Resveratrol imine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of development of anti-inflammatory and antioxidant drugs, and discloses a resveratrol imine derivative as well as a preparation method and application thereof. The resveratrol imine derivative is a compound with a structure as shown in a formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound of the compound with the structure as shown in the formula 2 or the pharmaceutically acceptable salt thereof. The resveratrol derivative belongs to a novel compound, the compounds are designed and successfully synthesized for the first time, and meanwhile, the structure of the resveratrol derivative is represented; the preparation method of the resveratrol derivative is simple and convenient to operate, and the compounds can be rapidly synthesized. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of anti-inflammatory and antioxidant drug development, and particularly relates to a resveratrol imine derivative and a preparation method and application thereof. Background Art

[0002] Resveratrol, chemical name is 3,4',5-trihydroxy-1,2-diphenylethylene, molecular formula is C 14 H 12 O3, molecular weight is 228.23, CAS number: 501-36-0, structure is as shown in formula 1. Resveratrol was first discovered and extracted from the roots of the poisonous plant Veratrum in 1939 by Japanese scientists. Resveratrol is widely found in many plants, such as grapes, knotweed, peanuts, mulberries, etc. It is a natural antitoxin secreted by plants when facing adversity or pathogen invasion. Resveratrol exists in plants in the form of free state and glycoside-bound state, among which the trans isomer has stronger biological activity.

[0003]

[0004] Resveratrol, as a non-flavonoid polyphenol containing stilbene structure, has multiple biological activities such as anti-aging, antioxidant, anti-inflammatory, anti-cancer and cardiovascular protection, and people are increasingly developing and utilizing it. Studies have shown that 600 mg / kg resveratrol can maintain the intestinal health of laying hens induced by tBHP-induced oxidative stress by downregulating the mRNA expression levels of NF-κB, TNF-α, etc., and reduce the decline in production performance and ovarian function of laying hens caused by oxidative stress. Meng et al. found through transcriptome and 16srRNA sequencing analysis that adding resveratrol to sow diets may reduce piglet diarrhea and intestinal inflammation caused by weaning by improving intestinal gene expression and regulating intestinal flora in weaned piglets. The above studies show that high-dose resveratrol can play an anti-stress enteritis role in livestock and poultry by regulating oxidative stress, inflammation-related signaling pathways and regulating intestinal flora.

[0005] However, the structure of resveratrol is unstable and easily oxidized, and the double bond is highly photosensitized, which can easily transform into a less active cis structure under ultraviolet light; it has low polarity, poor water solubility, and low oral bioavailability, about 12%, and a larger dosage is required to achieve an effective drug concentration in plasma or tissue. Therefore, rapid absorption, low bioavailability, and poor water solubility are key factors limiting the clinical use of resveratrol. Given that resveratrol has certain anti-inflammatory enteritis activity in livestock and poultry, its high in vivo dosage is only due to problems such as low bioavailability and poor water solubility. If its structure can be modified and characteristic groups are introduced into its parent nucleus, it is expected to obtain resveratrol derivatives with better biological activity and higher bioavailability.

[0006] Molecular hybridization refers to the formation of new active compounds by connecting two active molecular fragments through chemical synthesis. Molecular hybridization can enhance the pharmacological activity of active molecules, enhance drug stability, and reduce its toxic side effects; providing more possibilities for drug design. Summary of the invention

[0007] In order to overcome the shortcomings and deficiencies in the prior art, the primary purpose of the present invention is to provide a resveratrol imine derivative.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned resveratrol imine derivative; this method forms a new compound by extending an aldehyde group on the benzene ring of resveratrol and connecting it with glycine or benzylamine derivatives, thereby improving the structural stability and bioavailability.

[0009] Another object of the present invention is to provide a use of the above-mentioned resveratrol imine derivative. Since the resveratrol derivative has good in vitro antioxidant activity, it is suitable as a new drug for oxidative stress diseases.

[0010] The purpose of the present invention is achieved through the following technical solutions:

[0011] A resveratrol imine derivative, wherein the derivative is a compound having a structure shown in Formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound of the compound having a structure shown in Formula 2 or a pharmaceutically acceptable salt thereof:

[0012]

[0013] Wherein, R is one of the following groups:

[0014]

[0015] The specific groups of the above compounds are summarized in Table 1:

[0016] Table 1 Compound numbers and structures

[0017]

[0018]

[0019] The pharmaceutically acceptable salt is a salt formed by the compound of formula 2 and lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion and ammonium ion.

[0020] The preparation method of the above-mentioned resveratrol imine derivative comprises the following steps:

[0021] (1) reacting resveratrol with N,N-dimethylformamide and phosphorus oxychloride to obtain an intermediate I with a structure as shown in Formula 3;

[0022]

[0023] (2) Glycine, one of 2-F benzylamine, 4-F benzylamine and 4-OH benzylamine, together with the intermediate I, are used as raw materials, and a resveratrol imine derivative having a structure as shown in Formula 2 is obtained by condensation reaction and purification.

[0024] The molar ratio of resveratrol, N,N-dimethylformamide and phosphorus oxychloride in step (1) is 1:1.1:1.1; and the reaction is carried out at room temperature for 16 hours.

[0025] The step (1) is specifically performed as follows: using acetonitrile as a solvent, adding N,N-dimethylformamide and phosphorus oxychloride under stirring in an ice-salt bath, stirring for 5 minutes, then adding resveratrol, and reacting overnight; filtering to obtain a red solid, and washing with cold acetonitrile; transferring the obtained solid to a new reaction bottle, adding water, reacting at 55° C. for 3 to 5 hours, filtering, washing, and drying to obtain intermediate I.

[0026] In step (2), the molar ratio of glycine, 2-F benzylamine, 4-F benzylamine and 4-OH benzylamine to intermediate I is 1:1; and the condensation reaction is carried out at room temperature for 16 hours under nitrogen protection.

[0027] Application of the above-mentioned resveratrol imine derivatives in the preparation of drugs for preventing and treating oxidative stress.

[0028] The synthesis route of the resveratrol imine derivative is shown in the following formula, and the R groups are all groups in Table 1:

[0029]

[0030] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0031] (1) The resveratrol imine derivatives provided by the present invention are novel compounds that have never been reported. The present invention is the first to design and successfully synthesize these compounds and characterize their structures.

[0032] (2) The preparation method of the resveratrol imine derivatives of the present invention is simple and easy to operate, and these compounds can be synthesized quickly. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the NMR spectrum of compound 1.

[0034] Figure 2 This is the NMR spectrum of compound 2.

[0035] Figure 3 This is the NMR spectrum of compound 3.

[0036] Figure 4 This is the NMR spectrum of compound 4.

[0037] Figure 5 The DPPH method is used to determine the scavenging ability of resveratrol imine derivatives on DPPH free radicals.

[0038] Figure 6 This is the NMR spectrum of intermediate I. DETAILED DESCRIPTION

[0039] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0040] Example 1 Preparation of Intermediate I

[0041] 30 mL of acetonitrile was added to a single-diameter round-bottom flask, and the mixture was placed in an ice-salt bath for 5 min. N, N-dimethylformamide (1.76 g, 24.1 mmol) and phosphorus oxychloride (3.69 g, 24.1 mmol) were added. After stirring for 5 min, resveratrol (5 g, 21.9 mmol) was added. After stirring overnight, the solid was collected by suction filtration and washed with cold acetonitrile. The obtained solid was transferred to a new single-diameter round-bottom flask, 30 mL of water was added, and the mixture was reacted at 55° C. for 3 to 5 h. The solid was collected by suction filtration and washed with cold water, and then dried to obtain an intermediate I with a structure shown in Formula 3, with a yield of 80%. The NMR spectrum of the intermediate I is shown in FIG. Figure 6 The hydrogen spectrum integral and chemical shift of intermediate I are similar to the prediction.

[0042]

[0043] Example 2 Synthesis of 2-(((E)-2,4-dihydroxy-6-((E)-4-hydroxystyrene)benzylidene)amino)acetic acid (Compound 1)

[0044] Add glycine (0.16 g, 2.14 mmol) to a single-diameter round-bottom flask, add 5 mL of anhydrous methanol and potassium hydroxide powder (0.12 g, 2.14 mmol), stir at room temperature until the solid is dissolved, add intermediate I (0.5 g, 1.95 mmol) obtained in Example 1, continue stirring for 16 h, and monitor the reaction by TLC tracking. After the reaction is completed, filter the reaction solution to obtain a solid, and purify it by pulping to obtain the product resveratrol imine derivative. The NMR spectrum of the product is as follows Figure 1 As shown, 1H NMR (600MHz, DMSO-d6) δ14.62 (s, 1H), 10.37 (d, J = 285.8 Hz, 2H), 8.55 (s, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 15.9 Hz, 1H), 6.91 (d, J = 15.8 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 6.29 (d, J = 2.2 Hz, 1H), 5.90 (d, J = 2.2 Hz, 1H), 3.99 (s, 2H). The hydrogen spectrum integral and chemical shift of compound 1 are similar to those predicted, so the structure of the product is 2-(((E)-2,4-dihydroxy-6-((E)-4-hydroxystyrene)benzylidene)amino)acetic acid.

[0045] Example 3 Synthesis of Compounds 2 to 4

[0046] In a single-diameter round-bottom flask, the intermediate I (0.5 g, 1.95 mmol) obtained in Example 1 and 2-F benzylamine, 4-F benzylamine or 4-OH benzylamine (2.14 mmol) were added and dissolved in 5 mL of anhydrous methanol. The mixture was stirred at room temperature for 16 h and the reaction was monitored by TLC tracking. After the reaction was completed, the methanol was removed in vacuo and purified by beating to obtain resveratrol imine derivatives, namely compounds 2 to 4. The NMR spectra of compounds 2 to 4 are shown in FIG. Figures 2 to 4 shown.

[0047] The yields of the above compounds are summarized in Table 2.

[0048] Table 2 Yields of compounds 1 to 4

[0049]

[0050] Effect Example

[0051] DPPH free radical scavenging experiment

[0052] In a 96-well plate, add 190 μL of the prepared 100 μmol / L DPPH solution to each well, and then add 10 μL of compound 1-4 (resveratrol imine derivatives prepared in Example 2-3) with a final concentration of 5 to 50 μmol / L, and set up a control group so that their total volume is maintained at 200 μL. Incubate the reaction in the dark for 30 minutes at room temperature, and then measure their absorbance at 517 nm. Calculate the DPPH free radical scavenging rate as follows: DPPH scavenging rate = [1-(Am-An) / As] × 100%. Am represents the OD value of the sample group, An represents the OD value of the methanol solution, and As represents the OD value of the negative control group. Use the concentration of the resveratrol imine derivative as the horizontal coordinate, and the clearance rate corresponding to the concentration of the resveratrol imine derivative as the vertical coordinate to draw a curve. See the results. Figure 5 Compounds 1 to 4 all showed stronger DPPH free radical scavenging ability than water-soluble vitamin C.

[0053] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A resveratrol imine derivative, characterized in that: The derivative is a compound of the structure shown in Formula 2 or a pharmaceutically acceptable salt thereof, and a solvent compound of the compound of the structure shown in Formula 2 or a pharmaceutically acceptable salt thereof: Wherein, R is one of the following groups:

2. The resveratrol imine derivative according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt formed by the compound of formula 2 and lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion and ammonium ion.

3. The method for preparing the resveratrol imine derivative according to claim 1 or 2, characterized in that The following steps are included: (1) reacting resveratrol with N,N-dimethylformamide and phosphorus oxychloride to obtain an intermediate I with a structure as shown in Formula 3; (2) Glycine, one of 2-F benzylamine, 4-F benzylamine and 4-OH benzylamine, together with the intermediate I, are used as raw materials, and a resveratrol imine derivative having a structure as shown in Formula 2 is obtained by condensation reaction and purification.

4. The preparation method according to claim 3, characterized in that: The molar ratio of resveratrol, N,N-dimethylformamide and phosphorus oxychloride in step (1) is 1:1.1:1.1; and the reaction is carried out at room temperature for 16 hours.

5. The preparation method according to claim 3, characterized in that: The step (1) is specifically performed as follows: using acetonitrile as a solvent, adding N,N-dimethylformamide and phosphorus oxychloride under stirring in an ice-salt bath, stirring for 5 minutes, then adding resveratrol, and reacting overnight; filtering to obtain a red solid, and washing with cold acetonitrile; transferring the obtained solid to a new reaction bottle, adding water, reacting at 55° C. for 3 to 5 hours, filtering, washing, and drying to obtain intermediate I.

6. The preparation method according to claim 3, characterized in that: In step (2), the molar ratio of glycine, 2-F benzylamine, 4-F benzylamine and 4-OH benzylamine to intermediate I is 1:1; and the condensation reaction is carried out at room temperature for 16 hours under nitrogen protection.

7. Use of the resveratrol imine derivative according to claim 1 in the preparation of drugs for preventing and treating oxidative stress.

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