CN118324850B - A broad-spectrum macrolide compound and its preparation and application - Google Patents
A broad-spectrum macrolide compound and its preparation and application Download PDFInfo
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- CN118324850B CN118324850B CN202410343702.3A CN202410343702A CN118324850B CN 118324850 B CN118324850 B CN 118324850B CN 202410343702 A CN202410343702 A CN 202410343702A CN 118324850 B CN118324850 B CN 118324850B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 89
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000010499 C–H functionalization reaction Methods 0.000 claims abstract description 7
- 229940124350 antibacterial drug Drugs 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- 239000011259 mixed solution Substances 0.000 claims description 15
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
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- 125000006239 protecting group Chemical group 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 9
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 claims description 8
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 8
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 claims description 7
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 7
- 229940005561 1,4-benzoquinone Drugs 0.000 claims description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 7
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 6
- PMUNIMVZCACZBB-UHFFFAOYSA-N 2-hydroxyethylazanium;chloride Chemical compound Cl.NCCO PMUNIMVZCACZBB-UHFFFAOYSA-N 0.000 claims description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
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- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 1
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
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- 101800003223 Cecropin-A Proteins 0.000 description 1
- 241000192700 Cyanobacteria Species 0.000 description 1
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- 102000004190 Enzymes Human genes 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
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- HCQPHKMLKXOJSR-IRCPFGJUSA-N cecropin-a Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(N)=O)[C@@H](C)CC)C(C)C)[C@@H](C)CC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CCCCN)C1=CC=CC=C1 HCQPHKMLKXOJSR-IRCPFGJUSA-N 0.000 description 1
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
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- 238000005710 macrocyclization reaction Methods 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
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Classifications
-
- 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
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及大环内酯化合物合成技术领域，具体涉及一种广谱性大环内酯化合物及其制备与应用。本发明提供了一种如式(IX)表示的广谱性大环内酯化合物；通过将酯键引入多肽化合物的分子结构中，再通过C‑H活化反应一步构建得到。得到的广谱性大环内酯化合物具有广谱抗菌性，为抗菌新药筛选提供了研究基础。
The present invention relates to the technical field of macrolide compound synthesis, and in particular to a broad-spectrum macrolide compound and its preparation and application. The present invention provides a broad-spectrum macrolide compound represented by formula (IX); an ester bond is introduced into the molecular structure of a polypeptide compound, and then the compound is obtained by one-step construction through a C-H activation reaction. The obtained broad-spectrum macrolide compound has a broad-spectrum antibacterial property, and provides a research basis for the screening of new antibacterial drugs.
Description
Technical Field
The invention relates to the technical field of macrolide compound synthesis, in particular to a broad-spectrum macrolide compound, and preparation and application thereof.
Background
Many natural polypeptide compounds have good antibacterial activity, and particularly have good inhibition effects on gram-negative bacteria, gram-positive bacteria and fungi. The wide biological activity of the antibacterial peptide shows good application prospect in medicine, and the antibacterial peptide has high-efficiency broad-spectrum killing effect on gram-negative bacteria and gram-positive bacteria, and at least 113 different bacteria have been reported at home and abroad to be killed by the antibacterial peptide. The first antibacterial peptide with antifungal effect was found to be frog skin (MAGAININS) separated from the skin of amphibian frog, which acts on G+ and G-, and has killing effect on fungi and protozoa. DEFENSINS is an animal cell endogenous bactericidal polypeptide which is separated from phagocytes, has a very wide antibacterial spectrum, has a greater killing effect on G+ than G-, and also acts on fungi and part of eukaryotic cells. Cecropin A and analogues thereof such as Cecropin-melittin hybrid peptide have a certain killing effect on insect-infected fungi.
Antimicrobial macrocyclic peptides have more prominent advantages over traditional linear antimicrobial peptides, including higher binding affinity, target selectivity, cell permeability, proteolytic stability, and the ability to modulate protein-protein interactions (PPI). In order to better understand their physiological and pharmacological functions, in particular to inhibit the action of intracellular PPIs, the construction of macrocyclic peptides has proven to be a powerful tool and is therefore highly desirable in the pharmaceutical chemistry field. Macrolide antibiotics (macrolides antibiotics, MA) are a generic term for a class of antibacterial drugs having a 12-16 carbon lactone ring in their molecular structure, which belongs to a rapid bacteriostatic agent by blocking the activity of peptide acyltransferase in 50s ribosomes to inhibit bacterial protein synthesis. The macrolide peptide belongs to one of macrolide compounds, and the cyclic ester peptide component is mainly derived from secondary metabolites of microorganisms, including cyanobacteria (Cyanobacterium), bacteria (Bacterium), actinomycetes and other microorganisms, wherein marine bacteria mainly comprise Bacillus and Pseudomonas. The advantages of good antimicrobial broad spectrum and inhibitory activity of macrocyclic depsipeptides have led to their widespread use in the treatment of bacterial and fungal infections.
Disclosure of Invention
The present invention provides a novel macrolide compound having a broad-spectrum antibacterial effect.
In order to achieve the above object, the present invention provides the following technical solutions:
the present invention provides a broad-spectrum macrolide compound represented by the formula (IX):
The ester functional group is introduced into the polypeptide compound in advance, and then the broad-spectrum macrolide compound shown as the formula (IX) is constructed by using a C-H activation method. The broad-spectrum macrolide compound obtained by construction has antibacterial property, has obvious antibacterial activity on staphylococcus aureus CMCC26003, escherichia coli ATCC8099, multi-drug resistant acinetobacter baumannii and other bacteria, and the inhibition rate of the compound on the bacteria is further increased along with the increase of the concentration of a sample.
The invention also provides a method for preparing a broad-spectrum macrolide compound, which comprises the following steps:
S1, adding Fmoc-Ala-OH shown in a formula (II) and dichloro resin shown in the formula (II) into dichloromethane solution at room temperature, mixing, adding diethylenetriamine, washing with dimethylformamide after the substitution reaction is finished to obtain a compound A shown in the formula (IV),
S2, removing Fmoc protecting groups in the compound A at room temperature, washing with dimethylformamide after the reaction is finished to obtain a compound B shown as a formula (V),
S3, adopting a solid-phase synthesis method, mixing Fmoc-Gly-OH, a peptide coupling reagent and a compound B in dimethylformamide, adding diethylenetriamine, removing Fmoc protecting groups, mixing Boc-Trp-OH, a peptide coupling reagent and a compound B in dimethylformamide, adding diethylenetriamine, and synthesizing to obtain a tripeptide chain shown as a formula (VI), wherein the extension sequence from the N end to the C end of amino acid is Fmoc-Gly-OH and Boc-Trp-OH,
S4, adding the tripeptide chain obtained in the S3 into a mixed solution of hexafluoroisopropanol and dichloromethane to obtain a compound C shown in a formula (VII),
S5, adding the compound C and the 2-amino ethanol hydrochloride shown in the formula (I) into dimethylformamide at room temperature, mixing, adding carbodiimide, p-hydroxybenzonitrile and diethylenetriamine for condensation reaction to obtain a compound D shown in the formula (VIII),
S6, adding the compound D into a mixed solution of 1, 4-dioxane and acetic acid, mixing again, adding 1, 4-benzoquinone and palladium acetate for C-H activation reaction to obtain a broad-spectrum macrolide compound shown as a formula (IX),
The preparation provided by the invention comprises the steps of carrying out substitution reaction on Fmoc-Ala-OH (alanine containing a protecting group) and dichloro resin in dichloromethane solution under the action of diethylenetriamine to generate a compound (IV), and successfully linking amino acid to a resin carrier. The Fmoc protecting group is then removed and deprotected to allow the subsequent amino acid addition to be efficiently coupled to the exposed amino group.
Fmoc-Gly-OH and Boc-Trp-OH are added to the compound (V) according to the sequence from N end to C end, a peptide coupling reagent is used as a coupling agent, diethylenetriamine is used as alkali, and a tripeptide chain (compound VI) is obtained through polypeptide resin solid phase synthesis. This step constructs a tripeptide chain of a specific sequence, which is the basis for the subsequent macrocyclization reaction. After the tripeptide chain synthesis is completed, the tripeptide compound is cut off from the resin, and the tripeptide chain synthesized in a solid phase is released to be in a free state, so that the tripeptide chain is ready for the next reaction. Subsequent condensation is carried out in advance in order to build up the macrocyclic structure. Finally, the compound (VIII) is dissolved in a mixed solution of 1, 4-dioxane and acetic acid, 1, 4-benzoquinone and palladium acetate catalyst are added, and the cyclization of the compound is realized through C-H activation reaction, so that the final target compound (IX), namely, the macrolide compound with broad-spectrum antibacterial activity is obtained.
The whole proposal provided by the invention aims to synthesize the target molecule efficiently and accurately, and simultaneously retain and strengthen the antibacterial activity of the target molecule. Through reasonable protecting group selection, deprotection time and specific cyclization strategies, the macrolide polypeptide compound with excellent antibacterial property is finally prepared.
Preferably, in the step S1, the ratio of the amounts of Fmoc-Ala-OH, dichloro resin and dichloromethane is 3:1:4.
Preferably, in the step S3, the ratio of the amounts of Fmoc-Gly-OH, peptide coupling reagent, diethylenetriamine and compound B is 3:3:3:1, and the ratio of the amounts of Boc-Trp-OH, peptide coupling reagent, diethylenetriamine and compound B is 3:3:3:1.
Preferably, in the steps S2 and S3, the Fmoc protecting group is removed by eluting the Fmoc protecting group with a mixed solution of piperidine and dimethylformamide.
Further preferably, the volume ratio of the piperidine to the dimethylformamide in the mixed solution of the piperidine and the dimethylformamide is 1:3.
Preferably, in the step S4, the volume ratio of hexafluoroisopropanol to dichloromethane in the mixed solution of hexafluoroisopropanol and dichloromethane is 1:3.
Preferably, in the step S5, the amount ratio of the substances among the compound C, the 2-aminoethanol hydrochloride, the carbonized ethylenediamine and the diethylenetriamine is 1:1:1.5:3.
Preferably, in the step S5, the compound C, 2-aminoethanol hydrochloride is added into dimethylformamide at room temperature, and after mixing, the compound C, 2-aminoethanol hydrochloride is added into carbodiimide, p-hydroxybenzonitrile and diethylenetriamine for condensation reaction, and after the reaction is finished, the compound D shown in the formula (VIII) is obtained by separation and purification.
Further preferably, the conditions of separation and purification are column chromatography, wherein a mixed solution of dichloromethane and methanol in a volume ratio of (15-20): 1 is used as an eluent, and a target component is collected and spin-dried to obtain the broad-spectrum macrolide compound.
Preferably, in the step S6, the ratio of the amounts of the substances among the compound D, the 1, 4-benzoquinone and the palladium acetate is 1:2:0.1.
Preferably, in the step S6, the volume ratio of the 1, 4-dioxane to the acetic acid in the mixed solution of the 1, 4-dioxane and the acetic acid is 3:1, and the reaction temperature is 70-90 ℃.
Preferably, in the step S6, the compound D is added to a mixed solution of 1, 4-dioxane and acetic acid, mixed again, and then 1, 4-benzoquinone and palladium acetate are added to perform C-H activation reaction, and after the reaction is completed, the broad-spectrum macrolide compound represented by the formula (IX) is obtained by separation and purification.
Further preferably, the conditions of separation and purification are column chromatography, wherein a mixed solution of dichloromethane and methanol in a volume ratio of (15-20): 1 is used as an eluent, and a target component is collected and spin-dried to obtain the broad-spectrum macrolide compound.
The broad-spectrum macrolide compound provided by the invention is applied to antibiosis.
The broad-spectrum macrolide compound shown in the formula (IX) has stronger bactericidal activity on the multi-drug resistant strain of the acinetobacter baumannii than imipenem, and has extremely strong antibacterial effect on staphylococcus aureus CMCC26003, escherichia coli ATCC8099 and multi-drug resistant acinetobacter baumannii. Based on the antibacterial property of the macrolide compound, the macrolide compound can be applied to a plurality of antibacterial scenes, such as being used as an antibacterial drug for treating infections caused by gram-positive bacteria and gram-negative bacteria.
Therefore, the invention has the following beneficial effects:
(1) The invention introduces ester bond into the molecular structure of polypeptide compound in advance, and then builds new broad-spectrum macrolide compound through C-H activation reaction.
(2) The broad-spectrum macrolide compound provided by the invention has broad-spectrum antibacterial property, and provides a research foundation for screening new antibacterial drugs.
(3) The preparation method of the broad-spectrum macrolide compound provided by the invention has the advantages of simple preparation process, high yield and easiness in industrialization.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a broad-spectrum macrolide compound;
FIG. 2 is a nuclear magnetic resonance spectrum of a broad-spectrum macrolide compound.
Detailed Description
The invention is further described below in connection with specific embodiments. Those of ordinary skill in the art will be able to implement the invention based on these descriptions. In addition, the embodiments of the present invention referred to in the following description are typically only some, but not all, embodiments of the present invention. Therefore, all other embodiments, which can be made by one of ordinary skill in the art without undue burden, are intended to be within the scope of the present invention, based on the embodiments of the present invention.
EXAMPLE 1 Synthesis of broad-spectrum macrolide Compound
Fmoc-Ala-OH and dichloro resin shown in formula (II) are added into dichloromethane solution for mixing, diethylenetriamine is added, after the substitution reaction is finished, dimethylformamide is used for washing to obtain a compound A shown in formula (IV),
(1) Fmoc-Ala-OH 2.8g (9 mmol) of the compound (II) and 3g (3 mmol, substitution degree 1.0 mmol/g) of the dichloro resin of the compound III were placed in a solid phase synthesis reactor, 30mL of methylene chloride was added, and finally 1.55g (12 mmol) of diethylenetriamine was added, and after 2 hours of nitrogen bubbling reaction, 3mL of methanol was added for reaction for 10 minutes. The reaction mixture was washed 3 times with 30mL of dimethylformamide, and the washed mixture was used directly in the next reaction.
(2) To compound (IV) was added 30mL of a 25% piperidine/dimethylformamide solution, deprotected for 30 minutes, and washed with dimethylformamide 4 times, 30mL each, and the washed solution was used directly in the next reaction.
(3) The traditional solid phase synthesis operation steps of the compounds (V) to (VI) are sequentially adopted, wherein 3mmol of the compound (V), 2.8g (9 mmol) of Fmoc-Gly-OH, 3.42g (9 mmol) of peptide coupling reagent and 30mL of dimethylformamide are added, and finally 1.16g (9 mmol) of diethylenetriamine is added for reaction for 1 hour, ninhydrin detection solution shows colorless representation of reaction safety, the reaction is washed 3 times with 30mL of dimethylformamide each time, and the washing is directly used for the next reaction. 30mL of 25% piperidine/dimethylformamide solution was added and deprotected for 30 minutes, and washed with dimethylformamide 4 times, 30mL each, and the washes were used directly in the next reaction.
Boc-Trp-OH 2.73g (9 mmol), peptide coupling reagent 3.42g (9 mmol) and dimethylformamide 30mL were added, and finally diethylenetriamine 1.16g (9 mmol) was added to react for 1 hour, and ninhydrin detection solution showed no color to indicate safety of the reaction, and was washed 3 times with dimethylformamide and 3 times with methanol, 30mL each time, and was directly used for the next reaction by pumping.
(4) The compound (VI) is suspended in 50mL of 25% hexafluoroisopropanol/dichloromethane solution, reacted for 2 hours, filtered, the resin is washed 3 times with dichloromethane, 50mL each time, the organic phases are combined and dried by spinning to obtain 1.1g of white foam solid, namely the compound (VII).
(5) 864Mg (2 mmol) of the compound (VII), 209mg (2 mmol) of the compound (I), 298mg (3 mmol) of the carbonized ethylenediamine and 200mg (3 mmol) of the p-hydroxybenzonitrile were accurately weighed into a 100mL round bottom flask, 20mL of a dimethylformamide solution was added, 774mg (6 mmol) of diethylenetriamine was finally added to react for 3 hours at room temperature, after TLC monitoring the reaction was completed, methylene chloride and water were added, an organic phase layer was collected by extraction, and the organic phase was washed once with a 3% aqueous solution of phosphoric acid, saturated sodium bicarbonate and saturated sodium chloride, 50mL each time, and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed by rotary evaporation under reduced pressure, and the concentrate was subjected to silica gel column separation (dichloromethane: methanol=20:1, v/v) to obtain 650mg of a white foam-like compound, namely, compound VIII.
(6) 117Mg (0.2 mmol) of compound (VIII), 1, 4-benzoquinone (43.3 mg,0.4 mmol), 9mg (0.02 mmol) of palladium acetate, and a solution of 10mL of a 1, 4-dioxane/acetic acid mixture (1, 4-dioxane: acetic acid=3:1, v/v) were accurately weighed into a 100mL round bottom flask. The plug reaction was capped and heated to 80 ℃ for 24 hours. 40mL of ethyl acetate and 20mL of water were added to the reaction solution. The organic layer was washed with 20mL of 1n hydrochloric acid, 20mL of saturated sodium bicarbonate, 20mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and the concentrate was taken for silica gel column separation (dichloromethane: methanol=20:1, v/v) and collected to give 50mg of a white foam-like compound, namely compound IX: a broad-spectrum macrolide compound.
The nuclear magnetic pattern is shown in figure 1 and figure 2,1H NMR(600MHz,DMSO)δ11.37(s,1H),8.40(d,J＝7.6Hz,1H),8.31(dd,J＝7.4,4.7Hz,1H),8.12(d,J＝7.5Hz,1H),7.87(d,J＝8.0Hz,1H),7.82(d,J＝15.9Hz,1H),7.31(d,J＝8.2Hz,1H),7.19(t,J＝7.6Hz,1H),7.04–6.97(m,2H),6.38(d,J＝15.9Hz,1H),4.65–4.56(m,1H),4.51(dd,J＝11.1,3.0Hz,1H),4.46–4.41(m,1H),4.36–4.32(m,1H),4.16–4.01(m,2H),3.69(s,3H),3.55–3.49(m,1H),3.45(dd,J＝14.4,4.1Hz,1H),3.08(dd,J＝14.4,8.9Hz,1H),1.22(s,9H).13C NMR(151MHz,DMSO)δ172.22,171.67,169.94,169.76,166.16,155.63,137.96,133.72,130.97,129.03,127.47,124.66,120.86,119.32,114.26,110.73,78.52,62.62,57.35,52.74,52.25,48.82,43.01,29.46,28.43,18.13.
EXAMPLE 2 detection of the bactericidal Activity of broad-Spectrum macrolide Compound (IX)
The various strains used in the examples below were purchased from the chinese biological institute. The bactericidal activity of the cationic antibacterial cyclic peptide was examined by an agar punching method, and a linear peptide (VIII) was used as a control to evaluate the bactericidal activity of the broad-spectrum macrolide compound (IX) in the present invention. The antibacterial activity of the antibacterial peptide is determined by the following steps of resuscitating strains, inoculating drug-resistant Acinetobacter baumannii, streaking in an NA nutrient agar medium, and culturing in a constant-temperature incubator at 37 ℃ for 16-20 hours. And (3) culturing strains, namely picking single bacterial colonies, placing the bacterial colonies in 100mL of MHB culture medium for culturing, wherein the culture temperature is also 37 ℃ which is the optimum temperature for bacterial growth, the rotation speed of a shaking table is 160 revolutions per minute, and the shaking table is used for shaking culture (16-20 h) so that the bacterial growth state reaches the logarithmic phase. Bacterial suspension preparation the concentration of bacteria is generally determined by a Mirabilitum tube with turbidity of about 0.5 Mirabilitum turbidity, at which time the bacterial colony count is about 1.5x10 8 cfu/mL, and then diluted to 10 5-106 cfu/mL at 1:1000. The antibacterial experiment comprises uniformly coating diluted bacterial suspension on 25mL NA culture medium according to the amount of 0.1 mL/plate, and perforating (diameter is 9 mm) after bacterial liquid is solidified. The positive control was supplemented with 50. Mu.L (0.4 mg/mL, 0.2mg/mL, 0.1 mg/mL) imipenem, the negative control was supplemented with 50. Mu.L deionized water, and the other wells were supplemented with 50. Mu.L (0.4 mg/mL, 0.2mg/mL, 0.1 mg/mL) of IX antimicrobial cyclopeptide solution, respectively. Bacteria are cultivated in a 37 ℃ constant temperature incubator, and the size of a bacteriostasis zone of the bacteria is measured after 16 hours, so that the size of the bacteriostasis activity of the bacteria can be primarily determined, and three groups of parallel experiments are carried out. From Table 1 above, it can be seen that the broad-spectrum macrolide compound IX of the present invention is significantly superior in bactericidal ability to the control linear peptide VIII, especially to imipenem at a high concentration of 0.4 mg/mL.
TABLE 1 diameter (mm) of inhibition zone of broad-spectrum macrolide compounds of different concentrations against Acinetobacter baumannii multiple drug-resistant strains
EXAMPLE 3 detection of antibacterial Activity of broad-Spectrum macrolide Compound (IX)
The various strains used in the examples below were purchased from the chinese biological institute. The minimum inhibitory potency of the broad-spectrum macrolide compounds was determined and the linear peptide VIII prior to cyclization was used as a control to evaluate the inhibitory potency of the broad-spectrum macrolide compounds of the present invention. The antibacterial activity of the broad-spectrum macrolide compound IX was determined by collecting bacteria grown in log phase, centrifuging at 4℃at 8000 rpm for 2min, washing 3 times with physiological saline, and adding fresh broth medium to give a bacterial suspension concentration of 2.0X10 5 cfu/mL. 50. Mu.L of bacterial suspension (100. Mu. LPBS in four wells) and 50. Mu.L of peptide solution (imipenem solution) with different concentrations are added into experimental wells of a 96-well cell culture plate, so that the final concentration (mug/mL) of the peptide solution (imipenem solution) in each well in a transverse row is 512, 256, 128, 64, 32, 16, 12 and 4 respectively. Equal volumes of PBS buffer were used as growth control groups, three parallel groups were placed in each group, and after capping the cell culture plates, they were placed in a biochemical incubator at 37℃for 12h, and bacterial growth (OD 600 nm) in each well was determined by full-automatic enzyme labeling. The minimum inhibitory concentration (Minimum Inhibitory Concentrations, MIC) was defined as the peptide concentration of the well where bacterial growth was completely inhibited. The smaller the minimum inhibitory concentration values in the table, the stronger the antimicrobial ability of the peptide. As can be seen from Table 2, the macrolide peptide IX of the present invention has a lower minimum inhibitory concentration and a MIC much smaller than VIII compared to the control linear peptide, indicating that the antibacterial ability of the macrolide peptide IX of the present invention is much stronger than that of the control linear peptide VIII.
TABLE 2 comparison of MIC of broad-spectrum macrolide Compound IX against various bacteria
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