Preparation method and use of berberine derivatives

Abstract

The present invention discloses a preparation method and use of berberine derivatives, the structural formula of which is shown below: The berberine derivatives of the present invention have good antibacterial effects and are significantly better than the antibacterial effects of berberine itself, and can be widely used in agricultural prevention and control of crop diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of agricultural chemicals, and in particular to a preparation method and application of berberine derivatives. Background Art

[0002] Chemical pest control is the primary method for crop disease prevention, but large-scale application can lead to increased residues and severe environmental pollution. While highly lethal to pests and diseases, it also kills natural enemies, disrupting the ecological balance. Biopesticides, however, are highly selective, safer for humans and livestock, with minimal impact on non-target organisms, low or no toxicity, and minimal impact on the ecological environment. Therefore, the development of novel biocidal compounds is crucial to addressing the challenges facing the pesticide industry.

[0003] Berberine, also known as berberine, is widely distributed in the plant kingdom and is the main alkaloid active ingredient of the traditional Chinese medicine Coptis chinensis, which clears away heat and detoxifies. Studies have found that berberine has strong inhibitory activity against a variety of Gram-positive bacteria, Gram-negative bacteria, and fungi in vitro, and is widely used in clinical practice. In recent years, due to the sustainable development of green ecology and the promotion of the widespread use of biopesticides, berberine-like compounds have been widely used in the field of agricultural control of crop diseases. Existing studies have found that berberine has strong antibacterial activity against fungal diseases. In experiments studying the antibacterial mechanism, it was found that berberine had a significant effect on the permeability of the cell membrane of pathogenic fungi, reduced the content of soluble protein, weakened the activity of intracellular succinate dehydrogenase, and hindered the absorption of nutrients.

[0004] By modifying the structure of berberine, novel derivatives with better antibacterial activity were obtained. In view of this, the present application is hereby filed. Summary of the Invention

[0005] The present invention provides berberine derivatives, which are new compounds with better antibacterial effects than berberine itself. At the same time, the antibacterial effects on certain bacterial species are comparable to or even better than those of chemical pesticides. Therefore, this type of compound has good bactericidal potential.

[0006] The present invention also provides a method for preparing berberine derivatives, which can obtain a higher yield of berberine derivatives.

[0007] The present invention further provides an application of berberine derivatives, specifically applications in antibacterial and bactericidal aspects.

[0008] The present invention is achieved through the following technical solutions:

[0009] Berberine derivatives, the structural formula is as follows:

[0010]

[0011] Furthermore, the R is H, and the structural formula is as follows:

[0012]

[0013] Furthermore, the R is H3CO, and the structural formula is as follows:

[0014]

[0015] Furthermore, the R is Cl, and the structural formula is as follows:

[0016]

[0017] Furthermore, the R is F, and the structural formula is as follows:

[0018]

[0019] The present invention also provides a berberine derivative, the structural formula of which is shown below:

[0020]

[0021] The present invention also provides a berberine derivative, the structural formula of which is shown below:

[0022]

[0023] The present invention also provides a berberine derivative, the structural formula of which is shown below:

[0024]

[0025] The present invention also provides a berberine derivative, the structural formula of which is shown below:

[0026]

[0027] The present invention also provides a berberine derivative, the structural formula of which is shown below:

[0028]

[0029] The present invention also provides a method for preparing a berberine derivative, comprising the following steps: 1) berberine hydrochloride as a raw material is subjected to high-temperature vacuum cracking to obtain berberrubine; 2) berberrubine and 2-((3-bromopropyl)thio)-5-(4-R-phenyl)-1,3,4-oxadiazole undergo an electrophilic addition reaction to obtain a berberine derivative.

[0030] The specific preparation steps are as follows:

[0031] 1) Berberine hydrochloride was placed in an oven at 56°C and dried for 40 min. At the same time, the oil bath was heated to 195°C. The dried berberine hydrochloride (10 g, 29.75 mmol) was then placed in a round-bottom flask. The round-bottom flask was connected to an explosion-proof ball and a tap and then connected to a vacuum pump. The round-bottom flask was then moved to an oil bath at 195°C and reacted for about 25 min. The yellow powder in the round-bottom flask turned into a dark red solid. TLC was used to detect the reaction process. After the reaction was completed, the dark red solid was crushed and loaded into a silica gel chromatography column for purification (eluent DCM:MeOH=20:1) to obtain the intermediate berberine with a yield of approximately 32.8%. The synthesis equation of the intermediate berberine is as follows:

[0032]

[0033] The hydrogen spectrum data of the intermediate berberine is: 1 H NMR (400 MHz, DMSO) δ9.15 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.97 (s, 1H), 6.49 (d, J = 7.9 Hz, 1H), 6.10 (s, 1H), 4.52 (t, J = 6.0 Hz, 1H), 3.76 (s, 2H), 3.07 (d, J = 6.0 Hz, 1H), consistent with the above structure.

[0034] 2) The intermediate berberine obtained in the reaction of 1) and anhydrous potassium carbonate were dissolved in DMF and placed in an 85°C oil bath to react to fully activate the berberine; 3) 2-((3-bromopropyl)thio)-5-(4-R-phenyl)-1,3,4-oxadiazole was added to a reaction flask and reacted until a large amount of yellow solid suspension appeared. TLC was used to detect the reaction process. After the reaction was completed, an appropriate amount of acetone was added to the reaction flask to precipitate more solids in the reaction solution. The reaction solution was allowed to stand for 3 minutes, filtered, and the solid was washed with 30 mL of water, 30 mL of anhydrous ethanol, and 20 mL of acetone in sequence, and dried to obtain a berberine derivative. The synthesis equation is shown below:

[0035]

[0036] The present invention also provides an application of berberine derivatives, including the application of the original drug and the preparation in sterilization and inhibition of bacterial growth, which can be specifically used for preventing and controlling crop diseases.

[0037] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0038] The berberine derivatives provided in the embodiments of the present invention have good antibacterial effects and are significantly better than the antibacterial effects of berberine itself, and can be widely used in agriculture to prevent and control crop diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without making any creative efforts.

[0040] Figure 1 The hydrogen spectrum of the intermediate berberine provided in the embodiments of the present invention;

[0041] Figure 2 This is the NMR image of the berberine derivative provided in Example 1 of the present invention;

[0042] Figure 3 This is the mass spectrum of the berberine derivative provided in Example 1 of the present invention;

[0043] Figure 4 This is the NMR image of the berberine derivative provided in Example 2 of the present invention;

[0044] Figure 5 This is the mass spectrum of the berberine derivative provided in Example 2 of the present invention;

[0045] Figure 6 This is the NMR image of the berberine derivative provided in Example 3 of the present invention;

[0046] Figure 7 This is the mass spectrum of the berberine derivative provided in Example 3 of the present invention;

[0047] Figure 8 This is the NMR image of the berberine derivative provided in Example 4 of the present invention;

[0048] Figure 9 This is the mass spectrum of the berberine derivative provided in Example 4 of the present invention;

[0049] Figure 10 This is the NMR image of the berberine derivative provided in Example 5 of the present invention;

[0050] Figure 11 This is the mass spectrum of the berberine derivative provided in Example 5 of the present invention;

[0051] Figure 12 This is the NMR image of the berberine derivative provided in Example 6 of the present invention;

[0052] Figure 13 This is the mass spectrum of the berberine derivative provided in Example 6 of the present invention;

[0053] Figure 14This is the NMR image of the berberine derivative provided in Example 7 of the present invention;

[0054] Figure 15 This is the mass spectrum of the berberine derivative provided in Example 7 of the present invention;

[0055] Figure 16 This is the NMR image of the berberine derivative provided in Example 8 of the present invention;

[0056] Figure 17 This is the mass spectrum of the berberine derivative provided in Example 8 of the present invention;

[0057] Figure 18 This is the NMR image of the berberine derivative provided in Example 9 of the present invention;

[0058] Figure 19 This is the mass spectrum of the berberine derivative provided in Example 9 of the present invention. DETAILED DESCRIPTION

[0059] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with examples. The illustrative embodiments of the present invention and their descriptions are only used to explain the present invention and are not intended to limit the present invention.

[0060] In the following description, numerous specific details are set forth to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that these specific details are not necessarily required to practice the present invention. In other embodiments, well-known methods are not specifically described to avoid obscuring the present invention.

[0061] Throughout this specification, references to "one embodiment," "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present invention. Thus, appearances of the phrases "one embodiment," "an embodiment," "an example," or "an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features or characteristics may be combined in any suitable combinations and / or subcombinations in one or more embodiments or examples.

[0062] Example 1

[0063] The present invention provides a berberine derivative (hereinafter referred to as Compound 1) and a preparation method thereof, comprising the following steps:

[0064] 1) Key intermediate a: Phenylhydrazine (2 g, 0.014 mol, 1 eq) and KOH (785 mg, 0.014 mol, 1 eq) were dissolved in 160 ml of ethanol and stirred at 75 ° C for 20 min. CS2 (3.3 g, 0.044 mol, 3 eq) was added. After the reaction was complete, TLC was detected, and the ethanol was directly dried. After adding water, the insoluble matter was filtered out. The aqueous layer was removed and the pH was adjusted to 2. The solid was precipitated and filtered and dried to obtain the key intermediate a.

[0065] 2) Key intermediate c: Compound a (1 g, 5.6 mmol, 1 eq) and K2CO3 (1.55 g, 11.2 mmol, 2 eq) were dissolved in 60 ml of acetone. The mixture was stirred at 75°C for 20 min, and 1,3-dibromopropane (3.5 g, 17 mmol, 3 eq) was added. PE:EA = 10:1 (V / V) was added, and the mixture was purified by column chromatography to obtain the key intermediate c.

[0066] 3) Berberine (500 mg, 1.55 mmol, 1 eq) was dissolved in DMF, potassium carbonate (427.8 mg, 3.1 mmol, 2 eq) was added, and after activation for 25 min, key intermediate c (2.3 g, 7.75 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution, cooled to room temperature, filtered, washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, and dried to obtain the target compound 1;

[0067] The synthesis formula is as follows:

[0068]

[0069] Crop disease activity assay: The assay steps are as follows:

[0070] (1) First, compound 1 prepared from the compound was prepared into a 1% suspension, and the prepared methoxyacetophenone berberine was prepared into a mother solution with a concentration reduced by 10 times according to the experimental design;

[0071] (2) 1 mL of the mother solution and 9 mL of PDA medium were added to a 9 cm diameter culture dish, mixed thoroughly, cooled, and set aside; the blank control was to add 1 mL of sterile water, with the lead compound berberine and the positive control;

[0072] (3) Under sterile conditions, a 4 mm diameter bacterial cake was taken from the edge of the target bacterial colony using a hole puncher, with the mycelium side facing down, and inoculated in the center of the drug-coated plate. Sterile water containing the corresponding mass concentration and the lead compound were used as blank control and positive control. Three replicates were set for each treatment. The culture was cultured in the dark at 26°C for 4 days. The colony diameter was measured using the cross-cross method. The inhibition rate of the compound on each strain was calculated. The results were repeated three times and the average value was taken.

[0073] (4) Chemical control: pesticide Jianda (21.2% pyraclostrobin + 21.2% fluopicolide suspension concentrate).

[0074] The inhibition rate was calculated as follows: I = [(D0 - Dt) / (D0 - 4)] * 100%, where I is the mycelial growth inhibition rate; D0 is the diameter of the blank colony; and Dt is the diameter of the treated colony. The inhibition rates of compound 1 against various strains are shown in Table 1.

[0075] Table 1 Inhibitory rate of compound 1 against various strains (%)

[0076]

[0077] The results in Table 1 show that compound 1 has a certain antibacterial effect on various strains, and its inhibition rate against two pathogens (Fusarium and Strawberry Anthracnose) is higher than that of the lead compound. The lead compound is better than compound 1 against citrus gray mold.

[0078] Example 2

[0079] The present invention provides a berberine derivative (hereinafter referred to as Compound 2) and a preparation method thereof, comprising the following steps:

[0080] 1) Key intermediate b: p-Methoxyphenylhydrazine (2 g, 0.012 mol, 1 eq) and KOH (676 mg, 0.012 mol, 1 eq) were dissolved in 160 ml of ethanol and stirred at 75 ° C for 20 min, followed by addition of CS2 (2.75 g, 0.036 mol, 3 eq). After the reaction was complete, TLC was performed, and the ethanol was directly dried. After adding water, the insoluble matter was filtered out, the aqueous layer was removed, and the pH was adjusted to 2. The solid was precipitated and filtered and dried to obtain the compound key intermediate b.

[0081] 2) Key intermediate d: b (500m, 2.4mmol, 1eq) and K2CO3 (662.4g, 4.8mmol, 2eq) were dissolved in 60ml of acetone. The mixture was stirred at 75°C for 20min, and 1,3-dibromopropane (1.47g, 7.21mmol, 3eq) was added. PE:EA = 10:1 (V / V) and the mixture was purified by column chromatography to obtain key intermediate d.

[0082] 3) Berberine (500 mg, 1.55 mmol, 1 eq) was dissolved in DMF, potassium carbonate (427.8 mg, 3.1 mmol, 2 eq) was added, and after activation for 25 min, key intermediate c (2.5 g, 7.75 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution, cooled to room temperature, filtered, washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, and dried to obtain the target compound 2;

[0083] The synthesis formula is as follows:

[0084]

[0085] Crop disease activity assay:

[0086] The bacterial species and experimental methods used were the same as those in Example 1. The test results are shown in Table 2.

[0087] Table 2 Inhibition rate of compound 2 against various strains (%)

[0088]

[0089]

[0090] The results in Table 2 show that compound 2 has a certain antibacterial effect on various strains, and the inhibition rate against two pathogens (Fusarium and Strawberry Anthracnose) is higher than that of the lead compound.

[0091] Example 3

[0092] The present invention provides a berberine derivative (hereinafter referred to as compound 3) and a preparation method thereof, comprising the following steps:

[0093] Berberrubine (500 mg, 1.55 mmol, 1 eq) was dissolved in MeCN, potassium carbonate (427.8 mg, 3.1 mmol, 2 eq) was added, and the mixture was activated for 25 min. Then, key intermediate d (2.6 g, 7.75 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution. After cooling to room temperature, the mixture was filtered, washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, and dried to obtain the target compound 3.

[0094] Its synthesis formula is as follows:

[0095]

[0096] Crop disease activity determination: The experimental method is the same as that in Example 1. The determination results are shown in Table 3.

[0097] Table 3 Inhibitory rate of compound 3 against various strains (%)

[0098]

[0099]

[0100] The results in Table 3 show that compound 3 has a certain antibacterial effect on various strains, and the inhibition rate against the four pathogens is higher than that of the lead compound, which improves the inhibition rate against various strains.

[0101] Example 4

[0102] The present invention provides a berberine derivative (hereinafter referred to as compound 4) and a preparation method thereof, comprising the following steps:

[0103] Berberine (500 mg, 1.55 mmol, 1 eq) was dissolved in MeCN, potassium carbonate (427.8 mg, 3.1 mmol, 2 eq) was added, and the mixture was activated for 25 min. Then, key intermediate d (2.5 g, 7.75 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution. After cooling to room temperature, the mixture was filtered, washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, and dried to obtain the target compound 4.

[0104] Its synthesis formula is as follows:

[0105]

[0106] Crop disease activity determination: The experimental method is the same as that in Example 1. The determination results are shown in Table 4.

[0107] Table 4 Inhibition rate of compound 4 against various strains (%)

[0108]

[0109]

[0110] The results in Table 4 show that compound 4 has a certain antibacterial effect on each strain, and the inhibition rate against the four pathogens is higher than that of the lead compound, which improves the inhibition rate against each strain.

[0111] Example 5

[0112] The present invention provides a berberine derivative (hereinafter referred to as compound 5) and a preparation method thereof, comprising the following steps:

[0113] Berberrubine (500 mg, 2.36 mmol, 1 eq) was dissolved in MeCN, potassium carbonate (651 mg, 4.72 mmol, 2 eq) was added, and the mixture was activated for 25 min. Then, key intermediate d (4.29 g, 11.8 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution. After cooling to room temperature, the mixture was filtered, washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, and dried to obtain the target compound 5.

[0114] Its synthesis formula is as follows:

[0115]

[0116] Crop disease activity determination: The experimental method is the same as that in Example 1. The determination results are shown in Table 5.

[0117] Table 5 Inhibition rate of compound 5 against various strains (%)

[0118]

[0119]

[0120] The results in Table 5 show that compound 5 has a certain antibacterial effect on various strains, and the inhibition rate against the four pathogens is higher than that of the lead compound, which improves the inhibition rate against various strains.

[0121] Example 6

[0122] The present invention provides a berberine derivative (hereinafter referred to as compound 6) and a preparation method thereof, comprising the following steps:

[0123] Berberrubine (500 mg, 2.36 mmol, 1 eq) was dissolved in MeCN, potassium carbonate (651 mg, 4.72 mmol, 2 eq) was added, and the mixture was activated for 25 min. Then, key intermediate d (3.73 g, 11.8 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution. After cooling to room temperature, the mixture was filtered, washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, and dried to obtain the target compound 6.

[0124] Its synthesis formula is as follows:

[0125]

[0126] Crop disease activity determination: The experimental method is the same as that in Example 1. The determination results are shown in Table 6.

[0127] Table 6 Inhibition rate of compound 6 against various strains (%)

[0128]

[0129]

[0130] The results in Table 6 show that compound 6 has a certain antibacterial effect on various strains, and the inhibition rate against the four pathogens is higher than that of the lead compound, which improves the inhibition rate against various strains, and has a better inhibitory effect on Rhizoctonia solani.

[0131] Example 7

[0132] The present invention provides a berberine derivative (hereinafter referred to as compound 7) and a preparation method thereof, comprising the following steps:

[0133] Key intermediate e: 2-Hydroxyacetophenone (5 g, 0.037 mol, 1 eq) was dissolved in 50 ml of toluene (100 mL). In another small beaker, diethyl carbonate (9.15 g, 0.081 mol, 2.2 eq) and NaH (1.2 g, 0.222 mol, 6 eq) were mixed. The mixture was then added at 0°C and stirred at 120°C for 7 h. After the reaction was complete, TLC was performed, water was added to quench the NaH, and the mixture was extracted with methyl tert-butyl ether. The aqueous layer was removed and the pH was adjusted to 2. The precipitated solid was filtered and dried to obtain the key intermediate e.

[0134] Key intermediate f: 4-Hydroxycoumarin (400 mg, 2.47 mmol, 1 eq) and K2CO3 (681.72 mg, 4.94 mmol, 1 eq) were dissolved in 50 ml of acetone, stirred at 75 °C for 20 min, and then added with 1,3-dibromopropane (1.5 g, 7.41 mol, 3 eq). After the reaction was complete, TLC was detected, and the acetone was directly dried and purified by column chromatography with PE:EA=10:1 (V / V) to obtain the key intermediate f.

[0135] Berberine (500 mg, 1.55 mmol, 1 eq) was dissolved in dry MeCN, and potassium carbonate (427.8 mg, 3.1 mmol, 2 eq) was added. After activation for 25 min, key intermediate f (2.01 g, 7.75 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution. After cooling to room temperature, the solution was filtered and washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, respectively, and then dried to obtain the target compound 7.

[0136] Its synthesis formula is as follows:

[0137]

[0138] Crop disease activity determination: The experimental method is the same as that in Example 1. The determination results are shown in Table 7.

[0139] Table 7 Inhibition rate of compound 7 against various strains (%)

[0140]

[0141] The results in Table 7 show that compound 7 has a certain antibacterial effect on various strains, and the inhibition rate against the three pathogens is higher than that of the lead compound, which improves the inhibition rate against various strains.

[0142] Example 8

[0143] The present invention provides a berberine derivative (hereinafter referred to as compound 8) and a preparation method thereof, comprising the following steps:

[0144] Berberine (500 mg, 1.55 mmol, 1 eq) was dissolved in dry MeCN, and potassium carbonate (427.8 mg, 3.1 mmol, 2 eq) was added. After activation for 25 min, key intermediate f (2.42 g, 7.75 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution. After cooling to room temperature, the solution was filtered and washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, respectively, and then dried to obtain the target compound 8.

[0145] Its synthesis formula is as follows:

[0146]

[0147] Crop disease activity determination: The experimental method is the same as that in Example 1. The determination results are shown in Table 8.

[0148] Table 8 Inhibition rate of compound 8 against various strains (%)

[0149]

[0150]

[0151] The results in Table 8 show that compound 8 has a certain antibacterial effect on various strains, and the antibacterial rate against the four pathogens is higher than that of the lead compound, which improves the antibacterial rate against various strains.

[0152] Example 9

[0153] The present invention provides a berberine derivative (hereinafter referred to as compound 9) and a preparation method thereof, comprising the following steps:

[0154] Berberine (500 mg, 1.55 mmol, 1 eq) was dissolved in dry MeCN, and potassium carbonate (427.8 mg, 3.1 mmol, 2 eq) was added. After activation for 25 min, key intermediate f (2.42 g, 7.75 mmol, 5 eq) was added and reacted at 85°C. After TLC detection, 10 ml of acetone was added to the reaction solution. After cooling to room temperature, the solution was filtered and washed with 20 ml of water, 20 ml of ethanol, and 20 ml of acetone, respectively, and then dried to obtain the target compound 9.

[0155] Its synthesis formula is as follows:

[0156]

[0157] Crop disease activity determination: The experimental method is the same as that in Example 1. The determination results are shown in Table 9.

[0158] Table 9 Inhibition rate of compound 9 against various strains (%)

[0159]

[0160] The results in Table 9 show that compound 9 has a certain antibacterial effect on various strains, and the antibacterial rate against the four pathogens is higher than that of the lead compound, which improves the antibacterial rate against various strains.

[0161] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A berberine derivative, characterized in that The structural formula is shown below: Or the structural formula is as follows: Or the structural formula is as follows: Or the structural formula is as follows:

2. A berberine derivative, characterized in that The structural formula is shown below:

3. A berberine derivative, characterized in that The structural formula is shown below:

4. A berberine derivative, characterized in that The structural formula is shown below:

5. A berberine derivative, characterized in that The structural formula is shown below:

6. A berberine derivative, characterized in that The structural formula is shown below:

7. A method for preparing the novel berberine derivative according to claim 1, characterized in that: The method comprises the following steps: 1) berberine hydrochloride is used as a raw material and subjected to high-temperature vacuum cracking to obtain berberine; 2) berberine undergoes an electrophilic addition reaction with 2-((3-bromopropyl)thio)-5-(4-R-phenyl)-1,3,4-oxadiazole to obtain a berberine derivative.

8. The method for preparing a berberine derivative according to claim 7, wherein: The specific preparation steps are as follows: 1) berberine hydrochloride is dried and placed in a reaction flask, vacuumed, and then placed in an oil bath at 195°C for reaction until the yellow powder turns into a dark red solid to obtain the intermediate berberrubine; 2) the intermediate berberrubine obtained in the reaction in 1) and anhydrous potassium carbonate are dissolved in DMF, and placed in an oil bath at 85°C for reaction to fully activate the berberrubine; 3) 2-((3-bromopropyl)thio)-5-(4-R-phenyl)-1,3,4-oxadiazole is added to the reaction flask and reacted until a large amount of yellow solid suspension appears. After the reaction is completed, the berberine derivative is filtered, washed, and dried to obtain the berberine derivative. The synthesis formula is as follows:

9. Use of the berberine derivative according to any one of claims 1 to 6 or the berberine derivative prepared by the method according to claim 7 or 8, characterized in that: Application in the preparation of chemical preparations for sterilization and inhibition of bacterial growth.

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