CN110759866B - Metronidazole-glutamine dipeptide compound and preparation and application thereof - Google Patents
Metronidazole-glutamine dipeptide compound and preparation and application thereof Download PDFInfo
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- CN110759866B CN110759866B CN201910931094.7A CN201910931094A CN110759866B CN 110759866 B CN110759866 B CN 110759866B CN 201910931094 A CN201910931094 A CN 201910931094A CN 110759866 B CN110759866 B CN 110759866B
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
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- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses a metronidazole glutamine dipeptide compound, 2- (2-methyl-5-nitro-1H-imidazolyl) ethyl-L-alanyl-L-glutamic acid, the molecular formula is as follows: c 14 H 22 N 6 O 6 . The invention utilizes the special status of the glutamine dipeptide in the organism and the important role of the glutamine dipeptide in resisting inflammation to modify the glutamine dipeptide on the metronidazole, obviously increases the total number of lymphocytes, T lymphocytes and the ratio of CD4/CD8 in circulation of a patient by providing exogenous glutamine, increases the immune function of the organism to strengthen the antibacterial effect of the metronidazole, particularly strengthens the inhibiting effect of the exogenous glutamine on helicobacter pylori, greatly increases the market prospect of the metronidazole modifier, and has strong practicability and wide applicability.
Description
Technical Field
The invention relates to a metronidazole coupled glutamine dipeptide compound, in particular to a metronidazole coupled glutamine dipeptide compound and preparation and application thereof.
Background
Metronidazole (metronidazo 1 e), also known as metronidazole, is a nitroimidazole antibiotic, has powerful bactericidal action on gram-positive and gram-negative anaerobic bacteria and on bacteroides fragilis, and is a clinically common anti-infection basic drug. With the clinical wide application of metronidazole and the continuous and deep research on the pharmacological mechanism of metronidazole, various documents report that the adverse reaction of metronidazole is rare.
Helicobacter pylori (Hp) is a gram-negative, S-shaped or arc-shaped bent bacterium, and epidemiological, clinical and pathological studies show that Hp can induce chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue (mucosa-associated lymphoma) lymphoma and intestinal gastric cancer in human. The world health organization has listed helicobacter pylori as a class I carcinogen, which is a major causative factor of gastric cancer.
Therefore, there is a need for metronidazole modifications that improve its pharmacological action against gram-positive and gram-negative anaerobes, especially against helicobacter pylori, and reduce its adverse effects.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a metronidazole-glutamine dipeptide compound capable of enhancing the bacteriostatic effect of metronidazole and a preparation method thereof.
In order to achieve the above object, the present invention adopts the following technical solutions:
a metronidazole-glutamine dipeptide compound has a molecular formula as follows: c 14 H 22 N 6 O 6 The structural formula is as follows:
the metronidazole-glutamine dipeptide compound is prepared according to the following reaction formula:
the preparation method of the metronidazole-glutamine dipeptide compound comprises the following steps:
s1, dissolving metronidazole (compound 1) and glutamine dipeptide (compound 2) into a proper amount of dichloromethane solution, simultaneously adding a certain amount of DCC and DMAP, stirring for reaction, and then carrying out reduced pressure distillation to obtain a crude product;
s2, purifying the crude product by column chromatography to obtain white powder (compound 3).
Further, in the step S1, the molar ratio of metronidazole (compound 1) to glutamine dipeptide (compound 2) is 1.1.
Further, the DCC was 1.5equiv, and the DMAP was 0.3equiv.
Further, in the above step S1, the reaction was followed by TLC.
The metronidazole-glutamine dipeptide compound is applied to inhibiting helicobacter pylori.
The invention has the advantages that:
glutamine dipeptide is the most abundant free amino acid in the body, accounting for about 60% of the total free amino acid in the body. Glutamine dipeptide can promote mitosis, differentiation and proliferation of lymphocyte and macrophage, increase production of cell factors TNF, IL-1, etc. and synthesis of phospholipid mRNA.
The metronidazole-glutamine dipeptide compound of the invention modifies glutamine dipeptide on metronidazole by utilizing the special position of the glutamine dipeptide in an organism and the important function of the glutamine dipeptide in resisting inflammation, obviously increases the total number of lymphocytes, T lymphocytes and the ratio of CD4/CD8 in circulation of a patient by providing exogenous glutamine, increases the immunologic function of the organism, enhances the antibacterial action of the metronidazole, particularly enhances the inhibition effect of the exogenous glutamine on helicobacter pylori, greatly increases the market prospect of the metronidazole modifier, and has strong practicability and wide applicability.
Detailed Description
The following specific examples are intended to illustrate the invention.
The reagents used in the examples of the present invention are all commercially available.
DCC is dicyclohexylcarbodiimide and DMAP is 4-dimethylaminopyridine.
A metronidazole-glutamine dipeptide compound, namely 2- (2-methyl-5-nitro-1H-imidazolyl) ethyl-L-alanyl-L-glutamic acid, has a molecular formula as follows: c 14 H 22 N 6 O 6 The structural formula is as follows:
the reaction formula is as follows:
the preparation method comprises the following steps:
s1, dissolving metronidazole (compound 1) 200mg and glutamine dipeptide (compound 2) 279mg in a proper amount of dichloromethane solution according to a molar ratio of 1.1, simultaneously adding 1.5equiv DCC and 0.3equiv DMAP, stirring and reacting at room temperature, tracking and reacting by TLC, and after the reaction is completed, distilling a crude product under reduced pressure;
s2, the crude product was purified by column chromatography to give a white powder (Compound 3) (385 mg, 89% yield). 1 H NMR(500MHz,CDCl 3 )δ7.89(s,1H),7.61(d,J＝11.5Hz,1H),6.83(s,2H),6.57(dd,J＝7.9,6.4Hz,1H),6.48(dd,J＝7.8,6.3Hz,1H),4.63–4.52(m,2H),4.48–4.32(m,2H),4.17(q,J＝11.5Hz,1H),4.07(tq,J＝6.2,5.4Hz,1H),2.44(s,3H),2.39–2.22(m,2H),2.03–1.85(m,2H),1.42(d,J＝5.3Hz,3H)。
And (3) detecting the effect of the metronidazole-glutamine dipeptide compound on inhibiting the helicobacter pylori:
(I) test materials
Culture medium: nutrient agar
Fresh defibered horse blood
Starch
Mixing antibiotics: vancomycin, a xanthamine synergist TMP, amphotericin and polymyxin
Experimental strains: helicobacter pylori
The medicine solvent is as follows: ethanol
(II) culturing helicobacter pylori
The culture conditions are as follows: the temperature is 37 ℃, the pH value is 7.0-7.2, and the oxygen content is 2-8%
Culture medium: adding appropriate amount of horse blood, appropriate amount of mixed antibiotics and 1% starch into nutrient agar culture medium
Culturing time: 3-5 days
(III) the result of the detection
The experimental components were divided into four groups: filter paper without any drug, filter paper with metronidazole (10 mg/mL), filter paper with compound 2 (dipeptide complex of 10 mg/mL), filter paper with compound 3 (metronidazole-glutamine dipeptide complex of 10 mg/mL)
After the bacteria are cultured, the size of the inhibition zone is measured by a conventional filter paper diffusion method to carry out drug sensitivity experiments, and the experimental results are shown in the following table 1:
TABLE 1 inhibitory Effect of different Compounds on helicobacter pylori
| Components | Has no drug effect | Compound 2 | Metronidazole | Compound 3 |
| Size/ratio of zone of inhibition | 0 | 0.13 | 1 | 1.8 |
As can be seen from the experimental results in table 1 above, compound 3, i.e., the metronidazole-glutamine dipeptide compound of the present invention, has an inhibitory effect on helicobacter pylori that is significantly greater than metronidazole.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. It should be understood by those skilled in the art that the above embodiments do not limit the present invention in any way, and all technical solutions obtained by using equivalents or equivalent changes fall within the protection scope of the present invention.
Claims (6)
1. A metronidazole-glutamine dipeptide compound is characterized in that the molecular formula is as follows: c 14 H 22 N 6 O 6 The structural formula is as follows:
2. the preparation of a class of metronidazole-glutamine dipeptide compounds according to claim 1 wherein the reaction formula is as follows:
3. the preparation of a metronidazole-glutamine dipeptide compound according to claim 1, comprising the steps of:
s1, dissolving metronidazole (compound 1) and glutamine dipeptide (compound 2) into a proper amount of dichloromethane solution, simultaneously adding a certain amount of DCC and DMAP, stirring for reaction, and then carrying out reduced pressure distillation to obtain a crude product;
s2, purifying the crude product through column chromatography to obtain the metronidazole-glutamine dipeptide compound.
4. The preparation of a class of metronidazole-glutamine dipeptide compounds according to claim 3, wherein the molar ratio of metronidazole (compound 1) to glutamine dipeptide (compound 2) in step S1 is 1.1.
5. The method for preparing metronidazole glutamine dipeptide compounds according to claim 3 where in step S1 the reaction is followed by TLC.
6. The use of a metronidazole-glutamine dipeptide compound according to claim 1 in the manufacture of a medicament for the inhibition of helicobacter pylori.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467494A (en) * | 2015-08-21 | 2017-03-01 | 陕西合成药业股份有限公司 | Amino-acid ester soluble derivative of laevo-ornidazole and application thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106467494A (en) * | 2015-08-21 | 2017-03-01 | 陕西合成药业股份有限公司 | Amino-acid ester soluble derivative of laevo-ornidazole and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| Cinzia Bersani，等.PEG-metronidazole conjugates: synthesis, in vitro and in vivo properties.《Il Farmaco》.2005,783-788. * |
| Mohamed A. Ibrahim，等.Synthesis and antibacterial evaluation of amino acid–antibiotic conjugates.《Bioorganic & Medicinal Chemistry Letters》.2014,1856-1861. * |
| Permentier, Dirk，等.Synthesis of dipeptide esters of metronidazole and evaluation of their hydrolytic stability.《Bulletin des Societes Chimiques Belges》.1992,701-707. * |
| Rinku Baishya，等.Synthesis and Evaluation of Technetium-99m-Labeled Bioreductive Pharmacophores Conjugated with Amino Acids and Peptides for Tumor Imaging.《Chem Biol Drug Des》.2015,504-517. * |
| Roman N. Naumov，等.Synthesis and QSAR study of novel anti-inflammatory active mesalazine–metronidazole conjugates.《Bioorganic & Medicinal Chemistry Letters》.2015,2314-2320. * |
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