A quinine hydrazone derivative and its preparation method and application

Abstract

The present invention belongs to the field of plant antimicrobial agents, specifically relating to a quinine hydrazone derivative, its preparation method, and application. The quinine hydrazone derivative has a general structural formula as shown in Formula I. Antimicrobial experiments have demonstrated that the quinine hydrazone derivative provided by the present invention exhibits significant antibacterial activity against plant pathogenic fungi / oomycetes. Some compounds exhibit antibacterial activity exceeding that of currently marketed antimicrobial agents triadimefon / metalaxyl, and can be used to prepare botanical fungicides.

Description

Technical Field

[0001] The invention belongs to the field of plant antimicrobial agents, and particularly relates to a quinine hydrazone derivative, a preparation method and an application thereof. Background Art

[0002] Quinine, also known as cinchona alkaloids, is the main alkaloid found in the bark of the Rubiaceae plant Cinchona sinensis and its congeners. It has a wide range of pharmacological effects and biological activities. For example, (1) antibacterial activity shows that quinine derivatives have the activity to inhibit bacterial topoisomerase (Type IIA); (2) recent studies have shown that quinine derivatives have significant anti-malarial activity; (3) quinine dimers can reversibly inhibit P-glycoprotein-mediated paclitaxel resistance, thereby inhibiting cancer cell proliferation.

[0003] There are literature reports on the research on the activity of quinine ester derivatives in killing mythimna separate walkers. For example, Che Zhiping et al. reported the synthesis of quinine ester derivatives and their research on their activity in killing mythimna separate walkers (CheZhiping, Yang Jinming, Sun Di, Tian Yuee, Liu Shengming, Lin Xiaomin, Jiang Jia, Chen Genqiang, Combinatorial synthesis of novel 9R-acyloxyquinine derivatives as insecticidal agents, Combinatorial Chemistry & High Throughput Screening, 2020, 23(2): 111-118). Quinine has an effect on the gap junction channels between the smooth muscle cells of the mesenteric artery of guinea pigs, and it blocks the gap junction channels between the mesenteric artery cells in a concentration-dependent manner (Zhang Zhiping, Si Junqiang, Li Xinzhi, Li Li, Wei Lili, Ma Ketao, Effects of quinine and carbenoxolone on the gap junction channels between the smooth muscle cells of the mesenteric artery of guinea pigs, Medical Herald, 2014, 33(3): 279-283).

[0004] Quinine has a broad spectrum of biological activities, including insecticidal, antibacterial, and anticancer activities. Our research group previously studied the control effects of 9R-acyloxyquinine derivatives against lepidopteran agricultural pests (CN110759904A). However, the synthesis of quinine hydrazone derivatives and their anti-plant pathogenic fungi / oomycetes activity have not been reported. Summary of the Invention

[0005] The present invention aims to provide a quinine hydrazone derivative which has significant antibacterial activity against plant pathogenic fungi / oomycetes and can be used as a botanical fungicide active substance.

[0006] The second object of the present invention is to provide a method for preparing the above-mentioned quinine hydrazone derivatives to solve the above-mentioned problems.

[0007] The third object of the present invention is to provide the application of the above-mentioned quinine hydrazone derivatives to provide a new type of antibacterial active substance for plant pathogenic fungi / oomycetes.

[0008] In order to achieve the above objectives, the technical solution adopted by the present invention is:

[0009] A quinine hydrazone derivative, the general structural formula of which is shown in Formula I:

[0010]

[0011] In formula I, L is a single bond, One of the following;

[0012] R is selected from C1-C7 alkyl, cyano, phenyl, substituted phenyl, and heteroaryl; the number of substituents in the substituted phenyl is 1 to 3, and the substituents are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, and hydroxyl.

[0013] The quinine hydrazone derivatives provided by the present invention have been shown in antibacterial experiments to have significant antibacterial activity against plant pathogenic fungi / oomycetes. The antibacterial activity of some compounds exceeds that of the currently marketed antibacterial agents triadimefon / metalaxyl, and can be used to prepare botanical fungicides.

[0014] In order to significantly enhance the antibacterial activity, preferably, the general structural formula of the quinine hydrazone derivative is as shown in Formula II, Formula III, and Formula IV:

[0015]

[0016] In formula II, R1 is selected from C1-C7 alkyl or cyano;

[0017]

[0018] In formula III, R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, and hydroxyl;

[0019]

[0020] In formula IV, R3 and R4 are each independently selected from hydrogen and halogen.

[0021] More preferably, in formula II, R1 is selected from a C4-C5 alkyl group. The corresponding compound has a higher activity in inhibiting the plant pathogenic oomycete Phytophthora capsici than the commercial anti-oomycete agent Metalaxyl.

[0022] Further preferably, the quinine hydrazone derivatives are the following compounds:

[0023]

[0024] The above compounds have been shown to be more effective than the commercial anti-oomycete Metalaxyl in inhibiting the plant pathogenic oomycete Phytophthora capsici (P. capsici).

[0025] Further preferably, the quinine hydrazone derivatives are selected from the following compounds:

[0026] The above compounds have been shown to be more effective than the commercial antifungal agent triadimefon in inhibiting the plant pathogenic fungus Fusarium graminearum.

[0027] As a typical representative of heteroaryl substituents, preferably, the quinine hydrazone derivatives are selected from the following compounds:

[0028]

[0029] Preferably, in Formula I, L is

[0030] R is selected from phenyl or substituted phenyl; the number of substituents in the substituted phenyl group is 1 to 3, and the substituents are selected from C1-C3 alkyl and C1-C3 alkoxy groups. When L is a sulfonyl group and R is selected from phenyl or substituted phenyl, the corresponding quinine hydrazone derivatives also exhibit good inhibitory effects against plant fungi / oomycetes.

[0031] The preparation method of the above-mentioned quinine hydrazone derivative comprises the following steps: reacting intermediate A with the corresponding hydrazine to obtain the quinine hydrazone derivative represented by formula I; wherein intermediate A is:

[0032]

[0033] The preparation method of the quinine hydrazone derivatives of the present invention utilizes the aldehyde position of the intermediate A to further react with various hydrazines (hydrazide, phenylhydrazine hydrochloride and benzenesulfonylhydrazide) to prepare the quinine hydrazone derivatives. The preparation process is simple and suitable for large-scale promotion and application.

[0034] Application of the above-mentioned quinine hydrazone derivatives in the preparation of antimicrobial agents for plant pathogenic fungi and / or oomycetes.

[0035] The above-mentioned quinine hydrazone derivatives have good inhibitory activity against plant pathogenic fungi and / or oomycetes and can be used to prepare botanical fungicides, thereby improving the shortcomings of non-plant antibacterial agents in antibacterial use to a certain extent.

[0036] Preferably, the plant pathogenic fungus is Gibberella zeae; and the plant pathogenic oomycete is Phytophthora capsici. The quinine hydrazone derivatives exhibit excellent inhibitory effects on the above typical fungi / oomycetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is the hydrogen spectrum of compound 1 of the present invention;

[0038] Figure 2 1H spectrum of compound 2 of the present invention. DETAILED DESCRIPTION

[0039] The quinine hydrazone derivatives provided by the present invention are mainly used as botanical pesticides to prevent and control plant pathogenic fungi / oomycetes.

[0040] The quinine hydrazone derivatives are prepared from quinine, a plant secondary biomass, by first introducing a 4-formylbenzoyl group into the 9R-OH position of quinine to synthesize an important intermediate through esterification; the intermediate aldehyde position is further reacted with various hydrazines (hydrazide, phenylhydrazine hydrochloride and benzenesulfonylhydrazide) to prepare the quinine hydrazone derivatives.

[0041] The general reaction formula of this reaction is as follows:

[0042]

[0043] The above reaction mainly involves reacting intermediate A with the corresponding hydrazine to prepare the quinine hydrazone derivative shown in formula I.

[0044] The corresponding hydrazine is a hydrazine substance corresponding to the product. Depending on the product type, the corresponding hydrazine is acylhydrazine, phenylhydrazine hydrochloride, and benzenesulfonylhydrazine. The molar ratio of intermediate A to the corresponding hydrazine is 1.0:1.0-1.2.

[0045] The reaction of intermediate A and the corresponding hydrazine is carried out in a solvent in the presence of acetic acid. For every 0.1-0.3 mmol of intermediate A, the corresponding amount of solvent is 5 mL, and the corresponding amount of acetic acid is 2-3 drops. The solvent is preferably anhydrous ethanol. The reaction is preferably carried out at room temperature for 6-24 hours.

[0046] Typical hydrazines involved in the above reaction include: acetohydrazide, valeryl hydrazide, octyl hydrazide, cyanoacetohydrazide, benzohydrazide, p-methoxybenzohydrazide, p-aminobenzohydrazide, p-fluorobenzohydrazide, 2-chlorobenzohydrazide, 4-chlorobenzohydrazide, salicylic hydrazide, 2-thiophenecarboxylic acid hydrazide, nicotinic acid hydrazide, isoniazid, 4-fluorophenylhydrazine hydrochloride, 3,4-difluorophenylhydrazine hydrochloride, 2-chlorophenylhydrazine hydrochloride; benzenesulfonylhydrazide, 4-toluenesulfonylhydrazide, 2,4,6-triisopropylbenzenesulfonylhydrazide, etc.

[0047] The preparation method of intermediate A comprises: esterifying quinine and 4-formylbenzoic acid in a solvent. The shrinkage reaction uses 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as a shrinkage agent and 4-dimethylaminopyridine (DMAP) as a catalyst.

[0048] The molar ratio of quinine to 4-formylbenzoic acid is 1.0:1.0-1.2. The molar ratio of quinine to EDCI to DMAP is 1.0:1.0-1.2:0.1-0.2. For every 4-5 mmol of quinine, 50 mL of solvent is used. Dichloromethane is preferred as the solvent. The reaction is carried out at room temperature for 12-24 hours.

[0049] The implementation process of the present invention is described in detail below with reference to specific embodiments.

[0050] 1. Specific Examples of Quinine Hydrazone Derivatives and Their Preparation Methods

[0051] Examples 1 to 20

[0052] The quinine hydrazone derivatives of Examples 1 to 20 have the following general structural formula:

[0053]

[0054] Determine the corresponding substituent according to Table 1 ( represents the connection position), and the quinine hydrazone derivatives of Examples 1 to 20 were obtained, which are compounds 1 to 20, respectively.

[0055] Table 1 Quinine hydrazone derivatives of Examples 1 to 20

[0056]

[0057]

[0058] The preparation process of the quinine hydrazone derivatives of Examples 1 to 20 is described as follows:

[0059] Synthesis of intermediate A: Quinine (5 mmol), 4-formylbenzoic acid (6 mmol), EDCI (6 mmol), DMAP (0.5 mmol) were added to a 100 mL flask, and 50 mL of dichloromethane was added to completely dissolve it. The reaction was stirred at room temperature. TLC tracking was monitored until the reaction was completed. After the reaction was completed, 30 mL of saturated sodium bicarbonate solution was added and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and then dried over anhydrous sodium sulfate. The solvent was concentrated and purified by silica gel column chromatography to obtain intermediate A with a yield of 51%.

[0060] (1) Synthesis of quinine hydrazone derivatives 1-14 (Compounds 1-14)

[0061] In a 50 mL flask, intermediate A (0.22 mmol) and the corresponding hydrazide (0.27 mmol) were added and dissolved in 5 mL of anhydrous ethanol. Two drops of acetic acid were added dropwise to the solution at room temperature. After the addition of the above mixture, the reaction was stirred at room temperature for 6-24 hours and monitored by TLC until the reaction was complete. After the reaction was completed, the solvent was evaporated to dryness, 10 mL of dichloromethane was added to dissolve it, and then 10 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and then dried over anhydrous sodium sulfate. The solvent was concentrated and purified by silica gel column chromatography to obtain quinine hydrazone derivatives 1-14 with a yield of between 43-78%.

[0062] (2) Synthesis of quinine hydrazone derivatives 15-17 (Compounds 15-17)

[0063] In a 50 mL flask, intermediate A (0.22 mmol) and the corresponding phenylhydrazine hydrochloride (0.27 mmol) were added and dissolved in 5 mL of anhydrous ethanol. Two drops of acetic acid were added dropwise to the solution at room temperature. After the addition of the above mixture, the reaction was refluxed in an oil bath for 12-24 hours and monitored by TLC until the reaction was complete. After the reaction was completed, the solvent was evaporated to dryness, 10 mL of dichloromethane was added to dissolve it, and then 10 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and then dried over anhydrous sodium sulfate. The solvent was concentrated and purified by silica gel column chromatography to obtain quinine hydrazone derivatives 15-17 with a yield of between 40-70%.

[0064] (3) Synthesis of quinine hydrazone derivatives 18-20 (compounds 18-20)

[0065] Intermediate A (0.22 mmol) and the corresponding benzenesulfonyl hydrazide (0.27 mmol) were added to a 50 mL flask and dissolved in 5 mL of anhydrous ethanol. Two drops of acetic acid were added dropwise to the solution at room temperature. After the addition of the above mixture, the reaction was stirred at room temperature for 6-24 hours and monitored by TLC until the reaction was complete. After the reaction was completed, the solvent was evaporated to dryness, 10 mL of dichloromethane was added to dissolve it, and then 10 mL of saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and then dried over anhydrous sodium sulfate. The solvent was concentrated and purified by silica gel column chromatography to obtain quinine hydrazone derivatives 18-20 with a yield of 33-69%.

[0066] The physicochemical properties and characterizations of compounds 1 to 20 are described as follows:

[0067] Compound 1:

[0068] The physicochemical properties of the compound are as follows:

[0069] 1) White solid, melting point 234-235°C, yield 57%.

[0070] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0071] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 9.92 (s, 1H), 8.73 (dd, J = 4.4 Hz, 1.2 Hz, 1H), 8.12 (dd, J = 8.4 Hz, 1.6 Hz, 2H), 8.04 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 7.83 (s, 1H), 7.71 (dd, J = 8.4 Hz, 1.2 Hz, 2H), 7.52 (t, J = 1.6 Hz, 1H), 7.36-7.42 (m, 2H), 6. 77(d,J=6.4Hz,1H),5.79-5.88(m,1H),4.99-5.05(m,2H),3.99(s,3H),3.47-3.51(m,1H),3.21(s,1H),3.13(dd,J=13.6Hz,10Hz,1H),2.65-2.76(m,2H),2.40(s,3H),2.32(s,1H),1.90-1.96(m,2H),1.71-1.82(m,2H),1.60(s,1H). The corresponding spectrum is shown in Figure 2. Figure 1 shown.

[0072] 3) The reaction formula is:

[0073]

[0074] Compound 2:

[0075] The physicochemical properties of the compound are as follows:

[0076] 1) White solid, melting point 109-110°C, yield 78%.

[0077] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0078] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peaks were assigned as follows: δ: 9.45 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.12 (dd, J = 6.4 Hz, 1.6 Hz, 2H), 8.03 (d, J = 9.2 Hz, 1H), 7.78 (s, 1H), 7.75 (dd, J = 6.4 Hz, 2 Hz, 2H), 7.52 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.75 (s, 1 H), 5.80-5.89(m,1H),5.00-5.05(m,2H),3.99(s,3H),3.54(q,J=8Hz,1H),3.21(s,1H),3.06-3.12(m,1H),2.79(t,J=7.6Hz,2H),2.69(d,J=15.6Hz,2H),2.31(s,1H),1.91(s,1H),1.69-1.76(m,5H),1.59(s,1H),1.40-1.49(m,2H),0.99(t,J=6.4Hz,3H). The corresponding spectrum is shown in Figure 2. Figure 2 shown.

[0079] 3) The reaction formula is:

[0080]

[0081] Compound 3:

[0082] The physicochemical properties of the compound are as follows:

[0083] 1) White solid, melting point 83-84°C, yield 59%.

[0084] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0085] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 9.83 (d, J = 74 Hz, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.12 (dd, J = 6.4 Hz, 1.6 Hz, 2H), 8.03 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 4 Hz, 1H), 7.76 (dd, J = 6.4 Hz, 1.6 Hz, 2H), 7.52 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.77 (s, 1H), 5.80-5.88 (m ,1H),4.99-5.05(m,2H),3.99(s,3H),3.52(dd,J=8.8Hz,6.4Hz,1H),3.22(s,1H),3.13(dd,J=14Hz,10Hz,1H),2.78(t,J=7.6Hz,2H),2.73(dd, J=14.8Hz,11.2Hz,2H),2.32(s,2H),1.91-1.97(m,2H),1.75(t,J=7.6Hz,2H),1.63(d,J=10.4Hz,1H),1.25-1.45(m,9H),0.89(t,J=6.4Hz,3H).

[0086] 3) The reaction formula is:

[0087]

[0088] Compound 4:

[0089] The physicochemical properties of the compound are as follows:

[0090] 1) Light yellow solid, melting point 252-253°C, yield 43%.

[0091] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0092] Deuterated CDCl3 was used as solvent and TMS was used as internal standard. The peaks were assigned as follows: δ: 9.99 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 9.2 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.36-7.41 (m, 2H), 6.78 (s, 1H), 5.86 (t ,J=8.8Hz,1H),5.07(d,J=8.4Hz,1H),5.03(s,1H),4.01(s,3H),3.90(s,2H),3.56(s,1H),3.22(dd,J= 9.6Hz, 8Hz, 1H), 2.74 (s, 2H), 2.36 (d, J = 17.6Hz, 1H), 1.96 (d, J = 11.2Hz, 2H), 1.81 (s, 2H), 1.66 (s, 2H).

[0093] 3) The reaction formula is:

[0094]

[0095] Compound 5:

[0096] The physicochemical properties of the compound are as follows:

[0097] 1) White solid, melting point 135-136°C, yield 52%.

[0098] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0099] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 9.81 (s, 1H), 8.72 (d, J = 4.4 Hz, 1H), 8.43 (s, 1H), 8.08 (dd, J = 6.4 Hz, 1.6 Hz, 2H), 8.02 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 36 Hz, 4H), 7.52-7.56 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 4.4 Hz, 1H), 7.39 (dd, J = 9.2 Hz, 2H). 8Hz,1H),6.77(d,J=6.4Hz,1H),5.80-5.89(m,1H),5.00-5.05(m,2H),3.98(s,3H),3.54(q,J=8Hz,1H),3.20(d,J=14Hz,1H ), 3.12(dd,J=14Hz,10Hz,1H),2.66-2.75(m,2H),2.31(s,1H),1.91-1.95(m,2H),1.68-1.80(m,2H),1.60(d,J=4.8Hz,1H).

[0100] 3) The reaction formula is:

[0101]

[0102] Compound 6:

[0103] The physicochemical properties of the compound are as follows:

[0104] 1) Colorless oily liquid, yield is 62%.

[0105] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0106] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 9.93 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.41 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 9.2 Hz, 1H), 7.92 (s, 2H), 7.78 (d, J = 8 Hz, 2H), 7.55 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 4.8 Hz, 1H), 7.39 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.95 (d, J = 8. 4Hz,2H),6.81(s,1H),5.78-5.87(m,1H),5.02-5.05(m,1H),5.01(d,J=1.2Hz,1H),3.99(s,3H),3.84(s,3H),3.54(q,J=8Hz,1 H), 3.14 (dd, J = 13.6Hz, 10Hz, 1H), 2.69-2.76 (m, 2H), 2.41 (s, 1H), 2.33 (s, 1H), 1.93 (d, J = 2Hz, 2H), 1.77 (s, 2H), 1.19 (s, 1H).

[0107] 3) The reaction formula is:

[0108]

[0109] Compound 7:

[0110] The physicochemical properties of the compound are as follows:

[0111] 1) Yellow solid, melting point 158-159°C, yield 74%.

[0112] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0113] Deuterated CDCl3 was used as solvent and TMS was used as internal standard. The peak assignments were as follows: δ: 9.70 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 8.07 (d, J = 8 Hz, 2H), 8.02 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8 Hz, 4H), 7.51 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 4.8 Hz, 1H), 7.38 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.75 (d, J = 6 Hz, 1H), 6.65 (d, J = 6 Hz, 1H). =8.4Hz,2H),5.78-5.87(m,1H),4.98-5.04(m,2H),4.05(s,1H),3.98(s,1.5H),3.97(s,3H),3.52(q,J=8Hz,1H),3.16-3.23(m ,1H),3.12(dd,J=14Hz,10Hz,1H),2.63-2.73(m,3H),2.31(s,1H),1.89-1.95(m,2H),1.70-1.80(m,2H),1.60(t,J=4.8Hz,1H).

[0114] 3) The reaction formula is:

[0115]

[0116] Compound 8:

[0117] The physicochemical properties of the compound are as follows:

[0118] 1) White solid, melting point 120-121°C, yield 73%.

[0119] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0120] Deuterated CDCl3 was used as solvent and TMS was used as internal standard. The peaks were assigned as follows: δ: 10.01 (s, 0.7H), 9.76 (s, 0.4H), 8.71 (d, J = 4.4 Hz, 1H), 8.45 (s, 0.6H), 8.07 (d, J = 4 Hz, 2H), 8.02 (d, J = 9.2 Hz, 1H), 7.95 (s, 2H), 7.78 (s, 2.3H), 7.54 (d, J = 2.8 Hz, 1H), 7.36-7.41 (m, 2H), 7.11-7.16 (m, 2H),6.81(s,1H),5.79-5.88(m,1H),5.03-5.06(m,1H),5.01(t,J=2Hz,1H),3.99(s,3H),3.55(q,J=7.6Hz,1H),3.14 (dd,J=13.6Hz,10Hz,1H),2.73(d,J=14.4Hz,2H),2.34(s,2H),1.91-1.97(m,2H),1.82(t,J=12Hz,2H),1.61(s,1H).

[0121] 3) The reaction formula is:

[0122]

[0123] Compound 9:

[0124] The physicochemical properties of the compound are as follows:

[0125] 1) White solid, melting point 138-139°C, yield 47%.

[0126] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0127] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 10.28 (s, 0.5H), 9.53 (s, 0.5H), 8.73 (dd, J = 12.8 Hz, 4.8 Hz, 1H), 8.35 (s, 0.5H), 8.12 (d, J = 8 Hz, 1H), 8.02 (q, J = 4 Hz, 2H), 7.86-7.91 (m, 1.5H), 7.73-7.75 (m, 0.5H), 7.35-7.53 (m, 7.5H), 6.76 (dd, J = 10.4 Hz, 6. 4Hz,1H),5.78-5.89(m,1H),4.98-5.05(m,2H),3.98(s,1.5H),3.96(s,1.5H),3.43-3.55(m,1H),3.19(d,J=11.6Hz,1H), 3.05-3.12(m,1H),2.64-2.68(m,2H),2.31(d,J=4.4Hz,1H),1.87-1.92(m,2H),1.69-1.78(m,2H),1.60(d,J=8.8Hz,1H).

[0128] 3) The reaction formula is:

[0129]

[0130] Compound 10:

[0131] The physicochemical properties of the compound are as follows:

[0132] 1) White solid, melting point 143-144°C, yield 48%.

[0133] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0134] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peaks were assigned as follows: δ: 10.34 (s, 0.7H), 10.08 (s, 0.4H), 8.71 (d, J = 4.8 Hz, 1H), 8.43 (s, 0.6H), 8.06 (d, J = 8 Hz, 2H), 8.01 (dd, J = 9.2 Hz, 2 Hz, 1H), 7.87 (s, 2.3H), 7.74 (s, 2H), 7.53 (d, J = 2.8 Hz, 1H), 7.35-7.41 (m, 4H), 6.79(d,J=6.4Hz,1H),5.79-5.88(m,1H),5.00-5.05(m,2H),3.98(s,3H),3.52(t,J=8Hz,1H),3.21(s,1H),3.12( dd,J=13.6Hz,10Hz,1H),2.67-2.76(m,2H),2.32(s,1H),1.91-1.98(m,2H),1.69-1.81(m,2H),1.59-1.63(m,1H).

[0135] 3) The reaction formula is:

[0136]

[0137] Compound 11:

[0138] The physicochemical properties of the compound are as follows:

[0139] 1) Yellow solid, melting point 152-153°C, yield 76%.

[0140] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0141] Deuterated CDCl3 was used as solvent and TMS was used as internal standard. The peaks were assigned as follows: δ: 11.29 (s, 1H), 8.67-8.69 (m, 1H), 8.29 (s, 1H), 7.96-8.02 (m, 4H), 7.65-7.71 (m, 2H), 7.54 (t, J = 3.2 Hz, 1H), 7.42 (d, J = 4.8 Hz, 1H), 7.33-7.38 (m, 2H), 6.95-6.99 (m, 1H), 6.84-6.89 (m, 2H),5.77-5.86(m,1H),5.01-5.06(m,2H),3.91-3.93(m,3H),3.54(q,J=8Hz,1H),3.22(s,1H),3.17(dd,J=14 Hz, 10Hz, 1H), 2.74 (d, J = 11.6Hz, 2H), 2.36 (s, 1H), 1.95 (t, J = 12Hz, 2H), 1.81 (d, J = 11.6Hz, 2H), 1.62 (s, 1H).

[0142] 3) The reaction formula is:

[0143]

[0144] Compound 12:

[0145] The physicochemical properties of the compound are as follows:

[0146] 1) Pale yellow solid, melting point 146-147°C, yield 66%.

[0147] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0148] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 10.51 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 0.8 Hz, 1H), 8.17 (d, J = 8 Hz, 2H), 7.99-8.03 (m, 2H), 7.90 (d, J = 8.4 Hz, 2 Hz), 7.73 (d, J = 3.2 Hz, 1 Hz), 7.52 (d, J = 2.8 Hz, 1 Hz), 7.44 (d, J = 4.8 Hz, 1 Hz), 7.39 (dd, J = 9.2 Hz, 2.4 Hz, 1H) ,7.20(t,J=4.4Hz,1H),6.78(d,J=6.4Hz,1H),5.81-5.89(m,1H),5.00-5.06(m,2H),3.99(s,3H),3.48-3.54(m,1H),3.18-3.25(m ,1H),3.13(dd,J=14Hz,10Hz,1H),2.65-2.76(m,2H),2.30-2.32(m,1H),1.92-1.98(m,2H),1.71-1.83(m,2H),1.60-1.63(m,1H).

[0149] 3) The reaction formula is:

[0150]

[0151] Compound 13:

[0152] The physicochemical properties of the compound are as follows:

[0153] 1) White solid, melting point 132-133°C, yield 75%.

[0154] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0155] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 10.44 (s, 0.5H), 10.23 (s, 0.5H), 9.22 (s, 0.5H), 9.13 (s, 0.5H), 8.75 (s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.49 (d, J = 0.8 Hz, 0.5H), 8.24-8.27 (m, 1H), 8.09 (d, J = 8 Hz, 2H), 8.02 (d, J = 9.2 Hz, 1H), 7.94 (s, 0.5H), 7.81 (s, 1H), 7.68 (s, 1H) ,7.53(s,1H),7.36-7.42(m,3H),6.79(s,1H),5.79-5.88(m,1H),5.03-5.06(m,1H),5.00-5.02(m,1H),3.99(s,3H),3.53(d,J=7.6H z,1H),3.14(t,J=12Hz,1H),2.73(d,J=14.4Hz,2H),2.44(d,J=42.4Hz,2H),1.92-1.97(m,2H),1.79(t,J=13.6Hz,2H),1.61(s,1H).

[0156] 3) The reaction formula is:

[0157]

[0158] Compound 14:

[0159] The physicochemical properties of the compound are as follows:

[0160] 1) Light yellow solid, melting point 222-223°C, yield 74%.

[0161] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0162] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 10.27 (s, 0.5H), 10.04 (s, 0.5H), 8.79 (d, J = 11.6 Hz, 2H), 8.71 (d, J = 4.4 Hz, 1H), 8.50 (s, 0.5H), 8.08 (d, J = 8 Hz, 2H), 8.02 (d, J = 8 Hz, 2H), 7.89 (s, 0.5H), 7.82 (d, J = 8 Hz, 1H), 7.75 (dd, J = 4.4 Hz, 1.2 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.54 (d, J=8Hz,1H),7.42(d,J=4.4Hz,1H),7.39(dd,J=9.2Hz,2.4Hz,1H),6.81(s,1H),5.79-5.88(m,1H),5.03-5.06(m,1H),5.01(d,J=1.2Hz, 1H), 3.99 (s, 3H), 3.53 (s, 1H), 3.14 (t, J = 12Hz, 1H), 2.72 (s, 2H), 2.41 (d, J = 28Hz, 2H), 1.94 (d, J = 7.6Hz, 2H), 1.77 (s, 2H), 1.61 (s, 1H).

[0163] 3) The reaction formula is:

[0164]

[0165] Compound 15:

[0166] The physicochemical properties of the compound are as follows:

[0167] 1) Yellow oily liquid, yield 53%.

[0168] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0169] Deuterated DMSO-d6 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 10.60 (s, 1H), 8.70 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 7.6 Hz, 2H), 7.97 (d, J = 9.2 Hz, 2H), 7.89 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.07-7.11 (m, 4H), 6.55 (d, J = 8.4 Hz, 1H ),5.95-6.03(m,1H),4.99-5.06(m,2H),3.95(s,3H),3.56(q,J=8.4Hz,1H),3.10-3.22(m,2H),2.91(dd,J=13.6Hz,10Hz,1H),2.52-2.5 5(m,1H),2.25(d,J=2.8Hz,1H),2.06(dd,J=12.8Hz,9.6Hz,1H),1.80(s,1H),1.75(t,J=11.2Hz,1H),1.60(q,J=7.6Hz,1H),1.48(s,1H).

[0170] 3) The reaction formula is:

[0171]

[0172] Compound 16:

[0173] The physicochemical properties of the compound are as follows:

[0174] 1) Yellow oily liquid, yield 36%.

[0175] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0176] Deuterated DMSO-d6 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 10.74 (s, 1H), 8.70 (d, J = 4.4 Hz, 1H), 8.04 (dd, J = 6.8 Hz, 2 Hz, 2H), 7.97 (d, J = 9.2 Hz, 1H), 7.91 (s, 1H), 7.83 (dd, J = 6.4 Hz, 1.6 Hz, 2H), 7.61 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.32 (dd, J = 19.6 Hz, 9.2 Hz, 1H), 7.07-7.13 (m, 1H), 6.81-6.85(m,1H),6.54(d,J=8.8Hz,1H),5.95-6.04(m,1H),4.99-5.06(m ,2H),3.95(s,3H),3.48-3.58(m,2H),3.16(s,1H),2.91(dd,J=13.6Hz,10H z,1H),2.52-2.55(m,1H),2.45(s,1H),2.06(dd,J=13.2Hz,10Hz,1H),1.80 (s, 1H), 1.71 (d, J = 10Hz, 1H), 1.60 (dd, J = 13.6Hz, 7.2Hz, 1H), 1.48 (s, 1H).

[0177] 3) The reaction formula is:

[0178]

[0179] Compound 17:

[0180] The physicochemical properties of the compound are as follows:

[0181] 1) Yellow oily liquid, yield 70%.

[0182] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0183] Deuterated CDCl3 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 8.73 (d, J = 4.4 Hz, 1H), 8.29 (s, 1H), 8.09-8.11 (m, 2H), 8.03 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 1.2 Hz, 1H), 7.77 (dd, J = 6.4 Hz, 2 Hz, 2H), 7.65 (dd, J = 8 Hz, 1.2 Hz, 2H), 7.55 (s, 1H), 7.42 (d, J = 4.4 Hz, 1H), 7.40 (dd, J = 9.2 Hz, 2.4 Hz, 1H) ,7.24-7.30(m,1H),6.82-6.86(m,2H),5.79-5.88(m,1H),5.03-5.06(m,1H),5.00-5.02(m,1H),4.01(s,3H),3.54(q,J=8Hz,1H), 3.26(s,1H),3.16(t,J=12.4Hz,1H),2.73(s,2H),2.35(t,J=6.8Hz,1H),1.93(dd,J=9.2Hz,2.4Hz,2H),1.81(s,2H),1.62(s,1H).

[0184] 3) The reaction formula is:

[0185]

[0186] Compound 18:

[0187] The physicochemical properties of the compound are as follows:

[0188] 1) Yellow oily liquid, yield 57%.

[0189] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0190] Deuterated DMSO-d6 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 11.71 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.03-8.05 (m, 2H), 7.94-7.98 (m, 2H), 7.87-7.90 (m, 2H), 7.71-7.73 (m, 2H), 7.58-7.67 (m, 4H), 7.51-7.56 (m, 1H), 7.44 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.57 (d, J = 8 Hz, 1H), 5.93-6.02 (m, 1H), 4 .98-5.06(m,2H),3.94(s,3H),3.72(d,J=6.4Hz,1H),3.57(q,J=8.4Hz,1H),3.34-3.36(m,1H),2.94(dd,J=13.6Hz,9.6Hz,1H),2.5 8(d,J=10.4Hz,1H),2.27(s,1H),2.04(t,J=11.2Hz,1H),1.81(s,1H),1.76(t,J=11.2Hz,1H),1.63(t,J=11.2Hz,1H),1.49(s,1H).

[0191] 3) The reaction formula is:

[0192]

[0193] Compound 19:

[0194] The physicochemical properties of the compound are as follows:

[0195] 1) Light yellow solid, melting point 127-128°C, yield 69%.

[0196] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0197] Deuterated DMSO-d6 was used as the solvent and TMS was used as the internal standard. The peak assignments were as follows: δ: 11.64 (s, 1H), 8.69 (d, J = 4.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 9.2 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.39-7.44 (m, 3H), 6.56 (d, J = 8.4 Hz, 1H), 5.94-6.03 (m, 1H) ,4.98-5.06(m,2H),3.94(s,3H),3.56(q,J=8.4Hz,1H),3.25(s,1H),3.19(t,J=14Hz,1H),2.92(dd,J=13.6Hz,10Hz,1H),2.56(d,J=10 Hz,1H),2.35(s,3H),2.25(s,1H),2.02-2.05(m,1H),1.80(s,1H),1.75(t,J=11.2Hz,1H),1.60(dd,J=13.2Hz,7.6Hz,1H),1.48(s,1H).

[0198] 3) The reaction formula is:

[0199]

[0200] Compound 20:

[0201] The physicochemical properties of the compound are as follows:

[0202] 1) Yellow oily liquid, yield 33%.

[0203] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0204] Deuterated DMSO-d6 was used as the solvent and TMS was used as the internal standard. The peaks were assigned as follows: δ: 8.67-8.70 (m, 1H), 7.94-8.26 (m, 4H), 7.42-7.69 (m, 5H), 6.94-7.16 (m, 2H), 6.63 (q, J = 8 Hz, 1H), 5.95-6.02 (m, 1H), 4.98-5.07 (m, 2H), 4.13-4.27 (m, 1H), 3.94 (s, 3H), 3. 59(d,J=8.8Hz,1H),3.20(s,2H),2.77-3.00(m,2H),2.53-2.58(m,2H),2.30(s,1H),2.00(d,J=2.4Hz,1 H),1.83(s,1H),1.76(s,1H),1.66(d,J=7.2Hz,1H),1.53(s,1H),1.16-1.23(m,12H),1.09-1.15(m,6H).

[0205] 3) The reaction formula is:

[0206]

[0207] 2. Application of Quinine Hydrazone Derivatives in Experimental Examples

[0208] This experimental example is to test the activity of the above-mentioned quinine hydrazone derivatives in inhibiting plant pathogenic fungi / oomycetes.

[0209] 1. Test plant pathogens

[0210] (1) One plant pathogenic fungus, namely, wheat fusarium spp. (F. graminearum), was provided by the Laboratory of Plant Protection Department, College of Horticulture and Plant Protection, Henan University of Science and Technology.

[0211] (2) One plant pathogenic oomycete, Phytophthora capsici (P. capsici), was provided by the Laboratory of Plant Protection Department, College of Horticulture and Plant Protection, Henan University of Science and Technology.

[0212] 2. Test samples and reagents

[0213] Commercialized fungicides Metalaxyl and Triadimefon were used as positive controls, as were quinine hydrazone derivatives 1 to 20 prepared in Example 1, and acetone (analytical grade).

[0214] 3. Bioassay method

[0215] The mycelial growth rate method was used.

[0216] Culture medium: PDA medium (its ratio is: 200 g peeled potato, 20 g glucose, 20 g agar, and distilled water to 1000 mL) and V8 medium (its ratio is: 160 mL V-8 vegetable juice, 15 g agar, and 1500 mL distilled water).

[0217] The toxicity of quinine hydrazone derivatives 1-20 against two common plant pathogenic fungi / oomycetes was determined using a hyphal growth rate assay. A commercial fungicide, metalaxyl / triadimefon, was used as a positive control. Compounds 1-20 and metalaxyl / triadimefon were dissolved in acetone. After the sterilized culture medium cooled to 50-55°C, compounds 1-20 and metalaxyl / triadimefon were mixed with each of the compounds and the metalaxyl / triadimefon, respectively. After thorough mixing, a 50 mg / L drug-coated culture medium was prepared. A blank control (CK) without the drug was used, with three replicates for each treatment. After the culture medium had cooled sufficiently, 7 mm diameter discs of the test pathogenic fungi / oomycetes with uniform growth activity were inoculated and incubated at 28±1°C. Colonies in the different CK groups were observed when they grew to over 7.5 cm. Colony diameters were measured using the cross-hatch method, and the growth inhibition rate of each sample against the tested pathogen was calculated using the following formula.

[0218]

[0219] 4. The results of bactericidal activity determination are shown in Table 2

[0220] Table 2: Antibacterial effects of quinine hydrazone derivatives 1 to 20 on the test strains

[0221]

[0222]

[0223] 5. Conclusion

[0224] The results showed that the quinine hydrazone derivatives 1 to 20 disclosed in the present invention exhibited good antifungal activity against the two tested plant pathogenic fungi / oomycetes. In particular, compounds 2, 6, 8, and 9 showed higher antifungal activity against the plant pathogenic oomycete Phytophthora capsici (P. capsici) than the commercial anti-oomycete metalaxyl. Compounds 15 and 16 showed higher antifungal activity against the plant pathogenic fungus F. graminearum than the commercial antifungal agent triadimefon. Furthermore, it was demonstrated that different quinine hydrazone derivatives exhibited significant selectivity in inhibiting plant pathogenic fungi / oomycetes, suggesting the potential for the development of selective antifungal agents against plant pathogenic fungi / oomycetes. Therefore, the quinine hydrazone derivatives disclosed in the present invention exhibit significant activity against plant pathogenic fungi / oomycetes and are expected to be used in the preparation of new, highly effective botanical fungicides.

Claims

1. A quinine hydrazone derivative, characterized in that: Its general structural formula is shown in Formula I: In formula I, L is a single bond, One of the following; R is selected from C1-C7 alkyl, cyano, phenyl, substituted phenyl, and heteroaryl; the number of substituents in the substituted phenyl is 1 to 3, and the substituents are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, and hydroxyl; The heteroaryl group is selected from pyridyl and thienyl; When L is When; R is selected from phenyl, 4-Me phenyl.

2. The quinine hydrazone derivative according to claim 1, wherein The general structural formulas of the quinine hydrazone derivatives are shown in Formula II, Formula III, and Formula IV: In formula II, R1 is selected from C1-C7 alkyl or cyano; In formula III, R2 is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen, amino, and hydroxyl; In formula IV, R3 and R4 are each independently selected from hydrogen and halogen.

3. The quinine hydrazone derivative according to claim 2, wherein In formula II, R1 is selected from C4-C5 alkyl groups.

4. The quinine hydrazone derivative according to claim 2, wherein The quinine hydrazone derivatives are the following compounds:

5. The quinine hydrazone derivative according to claim 2, wherein The quinine hydrazone derivatives are selected from the following compounds:

6. The quinine hydrazone derivative according to claim 1, wherein The quinine hydrazone derivatives are selected from the following compounds:

7. A method for preparing a quinine hydrazone derivative according to any one of claims 1 to 6, characterized in that: The following steps are involved: Intermediate A reacts with the corresponding hydrazine to obtain a quinine hydrazone derivative shown in formula I; wherein intermediate A is:

8. Use of the quinine hydrazone derivative according to any one of claims 1 to 6 in the preparation of an antimicrobial agent for plant pathogenic fungi and / or oomycetes, characterized in that: The plant pathogenic fungus is wheat fusarium sphaeroides; the plant pathogenic oomycete is pepper phytophthora.

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