) and dimethyl sulfoxide (DMSO) system, introduces functional groups such as halogen, thioether and sulfonic acid groups into the imine structure, and synthesizes a series of osthole derivatives. The indoor mite-killing activity of the corresponding derivatives is then studied.

[0024] Osthole, its intermediates and eight derivatives showed acaricidal activity against both adult female and nymphal females of Tetranychus urticae at a concentration of 500 mg / L. Among them, the three derivatives 3h, 3f and 3g had higher toxicity, with the corrected mortality rates of adult females reaching 54.33%, 45.67% and 43.00% after 48 hours, respectively. Moreover, their acaricidal activity against nymphal females was higher than that against adult females, at 78.00%, 73.00% and 55.67%, respectively. Toxicity tests found that the toxicity of derivatives 3f, 3h, and 3g to female adult spider mites was 2 times higher than that of osthole, and their 48-h LC50 values ​​were 436.517 mg / L, 452.551 mg / L, and 537.512 mg / L, respectively. The acaricidal activity against nymphs was 4 times higher than that of osthole, and their 48-h LC50 values ​​were 145.207 mg / L, 153.014 mg / L, and 191.327 mg / L, respectively. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

[0026] Figure 1 The structural formula of the osthole intermediate 2a of the present invention is:

[0027] Figure 2 The structural formula of the osthole derivative 3f of the present invention is:

[0028] Figure 3 The structural formula of osthole derivative 3g of the present invention is:

[0029] Figure 4 This is the structural formula 3h of the osthole derivative of the present invention. DETAILED DESCRIPTION

[0030] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0031] Materials and Methods

[0032] Test mite source

[0033] The two-spotted spider mites used in the present invention were raised long-term by the agricultural mite research group of Gansu Agricultural University. They were raised in an intelligent light incubator using cowpea (Vigna unguiculata) seedlings of about one week old as hosts at a temperature of (25±1)°C, a relative humidity of (60±5)%, and a photoperiod of (L16:D8). They were not exposed to any pesticides during the raising period.

[0034] Reagents and instruments

[0035] Reagents: Osthole (purity ≥99%), selenium dioxide (SeO2), hydrochloric acid (HCl), NN-dimethylformamide (DMSO), anhydrous ethanol, 4-bromoaniline, 4-chloroaniline, p-methoxyaniline, nicotinamide, sulfonamide, 2,5-diaminobenzenesulfonic acid, 2-aminodiphenyl sulfide, 2,2-diaminodiphenyl sulfide, silver nitrate (AgNO3), anhydrous sodium sulfate, sodium carboxymethyl cellulose, iodine, petroleum ether, and acetone were purchased from Shanghai Aladdin Reagent Company; all were analytical grade, AR. 97% bifenazate technical was purchased from Shenzhen Nopoxin Agrochemical Co., Ltd.

[0036] Instruments: rotary evaporator (RE-201D, Shanghai LICHEN / Lichen), circulating water multi-purpose vacuum pump (TF / SHZ-DⅢ, Tengfang Instrument), heat-collecting constant temperature magnetic stirrer (DF-101 series, Xiniu Technology), vacuum freeze dryer (ZLGJ-10, Kewanda), electronic balance (BL320H, Shimadzu), BrukeravanceⅡ300MHz superconducting nuclear magnetic resonance instrument.

[0037] Example 1

[0038] Preparation of osthole intermediate 2a

[0039] 2a structural formula:

[0040]

[0041] Preparation method: Weigh 0.333 g (3 mmol) of selenium dioxide (SeO2) and place it in a 100 ml three-necked flask, add 50 ml of NN-dimethyl sulfoxide (DMSO), heat to 40°C and stir for 15 minutes until the crystalline SeO2 is completely dissolved.

[0042] 0.488 g (2 mmol) of osthole with a purity of 99% was weighed and placed in a 50 ml conical flask. 30 ml of anhydrous ethanol was added and dissolved at room temperature for 5 minutes under air-tight conditions.

[0043] At room temperature, osthole dissolved in anhydrous ethanol was added dropwise to a three-necked flask containing SeO2 using a dropping funnel over 17 minutes. After the addition was complete, the temperature was raised to 100°C and the reaction was monitored by TLC. The reaction was refluxed for 10 hours (under nitrogen atmosphere throughout). After the reaction was completed, the mixture was cooled to room temperature, filtered, and rotary evaporated to obtain the intermediate oxidation product of osthole, 7-methoxy-8-(2-methylbuten-2-aldehyde)-coumarin, chemical number 2a. The recovery rate was 70.5%.

[0044] 2a reaction formula:

[0045]

[0046] Example 2

[0047] Preparation of osthole derivative 3a

[0048] 3a Chemical name: 7-methoxy-8-(3-p-bromophenylaminobut-2-enyl)coumarin;

[0049] 3a structural formula:

[0050]

[0051] Preparation method: Dissolve 0.387g (1.5mmol) of 2a in 10ml of DMSO solution and place it in a 100ml three-necked flask. Accurately weigh 0.344g (2mmol) of 4-bromoaniline in a 50ml conical flask and add 10ml of anhydrous ethanol to dissolve it. The dissolution time is 5min. After the 4-bromoaniline is completely dissolved, slowly add the dissolved 4-bromoaniline dropwise to the three-necked flask containing intermediate 2a at a drop rate of 20 drops / min. The addition is completed over 12 minutes. The mixed solution is heated to 70°C and refluxed for 5 hours (under nitrogen protection throughout the process). TLC is used to monitor the reaction during the reaction. The reaction is stopped after a large amount of orange-yellow solid precipitates. After the temperature is cooled to room temperature, the product is filtered under reduced pressure, rinsed with ethanol, concentrated again by rotary evaporation, and dried at 50°C for 24 hours to obtain the crude product. The crude product was dissolved in a chromatographic column for separation and purification (petroleum ether:acetone = 3:1), and recrystallized to obtain the target product 3a in pure form with a yield of 65% as a light yellow solid.

[0052] 3a reaction formula:

[0053]

[0054] Example 3

[0055] Preparation of osthole derivative 3b

[0056] 3b Chemical name: 7-methoxy-8-(3-(p-chlorophenylaminobut-2-enyl)coumarin;

[0057] 3b structural formula:

[0058]

[0059] Preparation method: Dissolve 0.387g (1.5mmol) of 2a in 10ml of DMSO solution and place it in a 100ml three-necked flask. Use an electronic balance to accurately weigh 0.256g (2mmol) of 4-chloroaniline in a 50ml conical flask, add 8ml of anhydrous ethanol to dissolve, and dissolve for 8min. After the 4-chloroaniline is completely dissolved, slowly add the dissolved 4-chloroaniline dropwise to the three-necked flask containing intermediate 2a at a drop rate of 15 drops / min, and add the solution dropwise over 10-15 minutes. After the addition is complete, the mixed solution is heated to 70°C and refluxed for 5 hours (under nitrogen protection throughout the process). During the reaction, TLC is used to track the reaction. The reaction is stopped after a large amount of light yellow solid precipitates. After the temperature drops to room temperature, the mixture is filtered under reduced pressure, rinsed with ethanol, concentrated again by rotary evaporation, and dried at 55°C for 24 hours to obtain the crude product. The crude product was dissolved in a chromatographic column for separation and purification (petroleum ether: acetone = 3:1), and recrystallized to obtain the pure target product 3b as a light yellow solid.

[0060] Reaction formula of 3b:

[0061]

[0062] Example 4

[0063] Preparation of osthole derivative 3c

[0064] 3c Chemical name: 7-methoxy-8-(3-p-methoxyanilinobut-2-enyl)coumarin

[0065] 3c structural formula:

[0066]

[0067] Preparation method: Dissolve 0.387g (1.5mmol) of 2a in 10ml of DMSO solution and place it in a 100ml three-necked flask. Use an electronic balance to accurately weigh 0.246g (2mmol) of p-anisidine in a 50ml conical flask, add 6ml of anhydrous ethanol to dissolve, and dissolve for 10min. After the p-anisidine is completely dissolved, slowly add the dissolved p-anisidine dropwise to the three-necked flask containing intermediate 2a at a drop rate of 15 drops / min. The addition should be completed within 10-15 minutes. After the addition is complete, the mixed solution is heated to 75°C and refluxed for 6 hours (under nitrogen protection throughout the process). During the reaction, TLC is used to track the reaction. The reaction is stopped after a large amount of dark gray solid precipitates. After the temperature drops to room temperature, the mixture is filtered under reduced pressure, rinsed with ethanol, concentrated again by rotary evaporation, and dried at 60°C for 24 hours to obtain the crude product. The crude product was dissolved in a chromatographic column for separation and purification (petroleum ether:acetone = 3:1), and recrystallized to obtain the target product 3c in pure form with a yield of 82% as a dark gray solid.

[0068] Reaction formula of 3c:

[0069]

[0070] Example 5

[0071] Preparation of osthole derivative 3d

[0072] 3d Chemical name: 7-methoxy-8-(3-nicotinamidobut-2-enyl)coumarin

[0073] 3D structural formula:

[0074]

[0075] Preparation: Dissolve 0.387 g (1.5 mmol) of 2a in 10 ml of DMSO in a 100 ml three-necked flask. Accurately weigh 0.245 g (2 mmol) of nicotinamide using an electronic balance into a 50 ml conical flask and dissolve in 5 ml of anhydrous ethanol for 3 minutes. Once the nicotinamide is completely dissolved, slowly add the dissolved nicotinamide dropwise to the three-necked flask containing intermediate 2a at a rate of 20 drops / min over 10-15 minutes. After the addition is complete, heat the mixture to 70°C and reflux under condensation for 5 hours (under nitrogen throughout). TLC is used to monitor the reaction. After cooling to room temperature, filter under reduced pressure, rinse with ethanol, and concentrate again by rotary evaporation. Dry at 55°C for 24 hours to obtain the crude product. The crude product is purified by column chromatography (petroleum ether:acetone = 3:1) and recrystallized to obtain the target product 3d as a pale yellow solid in a 59% yield.

[0076] 3D reaction formula:

[0077]

[0078] Example 6

[0079] Preparation of osthole derivative 3e

[0080] 3e Chemical name: 7-methoxy-8-(3-sulfonylaminobut-2-enyl)coumarin;

[0081] 3e structural formula:

[0082]

[0083] Preparation method: 0.387g (1.5mmol) of 2a was dissolved in 10ml of DMSO solution and placed in a 100ml three-necked flask. 0.345g (2mmol) of sulfonamide was accurately weighed into a 50ml conical flask using an electronic balance, and 10ml of anhydrous ethanol was added to dissolve the mixture. The dissolution time was 10min. After the sulfonamide was completely dissolved, the dissolved sulfonamide was slowly added dropwise to the three-necked flask containing the intermediate 2a at a dropping rate of 10 drops / min. The addition was completed in 10-15 minutes. After the addition was completed, the mixed solution was heated to 80°C, refluxed under condensation for 8 hours (nitrogen protection throughout the process), and the reaction was tracked by TLC during the reaction. The reaction was stopped after a large amount of light yellow solid precipitated. After the temperature dropped to room temperature, the mixture was filtered under reduced pressure, washed with ethanol, concentrated again by rotary evaporation, and dried at 60°C for 24 hours to obtain the crude product. The crude product was dissolved in a chromatographic column for separation and purification (petroleum ether: acetone = 3:1), and recrystallized to obtain the target product 3e as a pure light yellow solid.

[0084] The reaction formula of 3e:

[0085]

[0086] Example 7

[0087] Preparation of osthole derivative 3f

[0088] 3f Chemical name: 7-methoxy-8-(3-2,5-diaminobenzenesulfonylbut-2-enyl)coumarin;

[0089] 3f structural formula:

[0090]

[0091] Preparation method: 0.387g (1.5mmol) of 2a was dissolved in 10ml of DMSO solution and placed in a 100ml three-necked flask. Use an electronic balance to accurately weigh 0.377g (2mmol) of 2,5-diaminobenzenesulfonic acid into a 50ml conical flask, add 5ml of anhydrous ethanol to dissolve, and dissolve for 3min. After the 2,5-diaminobenzenesulfonic acid is completely dissolved, the dissolved 2,5-diaminobenzenesulfonic acid is slowly added dropwise to the three-necked flask containing the intermediate 2a at a drop rate of 10 drops / min, and the addition is completed in 10-15 minutes. The mixed solution was heated to 75°C and refluxed for 5 hours (nitrogen protection throughout the process). TLC was used to track the reaction during the reaction. After the temperature was lowered to room temperature, the solution was filtered under reduced pressure, washed with ethanol, concentrated again by rotary evaporation, and dried at 50°C for 24 hours to obtain the crude product. The crude product was dissolved in a chromatographic column for separation and purification (petroleum ether: acetone = 3:1), and recrystallized to obtain the target product 3f as a pure black solid.

[0092] The reaction formula of 3f is:

[0093]

[0094] Example 8

[0095] Preparation of 3g of osthole derivatives

[0096] 3g Chemical name: 7-methoxy-8-(3-o-aminodiphenylsulfide-but-2-enyl) coumarin;

[0097] 3g structural formula:

[0098]

[0099] Preparation method: Dissolve 0.387g (1.5mmol) of 2a in 10ml of DMSO solution in a 100ml three-necked flask. Use an electronic balance to accurately weigh 0.403g (2mmol) of 2-aminodiphenyl sulfide into a 50ml conical flask and dissolve it in 5ml of anhydrous ethanol for 10 minutes. Once the 2-aminodiphenyl sulfide is completely dissolved, slowly add the dissolved 2-aminodiphenyl sulfide dropwise to the three-necked flask containing intermediate 2a at a rate of 20 drops / min over 10-15 minutes. After the addition is complete, the mixed solution is heated to 70°C and refluxed for 5 hours (under nitrogen protection throughout the process). TLC is used to monitor the reaction. The reaction is stopped after the precipitation of a large amount of light yellow solid. After cooling to room temperature, the mixture is filtered under reduced pressure, rinsed with ethanol, and concentrated again by rotary evaporation. The crude product is dried, purified by chromatography, and recrystallized to obtain 3g of the desired product as a light yellow solid.

[0100] The reaction formula of 3g is:

[0101]

[0102] Example 9

[0103] Preparation of osthole derivative 3h

[0104] 3h Chemical name: 7-methoxy-8-(3-(2,2'-diaminodiphenyl disulfide) but-2-enyl) coumarin;

[0105] 3h structural formula:

[0106]

[0107] Preparation method: Dissolve 0.387g (1.5mmol) of 2a in 10ml of DMSO solution and place it in a 100ml three-necked flask. Use an electronic balance to accurately weigh 0.5975g (2mmol) of 2,2'-diaminodiphenyl disulfide into a 50ml conical flask and add 10ml of anhydrous ethanol to dissolve it. Dissolve for 20 minutes. After the 2,2'-diaminodiphenyl disulfide is completely dissolved, slowly add the dissolved 2,2'-diaminodiphenyl disulfide dropwise to the three-necked flask containing intermediate 2a at a rate of 10-15 drops / min over 15-20 minutes. After the addition is complete, the mixed solution is heated to 75°C and refluxed under condensation for 8 hours (under nitrogen protection throughout the reaction). TLC is used to monitor the reaction during the reaction. The reaction was stopped after a large amount of light yellow solid precipitated. After the temperature dropped to room temperature, the product was filtered under reduced pressure, rinsed with ethanol, concentrated by rotary evaporation again, and dried to obtain a crude product. The product was dissolved and separated and purified by a chromatographic column, and recrystallized to obtain the target product 3h pure substance as a light yellow solid.

[0108] Reaction formula for 3h:

[0109]

[0110] Acaricidal activity assay

[0111] The leaf immersion method was adopted, and bifenazate was selected as the positive control and acetone as the blank control. The LC50 values ​​of the compounds synthesized in Examples 1-9 were determined. The mass concentration gradients of osthole, intermediates, and 8 derivatives were set to 2000, 1000, 500, 250, and 125 mg / L, and the concentration gradient of 97% bifenazate original drug was set to 8.25, 4.12, 2.06, 1.03, and 0.52 mg / L; 30 healthy and active female adults and nymphs of two-spotted spider mites of uniform size were taken. After the mite bodies were stable, the dead and inactive individuals were removed, and the actual number of mites was recorded as the test base. The leaves with two-spotted spider mites were immersed in the above-mentioned liquid for 5 seconds. After taking out, the excess liquid around the mite body and on the leaves was absorbed with absorbent paper, and then the leaf disc was returned. The leaf margins and petioles were rewrapped with soaked cotton strips to ensure that the leaves were sufficiently hydrated and to prevent the escape of two-spotted spider mites. Each concentration was repeated three times. After the treatment, the leaf discs were placed in an intelligent light incubator with cowpea seedlings about one week old as the host, and cultured under the conditions of temperature (25±1)℃, relative humidity (60±5)%, and photoperiod (L16:D8). After 48 hours, the two-spotted spider mites were lightly touched with the tip of a brush. Those without any reaction were considered dead. The toxicity regression equation was fitted based on the corrected mortality rate.

[0112] Data processing

[0113] Data were processed using Excel 2024 and IBM SPSS Statistic 29 software, and Duncan's new multiple range method was used to analyze significant differences between factors (a = 0.05). The mortality rate and adjusted mortality rate were calculated as follows:

[0114] Mortality rate = number of deaths / number of test insects × 100%

[0115] Adjusted mortality rate = treatment group mortality rate - control group mortality rate / 1 - control group mortality rate × 100%

[0116] Results and Analysis

[0117] Synthesis of Osthole Intermediates and Derivatives

[0118] As shown in Table 1, eight new derivatives (numbered 3a-3h) were synthesized based on the osthole intermediate 2a through structural modification. It can be seen that the yields of the derivatives ranged from 59% to 82%, among which 3c had the highest yield (82%) and 3d had the lowest (59%). The products were all solid, mainly light yellow in color, with a few being orange-yellow, dark gray or black. The structures of all derivatives were characterized by nuclear magnetic resonance spectroscopy. The chemical shift data showed that each molecule contained characteristic methyl (δ≈2.1-2.2), methoxy (δ≈3.7-3.8) and alkenyl / aromatic hydrogen signals (δ≈6.0-8.9), verifying the structure of the target derivative.

[0119] Table 1 Information of synthesized osthole intermediates and derivatives

[0120]

[0121]

[0122] Acaricidal activity of osthole and its derivatives

[0123] Table 2 shows the corrected mortality rates of the target compounds against female adults and nymphs of Tetranychus urticae (T. urticae) over 24 and 48 hours. It demonstrates that the different osthole derivatives exhibit distinct time-of-action characteristics. At a treatment concentration of 500 mg / L, the 3-hour derivative exhibited the most robust acaricidal activity among all nine derivatives: its corrected mortality rates against female adults were 37.67% and 54.33% over 24 and 48 hours, respectively; its corrected mortality rates against nymphs reached 65.00% (24 hours) and 78.00% (48 hours), demonstrating remarkable rapidity and sustained efficacy. The corrected mortality rates of all nine derivatives were superior to those of the parent osthole derivative for both female adults and nymphs over 48 hours. The efficacy of the parent osthole derivative was demonstrated by: corrected mortality rates of 13.67% and 22.33% for female adults treated with the 3-hour derivatives, and 16.33% and 23.33% for nymphs treated with the 3-hour derivatives. This highlights the efficacy advantages of the new compound.

[0124] Table 2 Indoor acaricidal activity of osthole and its derivatives against Tetranychus urticae at 500 mg / L

[0125]

[0126]

[0127] Note: Data are mean ± standard error; different lowercase letters indicate significant differences between different drugs tested by Duncan's new multiple range method at the ɑ = 0.05 level.

[0128] LC of osthole and its derivatives against Tetranychus urticae 50

[0129] The 48-hour LC50 values ​​of osthole and its derivatives against adult female and nymph Tetranychus urticae were further determined. The results are shown in Table 3. Intermediate 2a exhibited LC50 values ​​of 1036.916 and 515.447 mg / L for adult female and nymph females, respectively. Derivatives 3f, 3h, and 3g exhibited over twofold higher toxicity against adult female mites than the parent osthole, with LC50 values ​​of 436.517, 452.551, and 537.512 mg / L, respectively. Their LC50 values ​​against nymph females were 145.207, 153.014, and 191.327 mg / L, respectively, representing over fourfold increases compared to the parent. The LC50 values ​​for 3c and 3d against adult female mites were 721.049 and 623.645 mg / L, respectively; for 3b, 930.386 mg / L; and for 3a and 3e, 1556.903 and 1662.607 mg / L, respectively. The toxicity of the two mite stages to adult females was ranked as follows: 3f > 3h > 3g > 3d > 3c > 3b > 2a > 1 (osthole) > 3a > 3e. The toxicity of parent osthole to nymphs was the lowest, with the order being 3f > 3h > 3g > 3d > 3b > 2a > 3c > 3a > 3e > 1 (osthole).

[0130] Table 3 LC values ​​of osthole and its derivatives on female adult spider mites at 48h 50 value

[0131]

[0132]

[0133] Note: y is the observed probability value, and x is the logarithm of the measurement.

[0134] The present invention synthesized intermediate 2a using osthole as the parent compound. Based on this, eight novel derivatives 3a-3h were synthesized through structural modification. At a concentration of 500 mg / L, the intermediate and eight derivatives demonstrated superior 48-hour lethality against Tetranychus urticae compared to the parent compound. Derivative 3h, containing an ortho-sulfur group, achieved a 54.33% corrected 48-hour mortality rate against adult female mites and a 78% mortality rate against nymphs.

[0135] LC50 analysis showed that when the 8-methyl group of osthole was oxidized to an aldehyde, the resulting intermediate 2a exhibited only a slight improvement in acaricidal activity compared to the parent. Based on intermediate 2a, derivatives 3f, 3h, and 3g containing ortho- and meta-sulfur groups exhibited over fourfold lower LC50 values ​​against nymphs, with 3f exhibiting a nymph LC50 of only 16.29% of that of the parent. Derivatives 3a and 3e containing para-bromine and sulfur groups exhibited lower activity against adult female mites, suggesting that specific substituents exert a bidirectional regulatory effect on activity. Nymphs were significantly more sensitive to the derivatives than adult females (for example, the LC50 for 3f against nymphs was only 33.26% of that for females). The introduction of methoxy and sulfonamide groups into 3c and 3d, respectively, enhanced their activity, likely due to the methoxy and sulfonamide groups affecting insect metabolism. When a chlorine group was introduced at the para position (3b), the resulting derivative showed enhanced activity. This may be due to the chlorine inhibiting the metabolism of related enzymes in the insect, which warrants further investigation. Derivatives such as 3f exhibit both rapid and long-lasting effects, providing foundational data for the development of botanical pesticides and the green control of spider mites, validating the use of chemical modification as an effective path to overcome the limitations of natural products.

[0136] Research has shown that osthole is effective in controlling common pests such as termites and cabbage loopers, with particularly significant results in field trials against spider mites in date orchards. Compared to chemical pesticides, this natural ingredient not only avoids environmental pollution but also reduces the risk of pest resistance. In practical applications, osthole can be used alone for pest control or in combination with chemical pesticides, creating a more efficient and environmentally friendly pest control solution. While green pesticides have limitations such as poor stability and limited effectiveness compared to traditional chemical pesticides, modern chemical modification techniques can overcome these limitations. This "natural + low-toxic" combination effectively controls pests without impacting the ecological environment, providing a practical and viable technical option for promoting the green transformation of agriculture. To further expand the utility of osthole, this study uses osthole as a lead compound and, after introducing structures containing ortho- and meta-sulfur elements, demonstrates enhanced acaricidal activity in its derivatives. This finding mirrors the findings of Ren Zili et al., who found that the introduction of various substituted 1,3,4-oxadiazole groups bridged by thioether bonds into osthole enhanced acaricidal activity. Liu Guoli et al. also demonstrated that some synthetic osthole derivatives exhibit insecticidal and repellent properties. These studies not only validate the feasibility of chemical modification of natural products in pesticide development but also lay the theoretical foundation for the development of a new generation of green pesticides that combine high efficacy with ecological safety.

[0137] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An osthole derivative and a pharmaceutically acceptable salt thereof, characterized in that: The structural formula is one of the following structures: Osthole derivative 3f: Osthole derivative 3g: Osthole derivatives 3h:

2. A method for preparing the osthole derivative according to claim 1, characterized in that: The specific reaction formula of the osthole derivative 3f is as follows:

3. A method for preparing the osthole derivative according to claim 1, characterized in that: The specific reaction formula of the osthole derivative 3g is as follows:

4. A method for preparing the osthole derivative according to claim 1, characterized in that: The specific reaction formula of the osthole derivative 3h is as follows:

5. The method for preparing the osthole derivative according to claim 2-4 claim 1, characterized in that: The method also includes the preparation of osthole intermediate 2a, and the specific reaction formula is as follows:

6. The use of the osthole derivative according to claim 1 in agricultural pest control, characterized in that: The pest is the two-spotted spider mite.

Images