阅读说明：本技术 双吡啶酮腙-3-吲哚甲醛西弗碱的用途 (Application of bispyridone hydrazone-3-indole formaldehyde Schiff base ) 是由 谭学杰 秦玥 于志杰 孔曼 邢殿香 于 2021-09-17 设计创作，主要内容包括：本发明涉及药物化学领域,具体为双吡啶酮腙与3-吲哚甲醛反应生成的西弗碱在抗癌药物、抗菌药物或抗菌材料中的用途。双吡啶酮腙和3-吲哚甲醛反应生成的西弗碱,系统命名为：3-((二(吡啶-2-基)亚甲基)腙)甲基)-1H-吲哚,分子式为C-(20)H-(15)N-(5)；该西弗碱外观呈黄色粉末,熔点166.7-168.3℃；结构如下：。该化合物对小鼠乳腺癌细胞4T-(1)的IC50(药物的半数抑制浓度)为11.5μM,对人肝癌Hep G2细胞的IC50为13.0μM,具有良好的肿瘤抑制活性；并且可以有效抑制大肠杆菌和金黄色葡萄球菌的繁殖。(The invention relates to the field of medicinal chemistry, in particular to application of Schiff base generated by reaction of bispyridone hydrazone and 3-indole formaldehyde in anticancer drugs, antibacterial drugs or antibacterial materials. Schiff base generated by reaction of bipyridone hydrazone and 3-indole formaldehyde, and systematic name is: 3- ((di (pyridin-2-yl) methylene) hydrazone) methyl) -1H-indole with the molecular formula C 20 H 15 N 5 (ii) a The appearance of the Schiff base is yellow powder, and the melting point is 166.7-168.3 ℃; the structure is as follows: . The compound can be used for treating mouse breast cancer cell 4T 1 The IC50 (half inhibition concentration of the drug) is 11.5 mu M, the IC50 of human liver cancer Hep G2 cells is 13.0 mu M, and the drug has good tumor inhibition activity; and can effectively inhibit the propagation of escherichia coli and staphylococcus aureus.)

1. The application of the compound shown as the following or pharmaceutically acceptable salt thereof in preparing the medicine for preventing and/or treating tumors is characterized in that: the tumor is breast cancer or liver cancer; the appearance of the bipyridone hydrazone-3-indole formaldehyde Schiff base is yellow powder, the melting point is 166.7-168.3 ℃, and the molecular formula is C₂₀H₁₅N₅The structure is as follows:

。

2. use of a compound as claimed in claim 1 in an antibacterial medicament or material, which is effective in inhibiting the proliferation of escherichia coli or staphylococcus aureus.

Technical Field

The invention relates to the field of medicinal chemistry, in particular to application of Schiff base generated by reaction of bispyridone hydrazone and 3-indole formaldehyde in anticancer drugs, antibacterial drugs or antibacterial materials.

Background

Schiff base is a compound containing an imine or azomethine group, of the general formula R¹R²C=NR³. 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, the 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, lasers and the like.

Disclosure of Invention

The invention relates to a synthetic method of Schiff base, namely the Schiff base generated by the reaction of bispyridone hydrazone and 3-indole formaldehyde, which is systematically named as follows: 3- ((di (pyridin-2-yl) methylene) hydrazone) methyl) -1H-indole with the molecular formula C₂₀H₁₅N₅(ii) a The appearance of the Schiff base is yellow powder, and the melting point is 166.7-168.3 ℃; the structure is as follows.

。

And (5) structure identification.

The elemental analysis of the bipyridone hydrazone-3-indole carbaldehyde Schiff base showed that the C, H, N percentage content was 73.81%, 4.68% and 21.55% (theoretical value is respectively)73.83%, 4.65% and 21.52%), molecular weight 325.375; in connection with¹HNMR spectrum,¹³The CNMR spectra are shown in figure 1 and figure 2 respectively.

A synthetic method.

The bipyridyl ketone hydrazone-3-indole formaldehyde Schiff base has two synthesis methods: the first method takes bipyridone hydrazone and 3-indole formaldehyde as raw materials and comprises the following steps.

1) Dissolving the dipyridone hydrazone in a proper organic solvent, adding the 3-indole formaldehyde according to a certain substance amount ratio, and stirring and reacting for a certain time at a certain temperature to complete the preparation.

The first step can also adopt solid phase reaction, namely organic solvent is not used, the dipyridone hydrazone and the 3-indole formaldehyde are mixed according to a certain substance amount ratio and then are ground and reacted for a certain time at normal temperature, and the obtained solid is the crude product of the target product.

2) If liquid phase reaction is adopted, filtering is carried out after the reaction is finished, and yellow powder separated out is a target product after the filtrate is naturally volatilized; if solid phase reaction is adopted, the target product can be obtained by recrystallization with proper organic solvent after the reaction is finished.

The second method takes the bipyridone and the 3-indole formaldehyde hydrazone as raw materials, and is completed in one step in a proper organic solvent, and the steps are as follows.

1) Dissolving dipyridone in a proper organic solvent, adding 3-indole formaldehyde 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 the solid-phase reaction is adopted, an organic solvent is not used, the two are mixed according to a certain proportion and then the grinding reaction is carried out for a certain time, and the obtained solid is the crude product of the target product.

2) If liquid phase reaction is adopted, filtering is carried out after the reaction is finished, and yellow powder separated out is a target product after the filtrate is naturally volatilized; if solid phase reaction is adopted, the target product can be obtained by recrystallization with proper organic solvent after the reaction is finished.

The two preparation methods are different mainly in reactants, but the molar ratio of the reaction raw materials is between 4:1 and 1: 4.

The organic solvent (including the solvent for reaction or the solvent for recrystallization) in the above two preparation methods is selected from: methanol, ethanol, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, toluene, dioxane, etc.; the solid phase reaction does not use organic solvent, the raw materials react directly, and the solvent used for recrystallization can also be selected from the above solvents.

Preferably, the reaction temperature of the liquid phase reaction is normal temperature or heating reflux, and the reaction method is stirring; the solid phase reaction can be carried out at normal temperature, and the reaction method is grinding.

Preferably, the reaction time is selected from: 0.5-10 h.

The invention has the beneficial effects that: can synthesize more complex functional molecular materials by simpler steps and reactants.

In vitro antitumor activity.

Mice growing in log phase were breast cancer 4T₁The cells or human hepatoma Hep G2 cells were digested with 0.25% pancreatic enzyme to become single cells, and prepared into 1.25X 10 by using 10% fetal bovine serum-containing F12K culture medium⁷One cell/L suspension of single cells, cells were seeded in 96-well plates at 200. mu.L per well (2.5X 10 per well)³Individual cells). Place 96-well cell culture plates in CO₂In an incubator at 37 ℃ with 5% CO₂Culturing 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 96 h.

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, the calculation was performed as follows.

Cell inhibition% = (control OD value-experimental OD value)/control OD value × 100%.

TestingThe result shows that the dipyridone hydrazone-3-indole formaldehyde Schiff base is applied to 4T of mouse breast cancer cells₁IC50 (half maximal inhibitory concentration of drug) of 11.5 μ M; IC50 of Hep G2 cell of human liver cancer is 13.0 μ M; the inhibition rate of human foreskin fibroblast HFF-1 is 98.2 mu M; this indicates that the Schiff base molecule has a very good inhibitory effect on both cancer cells, and an inhibitory effect (IC) of cisplatin on both cancer cells₅₀=5.5 μ M and 4.9 μ M) and has a low inhibition rate on normal cells.

And (4) bacteriostatic activity.

The antibacterial effect is measured by adopting a filter paper diffusion method: soaking circular filter paper sheets (each sheet absorbs 10 microliters of liquid medicine) with the same size and the same diameter of 8mm into DMSO (dimethylsulfoxide) solution of a to-be-detected medicine with the concentration of 100 mug/mL, taking out the filter paper sheets after 30 minutes, airing, wherein the drug-loading capacity of each filter paper sheet is about 1 mug, then placing the filter paper sheets into the center of a plate coated with escherichia coli or staphylococcus aureus, pasting a label on a culture dish cover, marking, placing the culture dish into a constant-temperature incubator, culturing for 24 hours at 37 ℃, measuring the diameter of an antibacterial ring by using a vernier caliper, and comparing with penicillin potassium (the concentration of 10 mug/mL).

Test results show that the diameters of inhibition zones of the bispyridone hydrazone-3-indole formaldehyde Schiff base on escherichia coli/staphylococcus aureus are 13.1 mm and 12.6mm respectively; although smaller than 29.0 and 28.4mm of penicillin potassium, still has certain bacteriostatic activity.

Drawings

FIG. 1 shows the preparation of bispyridone hydrazone-3-indolecarboxaldehyde Schiff base¹H NMR spectrum (solvent DMSO-d 6).

FIG. 2 shows the preparation of bispyridone hydrazone-3-indolecarboxaldehyde Schiff base¹³CNMR spectrum (solvent DMSO-d 6).

Detailed Description

In order to better understand the present invention, the following embodiment further illustrates the technical solution of the present invention.

Example 1.

Weighing 1.98g (0.01 mol) of bispyridone hydrazone powder, placing the powder in a 100mL single-neck flask, pouring 30mL of toluene into the flask, stirring and dissolving at 50 ℃, weighing 1.45g (0.01 mol) of 3-indolylaldehyde after the toluene is completely dissolved, adding the mixture into the flask, heating to 80 ℃, refluxing and stirring for reaction for 8 hours, cooling to room temperature, filtering, placing the filtrate in a beaker for natural volatilization, and obtaining yellow powder at the bottom of the beaker after about 1 week, namely the bispyridone hydrazone-3-indolylaldehyde Schiff base which can be recrystallized by methanol to obtain a purer product.

Example 2.

Dissolving 1.84g (0.01 mol) of bipyridyl ketone in 30ml of ethyl acetate, adding 1.59g of 3-indolylformaldehyde hydrazone according to the mass ratio of 1:1, heating and refluxing for 3h, cooling to room temperature, filtering, placing the filtrate in a beaker for natural volatilization, and obtaining yellow powder after the solvent is volatilized to the residual about 5ml, namely bipyridyl ketone hydrazone-3-indolylformaldehyde Schiff base, and recrystallizing with methanol to obtain a purer product.

Example 3.

1.84g (0.01 mol) of bipyridyl ketone and 1.59g (0.01 mol) of 3-indole carbaldehyde hydrazone are mixed and ground for 8 hours to obtain yellow powder, namely bipyridyl ketone hydrazone-3-indole carbaldehyde Schiff base, and ethyl acetate can be used for recrystallization to obtain a purer product.