A bishydroxyindole compound and its preparation method and application in the preparation of antibacterial agent

Abstract

The present invention discloses a bishydroxyindole compound and a preparation method thereof and an application thereof in the preparation of an antibacterial agent. The present invention provides a new 3-alkenyl bishydroxyindole compound containing a quaternary carbon chiral center, using cheap and readily available raw materials, a quinine derivative whose C6' substituent is a diphenylmethyl group and has excellent asymmetric catalytic performance, to construct a new bishydroxyindole structure containing two pharmacophores, a 3-methylene-substituted oxindole and an oxindole containing a quaternary carbon chiral center at the 3-position, in one step. Activity evaluation found that compound Ⅰ-22 showed good inhibitory activity against Enterococcus faecalis and Acinetobacter baumannii. The present invention provides a new idea for the development of new antibiotics.

Description

(I) Technical field

[0001] The present invention belongs to the technical field of fine organic chemistry and biomedicine, and particularly relates to asymmetric S N A bishydroxyindole compound is constructed by V reaction, a preparation method thereof and its application in antibacterial agents. (II) Background technology

[0002] Oxindole is an important structural skeleton that exists in a large number of natural products and heterocyclic compounds with biological activity. 3-Methylene-substituted oxindole and oxindole containing a quaternary carbon chiral center at the 3-position are two very important pharmacophores with important pharmacological activities. Many indole derivatives have significant biological activities such as antibacterial, anticancer, and antiviral properties (Biomedicine & Pharmacotherapy, 2021, 141, 111842.). For example, Sunitinib is a targeted therapy drug, a dual-channel, multi-target tyrosine kinase inhibitor that can inhibit the growth of cancer cells and block the blood and nutrient supply required for tumor growth (Toxicology and Applied Pharmacology, 2017, 329: 282-292.). 3-Diferrocenyl-oxindole-N-triazole ring has good inhibitory activity against Gram-positive and Gram-negative strains (Applied Organometallic Chemistry, 2019, 33, 1–15.).

[0003] Chirality is one of the essential properties of nature. In the past thirty years, the huge demand for single enantiomer chiral compounds in the pharmaceutical industry and fine chemicals has promoted the rapid development of asymmetric synthesis methodologies. Due to the important role of the oxindole structure, a large number of asymmetric synthesis methodologies have been developed in the past two decades to construct optically active oxindole skeletons. N The V reaction can introduce multi-substituted CC double bonds into molecules, providing a powerful method for the construction of molecules containing alkenyl substitutions. N There are few reports on the construction of single enantiomer chiral olefinic compounds by V reaction. So far, scientists have constructed a series of oxindole derivative structures, but there is only one report on the construction of 3-olefin oxindole structure compounds containing quaternary carbon chiral centers (European Journal Of Organic Chemistry, 2019: 3040-3044.).

[0004] Asymmetric S N The V reaction can simultaneously introduce chiral centers and polysubstituted olefins into molecules, constructing a new type of bishydroxyindole structure containing both types of pharmacophores, which is of great significance for the discovery of lead compounds and drug development. (III) Summary of the invention

[0005] The present invention aims to provide a bishydroxyindole compound and a preparation method thereof and an application thereof in the preparation of an antibacterial agent. Through a reasonable reaction design, a nitroolefin derived from isatin is reacted with a nucleophilic reagent under the action of a quinine-derived catalyst, and the asymmetric construction of a 3-alkenylhydroxyindole containing a quaternary carbon chiral center is successfully achieved. The compound has a good inhibitory effect on Gram-positive and Gram-negative strains, providing a new choice for antibacterial agents.

[0006] The technical solution adopted by the present invention is:

[0007] In the first aspect, the present invention provides a (S, E)-3-alkenylbishydroxyindole compound represented by formula (I):

[0008]

[0009] In formula (I), R 2 , R 4 is monosubstituted or polysubstituted, wherein the polysubstituted includes ortho, para, and meta positions, and the R 1 , R 2 , R 3 , R 4 and Ar are each independently hydrogen, tert-butyloxycarbonyl, methoxy, o-methoxybenzyl, trifluoromethoxybenzyl, o-fluorobenzyl, o-chlorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-iodobenzyl, benzyl, o-trifluoromethylbenzyl, difluoromethylbenzyl, o-methylbenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl, 2,6-dimethylbenzyl, phenyl, dimethylphenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, o-methoxyphenyl, o-methylphenyl, o-nitrophenyl, o-trifluoromethylphenyl, o-bromophenyl, o-fluorophenyl, o-chlorophenyl, o-iodophenyl, m-methylphenyl, m-methoxyphenyl, m-nitrophenyl, m-trifluoromethylphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-iodophenyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, biphenyl, naphthalene, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyridine-2-methyl, pyridine-3-methyl, pyridine-4-methyl, pyrimidine, benzofuran, indole, benzothiazole, quinoline, isoquinoline, purine, pterin, tetrahydrofuran, hexahydropyran.

[0010] Preferably, in formula (I), R 1 is methyl, allyl, benzyl; R 2is hydrogen, 5-methyl, 5-chloro, 6-methoxy, 7-methyl, 7-fluoro; R 3 is hydrogen, benzyl, tert-butyloxycarbonyl; R 4 is hydrogen, 5-methyl, 5-methoxy, 5-fluoro, 5-bromo, 5-chloro, or 6-fluoro; Ar is phenyl, p-trifluoromethylphenyl, p-bromophenyl, p-methylphenyl, p-methoxyphenyl, biphenyl, o-bromophenyl, o-fluorophenyl, o-chlorophenyl, o-methoxyphenyl, m-chlorophenyl, m-methylphenyl, naphthalene, furan, or thiophene.

[0011] Preferably, the compound represented by formula (I) is one of the following: (1) R 1 When it is methyl, R 2 is hydrogen, R 3 is tert-butyloxycarbonyl, R 4 is hydrogen, Ar is phenyl; (2) R 1 When it is allyl, R 2 is hydrogen, R 3 is tert-butyloxycarbonyl, R 4 is hydrogen, Ar is phenyl; (3) R 1 When it is benzyl, R 2 is one of 5-methyl, 5-chloro, 6-methoxy, 7-methyl, and 7-fluoro; R 3 is tert-butyloxycarbonyl, R 4 is hydrogen, Ar is phenyl; (4) R 1 When it is benzyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, Ar is phenyl; (5) R 1 When it is benzyl, R 2 is hydrogen, R 3 is benzyl, R 4 is hydrogen, Ar is phenyl; (6) R 1 When it is benzyl, R 2 is hydrogen, R 3 is tert-butyloxycarbonyl, R 4 is one of 5-methyl, 5-methoxy, 5-fluoro, 5-bromo, 5-chloro, and 6-fluoro, and Ar is phenyl; (7) R 1 When it is benzyl, R 2 is hydrogen, R 3 is tert-butyloxycarbonyl, R 4 is hydrogen, and Ar is one of phenyl, p-trifluoromethylphenyl, p-bromophenyl, p-methylphenyl, p-methoxyphenyl, biphenyl, o-bromophenyl, o-fluorophenyl, o-chlorophenyl, o-methoxyphenyl, m-chlorophenyl, m-methylphenyl, naphthalene, furan, and thiophene.

[0012] Preferably, the (S, E)-3-alkenylbishydroxyindole compound represented by formula (I) is one of the following:

[0013]

[0014] In a second aspect, the present invention provides a method for preparing a (S, E)-3-alkenylbishydroxyindole compound represented by formula (I), the method comprising: stirring a compound represented by formula (II) and a compound represented by formula (III) at 25°C to -80°C for 12-48h in an air atmosphere in the presence of a base, a solvent and a catalyst, monitoring the completion of the reaction by TLC, and performing rotary evaporation under reduced pressure until no liquid flows out to obtain a yellow oily liquid; performing silica gel column chromatography on the yellow oily liquid using petroleum ether and ethyl acetate in a volume ratio of 10:1 as an eluent, collecting an effluent having an Rf value of 0.2-0.4, and performing rotary evaporation under reduced pressure to dryness to obtain a yellow foam solid (S, E)-3-alkenylbishydroxyindole compound represented by formula (I);

[0015] The catalyst C6' dibenzhydryl substituted quinine derivative is selected from natural cinchona alkaloids and C6' dibenzhydryl substituted quinine derivatives derived from quinine.

[0016] The base includes N-ethyldiisopropylamine, triethylamine, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate trihydrate, disodium hydrogen phosphate, potassium bicarbonate, sodium bicarbonate, preferably potassium carbonate; the solvent is an organic solvent, and the organic solvent includes dichloromethane, 1,2-dichloroethane, chloroform, ether, methyl tert-butyl ether, toluene, mesitylene, acetonitrile, ethyl acetate, n-hexane, preferably chloroform;

[0017] The reaction formula of the method is as follows:

[0018]

[0019] In formula (II) and formula (III), R 2 , R 4 is monosubstituted or polysubstituted, wherein the polysubstituted includes ortho, para, and meta positions, and the R 1 , R 2 , R 3 , R 4and Ar are each independently hydrogen, tert-butyloxycarbonyl, methoxy, o-methoxybenzyl, trifluoromethoxybenzyl, o-fluorobenzyl, o-chlorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-iodobenzyl, benzyl, o-trifluoromethylbenzyl, difluoromethylbenzyl, o-methylbenzyl, 3,5-dimethylbenzyl, 3,5-dibromobenzyl, 3,5-di-tert-butylbenzyl, 2,6-dimethylbenzyl, phenyl, dimethylphenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, o-methoxyphenyl, o-methylphenyl, o-nitrophenyl, o-trifluoromethylphenyl, o-bromophenyl, o-fluorophenyl, o-chlorophenyl, o-iodophenyl, m-methylphenyl, m-methoxyphenyl, m-nitrophenyl, m-trifluoromethylphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m-iodophenyl, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, ethynyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, biphenyl, naphthalene, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyridine-2-methyl, pyridine-3-methyl, pyridine-4-methyl, pyrimidine, benzofuran, indole, benzothiazole, quinoline, isoquinoline, purine, pterin, tetrahydrofuran, hexahydropyran.

[0020] In formula (I), R 1 , R 2 Same as R in formula (II) 1 , R 2 In formula (I), R 3 , R 4 , Ar is the same as R in formula (III) 3 , R 4 、Ar。

[0021] Preferably, the catalyst comprises a C6' benzhydryl substituted quinine derivative C1, a C6' benzhydryl substituted quinine derivative C2 and a C6' benzhydryl substituted quinine derivative C3;

[0022]

[0023] Preferably, the preparation method of the (S, E)-3-alkenylbishydroxyindole compound is carried out according to the following steps: under air atmosphere, the compound represented by formula (III), the catalyst and the base are added to the solvent, stirred at -40°C for 30 minutes, the compound represented by formula (II) is added, and stirred at -40°C for 12-48 hours. The reaction is completed by monitoring by TLC, and the reaction solution is evaporated under reduced pressure until no liquid flows out to obtain a yellow oily liquid; the yellow oily liquid is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 as eluent, and the effluent with an Rf value of 0.2-0.4 is collected, and the effluent is evaporated under reduced pressure to dryness to obtain a yellow foam solid (S, E)-3-alkenylbishydroxyindole compound represented by formula (I).

[0024] Preferably, the ratio of the amount of the compound represented by formula (III) to the amount of the compound represented by formula (II) is 1:1-5, preferably 1:1.5; the ratio of the amount of the compound represented by formula (III) to the amount of the catalyst is 1:0.01-0.1, preferably 1:0.1; the ratio of the amount of the compound represented by formula (III) to the amount of the base is 1:1-5, preferably 1:1; the volume of the solvent used is 10-30mL / mmol, preferably 20mL / mmol, based on the amount of the compound represented by formula (III).

[0025] In a third aspect, the present invention also provides an application of a (S,E)-3-alkenylbishydroxyindole compound in the preparation of an antibacterial agent, wherein the antibacterial agent includes an antibacterial agent for Enterococcus faecalis, Methicillin-resistant Staphylococcus aureus, Acinetobacterbaumannii, and Bacillus subtilis.

[0026] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0027] The present invention successfully realizes the dihydroxyindole compounds containing quaternary carbon chiral centers by reacting the nitroolefin derived from isatin with a nucleophilic reagent under the action of a quinine-derived catalyst through a reasonable reaction design. A simple and efficient synthesis strategy has been developed, which provides a more direct and simple idea for asymmetrically constructing dihydroxyindole compounds with a quaternary carbon chiral center adjacent to the vinyl group, a type of compound with a multi-pharmacophore combination structure. Activity evaluation shows that the compounds of the present invention have a good inhibitory effect on Gram-positive and Gram-negative strains, among which compound Ⅰ-22 shows good inhibitory activity against Enterococcus faecalis and Acinetobacter baumannii, with inhibition rates of 77.03% and 74.45%, respectively. The present invention provides a new idea for the development of new antibiotics. (IV) Description of the drawings

[0028] Figure 1 , hydrogen nuclear magnetic resonance spectrum of the compound represented by formula Ⅰ.

[0029] Figure 2 , hydrogen nuclear magnetic resonance spectrum of the compound represented by formula Ⅰ. (V) Specific implementation methods

[0030] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0031] Example 1. Preparation of (SE)-3-benzyl-3-((1-benzyl-2-oxoindolin-3-ylidene)methyl)-2-oxoindene-1-carboxylic acid tert-butyl ester I-1

[0032]

[0033]

[0034] At room temperature, tert-butyl 3-benzyl-2-oxoindoline-1-carboxylate III (0.05 mmol, 1.0 eq.), chloroform (1 mL), quinine derivative catalyst C1 (0.005 mmol, 0.1 eq.) with a C6' substituent being diphenylmethyl, and potassium carbonate (0.05 mmol, 1.0 eq.) were added to the reaction tube and the solution was placed in a low-temperature reactor at -40°C. After 15 minutes, indole nitroolefin II (0.075 mmol, 1.5 eq.) was added. The mixture was stirred at -40°C for 48 hours. The reaction was completed by TLC detection. The developing solvent was petroleum ether: ethyl acetate in a volume ratio of 10:1. The reaction solution was directly chromatographed on a silica gel column (eluent: petroleum ether: ethyl acetate = 10:1, volume ratio), and the effluent with an Rf value of 0.2-0.4 was collected and evaporated to dryness under reduced pressure to obtain a yellow foamy product Ⅰ-1 (86% yield, 96% ee, E / Z 94:6). The H NMR spectrum was as follows: Figure 1 shown.

[0035] The contents of (S, E)-3-benzyl-3-((1-benzyl-2-oxoindolin-3-ylidene)methyl)-2-oxoindolin-1-carboxylic acid tert-butyl ester and (R, E)-3-benzyl-3-((1-benzyl-2-oxoindolin-3-ylidene)methyl)-2-oxoindolin-1-carboxylic acid tert-butyl ester in product Ⅰ-1 were detected by high performance liquid chromatography, and the enantiomeric excess was calculated.

[0036] High performance liquid chromatography was performed using Shimadzu HPLC (AD-H, IA chiral columns), mobile phase: V n-hexane / V isopropanol = 80:20-90:10, flow rate: 1 mL / min, detection wavelength: 254 nm.

[0037] Example 2-30

[0038] According to the similar method of Example 1, only R in the compound shown in Formula I is replaced as shown in Table 1, and the effluent with Rf value of 0.2-0.4 is collected to obtain the corresponding compound shown in Formula I. The results of H NMR spectrum and high-resolution mass spectrum data of the above compounds are listed in Table 1. It can be seen from the above that the structures of the above compounds are correct and they are all compounds shown in Formula I.

[0039] Table 1 Nuclear magnetic resonance hydrogen spectrum data and high resolution mass spectrum data of the compound represented by formula I

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053] Example 31: Application of (S, E)-3-alkenylbishydroxyindole compounds in the evaluation of antibacterial activity

[0054] 1. Preparation before the experiment

[0055] (1) Cleaning of equipment:

[0056] Wash and wrap the test tubes, watch glasses, conical flasks, pipette tips and other experimental equipment, sterilize them under high pressure at 121℃ for 20min, and dry them in an oven for later use.

[0057] (2) Preparation of MHII solid culture medium:

[0058] MHII solid culture medium: acid-hydrolyzed casein 17.5 mg / mL, soluble starch 1.5 mg / mL, yeast extract 6 mg / mL, agar 17 mg / mL, and the solvent is water.

[0059] Preparation method: weigh 3.4g agar in a conical flask, add 200mL pure water, dissolve; weigh 3.5g acid casein in a conical flask, dissolve. Take 0.3g soluble starch and add it to the solution and dissolve. Add 1.2g yeast extract and dissolve. Ultrasound-assisted dissolution. Sterilize the prepared culture medium in an autoclave at 121℃ for 90min. After the agar cools down slightly, pour it into a plate on the clean bench (15-20ml per agar plate), solidify it, place it in a 37℃ constant temperature incubator overnight for sterility inspection, and place it on the clean bench for use after passing the test.

[0060] (3) Preparation of MHII liquid culture medium:

[0061] MHII liquid culture medium composition: yeast extract 5 mg / mL, trypsin 10 mg / mL, sodium chloride 10 mg / mL, the solvent is water.

[0062] Preparation: Weigh 1.0g yeast extract into a 250ml conical flask, add 200mL pure water and dissolve. Take 2.0g trypsin and add it to the solution and dissolve. Add 2.0g sodium chloride and dissolve. Ultrasound-assisted dissolution. Prepare two bottles of 250mL liquid culture medium in this way and divide them into four 250mL conical flasks, 100mL in each conical flask. Sterilize the prepared culture medium in an autoclave at 121℃ for 90min. Let it cool slightly and place it on a clean bench for use.

[0063] (4) Preparation and storage of drug stock solution:

[0064] Drug stock solution: The compound prepared in Example 1-30 was sterilized by high pressure and diluted with DMSO to a drug stock solution with a concentration of 20 μM.

[0065] Positive control: 20 μM ciprofloxacin in DMSO.

[0066] Blank control: DMSO.

[0067] (5) Preparation of bacterial solution:

[0068] Strains (provided by Jiangsu Key Laboratory of Modern Pathogenic Biology, Nanjing Medical University): Enterococcus faecalis, Methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, Bacillus subtilis.

[0069] Pick the strain, streak inoculate it onto the MHII solid plate, and culture it at 37℃ for 16-24h. On the next day, pick a single colony and inoculate it into MHII liquid culture medium, and culture it at 37℃ in a shaking incubator for 16-24h to prepare the test bacterial solution.

[0070] 2. Determination of antibacterial rate

[0071] (1) Add 1 μL of drug stock solution, positive control, and blank control to the middle 6×10 wells of a 96-well plate in groups of five. Perform 5 parallel groups for each drug. Use a pipette to draw 199 μL of the test bacterial solution and add it to the above 6×10 wells of the 96-well plate. The final drug concentration in each well is 20 μmol / mL. Check, shake slightly, and incubate in a 37°C incubator for 16-24 hours.

[0072] (2) Take out the 96-well plate, turn on the microplate reader, and measure the OD 600 , calculated the inhibition rate, and the results are shown in Table 2 and Table 3.

[0073] Inhibition rate calculation formula = (OD 600 control-OD 600 ) / OD 600 control×100%

[0074] Table 2 Inhibition rate of the compounds shown in formula I on bacteria (20 μM)

[0075]

[0076] Table 3 Inhibition rate of the compounds shown in formula I on bacteria (20 μM)

[0077]

[0078] The inhibition rate of the compound shown in Formula I on bacteria was determined to show that compound I-22 had good to excellent inhibition activity against Acinetobacter baumannii, MRSA, Bacillus subtilis, and Enterococcus faecalis, among which the inhibition rate of chiral compound I-22 on Enterococcus faecalis reached 77.03%. This further proves the significance of the asymmetric synthesis method we developed for this type of compound and expands the substrate adaptability range.

Claims

1. A (S, E)-3-alkenylbishydroxyindole compound, characterized in that: The compound is one of the following:

2. A method for preparing the (S, E)-3-alkenylbishydroxyindole compound according to claim 1, characterized in that: The method comprises: in an air atmosphere, in the presence of a base, a solvent and a catalyst, stirring a compound represented by Formula II and a compound represented by Formula III at 25°C to -80°C for 12-48 hours, monitoring the reaction by TLC, and performing vacuum rotary evaporation until no liquid flows out to obtain a yellow oily liquid; the yellow oily liquid is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 as eluent, collecting an effluent with an Rf value of 0.2-0.4, and vacuum rotary evaporating to dryness to obtain a (S, E)-3-alkenylbishydroxyindole compound represented by Formula I; The catalyst is a C6' benzhydryl-substituted quinine derivative; The base includes N-ethyldiisopropylamine, triethylamine, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate trihydrate, disodium hydrogen phosphate, potassium bicarbonate, sodium bicarbonate; The solvent is an organic solvent, and the organic solvent includes dichloromethane, 1,2-dichloroethane, chloroform, ether, methyl tert-butyl ether, toluene, mesitylene, acetonitrile, ethyl acetate, and n-hexane; R in Formula II and Formula III 2 , R 4 is hydrogen, R 3 is tert-butyloxycarbonyl, Ar is phenyl, R 1 is methyl or benzyl; In Formula I, R 1 , R 2 Same as R in Formula II 1 , R 2 In formula Ⅰ, R 3 , R 4 , Ar is the same as R in Formula III 3 , R 4 , Ar; when R 1 When R is methyl, formula I is I-22; 1 When it is benzyl, formula I is I-28.

3. The preparation method according to claim 2, characterized in that: The catalyst includes a C6' benzhydryl substituted quinine derivative C1, a C6' benzhydryl substituted quinine derivative C2 or a C6' benzhydryl substituted quinine derivative C3; 4. The preparation method according to claim 2, characterized in that: The preparation method of the (S, E)-3-alkenylbishydroxyindole compound is carried out according to the following steps: under air atmosphere, the compound shown in formula III, a catalyst and a base are added to a solvent, stirred at -40°C for 30 minutes, the compound shown in formula II is added, and stirred at -40°C for 12-48 hours. The reaction is completed by TLC monitoring, and the reaction solution is evaporated under reduced pressure until no liquid flows out to obtain a yellow oily liquid; the yellow oily liquid is subjected to silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 as eluent, and the effluent with an Rf value of 0.2-0.4 is collected, and the effluent is evaporated under reduced pressure to dryness to obtain the (S, E)-3-alkenylbishydroxyindole compound shown in formula I.

5. The preparation method according to claim 2, characterized in that: The ratio of the amount of the compound represented by formula III to the amount of the compound represented by formula II is 1:1-5; the ratio of the amount of the compound represented by formula III to the amount of the catalyst is 1:0.01-0.1; the ratio of the amount of the compound represented by formula III to the amount of the base is 1:1-5; the volume of the solvent used is 10-30mL / mmol based on the amount of the compound represented by formula III.

6. Use of the (S, E)-3-alkenylbishydroxyindole compound according to claim 1 in the preparation of an antibacterial agent, characterized in that: The antibacterial agent is an antibacterial agent for Acinetobacter baumannii.

7. Use of the compound I-28 according to claim 1 in the preparation of an antibacterial agent, characterized in that: The antibacterial agent is a bacteriostatic agent for methoxy-resistant Staphylococcus aureus.

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