A structural modification of cimigenol at 7 position and preparation method and application thereof

Abstract

The scheme discloses a structural modifier of osthole at 7th position with a general formula I, wherein R 1 is phenyl or substituted phenyl; or R 1 is a hydrocarbon group with 1-5 carbon atoms; or R 1 is thiazolyl or substituted thiazolyl; and R 2 is hydrogen or a hydrocarbon group with 1-3 carbon atoms. The compound with the general formula I has strong antibacterial activity, and can be used as a medicine for resisting S.aureus, E.coli, MRSA and FREC; meanwhile, the compound can also be used in combination with other antibacterial active substances.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, and specifically relates to a modified osthol 7-position structure, its preparation method, and its application. Background Technology

[0002] Antimicrobial drugs are one of the great discoveries of the 20th century; however, their overuse has led to the rapid emergence of multidrug-resistant bacteria in clinical practice, severely impacting people's daily lives and work. Currently, antibiotic resistance has become a major global healthcare problem. The successive emergence of different drug-resistant bacteria has led to a continuous increase in the morbidity and mortality rates of patients with various infectious diseases, posing a significant challenge to clinical treatment. Therefore, there is an urgent need for new antimicrobial drugs to overcome these worrying drug resistance problems. Summary of the Invention

[0003] This invention uses osthol, a natural product, as a raw material and applies relevant drug design and synthesis theories to modify the structure at the 7-position, obtaining a series of 7-position modified compounds. The results show that some compounds exhibit significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC), far exceeding the control drugs oxacillin and norfloxacin.

[0004] One of the modified osthol compounds at the 7-position of this scheme has the chemical structure shown in general formula I:

[0005]

[0006] Among them, R 1 It is a phenyl or substituted phenyl; or R 1 A hydrocarbon group consisting of 1 to 5 carbon atoms; or R 1 It is a thiazolyl or substituted thiazolyl group; R 2 It is a hydrogen or hydrocarbon group with 1-3 carbons.

[0007] The modified osthol 7-position structure of Formula I of this invention can be used for the treatment and / or prevention of Staphylococcus aureus.

[0008] The modified osthol 7-position structure of Formula I of this invention can be used to treat and / or prevent Escherichia coli (E. coli).

[0009] The modified osthol 7-position structure of Formula I of this invention can be used for the treatment and / or prevention of methicillin-resistant Staphylococcus aureus (MRSA).

[0010] The modified osthol 7-position structure of Formula I of this invention can be used to treat and / or prevent fluoroquinolone-resistant Escherichia coli (FREC).

[0011] Preferably, any of the following compounds exhibit strong inhibitory effects against Staphylococcus aureus, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC), with antibacterial activity superior to or comparable to the control drug.

[0012] Compound Ia: R 1 =Ph-,R 2 =H; Compound Ig:R 1 =2-FPh-,R 2 =H;

[0013] Compound Ih: R 1 =3-FPh-,R 2 =H; Compound Ij:R 1 =2-ClPh-,R 2 =H;

[0014] Compound Ⅰs: R 1 =2,4-diFPh-,R 2 =H; Compound Iu:R 1 =Me,R 2 =H;

[0015] Compound Ⅰv: R 1 =Et,R 2 =H; Compound I w:R 1 =Cyclopropyl,R 2 =H;

[0016] Compound Ix: R 1 =Thiazol-2-,R 2 =H; Compound Iz:R 1 =Me,R 2 =Me

[0017] The modified osthol 7-position structure of Formula I of this invention can be used in combination with clinical antibacterial drugs or with antibacterial active ingredients.

[0018] The following synthetic route describes the preparation method of the compound of general formula I of this invention:

[0019]

[0020] Includes the following steps:

[0021] Preparation of compound 1: Starting with osthol, cysteine, sodium hydride and DMF were added. After the reaction, water was added to dilute the mixture and the pH was adjusted to 5.5. The mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography to obtain compound 1.

[0022] Preparation of compound 2: Anhydrous potassium carbonate, ethyl bromoacetate and acetone were added to compound 1. After stirring at room temperature, the mixture was concentrated under reduced pressure. Water was added and extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure. Anhydrous ethanol was added and the mixture was stirred. Then, an appropriate amount of 6% sodium hydroxide solution was added dropwise. After the reaction was completed, the mixture was concentrated under reduced pressure. Water was added and the pH was adjusted to 1. The mixture was filtered and dried to obtain compound 2.

[0023] Preparation of compound 3: Thiourea, anhydrous ethanol, 2-bromosubstituted acetophenone or 3-bromo-2-butanone or 2-bromo-1-(1,3-thiazo-2-yl)ethyl ketone or 2-bromo-1-cyclopropylethyl ketone or 1-bromo-2-butanone or bromoacetone were added to a reaction vessel and stirred at 70°C. After the reaction was completed, the mixture was concentrated under reduced pressure, water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3.

[0024] Preparation of compound I: Compound 2, compound 3, HOBT, EDCI, DMAP and dichloromethane were added to a reaction vessel, and triethylamine was added dropwise. The reaction was stirred at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the modified osthol 7-position structure shown in general formula I.

[0025] Furthermore, during the preparation of compound 1, the pH was adjusted to 5.5 using a 1 mol / L dilute hydrochloric acid solution.

[0026] Furthermore, during the preparation of compound 2, the pH was adjusted to 1 using a 6 mol / L dilute hydrochloric acid solution.

[0027] Furthermore, in the preparation of compound I, the molar ratio of compound 2: compound 3: HOBT: EDCI: DMAP: triethylamine = 0.3-0.5: 0.3: 0.3-0.5: 0.3-0.5: 0.09-0.15: 0.6-1.2. Detailed Implementation

[0028] The present invention will be further described below with reference to the embodiments. However, the present invention is not limited to the following embodiments. It is foreseeable that various changes may occur in the implementation when those skilled in the art combine it with the prior art.

[0029] The synthetic route for preparing the compound of general formula I of this invention is as follows:

[0030]

[0031] In the synthetic route, Cys represents cysteine, and DMF represents N,N-dimethylformamide.

[0032] The chemical structures of some modified osthol at the 7-position of general formula I are shown in Table 1 below:

[0033] Table 1

[0034]

[0035] Example 1: Preparation of compound Ia

[0036] (1) Preparation of Compound 1: 24.56 mmol osthol, 73.68 mmol cysteine, 147.37 mmol sodium hydride (60%) and 100.00 mL DMF were weighed into a 250 mL reaction flask, refluxed, stirred, and monitored by TLC. After the reaction was complete, appropriate amounts of distilled water were added to dilute the solution, the pH was adjusted to 5.5 with 1 mol / L dilute hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0037] (2) Preparation of Compound 2: 8.69 mmol of Compound 1, 34.74 mmol of anhydrous potassium carbonate, 34.74 mmol of ethyl bromoacetate, and 20.00 mL of acetone were weighed and added to a 50 mL reaction flask. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was concentrated under reduced pressure, and appropriate amount of distilled water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and transferred to a 50 mL round-bottom flask. The solvent was concentrated under reduced pressure, and 20.00 mL of anhydrous ethanol was added. The mixture was stirred, and then an appropriate amount of 6% sodium hydroxide solution was added dropwise. The mixture was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, and an appropriate amount of distilled water was added. An appropriate amount of 6 mol / L dilute hydrochloric acid solution was added dropwise until pH = 1. The mixture was filtered, dried, and Compound 2 was obtained.

[0038] (3) Preparation of compound 3a: 1.50 mmol thiourea, 1.00 mmol 2-bromoacetophenone and 10.00 mL anhydrous ethanol were added to a 50 mL reaction flask and stirred at 70 °C. The reaction was monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, an appropriate amount of distilled water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3a.

[0039] (4) Preparation of compound Ia: 0.4 mmol of compound 2, 0.3 mmol of compound 3a, 0.45 mmol of HOBT, 0.45 mmol of EDCI, 0.09 mmol of DMAP and 10.00 mL of dichloromethane were added to a 50 mL reaction flask, and 0.9 mmol of triethylamine was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound Ia.

[0040] Example 2: Preparation of compound Ig

[0041] (1) Preparation of Compound 1: 24.56 mmol osthol, 73.68 mmol cysteine, 147.37 mmol sodium hydride (60%) and 100.00 mL DMF were weighed into a 250 mL reaction flask, refluxed, stirred, and monitored by TLC. After the reaction was complete, appropriate amounts of distilled water were added to dilute the solution, the pH was adjusted to 5.5 with 1 mol / L dilute hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0042] (2) Preparation of Compound 2: 8.69 mmol of Compound 1, 34.74 mmol of anhydrous potassium carbonate, 34.74 mmol of ethyl bromoacetate, and 20.00 mL of acetone were weighed and added to a 50 mL reaction flask. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was concentrated under reduced pressure, and appropriate amount of distilled water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and transferred to a 50 mL round-bottom flask. The solvent was concentrated under reduced pressure, and 20.00 mL of anhydrous ethanol was added. The mixture was stirred, and then an appropriate amount of 6% sodium hydroxide solution was added dropwise. The mixture was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, and an appropriate amount of distilled water was added. An appropriate amount of 6 mol / L dilute hydrochloric acid solution was added dropwise until pH = 1. The mixture was filtered, dried, and Compound 2 was obtained.

[0043] (3) Preparation of compound 3g: 1.50 mmol thiourea, 1.00 mmol 2-bromo-2'-fluoroacetophenone and 10.00 mL anhydrous ethanol were added to a 50 mL reaction flask and stirred at 70 °C. The reaction was monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, an appropriate amount of distilled water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3g.

[0044] (4) Preparation of compound I g: 0.4 mmol of compound 2, 0.3 mmol of compound 3 g, 0.45 mmol of HOBT, 0.45 mmol of EDCI, 0.09 mmol of DMAP and 10.00 mL of dichloromethane were added to a 50 mL reaction flask, and 0.9 mmol of triethylamine was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound I g.

[0045] Example 3: Preparation of compound Ij

[0046] (1) Preparation of Compound 1: 24.56 mmol osthol, 73.68 mmol cysteine, 147.37 mmol sodium hydride (60%) and 100.00 mL DMF were weighed into a 250 mL reaction flask, refluxed, stirred, and monitored by TLC. After the reaction was complete, appropriate amounts of distilled water were added to dilute the solution, the pH was adjusted to 5.5 with 1 mol / L dilute hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0047] (2) Preparation of Compound 2: 8.69 mmol of Compound 1, 34.74 mmol of anhydrous potassium carbonate, 34.74 mmol of ethyl bromoacetate, and 20.00 mL of acetone were weighed and added to a 50 mL reaction flask. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was concentrated under reduced pressure, and appropriate amount of distilled water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and transferred to a 50 mL round-bottom flask. The solvent was concentrated under reduced pressure, and 20.00 mL of anhydrous ethanol was added. The mixture was stirred, and then an appropriate amount of 6% sodium hydroxide solution was added dropwise. The mixture was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, and an appropriate amount of distilled water was added. An appropriate amount of 6 mol / L dilute hydrochloric acid solution was added dropwise until pH = 1. The mixture was filtered, dried, and Compound 2 was obtained.

[0048] (3) Preparation of compound 3j: 1.50 mmol thiourea, 1.00 mmol 2-bromo-2'-chloroacetophenone and 10.00 mL anhydrous ethanol were added to a 50 mL reaction flask and stirred at 70 °C. The reaction was monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, an appropriate amount of distilled water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3j.

[0049] (4) Preparation of compound Ij: 0.4 mmol of compound 2, 0.3 mmol of compound 3j, 0.45 mmol of HOBT, 0.45 mmol of EDCI, 0.09 mmol of DMAP and 10.00 mL of dichloromethane were added to a 50 mL reaction flask, and 0.9 mmol of triethylamine was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound Ij.

[0050] Example 4: Preparation of compound Iw

[0051] (1) Preparation of Compound 1: 24.56 mmol osthol, 73.68 mmol cysteine, 147.37 mmol sodium hydride (60%) and 100.00 mL DMF were weighed into a 250 mL reaction flask, refluxed, stirred, and monitored by TLC. After the reaction was complete, appropriate amounts of distilled water were added to dilute the solution, the pH was adjusted to 5.5 with 1 mol / L dilute hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0052] (2) Preparation of Compound 2: 8.69 mmol of Compound 1, 34.74 mmol of anhydrous potassium carbonate, 34.74 mmol of ethyl bromoacetate, and 20.00 mL of acetone were weighed and added to a 50 mL reaction flask. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was concentrated under reduced pressure, and appropriate amount of distilled water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and transferred to a 50 mL round-bottom flask. The solvent was concentrated under reduced pressure, and 20.00 mL of anhydrous ethanol was added. The mixture was stirred, and then an appropriate amount of 6% sodium hydroxide solution was added dropwise. The mixture was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, and an appropriate amount of distilled water was added. An appropriate amount of 6 mol / L dilute hydrochloric acid solution was added dropwise until pH = 1. The mixture was filtered, dried, and Compound 2 was obtained.

[0053] (3) Preparation of compound 3w: 1.50 mmol thiourea, 1.00 mmol 2-bromo-1-cyclopropyl ethyl ketone and 10.00 mL anhydrous ethanol were added to a 50 mL reaction flask and stirred at 70 °C. The reaction was monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, an appropriate amount of distilled water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3w.

[0054] (4) Preparation of compound Iw: 0.4 mmol of compound 2, 0.3 mmol of compound 3w, 0.45 mmol of HOBT, 0.45 mmol of EDCI, 0.09 mmol of DMAP, and 10.00 mL of dichloromethane were added to a 50 mL reaction flask, and 0.9 mmol of triethylamine was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound Iw.

[0055] Example 5: Preparation of compound Ix

[0056] (1) Preparation of Compound 1: 24.56 mmol osthol, 73.68 mmol cysteine, 147.37 mmol sodium hydride (60%) and 100.00 mL DMF were weighed into a 250 mL reaction flask, refluxed, stirred, and monitored by TLC. After the reaction was complete, appropriate amounts of distilled water were added to dilute the solution, the pH was adjusted to 5.5 with 1 mol / L dilute hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0057] (2) Preparation of Compound 2: 8.69 mmol of Compound 1, 34.74 mmol of anhydrous potassium carbonate, 34.74 mmol of ethyl bromoacetate, and 20.00 mL of acetone were weighed and added to a 50 mL reaction flask. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was concentrated under reduced pressure, and appropriate amount of distilled water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and transferred to a 50 mL round-bottom flask. The solvent was concentrated under reduced pressure, and 20.00 mL of anhydrous ethanol was added. The mixture was stirred, and then an appropriate amount of 6% sodium hydroxide solution was added dropwise. The mixture was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, and an appropriate amount of distilled water was added. An appropriate amount of 6 mol / L dilute hydrochloric acid solution was added dropwise until pH = 1. The mixture was filtered, dried, and Compound 2 was obtained.

[0058] (3) Preparation of compound 3x: 1.50 mmol thiourea, 1.00 mmol 2-bromo-1-(1,3-thiazolyl-2-yl)acetone and 10.00 mL anhydrous ethanol were added to a 50 mL reaction flask and stirred at 70 °C. The reaction was monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, an appropriate amount of distilled water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3x.

[0059] (4) Preparation of compound Ix: 0.4 mmol of compound 2, 0.3 mmol of compound 3x, 0.45 mmol of HOBT, 0.45 mmol of EDCI, 0.09 mmol of DMAP and 10.00 mL of dichloromethane were added to a 50 mL reaction flask, and 0.9 mmol of triethylamine was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound Ix.

[0060] Example 6: Preparation of compound Iz

[0061] (1) Preparation of Compound 1: 24.56 mmol osthol, 73.68 mmol cysteine, 147.37 mmol sodium hydride (60%) and 100.00 mL DMF were weighed into a 250 mL reaction flask, refluxed, stirred, and monitored by TLC. After the reaction was complete, appropriate amounts of distilled water were added to dilute the solution, the pH was adjusted to 5.5 with 1 mol / L dilute hydrochloric acid solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the solvent was concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound 1.

[0062] (2) Preparation of Compound 2: 8.69 mmol of Compound 1, 34.74 mmol of anhydrous potassium carbonate, 34.74 mmol of ethyl bromoacetate, and 20.00 mL of acetone were weighed and added to a 50 mL reaction flask. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was concentrated under reduced pressure, and appropriate amount of distilled water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and transferred to a 50 mL round-bottom flask. The solvent was concentrated under reduced pressure, and 20.00 mL of anhydrous ethanol was added. The mixture was stirred, and then an appropriate amount of 6% sodium hydroxide solution was added dropwise. The mixture was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure, and an appropriate amount of distilled water was added. An appropriate amount of 6 mol / L dilute hydrochloric acid solution was added dropwise until pH = 1. The mixture was filtered, dried, and Compound 2 was obtained.

[0063] (3) Preparation of compound 3z: 1.50 mmol thiourea, 1.00 mmol 3-bromo-2-butanone and 10.00 mL anhydrous ethanol were added to a 50 mL reaction flask and stirred at 70 °C. The reaction was monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, an appropriate amount of distilled water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3z.

[0064] (4) Preparation of compound Iz: 0.4 mmol of compound 2, 0.3 mmol of compound 3z, 0.45 mmol of HOBT, 0.45 mmol of EDCI, 0.09 mmol of DMAP and 10.00 mL of dichloromethane were added to a 50 mL reaction flask, and 0.9 mmol of triethylamine was added dropwise. The reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, the solvent was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain compound Iz.

[0065] Example 7: Preparation of compound Ig

[0066] The preparation process of compound Ig differs from that in Example 1 in that, in step (3), 1.00 mmol of 2-bromoacetophenone is replaced with 2-fluoroacetophenone.

[0067] Example 8: Preparation of compound Ih

[0068] The preparation process of compound Ih differs from that in Example 1 in that, in step (3), 1.00 mmol of 2-bromoacetophenone is replaced with 3-fluoroacetophenone.

[0069] Example 9: Preparation of compound Ⅰs

[0070] The preparation process of compound Ⅰs differs from that of Example 1 in that, in step (3), 1.00 mmol of 2-bromoacetophenone is replaced with 2,4-difluoroacetophenone.

[0071] Example 10: Preparation of compound Iu

[0072] The preparation process of compound Iu differs from that in Example 1 in that, in step (3), 1.00 mmol of 2-bromoacetophenone is replaced with bromoacetone.

[0073] Example 11: Preparation of compound Iv

[0074] The preparation process of compound IV differs from that of Example 1 in that, in step (3), 1.00 mmol of 2-bromoacetophenone is replaced with 1-bromo-2-butanone.

[0075] The relevant data for compound I are shown in Table 2:

[0076] Table 2

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] The antibacterial activity test of the present invention: using osthol, oxacillin, and norfloxacin as control drugs, the minimum inhibitory concentration (MIC) of the compound of general formula I against Staphylococcus aureus, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC) was determined by the two-fold dilution method. The data are shown in Table 3.

[0084] Table 3

[0085]

[0086]

[0087] The experimental results clearly demonstrate that the compounds of general formula I protected by this invention possess potential antibacterial activity and exhibit broad-spectrum activity. Some compounds show strong inhibitory effects against Staphylococcus aureus, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC), exhibiting antibacterial activity superior to or comparable to the control drugs, such as compounds Ig, Iw, and Ix. Furthermore, some compounds show particularly significant antibacterial activity against MRSA and FREC, far exceeding that of the control drugs oxacillin and norfloxacin, such as compounds Ia, Ig, Ih, Ij, Is, Iu, Iv, Iw, Ix, and Iz. The highly active compounds of this class of derivatives can be used against Staphylococcus aureus, Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC); they can also be used in combination with other antibacterial active substances.

[0088] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A modified osthol 7-position structure, characterized in that: The modified material has a chemical structure as shown in general formula I: Specifically, this includes any of the following compounds: Compound Ia: R 1 =Ph-, R 2 =H; Compound Ig:R 1 =2-FPh-, R 2 =H; Compound Ih: R 1 =3-FPh-, R 2 =H; Compound Ij: R 1 =2-ClPh-, R 2 =H; Compound Ⅰs: R 1 =2,4-diFPh-, R 2 =H; Compound Iu:R 1 =Me, R 2 =H; Compound Ⅰv: R 1 =Et, R 2 =H; Compound I w:R 1 =Cyclopropyl, R 2 =H; Compound Ix: R 1 =Thiazol-2-, R 2 =H; Compound Iz:R 1 =Me, R 2 =Me.

2. The method for preparing a modified osthol 7-position structure according to claim 1, characterized in that: The synthetic route of general formula I is as follows: Specifically, the steps include: Preparation of compound 1: Starting with osthol, cysteine, sodium hydride and DMF were added. After the reaction, water was added to dilute the mixture and the pH was adjusted to 5.

5. The mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure. The organic layer was then separated and purified by silica gel column chromatography to obtain compound 1. Preparation of compound 2: Anhydrous potassium carbonate, ethyl bromoacetate and acetone were added to compound 1. After the reaction was stirred at room temperature, the mixture was concentrated under reduced pressure. Water was added and ethyl acetate was used for extraction. The organic layer was washed, dried and concentrated under reduced pressure. Anhydrous ethanol was added and the mixture was stirred. Then, an appropriate amount of 6% sodium hydroxide solution was added dropwise. After the reaction was completed, the mixture was concentrated under reduced pressure. Water was added and the pH was adjusted to 1. The mixture was filtered and dried to obtain compound 2. Preparation of compound 3: Thiourea, anhydrous ethanol, 2-bromosubstituted acetophenone or 3-bromo-2-butanone or 2-bromo-1-(1,3-thiazo-2-yl)ethyl ketone or 2-bromo-1-cyclopropylethyl ketone or 1-bromo-2-butanone or bromoacetone were added to a reaction vessel and stirred at 70°C. After the reaction was completed, the mixture was concentrated under reduced pressure, water was added, the mixture was cooled to crystallize, filtered, and dried to obtain compound 3. Preparation of compound I: Compound 2, compound 3, HOBT, EDCI, DMAP and dichloromethane were added to a reaction vessel, and triethylamine was added dropwise. The reaction was stirred at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the modified osthol 7-position structure shown in general formula I.

3. The method for preparing a modified osthol 7-position structure according to claim 2, characterized in that: In the preparation of compound 1, the pH was adjusted to 5.5 using a 1 mol / L dilute hydrochloric acid solution.

4. The method for preparing a modified osthol 7-position structure according to claim 2, characterized in that: In the preparation of compound 2, the pH was adjusted to 1 using a 6 mol / L dilute hydrochloric acid solution.

5. The method for preparing a modified osthol 7-position structure according to claim 2, characterized in that: In the preparation of compound I, the molar ratio of compound 2: compound 3: HOBT: EDCI: DMAP: triethylamine = 0.3~0.5: 0.3: 0.3~0.5: 0.3~0.5: 0.09~0.15: 0.6~1.

2.

6. The application of the osthol 7-position structural modification according to claim 1 in the preparation of antibacterial and / or bacteriostatic drugs, wherein the bacteria are selected from: Staphylococcus aureus ( S. aureus ), Escherichia coli ( E. coli ).

7. The application according to claim 6, characterized in that, The Staphylococcus aureus is methicillin-resistant Staphylococcus aureus (MRSA), and the Escherichia coli is fluoroquinolone-resistant Escherichia coli (FREC).

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