CN110698383B - Structure, synthesis and application of benzil hydrazone-3-acetyl indole - Google Patents
Structure, synthesis and application of benzil hydrazone-3-acetyl indole Download PDFInfo
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- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- -1 benzil hydrazone-3-acetyl indole Chemical compound 0.000 title description 3
- VUIMBZIZZFSQEE-UHFFFAOYSA-N 1-(1h-indol-3-yl)ethanone Chemical compound C1=CC=C2C(C(=O)C)=CNC2=C1 VUIMBZIZZFSQEE-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000013078 crystal Substances 0.000 claims abstract description 31
- 239000002262 Schiff base Substances 0.000 claims abstract description 16
- 150000004753 Schiff bases Chemical class 0.000 claims abstract description 16
- ZWPOAAKGAFHAEX-HBKJEHTGSA-N (e)-[(2e)-2-hydrazinylidene-1,2-diphenylethylidene]hydrazine Chemical compound C=1C=CC=CC=1\C(=N/N)\C(=N\N)\C1=CC=CC=C1 ZWPOAAKGAFHAEX-HBKJEHTGSA-N 0.000 claims abstract description 8
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- 238000002844 melting Methods 0.000 claims abstract description 6
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- CDQPGWNBSOSEMZ-DTQAZKPQSA-N (2e)-2-hydrazinylidene-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(=N/N)\C(=O)C1=CC=CC=C1 CDQPGWNBSOSEMZ-DTQAZKPQSA-N 0.000 claims description 5
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- PQMPNCXALNJELA-UHFFFAOYSA-N 1-(1H-indol-3-yl)ethylidenehydrazine Chemical compound CC(=NN)c1c[nH]c2ccccc12 PQMPNCXALNJELA-UHFFFAOYSA-N 0.000 claims description 3
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- 230000002194 synthesizing effect Effects 0.000 claims description 3
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 claims description 2
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
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- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
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- CDQPGWNBSOSEMZ-UHFFFAOYSA-N 2-hydrazinylidene-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(=NN)C(=O)C1=CC=CC=C1 CDQPGWNBSOSEMZ-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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Abstract
The invention relates to the field of medicinal chemistry and functional materials, in particular to two Schiff base crystals generated by benzildihydrazone or benzildihydrazone and 3-acetyl indole, wherein the former is double Schiff base, the appearance of the double Schiff base is yellow rod-shaped crystal, the melting point is 270.2-271.7 ℃, and the molecular formula is C 34 H 28 N 6 Molecular weight 520.62; the latter is Shan Xifu alkali, and has yellow needle crystal appearance, melting point of 223.1-224.4 deg.C, and molecular formula C 24 H 19 N 3 O, molecular weight 365.43; the structures of the two are as follows:
Description
The technical field is as follows:
the invention relates to the field of medicinal chemistry and functional materials, in particular to a structure of Schiff base generated by reaction of benzildizone or benzildizone and 3-acetyl indole, application of the structure in fluorescent materials, anticancer drugs and antibacterial drugs, and application of the structure in the fields of medical materials, functional materials and the like.
Background art:
schiff base is a compound containing an imine or azomethine group, of the general formula R 1 R 2 C＝NR 3 . The Schiff base ligand with various structures and functions can be synthesized by introducing different substituent groups through the reaction design of a compound of an active carbonyl group and different amine compounds. Schiff base has many well-known obvious biological activities, such as antibiosis, antifungal, weeding, antituberculosis, anti-HIV, anticancer and the like, which makes it widely used in the fields of medicinal chemistry, functional materials and the like. In addition, schiff base with a large conjugated system often has good fluorescence property, and is widely applied to the fields of organic pigments, optical brighteners, photo-oxidizers, coatings, chemical and biochemical analysis, solar collectors, anti-counterfeiting marks, drug tracing, laser and the like; therefore, the synthesis and property research of the novel Schiff base have great significance.
Disclosure of Invention
The invention relates to a method for synthesizing two types of Schiff bases which are reaction products of benzil hydrazone and 3-acetyl indole, wherein the reaction products of the benzil dihydrazone and the 3-acetyl indole are called benzil dihydrazone-N, N' -di (3-acetyl indole), and the reaction products of the benzil monohydrazone and the 3-acetyl indole are called benzil monohydrazone-N-3-acetyl indole; the former being a bisSchiff base, yellow rod-shaped crystal in appearance, melting point of 270.2-271.7 deg.C, molecular formula C 34 H 28 N 6 Molecular weight 520.62; the latter is Shan Xifu alkali, and has yellow needle crystal appearance, melting point of 223.1-224.4 deg.C, and molecular formula C 24 H 19 N 3 O, molecular weight 365.43; the structures of the two are as follows:
1. and (5) structure identification.
The elemental analysis of the benzil dihydrazone-N, N' -bis (3-acetyl indole) shows that the percentage content of C, H, N is respectively as follows: c78.49 (78.44), H5.47 (5.42), N16.21% (16.14%) (theoretical values in parentheses); the analysis of the single crystal structure shows that the crystal is a triclinic system, P-1 space group,
α＝64.941(4)°，β＝79.573(3)°，γ＝76.829(4)°，/>
z =2; in connection with 1 HNMR spectrum, 13 The CNMR spectra are shown in figure 1 and figure 2 respectively; the structure diagram and the stacking diagram of the single crystal structure are shown in the attached figures 3 and 4 respectively.
Elemental analysis of benzil monohydrazone-N-3-acetyl indole showed that the percentage content of C, H, N is C79.24 (78.88), H6.11 (5.24), N12.03% (11.50%) (theoretical in parentheses); the analysis of the single crystal structure shows that the crystal is tetragonal system, P4 3 2 1 2 the space group is formed by the space group,
α＝β＝γ＝90°，/>
z =8; to aIs/are as follows 1 HNMR spectrum, 13 The CNMR spectra are shown in figure 5 and figure 6 respectively; the structure diagram and the stacking diagram of the single crystal structure are shown in figures 7 and 8 respectively.
2. A synthetic method.
There are two methods for synthesizing benzildihydrazone-N, N' -bis (3-acetylindole): the first method takes benzil dihydrazone and 3-acetyl indole as raw materials and comprises the following steps:
1) Dissolving benzildihydrazone in a proper organic solvent, adding 3-acetyl indole according to a certain substance amount ratio, and stirring and reacting for a certain time at a certain temperature to complete the reaction; if solid phase reaction is adopted, organic solvent is not used, and the grinding reaction of the two can be finished for a certain time.
2) Filtering, and naturally volatilizing the filtrate to precipitate yellow rod-shaped crystals which are target products; if solid phase reaction is adopted, the target product crystal can be obtained by recrystallization with proper organic solvent after the reaction is finished.
The second method takes diphenylethanedione and 3-acetyl indole hydrazone as raw materials, and is completed in one step in a proper organic solvent, and the steps are as follows:
1) Dissolving diphenylethanedione in a proper organic solvent, adding 3-acetyl indole hydrazone according to a certain substance amount ratio, and stirring and reacting at a certain temperature for a certain time to complete the reaction; if solid phase reaction is adopted, organic solvent is not used, and the grinding reaction of the two can be finished for a certain time.
2) Filtering, and naturally volatilizing the filtrate to precipitate yellow rod-shaped crystals which are target products; if solid phase reaction is adopted, the target product crystal can be obtained by recrystallization with proper organic solvent after the reaction is finished.
The difference of the two preparation methods is mainly that the reactants are different, but the molar ratio of the reaction raw materials is between 4:1 and 1:4.
The synthesis of the benzil monohydrazone-N-3-acetyl indole takes the benzil monohydrazone and the 3-acetyl indole as raw materials, other steps are the same as the synthesis method of the benzil dihydrazone-N, N' -di (3-acetyl indole), and the molar ratio of reactants is between 4:1 and 1:4.
The organic solvent (solvent for reaction or solvent for recrystallization) in the above two preparation methods is selected from: methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, acetone, etc.; in the solid-phase reaction, organic solvents are not used, and raw materials can be directly reacted.
Preferably, the reaction temperature is normal temperature or heating reflux, and the reaction method is stirring or grinding.
Preferably, the reaction time is selected from: 0.5-10h.
The beneficial effects of the invention are: can synthesize more complex functional molecular materials by simpler steps and reactants.
3. In vitro antitumor activity:
human lung cancer cells A549 or mouse breast cancer cells 4T growing in logarithmic phase 1 The cells were digested with 0.25% trypsin to give single cells, which were then prepared in a concentration of 1.25X 10 using a culture solution of F12K containing 10% fetal bovine serum 7 One cell/L suspension of single cells, cells were seeded in 96-well plates at 200. Mu.L per well (2.5X 10 per well) 3 Individual cells). Place 96-well cell culture plates in CO 2 In an incubator, 5% CO at 37% 2 Culturing for 48h under the condition.
When the cells in the wells are full (90% full), adding different doses of Schiff's base solution (200. Mu.L/well) according to experimental groups to make the final concentrations of the compounds to be tested respectively 5. Mu.M, 10. Mu.M, 30. Mu.M, 50. Mu.M and 100. Mu.M, setting 3 multiple wells in each group, and culturing for 96h.
mu.L of MTT at a concentration of 0.5g/L was added to each well, and the culture was continued for 4 hours to reduce MTT to Formazan (Formazan). After all the supernatants were aspirated, 200. Mu.L of DMSO was added to each well, and the mixture was shaken for 15min to dissolve formazan sufficiently, and then absorbance (OD value) at 490nm was measured using an ELISA detector. Then calculated according to the following formula:
cell inhibition% = (control OD value-experimental OD value)/control OD value × 100%
The test result shows that the benzil dihydrazone-N, N' -di (3-acetyl indole) is used for treating human lung cancer cell A549 and mouse breast cancer cell 4T 1 Has IC50 (half inhibitory concentration of the drug) of 8.5. Mu.M and 7.0Mu M; benzoylmonohydrazone-N-3-acetylindole as human lung cancer cell A549 and mouse breast cancer cell 4T 1 IC50 of (a) are 43.0. Mu.M and 30.0. Mu.M, respectively; this indicates that the two Schiff base molecules have good inhibitory effects on two cancer cells; compared with the cisplatin, the dicsfungine has better effect, and has better effect than the cisplatin in human lung cancer cells A549 and mouse breast cancer cells 4T 1 Inhibitory Effect (IC) 50 6.5 and 0.5 μ M, respectively).
4. Antibacterial activity:
the antibacterial effect is measured by adopting a filter paper diffusion method: circular filter paper sheets (each sheet absorbs 10 microliters of liquid medicine) with the same size and the same diameter and 8mm are immersed in DMSO solution of a to-be-detected medicine with the concentration of 100 mug/mL, the filter paper sheets are taken out after 30 minutes, air drying is carried out, the medicine carrying capacity of each filter paper sheet is about 1 mug, then the filter paper sheets are placed in the center of a flat plate coated with escherichia coli or staphylococcus aureus, a label is pasted on a culture dish cover, the culture dish is marked, the diameter of an antibacterial ring is measured by a vernier caliper after the culture dish is placed in a constant temperature incubator and is cultured for 24 hours at 37 ℃, and the diameter of the antibacterial ring is compared with that of penicillin potassium (the concentration of 10 mug/mL).
Test results show that the diameters of inhibition zones of the benzil dihydrazone-N, N' -bis (3-acetyl indole) to escherichia coli/staphylococcus aureus are 8.1 mm and 9.0mm respectively, and the diameters of inhibition zones of the benzil monohydrazone-N-3-acetyl indole to the escherichia coli/staphylococcus aureus are 8.2 mm and 9.5mm respectively; both are smaller than 29.0 and 28.4mm for potassium penicillin, but still have some bacteriostatic activity.
5. Ultraviolet and fluorescent properties
The benzil dihydrazone-N, N' -di (3-acetyl indole) has three strong absorption peaks near 210nm, 258nm and 340nm, and the ultraviolet spectrum is shown in figure 9; has strong fluorescence emission peak in the range of 300-400nm and a medium intensity fluorescence emission peak in the range of 420-500nm, and the fluorescence spectrum is shown in figure 10.
The benzil monohydrazone-N-3-acetyl indole has four strong absorption peaks near 203nm, 217nm, 251nm and 353nm, and the ultraviolet spectrum is shown in figure 11; has strong fluorescence emission peak in the range of 300-375nm, and the fluorescence spectrum is shown in figure 12.
The test results show that the two compounds have good fluorescence properties and can be used as fluorescent materials.
Detailed Description
In order to better understand the present invention, the following embodiment further illustrates the technical solution of the present invention.
Example 1.
0.238g of benzil dihydrazone is dissolved in 30ml of acetonitrile, 0.318g of 3-acetyl indole is added according to the mass proportion of 1:2, the mixture is heated and refluxed for 10 hours, and after the solvent is volatilized to leave about 5ml, a yellow rod-shaped crystal, namely benzil dihydrazone-N, N' -bis (3-acetyl indole), can be recrystallized by methanol to obtain a purer product.
Example 2.
0.224g of benzil monohydrazone is dissolved in 30ml of acetonitrile, 0.159g of 3-acetyl indole is added according to the mass proportion of 1:1, the mixture is heated and refluxed for 3 hours, and yellow needle-shaped crystals, namely the benzil monohydrazone-N-3-acetyl indole, can be obtained after the solvent is volatilized to about 5ml, and can be recrystallized by methanol to obtain a purer product.
Drawings
FIG. 1 is a drawing showing the preparation of benzildihydrazone-N, N' -bis (3-acetylindole) 1 H NMR spectrum (solvent DMSO-d 6).
FIG. 2 is a drawing showing the preparation of benzildihydrazone-N, N' -bis (3-acetylindole) 13 CNMR spectrum (solvent DMSO-d 6).
FIG. 3 is a crystal structure diagram of benzildihydrazone-N, N' -bis (3-acetylindole) with an ellipsoid probability of 30%.
FIG. 4 is a packing diagram of the crystal structure of benzildihydrazone-N, N' -bis (3-acetylindole) with 10% probability of ellipsoid.
FIG. 5 shows the preparation of benzil monohydrazone-N-3-acetyl indole 1 H NMR spectrum (solvent DMSO-d 6).
FIG. 6 shows the preparation of benzil monohydrazone-N-3-acetyl indole 13 CNMR spectrum (solvent DMSO-d 6).
FIG. 7 shows the crystal structure of benzil monohydrazone-N-3-acetyl indole with 30% probability of ellipsoid.
FIG. 8 is a crystal structure stacking diagram of benzil monohydrazone-N-3-acetylindole with 10% probability of ellipsoid.
FIG. 9 is a UV-VIS spectrum of benzildihydrazone-N, N' -bis (3-acetylindole) (10) -5 M ethanol solution).
FIG. 10 is a fluorescent spectrum of benzildihydrazone-N, N' -bis (3-acetylindole) (10) -5 M ethanol solution).
FIG. 11 is a UV-VIS spectrum of benzil monohydrazone-N-3-acetylindole (10) -5 M ethanol solution).
FIG. 12 shows the fluorescence spectrum of benzil monohydrazone-N-3-acetylindole (10) -5 M ethanol solution).
Claims (5)
1. Two Schiff base crystals are generated by benzildihydrazone or benzil monohydrazone and 3-acetyl indole, the former is double Schiff base, the appearance is yellow rod-shaped crystal, the melting point is 270.2-271.7 ℃, and the molecular formula C 34 H 28 N 6 Molecular weight 520.62; the latter is Shan Xifu alkali, and has yellow needle crystal appearance, melting point of 223.1-224.4 deg.C, and molecular formula C 24 H 19 N 3 O, molecular weight 365.43; the structures of the two are as follows:
the double schiff base is crystallized as a triclinic system, P-1 space group, a =10.2585 (4) A, b =11.9610 (5) A, c = 12.8232 (6) A, α = 64.941 (4) DEG, β = 79.573 (3) DEG, γ =76.829 (4) DEG, V = 1381.45 (11) A 3 Z =2; shan Xifu alkali crystallization is tetragonal system, P4 3 2 1 2 space group, a = b = 8.3580 (1), c = 54.6705 (7), a = β = γ =90 °, V = 3819.07 (10) a 3 ，Z=8。
2. The two synthesis methods of the benzildihydrazone-N, N' -bis (3-acetylindole) crystal as claimed in claim 1, wherein the first method is to use benzildihydrazone and 3-acetylindole as raw materials, dissolve the two raw materials in methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran or acetone organic solvent respectively, mix them according to the ratio of 4:1-1:4 substance, stir and react for 0.5-10h at normal temperature or under heating reflux, filter, evaporate the filtrate naturally, and precipitate yellow rod-shaped crystal as the target product; or solid phase reaction is adopted, organic solvent is not used, the two raw materials are mixed and ground for reaction for 0.5 to 10 hours according to the mass ratio of 4:1 to 1:4, and then methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran or acetone organic solvent is used for recrystallization to obtain target product crystals; the second method takes diphenylethanedione and 3-acetyl indole hydrazone as raw materials, and the steps are the same as the first method.
3. The method for synthesizing the benzil monohydrazone-N-3-acetylindole crystal as claimed in claim 1, dissolving the benzil monohydrazone and the 3-acetylindole in methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran or acetone organic solvent respectively, mixing according to the ratio of the amount of 4:1-1:4 substance, stirring and reacting for 0.5-10h at normal temperature or under heating reflux, filtering, and naturally volatilizing the filtrate to precipitate a yellow needle crystal which is the target product; or solid phase reaction is adopted, organic solvent is not used, the two raw materials are mixed and ground for reaction for 0.5 to 10 hours according to the mass ratio of 4:1 to 1:4, and then methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran or acetone organic solvent is used for recrystallization to obtain the target product crystal.
4. The use of two compounds according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of tumors, wherein: the tumor for inhibiting the benzil dihydrazone-N, N' -bis (3-acetyl indole) or the pharmaceutically acceptable salt thereof is breast cancer, and the tumor for inhibiting the benzil monohydrazone-N-3-acetyl indole or the pharmaceutically acceptable salt thereof is lung cancer or breast cancer.
5. Use of two compounds as claimed in claim 1 for the preparation of an antibacterial medicament or material, which is effective in inhibiting the proliferation of escherichia coli and staphylococcus aureus.
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Application publication date: 20200117 Assignee: Shandong Meiruida Pharmaceutical Technology Co.,Ltd. Assignor: Qilu University of Technology (Shandong Academy of Sciences) Contract record no.: X2024980017259 Denomination of invention: Structure, synthesis, and applications of benzoyl hydrazone 3-acetylindole Granted publication date: 20230324 License type: Common License Record date: 20241010 |