α-Mangostin derivatives and preparation methods and applications thereof

Abstract

The present invention discloses α-mangostin derivatives and preparation methods and applications thereof. The α-mangostin derivatives provided by the present invention have a structural formula as shown in Formula I. It solves the drawback that α-mangostin is only effective against Gram-positive bacteria, and proposes a method for imparting broad-spectrum antibacterial activity to α-mangostin. The results show that among the 20 synthesized derivatives, 7 derivatives including AMG-7, -10c, -11c, -11c-r, -11c-1, -12 and -14 all show good broad-spectrum antibacterial activity, not only having good antibacterial activity against most Gram-positive bacteria, but also having excellent antibacterial activity against most Gram-negative bacteria, among which AMG-11c and AMG-11c-1 have the best antibacterial effect.

Description

Technical Field

[0001] The invention relates to the technical fields of chemistry, agriculture and medicine, and in particular to an alpha-mangostin derivative and a preparation method thereof and an application thereof in the preparation of a broad-spectrum antibacterial drug. Background Art

[0002] The rapid increase and spread of bacterial resistance seriously threatens global public health security. Antimicrobial drugs are the most effective means of treating drug-resistant bacteria. However, there are fewer and fewer clinically available antimicrobial drugs, especially those for Gram-negative bacteria (Lancet, 2022, 399, 2347; Nature, 2019, 576, 459). No drugs against Gram-negative bacteria have been approved in the past 20 years (Cell, 2020, 181, 29-45). The main reason for this is that the presence of the outer membrane of Gram-negative bacteria hinders the entry of drugs into the cell, and the embedded efflux pumps prevent most molecules from accumulating in the cell, resulting in many drugs that are effective against positive bacteria being ineffective against negative bacteria (Nature, 2018, 559, 617). Therefore, we intend to explore an effective strategy to make existing Gram-positive antibiotics have broad-spectrum antibacterial activity.

[0003] Currently, the main methods reported are to achieve the broad spectrum of Gram-positive antibiotics by two means: synergistic enhancers or chemical derivatization. Compounds that enhance the activity of antibiotics through indirect mechanisms are generally called synergistic enhancers. Its advantage is that it can directly extend the service life of existing drugs and shorten the process of drug development; however, such drug combinations may bring more adverse reactions. Chemically modifying existing compounds that are effective against Gram-positive bacteria to activate them and obtain the ability to kill Gram-negative bacteria is one of the main means of developing Gram-negative antibiotics. The most successful case in the clinic is to obtain the derivative ampicillin by adding primary amines to penicillin G, thereby producing broad-spectrum antibacterial activity. The main difference is that they are easier to penetrate the outer membrane of Gram-negative bacteria than penicillin G. The purpose of the present invention is to confer broad-spectrum antibacterial activity to the plant-derived natural product α-mangostin (AMG) studied in the early stage by chemical derivatization.

[0004] In previous studies, we screened 85 prenylated flavonoids from 271 natural plant secondary metabolites, selected one lead compound from each of the five major flavonoid classes, and found that the flavonoids containing two isopentenyl groups were the most potent flavonoids in the wild. The ketone compound AMG has excellent anti-Gram-positive bacteria activity, but is inactive against Gram-negative bacteria (MIC value greater than 128 μg / mL) (Advanced Science, 2021, 8, e2100749; RSC Medicinal Chemistry, 2021, 13, 107). In addition, although AMG has many ideal pharmacological properties, such as molecular weight, number of hydrogen donors and acceptors, and number of rotatable bonds. However, the disadvantages of AMG's low amphiphilicity and low water solubility make it difficult to pass through the outer membrane of Gram-negative bacteria. Summary of the invention

[0005] Based on the deficiency that α-mangostin is only effective against Gram-positive bacteria, the present invention designs a series of α-mangostin derivatives (AMG 1-14), and explores their antibacterial activities against Gram-positive bacteria (including standard strains, clinically sensitive strains, and clinically resistant strains) such as Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus suis, and Gram-negative bacteria (including standard strains, clinically sensitive strains, and clinically resistant strains) such as Escherichia coli, Salmonella, Haemophilus parasuis, Acinetobacter baumannii, Klebsiella pneumoniae, Aeromonas, and fungi such as Candida albicans, Candida glabrata, Candida krusei, and Candida tropicalis.

[0006] The object of the present invention is to provide a series of α-mangostin derivatives having broad-spectrum antibacterial activity.

[0007] The α-mangostin derivative provided by the present invention has a structural formula as shown in Formula I:

[0008]

[0009] In Formula I, R 1 It can be halogen, H, and the halogen can specifically be chlorine;

[0010] R 2 , R 3 Each independently selected from Wherein n is an integer of 1-4, specifically 1-2; R 4 Can be selected from -CN, -CONH 2 、-NHCOCH 3 、-CONHCH 2 CH 2 OH, -COOCH 2 CH 2 -Ph-NH 2 、-CONH(CH 2 ) m N(R 5 )(R 6 )(m=1-6, specifically 1-4 or 1, 2, 3, 4, R5 , R 6 Each independently is H, C 1 -C 6 alkyl), halogen, -N(R 5 )(R 6 )(R 5 , R 6 Each independently is H, C 1 -C 6 Alkyl), -OH,

[0011] (l is an integer of 1-4, specifically 1, 2, R 5 , R 6 Each independently is H, C 1 -C 6 Alkyl) and At least one of them.

[0012] Specifically, the α-mangostin derivative is any one of the following compounds:

[0013]

[0014]

[0015] The application of the above-mentioned α-mangostin derivatives in the following aspects also falls within the protection scope of the present invention:

[0016] 1) Anti-bacterial infection;

[0017] 2) Anti-fungal infection;

[0018] 3) Preparation of antibacterial agents.

[0019] The bacteria include Gram-positive bacteria and Gram-negative bacteria;

[0020] The bacteria include standard strains, clinically sensitive strains, and clinically resistant strains;

[0021] The Gram-positive bacteria include Staphylococcus aureus, Enterococcus, Streptococcus suis, Clostridium perfringens, etc.

[0022] The Gram-negative bacteria include Escherichia coli, Salmonella, Haemophilus parasuis, Acinetobacter baumannii, Klebsiella pneumoniae, Aeromonas and the like.

[0023] The fungi include standard strains and clinically sensitive strains;

[0024] The fungal strains include Candida albicans, Candida glabrata, Candida krusei, and Candida tropicalis.

[0025] The Staphylococcus aureus includes: Staphylococcus aureus ATCC 29213, Staphylococcus aureus 231, Staphylococcus aureus 232, Staphylococcus aureus 224, Staphylococcus aureus 233-2, Staphylococcus aureus 223-1, methicillin-resistant Staphylococcus aureus DL44, methicillin-resistant Staphylococcus aureus DY82, methicillin-resistant Staphylococcus aureus SF30, methicillin-resistant Staphylococcus aureus 74, and methicillin-resistant Staphylococcus aureus 155;

[0026] Enterococci include Enterococcus faecium 20HB9RX11, Enterococcus faecium 20HB9RX12, Enterococcus faecium 20HB9RX15, Enterococcus faecium 20HB9RX27, Enterococcus faecium 20HB9RX36, Enterococcus faecalis 20HB9RX13, Enterococcus faecalis 20HB9RX19, Enterococcus faecalis 20HB9RX24, Enterococcus faecalis 20HB9RX2, and Enterococcus faecalis 20HB9RX2;

[0027] Streptococcus suis includes Streptococcus suis ATCC43765, Streptococcus suis T73, Streptococcus suis B73-1, Streptococcus suis B40, Streptococcus suis B41, Streptococcus suis B58, Streptococcus suis B57, Streptococcus suis B56, Streptococcus suis B43;

[0028] Clostridium perfringens includes Clostridium perfringens 2020sj5rx165, Clostridium perfringens 21sx4pky10, Clostridium perfringens 2020sj5rx13, Clostridium perfringens 20HB8PK32, Clostridium perfringens 20HB9RX14, Clostridium perfringens 19SX3RX70, Clostridium perfringens 19NM2CM20, Clostridium perfringens 19NM1CM25, Clostridium perfringens 19SX3FX100, Clostridium perfringens 19NM1CM9;

[0029] Escherichia coli includes Escherichia coli ATCC 25922, Escherichia coli 1DM25, Escherichia coli 1DM27, Escherichia coli 1DM31, Escherichia coli 1DM33, Escherichia coli 1DM30, Escherichia coli 1DM4, Escherichia coli 1DM47, Escherichia coli 1DM50, Escherichia coli 1DM44, Escherichia coli B2, Escherichia coli 16DQZXRF1SBC, Escherichia coli 16QD8DZ68BC, Escherichia coli 16QD1AE8RC, Escherichia coli 16QD1AZ6RC, Escherichia coli 17QD3AZ38RC, Escherichia coli 16QDZAE6RC, Escherichia coli 16QD21SDZ87BC, Escherichia coli 16QD1AZ1RC, Salmonella enterica SH170, Escherichia coli 15QDHSDZ80BC, Escherichia coli 16QD2AZ1RC, Escherichia coli SH130, Escherichia coli 32-2, Escherichia coli 10R1-1, Escherichia coli 19QD1DZ21R, Escherichia coli 30-1R, Escherichia coli 14-3R, Escherichia coli 26-1, Escherichia coli 6-1, Escherichia coli 18QD2DZ22WR, Escherichia coli 18QD11MM2-1R, Escherichia coli 1 8QD2NN7WR, E. coli 18QD2DZ56-3-5R, E. coli 18QD3DZ3RR, E. coli 50-2R, E. coli 45-1R, E. coli 18QD11MM2-35R, E. coli 18QD4NM2RR, E. coli 17QD5RH11RK, E. coli 17QD5RZ8RK, E. coli 17QD5KZ18RK, E. coli 17QD3RP3RK, E. coli 17QD3RP2RK, E. coli 17QD3RP15RK, E. coli 17 QD5RH5RK, E. coli 17QD3RH5RK, E. coli 17QD5RZ22RK, E. coli 17QD5RZ17RK, E. coli 18QD2RY1RK, E. coli 17QD5RZ35RK, E. coli 17QD5RZ28RK, E. coli 17QD5RZ25RK, E. coli 17QD5RZ23RK, E. coli 17QD3RF20RK, E. coli 17QD3RF14RK, E. coli 17QD5RH4RK, E. coli 17QD5RZ2RK;

[0030] Salmonella includes Salmonella 90, Salmonella 89, Salmonella 181, Salmonella 236, Salmonella 206, Salmonella 92, Salmonella 61, Salmonella 190, and Salmonella 88;

[0031] Haemophilus parasuis includes Haemophilus parasuis 2BY2, Haemophilus parasuis BY20-2, Haemophilus parasuis BY27, Haemophilus parasuis BY59-1, Haemophilus parasuis TZ73-2, Haemophilus parasuis CY12, Haemophilus parasuis SD101-1, Haemophilus parasuis BY29-2, Haemophilus parasuis BY10-2, and Haemophilus parasuis BY13;

[0032] Pasteurella includes Pasteurella PMSH-2, Pasteurella PMSX-20, Pasteurella PMSX-4, Pasteurella PMSC-5, Pasteurella PMSC-3, Pasteurella PMSH-1, Pasteurella PMSX-24, Pasteurella PMSC-1, Pasteurella PMSC-2;

[0033] Klebsiella pneumoniae includes Klebsiella pneumoniae ATCC 43816, Klebsiella pneumoniae JQ2707, Klebsiella pneumoniae JC4209, Klebsiella pneumoniae JC4279, Klebsiella pneumoniae JC4057, Klebsiella pneumoniae JC4152, Klebsiella pneumoniae JC3619, Klebsiella pneumoniae JC3853, Klebsiella pneumoniae JC3493, and Klebsiella pneumoniae JQ2989;

[0034] Aeromonas includes Aeromonas 17QDFSK8BW, Aeromonas 17QDFSK7BG, Aeromonas 17QDFSK3BG, Aeromonas 17QDFSK2BG, Aeromonas 17QDFSK5BW, Aeromonas 17QDFSK5BG, Aeromonas 17QDFSK1BW, and Aeromonas 17QDFSK5BB.

[0035] The Candida albicans include Candida albicans ATCC10231, Candida albicans CAUF1, Candida albicans CAUF3, and Candida albicans CAUF4;

[0036] The Candida glabrata includes Candida albicans ATCC 2001;

[0037] The Candida kruseii includes Candida kruseii ATCC 6258;

[0038] The tropical Candida includes Candida tropicalis CAUF 2.

[0039] Among the 20 synthesized derivatives, eight derivatives, AMG-7, -10c, -11c, -11c-r, -11c-1, -12, -12-d, and -14, all showed good antibacterial activity against Gram-positive bacteria, including the MIC of AMG-7 against Staphylococcus spp. 50 The MIC value is 2 μg / mL, Enterococcus bacteria 50 The MIC value is 1 μg / mL, Streptococcus bacteria 50 The value is 8μg / mL; the MIC of AMG-10c against Staphylococcus 50 The MIC value is 1 μg / mL, Enterococcus bacteria 50 The MIC value is 0.5 μg / mL, Streptococcus bacteria 50 The value is 2 μg / mL; the MIC of AMG-11c against Staphylococcus 50 The MIC value is 1 μg / mL, Enterococcus bacteria 50 The MIC value is 1 μg / mL, Streptococcus bacteria 50 The MIC value is 1 μg / mL, Clostridium bacteria 50 The value is 2 μg / mL; the MIC of AMG-11c-r against Staphylococcus 50 The MIC value is 2 μg / mL, Enterococcus bacteria 50 The MIC value is 1 μg / mL, Streptococcus bacteria 50 The MIC value is 2 μg / mL, Clostridium bacteria 50 The value is 4 μg / mL; the MIC of AMG-11c-1 against Staphylococcus 50 The MIC value is 1 μg / mL, Enterococcus bacteria 50 The MIC value is 1 μg / mL, Streptococcus bacteria 50 The MIC value is 1 μg / mL, Clostridium bacteria 50 The value is 2μg / mL; the MIC of AMG-12 against Staphylococcus 50 The MIC value is 0.5 μg / mL, Enterococcus bacteria 50 The MIC value is 0.5 μg / mL, Streptococcus bacteria 50 The value is 2μg / mL; the MIC of AMG-12-d against Staphylococcus 50 The MIC value is 1 μg / mL, Enterococcus bacteria 50 The MIC value is 1 μg / mL, Streptococcus bacteria 50 The value is 2 μg / mL; the MIC of AMG-14 against Staphylococcus 50 The MIC value is 0.5 μg / mL, Enterococcus bacteria 50The MIC value is 0.5 μg / mL, Streptococcus bacteria 50 The value is 0.13μg / mL.

[0040] Among the 20 synthesized derivatives, eight derivatives, AMG-7, -10c, -11c, -11c-r, -11c-1, -12, -12-d and -14, all effectively expanded their antibacterial activity and showed good antibacterial activity against Gram-negative bacteria, including the MIC of AMG-7 against Escherichia coli. 50 The MIC value of Salmonella is 4 μg / mL. 50 The MIC value is 4 μg / mL, Acinetobacter 50 The MIC value of Klebsiella is 2 μg / mL. 50 The value is 4 μg / mL; the MIC of AMG-10c against Escherichia coli 50 The MIC value of Salmonella is 2 μg / mL. 50 The MIC value is 4 μg / mL, Acinetobacter 50 The MIC value of Klebsiella is 2 μg / mL. 50 The value is 2μg / mL; the MIC of AMG-11c against Escherichia coli 50 The MIC value of Salmonella is 2 μg / mL. 50 The MIC value is 4 μg / mL, Haemophilus bacteria 50 The MIC value is 8 μg / mL, Acinetobacter 50 The MIC value of Klebsiella is 2 μg / mL. 50 The MIC value of Aeromonas bacteria is 3 μg / mL. 50 The value is 4 μg / mL; the MIC of AMG-11c-r against Escherichia coli 50 The MIC value of Salmonella is 8 μg / mL. 50 The MIC value is 16 μg / mL, and the MIC value of Haemophilus 50 The MIC value is 32 μg / mL, and the MIC of Acinetobacter spp. 50 The MIC value of Klebsiella is 4 μg / mL. 50 The MIC value of Aeromonas bacteria is 12 μg / mL. 50 The value is 16μg / mL; the MIC of AMG-11c-1 against Escherichia coli 50 The MIC value of Salmonella is 2 μg / mL. 50 The MIC value is 4 μg / mL, Haemophilus bacteria 50 The MIC value is 8 μg / mL, Acinetobacter 50The MIC value of Klebsiella is 2 μg / mL. 50 The MIC value of Aeromonas bacteria is 4 μg / mL. 50 The value is 4μg / mL; the MIC of AMG-12 against Escherichia coli 50 The MIC value of Salmonella is 2 μg / mL. 50 The MIC value is 2 μg / mL, Acinetobacter 50 The MIC value of Klebsiella is 2 μg / mL. 50 The value is 2μg / mL; the MIC of AMG-14 against Escherichia coli 50 The MIC value of Salmonella is 2 μg / mL. 50 The MIC value is 4 μg / mL, Acinetobacter 50 The MIC value of Klebsiella is 4 μg / mL. 50 The value is 4μg / mL.

[0041] Table 1 shows the physicochemical properties of 20 derivatives synthesized by the present invention.

[0042] Table 1. Physicochemical properties of α-mangostin derivatives

[0043]

[0044] The present invention also provides an antibacterial agent, which is used for resisting bacterial infection and antifungal infection.

[0045] The antibacterial agent provided by the present invention contains at least one of the above-mentioned α-mangostin derivatives.

[0046] The present invention combines the structural characteristics of the cell membrane of Gram-negative bacteria, introduces groups of different polarity into the AMG molecule to increase its binding to the outer membrane or improve the possibility of its accumulation in the bacterial cell, and further explores the changes in its antibacterial activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The growth curves of E.coli B2 under the action of different concentrations of AMG derivatives. (A) The inhibitory effect of polymyxin E on the growth of E.coli B2 at different concentrations; (B) The inhibitory effect of the derivative AMG-9c on the growth of E.coli B2 at different concentrations; (C) The inhibitory effect of the derivative AMG-10c on the growth of E.coli B2 at different concentrations; (D) The inhibitory effect of the derivative AMG-11c on the growth of E.coli B2 at different concentrations.

[0048] Figure 2Safety assessment of the derivative AMG-11c. (A) AMG-11c has low hemolytic activity against sheep red blood cells; (B) AMG-11c has a wide safety therapeutic index.

[0049] Figure 3 It is the accumulation amount of the derivative AMG-11c in E.coli B2 cells at different times.

[0050] Figure 4 This is the survival curve of G. mellonella after 72 hours of infection with E. coli B2. DETAILED DESCRIPTION

[0051] The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

[0052] The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

[0053] Strains used in the experiment: The standard strains used in this experiment were purchased from the China General Microbiological Culture Collection Center (CGMCC); the remaining clinical resistant strains were isolated by this laboratory.

[0054] Main reagents and consumables: MH medium (MHB) was purchased from Beijing Luqiao Technology Co., Ltd.; α-mangostin was purchased from Chengdu Purifa Technology Development Co., Ltd.;

[0055] Example 1: Synthesis of α-mangostin derivatives

[0056] A series of nitrogen atom or halogen atom-containing groups are simultaneously introduced into the hydroxyl groups at the 3rd and 5th positions of α-mangostin, thereby obtaining an α-mangostin derivative (AMG-1-14).

[0057] Synthetic AMG-1:

[0058]

[0059] α-Mangostin (100 mg, 0.24 mM) was dissolved in 2 mL of dichloromethane, and N-chlorosuccinimide (70 mg, 0.53 mM) was added for stirring and dissolving. The reaction was allowed to react at room temperature with nitrogen as protection for 30 min. The reaction solution was diluted with a saturated aqueous sodium thiosulfate solution and then extracted with dichloromethane. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted with a petroleum ether-ethyl acetate (9:1, V / V) system through a silica gel column to obtain the product AMG-1 (26 mg) with a yield of 24%.

[0060] Synthetic AMG-2:

[0061]

[0062] α-Mangostin (100 mg, 0.24 mM) was dissolved in 5 mL of acetone, and potassium carbonate (100 mg, 0.73 mM) and dibromomethane (130 mg, 0.75 mM) were added and stirred to dissolve. The mixture was reacted at 100 ° C for 12 h and then cooled to room temperature. Cuprous cyanide (67 mg, 0.75 mM) was added to the resulting solution, the reaction was heated to 130 ° C, and the reaction was stirred for 24 h, then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted with a petroleum ether-ethyl acetate (3:1, V / V) system through a silica gel column to obtain the product AMG-2 (26 mg) with a yield of 91%.

[0063] Synthesis of AMG-3, -5, -6:

[0064]

[0065] α-Mangostin (1.0 g, 7.29 mM) was dissolved in 20 mL of acetonitrile, potassium carbonate (1.0 g, 7.29 mM) and ethyl chloroacetate (0.89 g, 7.29 mM) were added and stirred to dissolve. After the mixture was refluxed for 12 h, it was cooled to room temperature. The reaction solution was extracted with ethyl acetate, then washed with a saturated saline solution, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted with a petroleum ether-ethyl acetate (8:1, V / V) system through a silica gel column to obtain product a (1.30 g) with a yield of 92%. Product a (1.0 g, 1.71 mM) was dissolved in 5 mL of tetrahydrofuran, 8 mL of 5% lithium hydroxide aqueous solution was added, the reaction system was stirred at room temperature for 2 h, and then neutralized with acetic acid. The reaction solution was extracted with ethyl acetate, then washed with a saturated saline solution, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was passed through a silica gel column and eluted with a petroleum ether-ethyl acetate (1:1, V / V) system to obtain product b (753 mg) with a yield of 84%.

[0066] The mixture was dissolved in 3 mL of dimethylformamide, and ammonium chloride (30 mg, 0.57 mM), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (218 mg, 1.14 mM) and dimethylaminopyridine (100 mg, 0.19 mM) were added for stirring and dissolving. The reaction mixture was stirred at room temperature for 12 h, the reaction solution was extracted with ethyl acetate, then washed with saturated saline solution, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted by silica gel chromatography with petroleum ether-ethyl acetate (20:1, V / V) system to obtain AMG-3 (92 mg) with a yield of 92%.

[0067] The product b (100 mg, 0.19 mM) was dissolved in 3 mL of dimethylformamide, and ethanolamine (35 mg, 0.57 mM), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (218 mg, 1.14 mM) and dimethylaminopyridine (100 mg, 0.19 mM) were added for stirring and dissolving. The reaction mixture was stirred at room temperature for 12 h, and the reaction solution was extracted with ethyl acetate, then washed with saturated saline solution, and the organic phase was dried with anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product was passed through a silica gel column and eluted with a dichloromethane-methanol (20:1, V / V) system to obtain AMG-5 (76 mg) with a yield of 65%.

[0068] The product b (100 mg, 0.19 mM) was dissolved in 3 mL of dimethylformamide, and p-Fmoc-4-(2-chloroethyl)aniline (147 mg, 0.57 mM), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg, 1.14 mM) and dimethylaminopyridine (5 mg, 0.04 mM) were added for stirring and dissolving. The reaction mixture was stirred at room temperature for 12 h, and the reaction solution was extracted with ethyl acetate, then washed with saturated saline solution, and the organic phase was dried with anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product was eluted by silica gel chromatography with petroleum ether-ethyl acetate (5:1, V / V) system to obtain product c (76 mg) with a yield of 88%. Product c (100 mg, 0.08 mM) was dissolved in 5 mL of tetrahydrofuran, piperidine (15 mg, 0.32 mM) was added and stirred to dissolve, the reaction system was stirred at room temperature for 2 h, the reaction solution was extracted with ethyl acetate, then washed with saturated saline solution, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was passed through a silica gel column and eluted with a petroleum ether-ethyl acetate (2:1, V / V) system to obtain AMG-6 (52 mg) with a yield of 80%.

[0069] Synthetic AMG-4:

[0070]

[0071] α-Mangostin (400 mg, 0.96 mM) was dissolved in 5 mL of acetone, and potassium carbonate (672 mg, 4.88 mM) and 1,2-dibromoethane (2.74 g, 14.60 mM) were added for stirring and dissolving. After the mixture was refluxed for 24 h, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Then it was redissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted by silica gel chromatography with petroleum ether-ethyl acetate (20:1, V / V) system to obtain product a (396 mg) with a yield of 65%. Product a (374 mg, 0.60 mM) was dissolved in 5 mL of anhydrous dimethylformamide, and potassium phthalimide (222 mg, 1.20 mM) was added for stirring and dissolving. After the mixture was stirred at 90 ° C for 12 h, it was cooled to room temperature. Dilute with ethyl acetate, wash with saturated sodium bicarbonate aqueous solution and salt solution in turn, dry the organic phase with anhydrous sodium sulfate, and concentrate on a rotary evaporator. The crude product is eluted by a silica gel column with a petroleum ether-ethyl acetate (2:1, V / V) system to obtain product b (322 mg) with a yield of 71%. Product b (302 mg, 0.40 mM) is dissolved in a mixed solution of 5 mL methylamine (40% water) and 10 mL methanol, and the mixture system is refluxed at 70 ° C for 7 h and cooled to room temperature. The reaction mixture is extracted with ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution and salt solution in turn, and the organic phase is dried with anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude product is eluted by a silica gel column with a dichloromethane-methanol-acetamide (50:1:0.5-15:1:0.15, V / V) system to obtain product AMG-11c (66 mg) with a yield of 35%. AMG-11c (37 mg, 0.08 mM) was dissolved in 1 mL of acetic acid solution, and acetic anhydride (25 mg, 0.24 mM) and methanesulfonic acid (23 mg, 0.24 mM) were added and stirred to dissolve. The resulting mixture was stirred at 70 ° C for 30 min, diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted by silica gel chromatography with petroleum ether-ethyl acetate (10:1, V / V) system to obtain the product AMG-4 (23 mg) with a yield of 52%.

[0072] Synthetic AMG-7:

[0073]

[0074] α-Mangostin (1.0g, 2.43mM) was dissolved in 20mL acetone, potassium carbonate (1.0g, 7.29mM) and ethyl chloroacetate (0.89g, 7.29mM) were added and stirred to dissolve. After the mixture was refluxed for 12h, it was cooled to room temperature, and then an appropriate amount of ethyl acetate was added, and washed with saturated saline solution, the organic phase was dried with anhydrous sodium sulfate, extracted, and the organic phase was concentrated with a rotary evaporator. The crude product was eluted with a petroleum ether-ethyl acetate (8:1, V / V) system through a silica gel column to obtain product a (1.3g) with a yield of 92%. Product a (1.0g, 1.71mM) was dissolved in 5mL tetrahydrofuran, and 5% lithium hydroxide aqueous solution (8mL) was added to stir and dissolve. After the mixture was stirred at room temperature for 2h, acetic acid was added for neutralization. Then an appropriate amount of ethyl acetate was added, and washed with saturated saline, the organic phase was dried with anhydrous sodium sulfate, and concentrated with a rotary evaporator. The crude product was eluted by a silica gel column with a petroleum ether-ethyl acetate (1:1, V / V) system to obtain product b (753 mg) with a yield of 84%. Product b (100 mg, 0.19 mM) was dissolved in 3 mL of tetrahydrofuran, and N-tert-butyloxycarbonylethylenediamine (91 mg, 0.57 mM), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (218 mg, 1.14 mM) and 4-dimethylaminopyridine (5 mg, 0.04 mM) were added, and the reaction was stirred at room temperature for 12 h. An appropriate amount of ethyl acetate was added to the reaction solution, washed with a saturated saline solution, extracted, and the organic phase was dried with anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude product was eluted by a silica gel column with a petroleum ether-ethyl acetate (5:1, V / V) system to obtain product c (121 mg) with a yield of 79%. The product c (100 mg, 0.12 mM) was dissolved in 3 mL of tetrahydrofuran, sodium tert-butoxide (71 mg, 0.73 mM) was added, and the resulting mixture was refluxed for 3 h, cooled to room temperature, and neutralized with acetic acid. After stirring for 30 min, 6 M sodium hydroxide aqueous solution was added to adjust the pH to 10.0. An appropriate amount of ethyl acetate was added to the resulting mixture, washed with a saturated saline solution, extracted, and the organic phase was dried with anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude product was eluted by a silica gel column with a dichloromethane-methanol-acetamide (10:1:0.1, V / V) system to obtain the product AMG-7 (40 mg) with a yield of 54% (Journal of Medicinal Chemistry, 2011, 59, 171193).

[0075] Synthetic AMG-8:

[0076]

[0077] α-Mangostin (100 mg, 0.24 mM) was dissolved in 3 mL of acetone, and potassium carbonate (168 mg, 1.22 mM) and 1,4-dibromobutane (788 mg, 3.65 mM) were added for stirring and dissolving. After the mixture was refluxed for 24 hours, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. It was then redissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted by a silica gel column with a petroleum ether-ethyl acetate (20:1, V / V) system to obtain product a (119 mg) with a yield of 72%. Product a (102 mg, 0.15 mM) was dissolved in dimethyl sulfoxide, diethylamine (110 mg, 1.5 mM) was added, the mixture was stirred at room temperature for 4 h, an appropriate amount of ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted by silica gel chromatography with petroleum ether-ethyl acetate (20:1, V / V) system to obtain AMG-8 (65 mg), with a yield of 65% (Journal of Medicinal Chemistry, 2011, 59, 171193).

[0078] Synthesis of AMG-9a-11c:

[0079]

[0080] α-Mangostin (400 mg, 0.96 mM) was dissolved in 5 mL of acetone, and potassium carbonate (672 mg, 4.88 mM) and 1,2-dibromoethane (2.74 g, 14.60 mM) (or 1,3-dibromopropane or 1,4-dibromobutane) were added for stirring and dissolving. After the mixture was refluxed for 24 hours, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Then it was redissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted by silica gel chromatography with petroleum ether-ethyl acetate (20:1, V / V) system to obtain product a (396 mg) with a yield of 65%. Product a (374 mg, 0.60 mM) was dissolved in 5 mL of anhydrous dimethylformamide, and potassium phthalimide (222 mg, 1.20 mM) was added for stirring and dissolving. The mixture was stirred at 90°C for 12 hours and then cooled to room temperature. Diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted with a petroleum ether-ethyl acetate (2:1, V / V) system through a silica gel column to obtain product b (322 mg) with a yield of 71%. Product b (302 mg, 0.40 mM) was dissolved in a mixed solution of 5 mL methylamine (40% water) and 10 mL methanol, and the mixture system was refluxed at 70°C for 7 hours and cooled to room temperature. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted by silica gel chromatography using a dichloromethane-methanol-ammonium acetate (50:1:0.5-15:1:0.15, V / V) system to obtain the product AMG-11c (66 mg) (or AMG-10c or AMG-9c) with a yield of 35% (Journal of Medicinal Chemistry, 2011, 59, 171193).

[0081] Optimized route for synthesizing AMG-11c:

[0082]

[0083] α-Mangostin (400 mg, 0.96 mM) was dissolved in 5 mL of acetone, potassium carbonate (672 mg, 4.88 mM) and N-(2-bromopropyl)phthalimide (3.51 g, 13.76 mM) were added for stirring and dissolving, the mixed solution was refluxed for 24 h, cooled to room temperature, and concentrated under reduced pressure to remove the solvent. Then it was redissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted by a silica gel column with a petroleum ether-ethyl acetate (5:1, V / V) system to obtain product a (701 mg) with a yield of 65%. Product a (701 mg, 0.80 mM) was dissolved in a mixed solution of 5 mL of methylamine (40% water) and 10 mL of methanol, and the mixture system was refluxed at 70 ° C for 7 h and cooled to room temperature. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution, and the organic phase was dried with anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude product was eluted by silica gel chromatography with dichloromethane-methanol-acetamide (50:1:0.5-15:1:0.15, V / V) system to obtain the product AMG-11c (120 mg) with a yield of 52%.

[0084] Compared with the literature report (Journal of Medicinal Chemistry, 2011, 59, 171193), the optimized synthesis route uses a simple intermediate, which has the advantage of reducing the loss of the parent core and thus increasing the yield of the final product.

[0085] Synthesis of AMG-11c-r:

[0086]

[0087] α-Mangostin (300 mg, 0.72 mM) was dissolved in 5 mL of methanol, and a palladium carbon catalyst (15 mg (5%, w / w)) was added. Hydrogen was vigorously stirred at room temperature for 8 h. The reaction solution was filtered on diatomaceous earth to remove the precipitate, and the filtrate was concentrated under reduced pressure to obtain intermediate a. a (200 mg, 0.48 mM) was dissolved in 3 mL of acetone, potassium carbonate (336 mg, 2.44 mM) and 1,2-dibromoethane (1.37 g, 7.3 mM) were added, refluxed for 24 h, and cooled to room temperature. The concentrate was concentrated under reduced pressure, dissolved in ethyl acetate, and then washed with saturated sodium bicarbonate aqueous solution and salt solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was passed through a silica gel column and eluted with petroleum ether-ethyl acetate (20:1, V / V) to obtain intermediate b (205 mg) with a yield of 68%. Product b (187 mg, 0.3 mM) was dissolved in anhydrous DMF, potassium phthalimide (111 mg, 0.6 mM) was added, stirred and reacted at 90 ° C for 12 h, and cooled to room temperature. Diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted with petroleum ether-ethyl acetate (20:1, V / V) through a silica gel column to obtain product c (171 mg) with a yield of 75%. Intermediate c (151 mg, 0.2 mM) was dissolved in a mixed solution of 5 mL methylamine (40% aqueous solution) and 10 mL methanol, and the mixed solution was refluxed at 70 ° C for 7 h, and then cooled to room temperature. The reaction solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saline solution in turn, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was passed through a silica gel column and eluted with a dichloromethane-methanol-ammonium acetate (50:1:0.5-15:1:0.15, V / V) system to give the product AMG-11c-r (88 mg) with a yield of 88%.

[0088] Synthesis of AMG-11c-1:

[0089]

[0090] α-Mangostin (200 mg, 0.48 mM) was dissolved in 3 mL of acetone, and potassium carbonate (336 mg, 2.44 mM) and 1,2-dibromoethane (1.37 g, 7.30 mM) were added for stirring and dissolving. After the mixture was heated to reflux for 24 h, it was cooled to room temperature and evaporated to remove the solvent. It was dissolved in ethyl acetate, then washed with saturated sodium bicarbonate and sodium chloride, the organic phase was dried with anhydrous sodium sulfate, and concentrated on a rotary evaporator. The crude product was eluted with a petroleum ether-ethyl acetate (20:1, V / V) system through a silica gel column to obtain intermediate a (198 mg) with a yield of 65%. Intermediate a (187 mg, 0.3 mM) was dissolved in 5 mL of methylamine solution (containing 2.0 M tetrahydrofuran), stirred at room temperature for 96 h, and then evaporated to remove the solvent. The crude product was passed through a silica gel column and gradient eluted with a dichloromethane-methanol-ammonium acetate (50:1:0.5-30:1:0.5, V / V) system to obtain the product AMG-11c-1 (113 mg) with a yield of 72%.

[0091] Synthetic AMG-12:

[0092]

[0093] α-Mangostin (100 mg, 0.24 mM) was dissolved in 5 mL of ethanol, potassium hydroxide (68 mg, 1.22 mM) was added, stirred at room temperature for 10 min, epibromopropane (500 mg, 3.65 mM) was added, stirred at 75 ° C for 8 h, cooled to room temperature, an appropriate amount of ethyl acetate was added, washed with saturated salt water solution, extracted, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted by a silica gel column with a petroleum ether-ethyl acetate (4:1, V / V) system to obtain product a (64 mg) with a yield of 50%. Product a (60 mg, 0.11 mM) was dissolved in 1 mL of 40% methylamine aqueous solution and 2 mL of ethanol was added. After stirring at room temperature for 5 h, an appropriate amount of n-butanol was added, washed with saturated salt water solution, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was purified by reverse phase HPLC using isocratic 60% (methanol-water, 0.1% formic acid) as eluent to obtain the product AMG-12 (27 mg) with a yield of 40% (Journal of Medicinal Chemistry, 2011, 59, 171193).

[0094] Synthesis of AMG-12-d:

[0095]

[0096] α-Mangostin (200 mg, 0.48 mM) was dissolved in 8 mL of ethanol, potassium hydroxide (136 mg, 2.44 mM) was added, stirred and reacted at room temperature for 10 min, epibromopropane (1 g, 7.30 mM) was added, stirred and reacted at 75 ° C for 8 h, cooled to room temperature, an appropriate amount of ethyl acetate was added, washed with saturated saline solution, extracted, the organic phase was dried with anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted with petroleum ether-ethyl acetate (4:1, V / V) system through a silica gel column to obtain product a (128 mg) with a yield of 50%. Intermediate a (120 mg, 0.22 mM) was dissolved in a mixture of 1 mL of ammonia water and 4 mL of methanol, and the mixture was stirred and reacted at room temperature for 5 h. The reaction solution was diluted with 1-butanol and then washed with saturated saline. The organic phase was dried with anhydrous sodium sulfate and concentrated by rotary evaporator. The crude product was purified by reverse phase HPLC using isocratic 60% (methanol-water, 0.1% formic acid) to give the product AMG-12-d (22 mg) in 18% yield.

[0097] Synthetic AMG-13:

[0098]

[0099] α-Mangostin (100 mg, 0.24 mM) was dissolved in 5 mL of dimethylformamide, and potassium carbonate (168 mg, 1.22 mM) and 2-bromoethanol (304 mg, 2.44 mM) were added to stir and dissolve. The reaction mixture was stirred at 90 ° C for 5 h and cooled to room temperature. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator. The crude product was eluted by silica gel chromatography with dichloromethane-methanol (100: 1-50: 1, V / V) system to obtain AMG-13 (79 mg) with a yield of 65% (Journal of Medicinal Chemistry, 2011, 59, 171193).

[0100] Synthetic AMG-14:

[0101]

[0102] AMG-11c (37 mg, 0.08 mM) was dissolved in 1 mL of dimethylformamide solution, 1H-pyrazole-1-carboxamidine hydrochloride (35 mg, 0.24 mM) and N,N-diisopropylethylamine (31 mg, 0.24 mM) were added, the reaction was stirred at room temperature overnight, an appropriate amount of ether was added, the insoluble solid was filtered and washed with ether. The crude product was recrystallized from methanol-methyl tert-butyl ether to obtain AMG-14 (27 mg) with a yield of 62% (Journal of Medicinal Chemistry, 2011, 59, 171193).

[0103] Structure confirmation data:

[0104] AMG: HRESI-MS: calculated value is C 24 H 26 O 6 [MH] - 409.1657, the measured value is 409.1654. 1 H NMR (400 MHz, DMSO-d 6 )δ: 13.72(s,1H,OH), 11.01(s,1H,OH), 10.82(s,1H,OH), 6.80(s,1H,Ar–H), 6.34(s,1H,Ar–H), 5.16(m,2H,2×CH), 4.01(d,2H,CH) 2 ), 3.70(s,3H,OCH 3 ), 3.20(d,2H,CH 2 ), 1.77(s,3H,CH 3 ), 1.72(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0105] AMG-1: HRESI-MS: calculated value is C 24 H 25 C1O 6 [MH] - 443.1267, the measured value is 443.1268. 1 H NMR (400 MHz, DMSO-d 6 )δ: 13.73(s,1H,OH), 11.23(brs,1H,Ar–OH), 10.63(brs,1H,Ar–OH), 6.86(s,1H,Ar–H), 5.15(m,2H,2×CH), 4.00(d,2H,CH 2 ), 3.72(s,3H,OCH 3), 3.30(d,2H,CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0106] AMG-2: HRESI-MS: calculated value is C 28 H 28 N 2 O 6 [MH] - 487.1875, the measured value is 487.1878. 1 HNMR (400 MHz, DMSO-d 6 )δ: 13.47(s,1H,OH), 7.34(s,1H,Ar–H), 6.83(s,1H,Ar–H), 5.44(s,2H,CH 2 ), 5.39(s,2H,CH 2 ), 5.15(m,2H,2×CH), 4.04(d,2H,CH 2 ), 3.74(s,3H,OCH 3 ), 3.27(d,2H,CH 2 ), 1.79(s,3H,CH 3 ), 1.75(s,3H,CH 3 ), 1.63(s,6H,2×CH 3 ).

[0107] AMG-3: HRESI-MS: calculated value is C 28 H 32 N 2 O 8 [MH] - 523.2086, the measured value is 523.2082. 1 H NMR (400 MHz, DMSO-d 6 )δ: 13.51(s,1H,OH), 7.54(s,1H,NH), 7.49(s,2H,2×NH), 7.40(s,1H,NH), 6.97(s,1H,Ar–H), 6.52(s,1H,Ar–H), 5.18(m,2H,2×CH), 4.73(s,2H,CH) 2 ), 4.63(s,2H,CH 2 ), 4.04(d,2H,CH 2 ), 3.77(s,3H,OCH 3 ), 3.32(d,2H,CH2 ), 1.79(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0108] AMG-4: HRESI-MS: calculated value is C 32 H 40 N 2 O 8 [MH] - 579.2712, the measured value is 579.2714. 1 HNMR (400MHz, CDCl3) δ: 13.49(s,1H,OH), 6.74(s,1H,Ar–H), 6.30(s,1H,Ar–H), 6.05(t,1H,NH), 5.89(t,1H,NH), 5.22(m,2H,2×CH), 4.17(t,2H,CH) 2 ), 4.13(t,2H,2×CH 2 ), 3.80(s,3H,OCH 3 ), 3.75(m,4H,2×CH 2 ), 3.37(d,2H,CH 2 ), 2.03(s,3H,CH 3 ), 2.01(s,3H,CH 3 ), 1.85(s,3H,CH 3 ), 1.81(s,3H,CH 3 ), 1.70(s,3H,CH 3 ), 1.69(s,3H,CH 3 ).

[0109] AMG-5: HRESI-MS: calculated value is C 32 H 40 N 2 O 10 [MH] - 611.2610, the measured value is 611.2612. 1 H NMR (400 MHz, DMSO-d 6 )δ: 13.52(s,1H,OH), 8.07(t,1H,NH), 7.93(t,1H,NH), 6.99(s,1H,Ar–H), 6.52(s,1H,Ar–H), 5.18(m,2H,2×CH), 4.77(s,2H,CH 2 ), 4.77(m,2H,2×OH), 4.68(s,2H,CH2 ), 4.04(d,2H,CH 2 ), 3.77(s,3H,OCH 3 ), 3.45(m,4H,2×CH 2 ), 3.32(d,2H,CH 2 ), 3.22(m,4H,2×CH 2 ), 1.79(s,3H,CH 3 ), 1.73(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0110] AMG-6: HRESI-MS: calculated value is C 44 H 48 N 2 O 10 [MH] - 763.3236, the measured value is 763.3242. 1 HNMR (400 MHz, DMSO-d 6 )δ: 13.53(s,1H,OH), 7.05(s,1H,Ar–H), 6.87(d,4H,4×Ar–H), 6.53(s,1H,Ar–H), 6.47(d,4H,4×Ar–H), 5.20(m,2H,2×CH), 5.07(s,2H,CH 2 ), 4.98(s,2H,CH 2 ), 4.89(s,4H,2×NH 2 ), 4.25(q,4H,2×CH 2 ), 4.05(d,2H,CH 2 ), 3.75(s,3H,OCH 3 ), 3.30(d,2H,CH 2 ), 2.73(m,4H,2×CH 2 ), 1.79(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.63(s,3H,CH 3 ), 1.62(s,3H,CH 3 ).

[0111] AMG-7: HRESI-MS: calculated value is C 32 H 42 N 4 O 8 [MH] - 609.2930, the measured value is 609.2930.1 HNMR (400 MHz, DMSO-d 6 )δ: 8.22(t,1H,NH), 8.08(t,1H,NH), 6.99(s,1H,Ar–H), 6.51(s,1H,Ar–H), 5.18(m,2H,2×CH), 4.77(s,2H,CH 2 ), 4.67(s,2H,CH 2 ), 4.03(d,2H,CH 2 ), 3.77(s,3H,OCH 3 ), 3.37(m,4H,2×CH 2 ), 3.33(d,2H,CH 2 ), 3.17(m,4H,2×CH 2 ), 1.78(s,3H,CH 3 ), 1.73(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0112] AMG-8: HRESI-MS: calculated value is C 40 H 60 N 2 O 6 [MH] - 664.4451, the measured value is 664.4449. 1 H NMR (400 MHz, CDCl 3 )δ: 13.50(s,1H,OH), 6.72(s,1H,Ar–H), 6.29(s,1H,Ar–H), 5.25(m,2H,2×CH), 4.13(d,2H,CH 2 ), 4.10(t,2H,CH 2 ), 4.06(t,2H,CH 2 ), 3.80(s,3H,OCH 3 ), 3.36(d,2H,CH 2 ), 2.55(m,12H,6×CH 2 ), 1.68(m,4H,2×CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ), 1.04(s,12H,4×CH 3 ).

[0113] AMG-9a: calculated value is C32 H 40 Br 2 O 6 [M+H] + 679.1264, the measured value is 679.1262. 1 HNMR (400MHz, CDCl 3 )δ: 13.48(s,1H,OH), 6.71(s,1H,Ar–H), 6.28(s,1H,Ar–H), 5.25(m,2H,2×CH), 4.13(t,2H,CH 2 ), 4.09(t,2H,CH 2 ), 4.07(d,2H,CH 2 ), 3.80(s,3H,OCH 3 ), 3.53(t,2H,CH 2 ), 3.50(t,2H,CH 2 ), 3.35(d,2H,CH 2 ), 2.14(m,8H,4×CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0114] AMG-9c:HRESI-MS: calculated value is C 32 H 44 N 2 O 6 [MH] - 551.3127, the measured value is 551.3125. 1 HNMR (400 MHz, DMSO-d 6 )δ: 13.50(s,1H,OH), 6.72(s,1H,Ar–H), 6.29(s,1H,Ar–H), 5.24(m,2H,2×CH), 4.13(d,2H,CH 2 ), 4.10(t,2H,CH 2 ), 4.06(t,2H,CH 2 ), 3.80(s,3H,OCH 3 ), 3.36(d,2H,CH 2 ), 2.55(m,12H,6×CH 2 ), 1.92(m,4H,2×CH 2 ), 1.82(s,3H,CH 3 ), 1.80(s,3H,CH 3), 1.62(s,6H,2×CH 3 ).

[0115] AMG-10a:HRESI-MS: calculated value is C 30 H 36 Br 2 O 6 [M+H] + 651.0951, the measured value is 651.0949. 1 HNMR (400MHz, CDCl 3 )δ: 13.48(s,1H,OH), 6.76(s,1H,Ar–H), 6.33(s,1H,Ar–H), 5.25(m,2H,2×CH), 4.24(t,2H,CH 2 ), 4.20(t,2H,CH 2 ), 4.13(d,2H,CH 2 ), 3.79(s,3H,OCH 3 ), 3.67(t,2H,CH 2 ), 3.62(t,2H,CH 2 ), 3.36(d,2H,CH 2 ), 2.45(m,2H,CH 2 ), 2.37(m,2H,CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0116] AMG-10c:HRESI-MS: calculated value is C 30 H 40 N 2 O 6 [MH] - 523.2814, the measured value is 523.2812. 1 HNMR (400 MHz, DMSO-d 6 )δ: 13.50(s,1H,OH), 6.73(s,1H,Ar–H), 6.30(s,1H,Ar–H), 5.25(m,2H,2×CH), 4.13(d,2H,CH 2 ), 4.09(t,2H,CH 2 ), 4.07(t,2H,CH 2 ), 3.79(s,3H,OCH 3 ), 3.36(d,2H,CH 2), 2.58(m,16H,2×CH 2 ), 2.45(m,2H,CH 2 ), 2.37(m,2H,CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0117] AMG-11a:HRESI-MS: calculated value is C 28 H 32 Br 2 O 6 [M+H] + 623.0638, the measured value is 623.0636. 1 HNMR (400 MHz, DMSO-d 6 )δ: 13.47(s,1H,OH), 6.69(s,1H,Ar–H), 6.26(s,1H,Ar–H), 5.25(m,2H,2×CH), 4.41(t,2H,CH 2 ), 4.37(t,2H,CH 2 ), 4.14(d,2H,CH 2 ), 3.86(s,3H,OCH 3 ), 3.76(t,2H,CH 2 ), 3.70(t,2H,CH 2 ), 3.38(d,2H,CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0118] AMG-11c: HRESI-MS: calculated value is C 28 H 36 N 2 O 6 [MH] - 495.2501, the measured value is 495.2498. 1 HNMR (400 MHz, DMSO-d 6 )δ: 7.03(s,1H,Ar–H), 6.52(s,1H,Ar–H), 5.16(m,2H,2×CH), 4.11(t,2H,CH 2 ), 4.04(t,2H,CH 2 ), 4.01(d,2H,CH2 ), 3.74(s,3H,OCH 3 ), 3.25(d,2H,CH 2 ), 2.97(t,2H,CH 2 ), 2.93(t,2H,CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0119] AMG-11c-r: HRESI-MS: calculated value is C 28 H 40 N 2 O 6 [MH] - 499.2814, the measured value is 499.2814. 1 HNMR (400 MHz, DMSO-d 6 )δ: 6.92(s,1H,Ar–H), 6.43(s,1H,Ar–H), 4.07(t,2H,CH 2 ), 4.00(t,2H,CH 2 ), 3.75(s,3H,OCH 3 ), 2.97(t,2H,CH 2 ), 2.92(t,2H,CH 2 ), 2.50(m,4H,2×CH 2 ), 1.66(m,1H,CH), 1.52(m,1H,CH), 1.32(m,4H,2×CH 2 ), 0.95(s,3H,CH 3 ), 0.93(s,3H,CH 3 ), 0.91(s,3H,CH 3 ), 0.89(s,3H,CH 3 ).

[0120] AMG-11c-1: HRESI-MS: calculated value is C 30 H 40 N 2 O 6 [M+H] + 525.2959, the measured value is 525.2955. 1 HNMR (400 MHz, DMSO-d 6) δ: 7.05 (s, 1H, Ar–H), 6.55 (s, 1H, Ar–H), 5.15 (m, 2H, 2×CH), 4.20 (t, 2H, CH 2 ), 4.14 (t, 2H, CH 2 ), 4.02 (d, 2H, CH 2 ), 3.73 (s, 3H, OCH 3 ), 3.25 (d, 2H, CH 2 ), 2.92 (t, 2H, CH 2 ), 2.88 (t, 2H, CH 2 ), 2.37 (s, 3H, CH 3 ), 2.36 (s, 3H, CH 3 ), 1.77 (s, 3H, CH 3 ), 1.73 (s, 3H, CH 3 ), 1.62 (s, 6H, 2×CH 3 ).

[0121] AMG - 12: HRESI - MS: Calculated for C 32 H 44 N 2 O 8 [M - H] - 583.3025, found 583.3025. 1 H NMR (400 MHz, DMSO - d 6 ) δ: 8.32 (s, 2H, 2×NH), 7.09 (s, 1H, Ar–H), 6.59 (s, 1H, Ar–H), 5.17 (m, 2H, 2×CH), 4.17 (dd, 2H, CH 2 ), 4.12 (dd, 2H, CH 2 ), 4.10 (brs, 2H, 2×CH), 4.04 (d, 2H, CH 2 ), 3.75 (s, 3H, OCH 3 ), 3.28 (d, 2H, CH 2 ), 2.93 (m, 2H, CH 2 ), 2.84 (m, 2H, CH 2 ), 2.47 (s, 3H, CH 3 ), 2.46 (s, 3H, CH 3 ), 1.78 (s, 3H, CH 3 ), 1.74 (s, 3H, CH 3 ), 1.62 (s, 6H, 2×CH 3 ).

[0122] AMG-12-d: HRESI-MS: calculated value is C 30 H 40 N 2 O 8 [MH] - 555.2712, the measured value is 555.2709. 1 HNMR (400 MHz, DMSO-d 6 )δ: 8.34(s,2H,2×NH), 7.11(s,1H,Ar–H), 6.55(s,1H,Ar–H), 5.14(m,2H,2×CH), 4.16(dd,2H,CH 2 ), 4.11(dd,2H,CH 2 ), 4.09(brs,2H,2×CH), 4.03(d,2H,CH 2 ), 3.73(s,3H,OCH 3 ), 3.27(d,2H,CH 2 ), 2.93(m,2H,CH 2 ), 2.84(m,2H,CH 2 ), 1.76(s,3H,CH 3 ), 1.72(s,3H,CH 3 ), 1.60(s,6H,2×CH 3 ).

[0123] AMG-13: HRESI-MS: calculated value is C 28 H 34 O 8 [MH] - 497.2181, the measured value is 497.2180. 1 H NMR (400 MHz, DMSO-d 6 )δ: 13.53(s,1H,OH), 7.07(s,1H,Ar–H), 6.56(s,1H,Ar–H), 5.17(m,2H,2×CH), 4.98(t,1H,OH), 4.92(t,1H,OH), 4.20(t,2H,CH 2 ), 4.13(t,2H,CH 2 ), 4.03(d,2H,CH 2 ), 3.80(m,4H,2×CH 2 ), 3.75(s,3H,OCH 3 ), 3.27(d,2H,CH 2 ), 1.78(s,3H,CH 3), 1.73(s,3H,CH 3 ), 1.62(s,6H,2×CH 3 ).

[0124] AMG-14: HRESI-MS: calculated value is C 32 H 44 N 2 O 8 [M+H] + 581.3082, the measured value is 581.3061. 1 H NMR (400 MHz, DMSO-d 6 )δ: 13.54(s,1H,OH), 7.78(t,2H,2×NH), 7.11(s,1H,Ar–H), 6.61(s,1H,Ar–H), 5.17(m,2H,2×CH), 4.27(t,2H,CH 2 ), 4.23(t,2H,CH 2 ), 4.04(d,2H,CH 2 ), 3.74(s,3H,OCH 3 ), 3.67(dd,2H,CH 2 ), 3.63(dd,2H,CH 2 ), 3.29(d,2H,CH 2 ), 1.78(s,3H,CH 3 ), 1.74(s,3H,CH 3 ), 1.63(s,6H,2×CH 3 ).

[0125] Example 2, Determination of antibacterial activity of α-mangostin derivatives

[0126] Referring to the microbroth dilution method recommended by the U.S. Committee for Clinical Laboratory Standards (CLSI 2022), the minimum inhibitory concentration (MIC) of AMG and its derivatives, including standard strains, clinically sensitive strains, and clinically resistant strains, was determined. The MIC result was mainly determined in accordance with the CLSI M100-32st Edition (2022) standard. The steps for detecting the minimum inhibitory concentration are as follows:

[0127] a) Dissolve the test compound in an appropriate amount of dimethyl sulfoxide (DMSO), add 100 μL of MHB broth medium to a 96-well U-shaped plate, take 100 μL of a certain concentration of compound and add it to the first column of the 96-well U-shaped plate, and dilute it to the tenth column in multiple ratios.

[0128] b) Pick a single colony of the test strain and place it in BHI broth, and culture it on a shaker at 37°C until the bacterial logarithmic growth phase. Use a McFarland turbidimeter to adjust the bacterial turbidity to 0.5, and dilute it 100 times (about 10) with MHB broth. 6 CFU / mL), and 100 μL of the above bacterial solution was added to a 96-well U-shaped plate.

[0129] c) Columns 11 and 12 contain only MHB broth and the test bacteria, respectively, and serve as negative and positive controls. The 96-well U-shaped plate was placed in a 37°C constant temperature incubator for 16-18 hours, and the experimental results were read. The lowest drug concentration that inhibited bacterial growth visible to the naked eye was the MIC value of the compound. Three replicates were set for each experiment.

[0130] Results: The drug sensitivity test showed that compared with AMG, some of the derivatives of the present invention had better effects on Gram-positive bacteria, which may be related to the enhanced destructive power of AMG on bacterial membrane integrity after modification. It is worth noting that some AMG derivatives can reverse the antibacterial activity against Gram-negative bacteria, including standard strains, clinical sensitive strains, and clinical resistant strains, especially AMG-7, -9c, -11c, -11c-r, -11c-1, -12, -12-d, and -14, which have the best antibacterial effects, with a minimum inhibitory concentration of 0.5-4μg / mL, as shown in Table 2. These data show that after modification, AMG has achieved a broad spectrum of antibacterial activity.

[0131] Table 2. Antibacterial activity of α-mangostin derivatives

[0132]

[0133]

[0134] Note: The X in AMG-X stands for numbers 1-14.

[0135] Table 2. Antibacterial activity of α-mangostin derivatives

[0136]

[0137] Note: The X in AMG-X stands for numbers 1-14.

[0138] Example 3. Determination of the antibacterial spectrum of α-mangostin derivatives, 11c, 11c-r and 11c-1

[0139] The test method was the same as in Example 2. The derivatives AMG-11c, 11c-r and 11c-1 with excellent antibacterial effects were selected to compare their antibacterial spectra with the known derivative AMG-9c. The strains tested included standard strains, clinically sensitive strains, and clinically resistant strains, totaling 144 strains. The test results were mainly judged in accordance with the CLSI M100-32st Edition (2022) standard.

[0140] Results: The drug sensitivity test showed that the derivatives AMG-11c, 11c-r and 11c-1 with excellent antibacterial effects showed good antibacterial activity against 144 selected strains, including Gram-positive and Gram-negative bacteria. Among them, the MIC values ​​of 40 Gram-positive bacteria, including Staphylococcus aureus, Enterococcus, Streptococcus suis, Clostridium perfringens, etc., were 0.5-2μg / mL, 1-4μg / mL, and 0.5-2μg / mL, respectively; MIC 50 1μg / mL, 2μg / mL, 1μg / mL respectively; MIC 90 The MIC values ​​of 104 strains of Gram-negative bacteria, including Escherichia coli, Salmonella, Haemophilus parasuis, Pasteurella, Klebsiella pneumoniae, Aeromonas, etc., were 1-8μg / mL, 4-32μg / mL, 1-8μg / mL, respectively; 50 2μg / mL, 8μg / mL, 4μg / mL respectively; MIC 90 In summary, the selected derivatives AMG-11c, 11c-r and 11c-1 are more potent than the known derivative AMG-9c (MIC G+ The values ​​ranged from 1 to 4 μg / mL; MIC 50 4 μg / mL; MIC 90 4 μg / mL; MIC G- The values ​​ranged from 8 to 128 μg / mL; MIC 50 32 μg / mL; MIC 90 Therefore, the above data show that after modification, α-mangostin can not only retain its good antibacterial activity against Gram-positive bacteria, but also expand its antibacterial activity against Gram-negative bacteria, making it a better broad-spectrum antibacterial compound.

[0141] Table 3 Antibacterial activity of α-mangostin derivatives AMG-9c, 11c, 11c-r and 11c-1

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] Example 4. Comparison of antibacterial activity of α-mangostin derivatives AMG-9c, 11c, 11c-r and 11c-1 with different types of antibacterial drugs

[0148] The experimental method was the same as that in Example 2. The minimum inhibitory concentrations (MICs) of the derivatives AMG-9c, 11c, 11c-r and 11c-1 were compared with different types of commonly used antibacterial drugs against 28 standard strains and clinically resistant strains. The MIC results were mainly judged according to the CLSIM100-32st Edition (2022) standard.

[0149] Results: The drug sensitivity test showed that AMG-9c, 11c, 11c-r and 11c-1 showed good antibacterial activity against 28 selected standard strains and clinical resistant strains (including Gram-positive and Gram-negative bacteria), and their antibacterial effects were even stronger than those of commonly used antibacterial drugs such as florfenicol, doxycycline and erythromycin. In particular, AMG-11c, 11c-r and 11c-1 showed good antibacterial effects. Therefore, the above data show that after modification, α-mangostin can not only retain good antibacterial activity against Gram-positive bacteria, but also expand the antibacterial activity of α-mangostin against Gram-negative bacteria, making it a better broad-spectrum antibacterial compound.

[0150] Table 4. Comparison of antibacterial activity of α-mangostin derivatives AMG-9c, 11c, 11c-r and 11c-1 with commonly used antibacterial drugs

[0151]

[0152]

[0153] Table 4. Comparison of antibacterial activity of α-mangostin derivatives AMG-9c, 11c, 11c-r and 11c-1 with commonly used antibacterial drugs

[0154]

[0155]

[0156] Example 5: Antifungal activity of α-mangostin derivatives

[0157] The NCCLS protocol was followed with a slight modification: Each tested Candida albicans strain was inoculated twice on Sabouraud medium to ensure its growth purity and viability. After 24 h of culture, the colonies with better growth were selected and made into bacterial suspension with sterile saline. When inoculating, it was diluted to (0.5-0.25)×10 with RPMI 1640 medium. 3 CFU / mL. Use RPMI 1640 culture medium to dilute the α-mangostin derivative in multiple ratios to make the final concentration of 128-0.25μg / mL, add 100μL of the serial dilution solution to each well of 1-10 columns in each row of the 96-well culture plate, and make 3 rows of duplicate wells in the same row. Each 11 wells are negative controls, and 12 wells are positive controls. Add 100μL of the prepared Candida albicans suspension to each well, and do not add it to the negative control. Then add 10μL of alamar blue to each well, and each well will turn blue. After culturing at 35℃ for 48h, observe the results. The wells with Candida albicans growth change from blue to purple or bright red; the negative control wells all remain blue, and the positive control wells all turn bright red. The concentration of the previous well that just changed color is taken as the MIC value.

[0158] Results: Among the selected α-mangostin derivatives, except for AMG-12 which had weak antifungal activity, the other derivatives had good antifungal activity and the effect was consistent with AMG. Therefore, after modification, this type of compound can still maintain a certain antifungal effect.

[0159] Table 5 Antifungal activity of some α-mangostin derivatives

[0160]

[0161] Example 6 Growth curve determination of α-mangostin derivative AMG-11c

[0162] Pick out E. coli B2 monoclone and put it into BHI broth medium, and culture it in a shaker at 37°C, 200 rpm until the logarithmic growth phase. Use McFarland turbidimeter to adjust the bacterial turbidity to McFarland turbidity 0.5, and dilute it 100 times (about 1.0×10 6 CFUs / mL) for later use. Dilute the drug to be tested to the required concentration with MH broth medium, take 100 μL and add it to a 96-well flat-bottom plate, and add 100 μL of the diluted test solution to each well. Set up negative and positive controls containing only MH broth medium and the test solution. Set the microplate reader system temperature to 37°C and detect OD 600nm The absorbance at the 400 nm position was measured once every hour for a total of 24 h. Three biological replicates were set for each treatment.

[0163] Results Figure 1From the bacterial growth curve, it was found that the compounds AMG-9c (at a concentration of 16 μg / mL), AMG-10c (at a concentration of 4 μg / mL), and AMG-11c (at a concentration of 4 μg / mL) could significantly inhibit the growth of E. coli B2 in a dose-dependent manner, especially the compound AMG-11c, which had the most obvious antibacterial effect, which was consistent with the results of the drug sensitivity test.

[0164] Example 7: Safety Determination of α-mangostin derivative AMG-11c

[0165] The safety of a drug is one of the key factors that determine whether it has potential research and development value. Therefore, we evaluated the safety of AMG derivatives, mainly measuring the hemolytic activity of sheep red blood cells. a) Add 100 μL / well of PBS solution to the first 11 columns of a 96-well plate, and add 100 μL of 0.2% Triton X-100 to the last column as a positive control. Add 100 μL of the drug solution of AMG and its derivatives to the first column, and dilute them in multiple proportions to the 10th column in turn. The 11th column is used as a negative control.

[0166] b) 2 mL of defibrinated sheep blood was centrifuged at 3,000 g for 5 min at 4°C, rinsed twice with PBS, and resuspended in 2 mL of PBS (100% red blood cells). 1 mL of red blood cells was added to 11.5 mL of PBS to prepare an 8% red blood cell suspension, and 100 μL / well was added to a 96-well plate.

[0167] c) After standing at 37°C for 1 hour, 120 μL of the supernatant was transferred to a new 1.5 mL centrifuge tube, and 100 μL was taken out after centrifugation at 3,000 g for 10 minutes to measure its absorbance at 576 nm.

[0168] The hemolysis rate is calculated as follows:

[0169] Hemolysis (%) = [(OD 576sample -OD 576blank ) / (OD 5760.2％TritonX-100 -OD 576 blank )]×100%

[0170] Results Figure 2 We evaluated the safety of compound AMG-11c and found that the half hemolytic concentration (Hly 50 ) was 42.13 μg / mL, and the safety therapeutic index of AMG-11c was greatly increased compared with AMG. These results show that after structural modification, the hemolytic activity of AMG is significantly reduced and it has good safety.

[0171] Example 8: In vitro cytotoxicity test of α-mangostin derivatives

[0172] In vitro cytotoxicity is the main indicator for evaluating drug safety and provides research directions for the modification of compounds. According to the size and growth rate of the cells, an appropriate amount of cells are inoculated into a 96-well cell culture plate so that the cell density does not exceed 80-90% full when tested. Different drugs are added for treatment and controls are set. After drug stimulation, the cell culture plate is centrifuged at 400g for 5 minutes in a multi-well plate centrifuge. Try to remove the supernatant, add 150μL of the LDH release reagent provided by the kit diluted 10 times with PBS (add 1 volume of LDH release reagent to 10 times the volume of PBS and mix well), shake the culture plate appropriately to mix, and then continue to incubate in the cell culture incubator for 1 hour. Subsequently, the cell culture plate is centrifuged at 400g for 5 minutes in a multi-well plate centrifuge. Take 120μL of the supernatant from each well and add it to the corresponding well of a new 96-well plate, and then measure the absorbance at 490nm with an enzyme reader.

[0173] Results: Among the selected derivatives, the in vitro cytotoxicity of 12 and 12-d was weaker than that of AMG. Therefore, the in vitro safety of the modified derivatives was improved to a certain extent. The structure-activity relationship analysis showed that the cytotoxicity of secondary amine derivatives was weaker than that of primary amine derivatives.

[0174] Table 6 In vitro cytotoxicity of some α-mangostin derivatives

[0175]

[0176] Example 9: Intracellular accumulation test of α-mangostin derivative AMG-11c

[0177] Most small molecules are unable to rapidly cross the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the search for drugs against these pathogens challenging. Therefore, it is of great significance to evaluate the intracellular accumulation of α-mangostin derivatives.

[0178] a) Pick a single colony of E. coli ATCC25922 on BHI agar medium, inoculate it into BHI broth medium, and culture it at 37°C, 200 rpm until the logarithmic growth phase. Centrifuge the culture solution at 4°C, 3000g for 10 min, collect the bacterial precipitate, and wash it three times with PBS (0.01M, pH=7.4). Resuspend the bacteria in fresh sterile PBS (0.01M, pH=7.4), aliquot into sterile 1.5mL tubes, and adjust the bacterial concentration to 10 10 CFU / mL.

[0179] b) Add different concentrations of α-mangostin derivative AMG-11c in sequence, mix well, and place in a 37°C incubator for shaking and incubation for 10, 20, 30, 60, and 120 minutes. Centrifuge at 4°C, 1200 rpm for 3 minutes to collect the bacterial precipitate. Add 400 μL of sterile water to resuspend the bacterial precipitate, and freeze and thaw repeatedly in liquid nitrogen and 65°C water bath three times (3 minutes each time) to fully lyse the bacteria.

[0180] c) Centrifuge at 4°C, 1200 rpm for 3 min, collect the supernatant. Resuspend the remaining bacterial pellet in 200 μL methanol, vortex and centrifuge, collect the supernatant. Combine the two supernatants, centrifuge at 1200 rpm for 3 min, and filter through a membrane for later use.

[0181] d) The content of α-mangostin derivative AMG-11c in the supernatant was determined by LC-MS 8045 mass spectrometer. The liquid chromatography column was Waters Acquity UPLCT3 (2.1×100 mm, 3 μm); the injection volume was 1 μL; the mobile phase A was 0.1% formic acid-acetonitrile, and the mobile phase B was 0.1% formic acid-water. The elution conditions are shown in Table 4. The positive ion mode of multiple reaction monitoring (MRM) was used to quantify the intracellular AMG-11c content [m / z=355.05 (quantitative ion), m / z=398.15 and 381.20 (qualitative ions)].

[0182] Results Figure 3 We measured the intracellular accumulation of compound AMG-11c and found that the intracellular accumulation of compound AMG-11c increased in a concentration-dependent manner after treatment for different time periods, and the increase in the high-concentration treatment group was more obvious. These results indicate that after structural modification, AMG increases its intracellular accumulation, thereby showing an antibacterial effect against Gram-negative bacteria.

[0183] Table HPLC gradient elution conditions

[0184]

[0185] Example 8. Galleria mellonella infection model using the α-mangostin derivative AMG-11c

[0186] Animal test models of drugs can predict the therapeutic effects of compounds. Therefore, we conducted a G. mellonella infection model experiment to predict the therapeutic effect of compound AMG-11c.

[0187] About 500 mg of G. mellonella larvae were randomly divided into 5 groups with 8 larvae in each group. Each G. mellonella was injected with 10 μL of E. coli B2 suspension (final concentration 7×10 6CFU / mouse). One hour after bacterial infection, 10 μL of compound AMG-11c was injected into the right parapodia of four groups of G. mellonella, with concentrations of 0, 4, 8, 20 mg / kg and polymyxin 8 mg / kg. After 72 hours of treatment, the survival rate of G. mellonella was calculated.

[0188] Results Figure 4 The wax moth infection model has been widely used in drug screening and verification of its in vivo effectiveness. In the acute wax moth infection model of E. coli B2, the AMG-11c administration group had a good therapeutic effect and was stronger than polymyxin. Therefore, this type of derivative has a good in vivo therapeutic effect.

[0189] The present invention has been described in detail above. For those skilled in the art, without departing from the purpose and scope of the present invention, and without the need to carry out unnecessary experimental conditions, the present invention can be implemented in a wide range under equivalent parameters, concentrations and conditions. Although the present invention provides specific embodiments, it should be understood that the present invention can be further improved. In a word, according to the principles of the present invention, the application is intended to include any changes, uses or improvements to the present invention, including departure from the disclosed scope in the application, and changes made with conventional techniques known in the art.

Claims

1. α - a mangostin derivative, which is any one of the following: 、 、 。 2. The method according to claim 1 α - Use of mangostin derivatives in the preparation of antibacterial agents, wherein the antibacterial agents are used to fight bacterial infections, wherein the bacteria are selected from Staphylococcus aureus, Enterococcus, Streptococcus suis, Clostridium perfringens, Escherichia coli, Salmonella, Haemophilus parasuis, Acinetobacter baumannii, Klebsiella pneumoniae, and Aeromonas.

3. The method according to claim 1 α - Use of AMG-11c and AMG-11c-r compounds among mangostin derivatives in the preparation of antifungal agents, wherein the antifungal agents are used to fight fungal infections, and the fungal strains are selected from Candida albicans, Candida glabrata, Candida krusei, and Candida tropicalis.

4. An antibacterial agent, characterized in that: The antibacterial agent contains at least one of the α-mangostin derivatives according to claim 1.

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