CN110642922B - Metronidazole-serine dipeptide compounds and preparation and application thereof - Google Patents
Metronidazole-serine dipeptide compounds and preparation and application thereof Download PDFInfo
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- CN110642922B CN110642922B CN201910931000.6A CN201910931000A CN110642922B CN 110642922 B CN110642922 B CN 110642922B CN 201910931000 A CN201910931000 A CN 201910931000A CN 110642922 B CN110642922 B CN 110642922B
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- serine
- metronidazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
- C07K5/06069—Ser-amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention discloses a metronidazole-serine dipeptide compound, 2- (2-methyl-5-nitro-1H-imidazolyl) ethyl seryl serine, the molecular formula of which is C 12 H 19 N 5 O 7 . The advantages of serine are utilized, serine and serine are synthesized into serine-serine dipeptide, and the serine-serine dipeptide is modified on metronidazole, so that the drug resistance of helicobacter pylori is reduced, the inhibiting effect of metronidazole drugs on helicobacter pylori is enhanced, the inhibiting effect of metronidazole on helicobacter pylori is optimized, the side reaction of metronidazole on a human body is reduced, the immunity of the human body is improved, raw materials are easy to obtain, the synthesis process is simple and easy to operate, the market prospect of metronidazole modifier is greatly increased, and the methionine modifier has strong practicability and wide applicability.
Description
Technical Field
The invention relates to a metronidazole-serine dipeptide SS compound, in particular to a metronidazole-serine dipeptide SS compound and preparation and application thereof.
Background
Metronidazole (metronidazole 1 e), also known as metronidazole, is an azomycin antibiotic, has powerful bactericidal effect on gram-positive and gram-negative anaerobic bacteria and fragile bacteroides, and is a clinically common anti-infective 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. Therefore, modification of metronidazole to enhance its antibacterial action and reduce adverse reactions is a popular topic in the field of medicinal chemistry.
Helicobacter pylori (Hp) is a gram-negative, S-shaped or arcuately curved bacterium, and has been shown by epidemiological, clinical and pathological studies to induce chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue (mucoid tissue) lymphoma, and intestinal gastric cancer in humans. The world health organization has listed helicobacter pylori as a class I carcinogen, which is a major causative factor of gastric cancer. The incidence of Hp resistant strains has increased due to the widespread use of antibiotics in recent years.
Therefore, metronidazole needs to be modified to enhance the inhibition effect of metronidazole drugs on helicobacter pylori and enhance the antibacterial capability of organisms.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a metronidazole serine dipeptide compound capable of effectively enhancing the inhibition effect of metronidazole drugs on helicobacter pylori and a preparation method thereof.
In order to achieve the above object, the present invention adopts the following technical solutions:
a metronidazole-serine dipeptide compound has a molecular formula as follows: c 12 H 19 N 5 O 7 The structural formula is as follows:
the preparation of the metronidazole-serine dipeptide compounds has the following reaction formula:
the preparation method of the metronidazole serine dipeptide compounds comprises the following steps:
s1, dissolving metronidazole (compound 1) and serine-serine 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, the molar ratio of metronidazole (compound 1) to serine-serine dipeptide (compound 2) was 1.
Further, the DCC was 1.5equiv, and the DMAP was 0.3equiv.
In step S1 above, the reaction was followed by TLC.
The serine-serine dipeptide is synthesized by a polypeptide synthesizer;
Fmoc/tBu solid-phase polypeptide synthesis method is utilized, then 20wt% of piperidine and dimethylformamide are used for removing Fmoc, and the prepared crude product is purified by column chromatography to obtain pure Ser-Ser.
The metronidazole-serine dipeptide compounds are applied to inhibiting helicobacter pylori.
The invention has the advantages that:
the metronidazole-serine dipeptide compound is a novel metronidazole modifier, and utilizes the advantages of serine to synthesize serine and serine into serine-serine dipeptide, and the serine-serine dipeptide compound is modified on metronidazole, so that the antibacterial effect of the metronidazole is enhanced, particularly the inhibition effect of the metronidazole on helicobacter pylori is enhanced, the side effect of the metronidazole on a human body is reduced, and the immunity of the human body is enhanced.
Serine, also known as beta-hydroxy alanine, is a non-essential amino acid that plays a role in the metabolism of fats and fatty acids and in muscle growth, contributes to the production of immunocytokines and antibodies, and is also required to maintain a healthy immune system. Serine plays a role in the production and processing of cell membranes, and in the synthesis of muscle tissues and sheaths surrounding nerve cells.
The metronidazole serine dipeptide compound has the advantages of easily obtained raw materials, simple synthesis process and easy operation, effectively reduces the drug resistance of helicobacter pylori, enhances the inhibition effect of metronidazole drugs on the helicobacter pylori, optimizes the inhibition effect of metronidazole on the helicobacter pylori, greatly increases the market prospect of metronidazole modifiers, and has strong practicability and wide applicability.
Detailed Description
The present invention will be described in detail with reference to the following examples.
The reagents used in the examples of the present invention are all commercially available.
DCC is dicyclohexylcarbodiimide and DMAP is 4-dimethylaminopyridine.
A metronidazole-serine dipeptide compound, namely 2- (2-methyl-5-nitro-1H-imidazolyl) ethyl seryl serine (compound 3), has a molecular formula as follows: c 12 H 19 N 5 O 7 The structural formula is as follows:
the reaction formula is as follows:
the preparation method comprises the following steps:
s1, dissolving 210mg of metronidazole (compound 1) and 256mg of serine-serine dipeptide (compound 2) in a proper amount of dichloromethane solution according to a molar ratio of 1:1.1, simultaneously adding 1.5equiv DCC and 0.3equiv DMAP, stirring for reaction at room temperature, tracking the reaction 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) (390 mg, 92% yield). 1 H NMR(500MHz,CDCl 3 )δ7.90(s,1H),7.49(d,J＝12.2Hz,1H),5.87(dd,J＝8.8,8.0Hz,1H),5.66(dd,J＝8.7,8.0Hz,1H),4.58(td,J＝7.7,1.2Hz,2H),4.54–4.42(m,3H),4.29–4.12(m,2H),4.00–3.90(m,1H),3.84–3.59(m,4H),2.43(s,3H)。
Serine-serine dipeptide, which can be synthesized by a polypeptide synthesizer; the Fmoc/tBu solid-phase polypeptide synthesis method is utilized, then 20wt% of piperidine and dimethylformamide are used for removing Fmoc, and the prepared crude product is purified by column chromatography to obtain a pure product Ser-Ser (compound 2).
Detecting the effect of the metronidazole connected serine-serine dipeptide complex on inhibiting the helicobacter pylori:
(I) test materials
Culture medium: nutrient agar;
fresh defibrinated horse blood;
starch;
mixing antibiotics: vancomycin, a xanthamine synergist TMP, amphotericin, polymyxin;
experimental strains: helicobacter pylori;
medicine solvent: and (3) ethanol.
(II) culture of 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 a proper amount of horse blood, a proper amount of nutrient agar culture medium mixed with antibiotics and 1% of starch;
culturing time: 3-5 days.
(III) results 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-serine dipeptide complex of 10 mg/mL)
After the bacteria are cultured, the experiment results of the drug sensitivity test by measuring the size of the inhibition zone by the conventional filter paper diffusion method 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 | 0.31 | 1 | 1.7 |
As can be seen from the experimental results of table 1 above, compound 3, i.e., the metronidazole serine 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 equivalent alternatives or equivalent variations fall within the scope of the present invention.
Claims (7)
1. A metronidazole-serine dipeptide compound is characterized in that the molecular formula is as follows: c 12 H 19 N 5 O 7 The structural formula is as follows:
2. the preparation of a metronidazole serine dipeptide compound according to claim 1 wherein the reaction is as follows:
3. the preparation of a metronidazole serine dipeptide compound according to claim 1 comprising the steps of:
s1, dissolving metronidazole (compound 1) and serine-serine 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 a metronidazole-serine dipeptide compound (compound 3)
The structural formula of the serine-serine dipeptide (compound 2) is as follows:
the structural formula of the metronidazole-serine dipeptide compound (compound 3) is as follows:
4. the preparation of a class of metronidazole-serine dipeptide compounds according to claim 3 wherein the molar ratio of metronidazole (compound 1) to serine-serine dipeptide (compound 2) is 1.1.
5. The method of claim 3, wherein in step S1, TLC is used to follow the reaction.
6. The preparation of metronidazole to serine dipeptide compounds of one class according to claim 2 or 3, wherein the serine-serine dipeptide is synthesized by a polypeptide synthesizer;
Fmoc/tBu solid-phase polypeptide synthesis method is utilized, then 20wt% of piperidine and dimethylformamide are used for removing Fmoc, and the prepared crude product is purified by column chromatography to obtain the pure serine-serine dipeptide.
7. The use of a class of metronidazole to serine dipeptide compounds as claimed in claim 1 in the manufacture of a medicament to inhibit 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 (3)
| Title |
|---|
| Synthesis and Evaluation of Technetium-99m-Labeled Bioreductive Pharmacophores Conjugated with Amino Acids and Peptides for Tumor Imaging;Rinku Baishya，等;《Chem Biol Drug Des》;20151231;504-517 * |
| SYNTHESIS OF DlPEPTlDE ESTERS OF METRONIDAZOLE AND EVALUATION OF THEIR HYDROLYTIC STABILITY;Dirk Permentier，等;《Bull. SOC. Chlrn. Belg.》;19921231;701-707 * |
| 幽门螺杆菌对甲硝唑耐药相关基因片段的筛选及克隆分析;李爱清，等;《浙江大学学报（医学版）》;20071231;465-469 * |
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