Ciprofloxacin-indole hybrid and preparation method and application thereof

Abstract

The present invention belongs to the technical field of antibacterial drugs, and specifically relates to a ciprofloxacin-indole heterocompound and a preparation method and application thereof. The ciprofloxacin-indole heterocompound has a chemical structural formula as shown in formula (I), wherein R is selected from NHCONH2, NHCSNH2, NHCOPh or OCH3. The present invention introduces the antibacterial pharmacophore indole-3-imine on the nitrogen atom of the piperazine group at the C-7 position of ciprofloxacin, and designs and synthesizes a series of ciprofloxacin-indole heterocompounds with a completely new structure. This type of ciprofloxacin-indole heterocompound has good antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus, and can be used as an antibacterial candidate compound. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the technical field of antibacterial drugs, and specifically relates to a ciprofloxacin-indole hybrid and a preparation method and application thereof. Background Art

[0002] Fluoroquinolone antibacterial drugs were discovered in 1962. After 60 years of development, fluoroquinolones have become the most widely used broad-spectrum, highly effective, and low-toxic first-line anti-infective chemotherapy drugs in clinical practice after cephalosporins. However, with the widespread use and even abuse of such drugs, bacterial resistance has increased year by year. It is reported that in 2019, the direct death toll from drug-resistant infections worldwide reached 1.27 million, and the indirect death toll reached 5 million (Lancet.2022, 399(10325):629). Drug-resistant infections have seriously threatened human health. Among these pathogens, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa are still the main lethal strains.

[0003] Ciprofloxacin belongs to the third generation of quinolone drugs. Due to its broad antibacterial spectrum, strong antibacterial activity and few adverse reactions, its application covers almost the entire clinical department. The number of resistant strains has also gradually increased, which has limited its application. For Staphylococcus aureus, which is more likely to produce β-lactamases, and Staphylococcus epidermidis, which occasionally causes disease, domestic researchers reported that the drug resistance rate is as high as 58.2% to 62.2%, and it is increasing year by year; the drug resistance rate of enterococci, which is prone to cause purulent infection, is as high as 63.6%; and some conditional pathogens such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Enterobacter also show varying degrees of resistance to ciprofloxacin. Therefore, it is of great significance to research and develop new ciprofloxacin-type fluoroquinolone antibacterial drugs that are effective against these pathogens, especially resistant bacteria. Summary of the invention

[0004] The present invention provides a ciprofloxacin-indole heterocomplex and a preparation method and application thereof. Based on previous research on antibacterial drugs, the present invention combines modern drug design theory and organic synthesis experimental technology to transform ciprofloxacin in fluoroquinolone drugs, introduces an antibacterial pharmacophore indole-3-imine on the nitrogen atom of the piperazine group at the C-7 position of ciprofloxacin, and designs and synthesizes a series of ciprofloxacin-indole heterocomplexes with new structures. The ciprofloxacin-indole heterocomplexes have significant antibacterial activity, are resistant to drug-resistant bacteria, and are not easily resistant to drug resistance, and have the development potential as antibacterial candidates.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The first object of the present invention is to provide a ciprofloxacin-indole heterocomplex or a pharmaceutically acceptable salt thereof, wherein the ciprofloxacin-indole heterocomplex has a chemical structural formula as shown in formula (I):

[0007]

[0008] Wherein, R is selected from -NHCONH2, -NHCSNH2, -NHCOPh or -OCH3.

[0009] A second object of the present invention is to provide a method for preparing the above-mentioned ciprofloxacin-indole heterocomplex, comprising the following steps:

[0010] S1, mixing N-3-bromopropylindole-3-carboxaldehyde, ciprofloxacin and sodium carbonate in a first solvent for reflux reaction, after the reaction is completed, removing the solvent, adding water and adjusting the pH to 7, filtering and drying and purifying to obtain an intermediate (II);

[0011] S2, mixing the intermediate (II), amine and sodium acetate in a second solvent for reflux reaction, and after the reaction is completed, adding water and concentrating to half of its volume, and filtering and washing at 4° C. overnight to obtain a ciprofloxacin-indole hybrid;

[0012] The synthetic reaction formula is as follows:

[0013]

[0014] Preferably, in S1, the molar volume ratio of the N-3-bromopropylindole-3-carboxaldehyde, ciprofloxacin, sodium carbonate and the first solvent is 0.0012 mol:0.001 mol:0.004 mol:30 mL, and the first solvent is acetonitrile.

[0015] Preferably, in S1, the temperature of the reflux reaction is 90° C., the time is 36 h, the volume ratio of the first solvent to water is 1:1, and a hydrochloric acid solution with a mass concentration of 10% is used to adjust the pH.

[0016] Preferably, in S2, the molar volume ratio of the intermediate (II), amine, sodium acetate and the second solvent is 0.0001 mol:0.0003 mol:0.0003 mol:9 mL, and the second solvent is methanol.

[0017] Preferably, in S2, the temperature of the reflux reaction is 90° C., the time is 42-72 hours, and the volume ratio of the second solvent to water is 3:1.

[0018] The third object of the present invention is to provide the use of the above ciprofloxacin-indole hybrid or a pharmaceutically acceptable salt thereof in the preparation of antibacterial drugs.

[0019] Preferably, the antibacterial drug is a drug against Staphylococcus aureus, Escherichia coli and / or Pseudomonas aeruginosa.

[0020] The fourth object of the present invention is to provide an antibacterial drug containing the ciprofloxacin-indole hybrid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. Based on the previous research on antibacterial drugs, the present invention combines modern drug design theory and organic synthesis experimental technology to transform ciprofloxacin in the fluoroquinolone drugs, introduces the antibacterial pharmacophore indole-3-imine on the nitrogen atom of the piperazine group at the C-7 position of ciprofloxacin, and designs and synthesizes a series of ciprofloxacin-indole heterocomplexes with new structures. The ciprofloxacin-indole heterocomplexes have significant antibacterial activity, among which the preferred compound (Ia) has an antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa that is comparable to that of the control drug ciprofloxacin.

[0023] 2. The preferred compound (Ia) of the present invention showed no trend of drug resistance development in the 20-day drug resistance induction experiment. The bacteria under the same conditions showed a significant trend of drug resistance development to ciprofloxacin, indicating that the preferred compound (Ia) is not only resistant to drug-resistant bacteria, but also not easily resistant, and has the potential to be developed as an antibacterial candidate. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The figure is a diagram showing the drug resistance development trend of the compound (Ia) of the present invention in the drug resistance induction experiment. DETAILED DESCRIPTION

[0025] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0026] It should be noted that the professional terms used in the present invention are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention. Unless otherwise specifically stated, the various raw materials, reagents, instruments and equipment used in the following embodiments of the present invention can be purchased from the market or prepared by existing methods.

[0027] Example 1

[0028] A method for preparing 1-cyclopropyl-6-fluoro-7-(4-(3-(3-formyl-1H-indol-1-yl)propyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (intermediate (II)), comprising the following steps:

[0029] Weigh N-3-bromopropylindole-3-carboxaldehyde (0.31 g, 0.0012 mol), ciprofloxacin (0.33 g, 0.001 mol) and sodium carbonate (Na2CO3: 0.42 g, 0.004 mol) in 30 mL of acetonitrile (CH3CN) solvent, then place in a clean and dried round-bottom flask, reflux at 90°C for 36 h, and detect by TLC (thin layer chromatography: V 二氯甲烷 :V 甲醇 =15:1) to monitor the reaction. After the reaction was completed, the solvent was evaporated, and then 30 mL of water was added. The pH was adjusted to 7 with 10% hydrochloric acid, and the filter cake was dried and then subjected to silica gel column chromatography (V 二氯甲烷 :V 甲醇 =15:1) to obtain intermediate (II); yellow solid, mp 207-210°C, yield 44%; the synthetic reaction formula is as follows:

[0030]

[0031] 1 H-NMR (DMSO-d6, 300MHz): δ1.14-1.23 (m, 4H, Cyclopropyl-H), 2.04 (t, 2H, J = 6.1Hz, CH2), 2.35 (t, 2H, J = 5.9Hz, BrCH2 ),2.54(s,4H,piperazine-H),3.31(s,4H,piperazine-H),3.83(s,1H,NCH),4.37(t,2H,J=6.5Hz,NCH2),7.26(t,1H, J=7.5Hz, Ph-H),7.33(t,1H,J=7.6Hz,Ph-H),7.54(d,1H,J=7.3Hz,Ph-H),7.68(d,1H,J=8.2Hz,Ph-H),7.88(d,1H,J=1 3.3Hz,Ph-H),8.11(d,1H,J=7.8Hz,Ph-H),8.35(s,1H,Ph-H),8.66(s,1H,PH-H),9.93(s,1H,CHO),15.20(s,1H,COOH).

[0032] 13 C NMR(75MHz,DMSO)δ184.9,176.8,166.4,153.5(d, 1 J c-f =247.5Hz),148.4,145.6(d, 2 J c-f=10.5Hz),141.4,139.6,137.6,125.1,123.9,122.9,121.5,119.1(d, 3 J c-f =7.5Hz),117.6,111.6,111.2,107.2,106.8(d, 4 J c-f =2.9Hz),54.7,52.7,49.8,44.8,36.3,26.7,8.0.

[0033] ESI-HRMS calculation for C 29 H 30 FN4O4 + ([M+H] + ):517.2246; found:517.2250.

[0034] Example 2

[0035] The preparation method of (Z)-7-(4-(3-(((2-aminohydrazide)methyl)-1H-indol-1-yl)propyl)piperazine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Ia) comprises the following steps:

[0036] The intermediate (II) (0.052 g, 0.0001 mol) of Example 1, semicarbazide hydrochloride (0.033 g, 0.0003 mol) and sodium acetate (0.024 g, 0.0003 mol) were weighed and mixed in methanol (CH3OH: 9 mL), and then placed in a clean and dried round-bottom flask, refluxed at 90°C for 42 h, and detected by TLC (thin layer chromatography: V 二氯甲烷 :V 甲醇 =20:1) to monitor the reaction. After the reaction was completed, 3 mL of water was added, half of the solvent was evaporated, and then the mixture was placed in a refrigerator at 4°C overnight. After overnight, the mixture was filtered, and the filter cake was washed with methanol and dried to obtain ciprofloxacin-indole hybrid (Ia); yellow solid, mp 251-254°C, yield 53%; the synthetic reaction formula is as follows:

[0037]

[0038] 1H-NMR (CDCl3, 500MHz): δ1.18-1.34 (m, 4H, Cyclopropyl-H), 2.31 (t, 2H, J = 6.4Hz, NCH2), 2.51 (s, 4H, piperazin e-H),3.31(s,4H,piperazine-H),3.63(s,1H,NCH),3.76-3.87(m,2H,CH2),4.34(t,2H,J=6.4Hz,NCH2),6.20(s ,2H,CONH2),7.14-7.28(m,2H,Ph-H),7.56-7.60(m,2H,Ph-H),7.76-7.78(m,1H,Ph-H),7.92-7.97(d,1H,Ph-H) ,8.07(s,1H,Ph-H),8.16-8.20(m,1H,Ph-H),8.69(d,1H,J=4.6Hz,Ph-H),9.91(s,1H,CONH),15.08(s,1H,COOH).

[0039] ESI-HRMS calculation for C 30 H 33 FN7O4 + ([M+H] + ):574.2573; found:574.2581.

[0040] Example 3

[0041] The preparation method of (Z)-7-(4-(3-(((2-aminothiohydrazide)methyl)-1H-indol-1-yl)propyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Ib) comprises the following steps:

[0042] The intermediate (II) (0.052 g, 0.0001 mol) of Example 1, thiosemicarbazone (0.027 g, 0.0003 mol) and sodium acetate (0.024 g, 0.0003 mol) were weighed and mixed in CH3OH (9 mL), and then placed in a clean and dried round-bottom flask, and refluxed at 90°C for 72 h. The mixture was detected by TLC (thin layer chromatography: V 二氯甲烷 :V 甲醇 =20:1) to monitor the reaction. After the reaction was completed, 3 mL of water was added, half of the solvent was evaporated, and then the mixture was placed in a refrigerator at 4°C overnight. After overnight, the mixture was filtered, and the filter cake was washed with methanol and dried to obtain ciprofloxacin-indole hybrid (Ib); yellow solid, mp 218-221°C, yield 52%; the synthetic reaction formula is as follows:

[0043]

[0044] 1 H-NMR(DMSO-d6,300MHz):δ1.19-1.33(m,4H,Cyclopropyl-H),2.00(t,2H,J=6.5Hz,NCH2CH2),2.32(t,2H,J=6.4Hz,NCH2),2.54(s,4H,piperazine-H),3.31(s,4H,piperazine-H),3.81(s,1H,NCH),4.27(t,2H,J=6.7Hz,NCH2),7.16(t,1H,J=7.6Hz,Ph-H),7.26(t,1H,J=7.6Hz,Ph-H),7.40(s,1H,Ph-H),7.51-7.58(m,2H,Ph-H),7.84(d,1H,J=7.9Hz,Ph-H),7.87(s,1H,Ph-H),8.01(s,1H,Ph-H),8.22(d,1H,J=7.9Hz,Ph-H),8.29(s,1H,Ph-H),8.64(s,1H,Ph-H),11.47(s,1H,NHCS),15.18(s,1H,COOH).

[0045] 13 C NMR(75MHz,DMSO-d6):δ177.0,176.8,166.4,153.5(d, 1 J c-f =248.0Hz),148.4,145.6(d, 2 J c-f =9.9Hz),140.8,139.6,137.5,134.3,124.9,123.1,122.9,121.3,119.0(d, 3 J c-f =7.7Hz),111.4(d, 2 J c-f =23.2Hz),110.8,110.7,107.2,106.7(d, 4 J c-f =2.7Hz),54.8,52.7,49.8,44.2,36.3,27.0,8.0.

[0046] ESI-HRMS calcd for C 30 H 33 FN7O3S + ([M+H] +):590.2344; found:590.2355.

[0047] Example 4

[0048] The preparation method of (Z)-7-(4-(3-(((2-benzoylhydrazide)methyl)-1H-indol-1-yl)propyl)piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Ic) comprises the following steps:

[0049] The intermediate (II) (0.052 g, 0.0001 mol) of Example 1, benzoyl hydrazide (0.04 g, 0.0003 mol) and sodium acetate (0.024 g, 0.0003 mol) were weighed and mixed in CH3OH (9 mL), and then placed in a clean and dried round-bottom flask, and refluxed at 90°C for 72 h. The mixture was detected by TLC (thin layer chromatography: V 二氯甲烷 :V 甲醇 =20:1) to monitor the reaction. After the reaction was completed, 3 mL of water was added, half of the solvent was evaporated, and then the mixture was placed in a refrigerator at 4°C overnight. After overnight, the mixture was filtered, and the filter cake was washed with methanol and dried to obtain ciprofloxacin-indole hybrid (Ic); yellow solid, mp 249-252°C, yield 44%; the synthetic reaction formula is as follows:

[0050]

[0051] 1 H-NMR (DMSO-d6, 400MHz): δ1.18-1.34 (m, 4H, Cyclopropyl-H), 2.01 (t, 2H, J = 7.5Hz, NCH2), 2.33 (t, 2H, J =6.9Hz,NCH2),2.54(s,4H,piperazine-H),3.31(s,4H,piperazine-H),3.84(s,1H,NCH),4.30(t,2H,J= 6.9Hz, NCH2), 7.20 (t, 1H, J = 7.5Hz, Ph-H), 7.28 (t, 1H, J = 7.6Hz, Ph-H), 7.50-7.60 (m, 5H, Ph-H), 7.81-7. 93(m,4H,Ph-H),8.32(d,1H,J=7.8Hz,Ph-H),8.63(s,1H,Ph-H),11.55(s,1H,CONH),15.19(s,1H,COOH).

[0052] 13 C NMR(101MHz,DMSO)δ176.7,166.4,162.9,153.5(d,1 J c-f =249.6Hz),148.4,144.9,139.6,137.5,134.5,133.6,133.6,131.8,128.8,128.7,127.9,127.4, 125.3,123.1,122.7,121.0,111.5,111.4,110.8,106.7,54.9,52.7,49.9,44.2,36.3,27.1,8.0.

[0053] ESI-HRMS calculation for C 36 H 36 FN6O4 + ([M+H] + ):635.2777; found:635.2787.

[0054] Example 5

[0055] The preparation method of (Z)-1-cyclopropyl-6-fluoro-7-(4-(3-(3-(1-(methoxyimino)ethyl)-1H-indol-1-yl)propyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Id) comprises the following steps:

[0056] The intermediate (II) (0.052 g, 0.0001 mol) of Example 1, methoxyamine hydrochloride (0.025 g, 0.0003 mol) and sodium acetate (0.024 g, 0.0003 mol) were weighed and mixed in CH3OH (9 mL), and then placed in a clean and dried round-bottom flask, and refluxed at 90°C for 72 h. The mixture was detected by TLC (thin layer chromatography: V 二氯甲烷 :V 甲醇 =20:1) to monitor the reaction. After the reaction was completed, 3 mL of water was added, half of the solvent was evaporated, and then the mixture was placed in a refrigerator at 4°C overnight. After overnight, the mixture was filtered, and the filter cake was washed with methanol and dried to obtain ciprofloxacin-indole hybrid (Id); yellow solid, mp 225-228°C, yield 56%; the synthetic reaction formula is as follows:

[0057]

[0058] 1H-NMR(DMSO-d6,400MHz): δ1.17-1.35(m,4H,Cyclopropyl-H),2.34(s,2H,NCH2),3.23-3. 35(m,8H,piperazine-H),3.63(s,2H,CH2),3.87(s,4H,NCH,OCH3),4.38(t,2H,J=6.8Hz,N CH2),7.18(t,1H,J=7.5Hz,Ph-H),7.27(t,1H,J=7.6Hz,Ph-H),7.57-7.67(m,2H,Ph-H),7. 80-8.03(m,3H,Ph-H),8.29(d,1H,J=7.8Hz,Ph-H),8.66(s,1H,CH=N),15.12(s,1H,COOH).

[0059] 13 C NMR(101MHz,DMSO)δ176.8,166.3,153.3(d, 1 J c-f =250.3Hz),148.6,145.1,139.5,138.9,137.2,135.3,127.3,125.1,123.2,122.8,122.3,121.1(d, 3 J c-f =12.6Hz),119.1,111.6(d, 2 J c-f =22.3Hz),110.9(d, 4 J c-f =3.5Hz),107.3,62.2,61.6,55.4,51.0,46.7,43.8,36.4,8.1.

[0060] ESI-HRMS calculation for C 30 H 33 FN5O4 + ([M+H] + ):546.2511; found:546.2515.

[0061] Example 6 Antibacterial activity test of target compound

[0062] Using ciprofloxacin as the control drug, the MIC of the target compound was determined by microdilution method. MIC (ug / mL): the minimum inhibitory concentration of the compound for the test bacteria. The antibacterial activity of the target compound against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa was determined.

[0063] The experimental steps of microdilution method are as follows:

[0064] Add 100 μL of MH broth to columns 1-12 of the 96-well plate, add 4 μL of the sample to be tested (6400 μg / mL) to one column and mix, then take 100 μL from column 1 and add it to column 2 and mix, then take 100 μL from column 2 and add it to column 3 and mix, and so on, finally take 100 μL from column 9 and add it to column 10 and mix, then take out 100 μL of excess liquid and discard. Take 100 μL of a concentration of 10 5 -10 6 cfu / mL of bacterial solution was added to each well of the 1st to 11th columns, and 100 μL of MH broth was added to each well of the 12th column. The final volume of each well was 200 μL. The concentrations of the samples to be tested in the 1st to 10th columns were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, and 0.125 μg / mL, respectively. The 11th column was for bacteria without drugs (positive growth control), and the 12th column was for bacteria without drugs (sterile control). Three replicates were made for each sample to be tested. After the 96-well plate was cultured in a 35°C oven for 16 hours, the OD630 value was measured with an enzyme marker. The concentration of the well with an OD630 value close to the sterile control was the minimum inhibitory concentration MIC.

[0065] The results are shown in Tables 1 and 2. The target compounds showed significant antibacterial activity against the tested strains, among which compound Ia had the best antibacterial activity. The antibacterial activity of compound Ia against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa was comparable to that of ciprofloxacin, and the antibacterial activity of compound Ia against drug-resistant Staphylococcus aureus and multidrug-resistant Escherichia coli was similar to that of ciprofloxacin.

[0066] Table 1 Inhibitory activity of compounds Ia-Id against clinical pathogenic Gram-positive bacteria (MIC, μg / mL)

[0067]

[0068]

[0069] a Staphylococcus aureus ATCC 6538 (Staphylococcus aureus); bStaphylococcusaureus CMCC 25923 (Staphylococcus aureus); c Escherichia coli CMCC 44568 (Escherichia coli); d Pseudomonas aeruginosa CMCC 10104 (Pseudomonas aeruginosa).

[0070] Table 2 Inhibitory activity of compounds Ia-Id against clinical pathogenic Gram-negative bacteria (MIC, μg / mL)

[0071]

[0072] a Staphylococcus aureus ATCC 43300 (methicillin-resistant Staphylococcus aureus); b Staphylococcus aureus ATCC 33591 (methicillin-resistant Staphylococcus aureus); c multi-drug resistant Escherichia coliATCC BAA-196 (multi-drug resistant Escherichia coli).

[0073] Example 7

[0074] Drug resistance development trend test for compound (Ia): Using ciprofloxacin as a control drug, the drug resistance development trend of Staphylococcus aureus and Escherichia coli to compound (Ia) was determined in a drug resistance induction experiment.

[0075] The specific method includes the following steps:

[0076] First, the MIC values ​​of Ia and ciprofloxacin against Staphylococcus aureus CMCC 25923 and Escherichia coli CMCC 44568 were determined. Subsequently, the bacteria were cultured at sub-MIC (MIC / 2) concentrations of compound Ia and ciprofloxacin. A portion was transferred to a new culture tube and continued to be treated with a drug of MIC / 2, while another portion was taken to determine the new MIC values ​​of compound Ia and ciprofloxacin. This process was repeated for 20 generations for each strain. The MIC values ​​of compound Ia and ciprofloxacin were plotted over time in days (number of passages). As the number of passages increases, if the drug MIC value increases by more than 4 times compared to the initial value, it indicates that the drug has a tendency to develop bacterial resistance.

[0077] The drug resistance development trend diagram of the compound (Ia) of the present invention in the drug resistance induction experiment, Figure 1In the above figure, A is Staphylococcus aureus CMCC 25923, and B is Escherichia coli CMCC 44568. Figure 1 The results showed that compound (Ia) showed no resistance development trend in the 20-day resistance induction experiment (MIC value did not increase by more than 4 times), while bacteria showed a clear resistance development trend to ciprofloxacin under the same conditions, indicating that the preferred compound (Ia) can effectively resist bacterial resistance.

[0078] It should be noted that when the present invention involves a numerical range, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as those in the embodiments, in order to avoid redundancy, the present invention describes a preferred embodiment. Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the attached claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0079] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A ciprofloxacin-indole hybrid or a pharmaceutically acceptable salt thereof, characterized in that: The ciprofloxacin-indole hybrid has a chemical structural formula as shown in formula (I): Wherein, R is selected from -NHCONH2, -NHCSNH2, -NHCOPh or -OCH3.

2. A method for preparing the ciprofloxacin-indole hybrid according to claim 1, characterized in that: The following steps are involved: S1, mixing N-3-bromopropylindole-3-carboxaldehyde, ciprofloxacin and sodium carbonate in a first solvent for reflux reaction, after the reaction is completed, removing the solvent, adding water and adjusting the pH to 7, filtering and drying and purifying to obtain an intermediate (II); S2, mixing the intermediate (II), amine and sodium acetate in a second solvent for reflux reaction, and after the reaction is completed, adding water and concentrating to half of its volume, and filtering and washing at 4° C. overnight to obtain a ciprofloxacin-indole hybrid; The synthetic reaction formula is as follows:

3. The method for preparing the ciprofloxacin-indole heterocomplex according to claim 2, characterized in that: In S1, the molar volume ratio of the N-3-bromopropylindole-3-carboxaldehyde, ciprofloxacin, sodium carbonate and the first solvent is 0.0012 mol:0.001 mol:0.004 mol:30 mL, and the first solvent is acetonitrile.

4. The method for preparing the ciprofloxacin-indole heterocomplex according to claim 2, characterized in that: In S1, the temperature of the reflux reaction is 90° C., the time is 36 hours, the volume ratio of the first solvent to water is 1:1, and a hydrochloric acid solution with a mass concentration of 10% is used to adjust the pH.

5. The method for preparing the ciprofloxacin-indole heterocomplex according to claim 2, characterized in that: In S2, the molar volume ratio of the intermediate (II), amine, sodium acetate and the second solvent is 0.0001 mol:0.0003 mol:0.0003 mol:9 mL, and the second solvent is methanol.

6. The method for preparing the ciprofloxacin-indole heterocomplex according to claim 2, characterized in that: In S2, the temperature of the reflux reaction is 90°C, the time is 42-72 hours, and the volume ratio of the second solvent to water is 3:

1.

7. Use of the ciprofloxacin-indole hybrid or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of antibacterial drugs.

8. The use according to claim 7, characterized in that: The antibacterial drug is a drug against Staphylococcus aureus, Escherichia coli and / or Pseudomonas aeruginosa.

9. An antibacterial drug, characterized in that: Contains the ciprofloxacin-indole heterocomplex or a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient.

Images