CN117024262A - Synthesis method and application of natural product Ivesinol and derivative thereof - Google Patents
Synthesis method and application of natural product Ivesinol and derivative thereof Download PDFInfo
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- CN117024262A CN117024262A CN202310487528.5A CN202310487528A CN117024262A CN 117024262 A CN117024262 A CN 117024262A CN 202310487528 A CN202310487528 A CN 202310487528A CN 117024262 A CN117024262 A CN 117024262A
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- ivesinol
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- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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Abstract
The invention discloses a synthesis method and application of a natural product Ivesinol and derivatives thereof, wherein the method comprises the following steps: the compound 12,4,6-trihydroxybenzaldehyde is subjected to methylation and aldehyde reduction reaction to prepare a compound 3, and the compound 3 is subjected to Friedel-crafts acylation reaction to obtain a compound 4; the compound 7 is prepared by methylation and Friedel-crafts reaction of the compound 5, aldehyde groups are introduced into the compound 7 through Vilsmeier reaction, and the aldehyde groups are reduced to obtain a compound 9; the compounds 4 and 9 are subjected to a coupling reaction to obtain compounds IVE-1 and/or IVE-2, namely natural products IVesinel and derivatives thereof; the invention explores and completes the total synthesis route of the natural product Ivesinol and the derivatives thereof by using the commercialized reagent as the initial raw material through inverse synthetic analysis, constructs a series of compound libraries of the Ivesinol derivatives, lays a foundation for further exploring the structure-activity relationship of the natural product and the derivatives thereof and researching the antibacterial activity and the pharmacy of the compounds, and has important significance for treating infectious diseases caused by drug-resistant bacteria.
Description
Technical Field
The invention relates to the technical field of organic synthesis and medicinal chemistry, in particular to a synthesis method and application of a natural product Ivesinol and derivatives thereof.
Background
In 1928, british doctor fleming discovered penicillins, thoroughly changed the treatment of bacterial infections, and scientists have since been continually looking for new antibiotics to address the various infectious diseases faced by humans. In the past hundred years, the use of antibiotics by human beings has made an important breakthrough in treating infectious diseases, preventing and treating animal epidemic diseases and guaranteeing public health safety, and the death rate caused by infectious diseases is greatly reduced. However, the research and development of novel antibiotics are very difficult, only two types of novel antibiotics are marketed in recent 50 years, most antibiotics are found before 70 years of the last century, and due to the long service life, the medical and breeding industries do not reasonably use antibiotics, people have low awareness of reasonable medication and other factors, the existing antibiotics generally generate drug resistance, and the treatment effect is greatly compromised. With the continuous enhancement of pathogenic bacteria resistance, superbacteria frequently appear, which seriously threatens the life health of human beings, more and more infectious diseases become more difficult to treat, and the human beings possibly face the arrival of a 'post-antibiotic age' in which no effective antibiotics are available.
In recent years, antibiotic resistance has risen to one of three health problems worldwide, with a consequent large number of medical and health and economic impacts, estimated that 1000 tens of thousands of people die annually from drug-resistant bacterial infection by 2050 and economic losses will reach $100 trillion. In view of the current severe bacterial drug-resistant situation, WHO published in 2017 the twelve classes of antibiotic-resistant "major pathogens" currently most resistant, most threatening to human health, most urgently requiring new antibiotic treatment, among which enterococcus faecium (e.faecium), staphylococcus aureus (s. Aureus), klebsiella pneumoniae (k. Pneumaonia), acinetobacter baumannii (a. Baumannii), pseudomonas aeruginosa (p. Aeromonas) and Enterobacter (Enterobacter spp.) six major "superbacteria", collectively referred to as "ESKAPE", which have a strong resistance to existing antibiotics, can "evade" the killed risk, cause refractory multi-drug-resistant infections, are drug-resistant pathogens that are urgent needs to be focused by the world health organization.
In order to cope with the outbreak of infectious diseases caused by multi-drug resistant bacteria, there is a great clinical need for novel antibiotics with novel action mechanisms. The diversity and complexity of natural product antibiotics is particularly pronounced relative to chemically synthesized antibiotics, and for decades, about 28000 antibiotics have been isolated from natural products, 200 of which have become straightforward drugs to market. Based on the natural product antibiotic skeletons on the market, 200-300 semisynthetic antibiotics are marketed, so that the application selection range of the antibiotics is greatly improved. Currently, most of the first-line drugs for treating infections commonly used in clinic are derived from natural products, such as β -lactams, aminoglycosides, tetracyclines, rifamycins, macrolides, and the like, and are derived from natural products as lead compounds. However, many natural products containing pharmaceutical ingredients are not only limited in distribution in nature, but also have very low content of active ingredients therein. Therefore, the requirement of human beings on medicines is obviously far from satisfied only by natural sources, and thus synthetic chemists are required to continuously explore and discover more concise and efficient synthetic strategies, and fully synthesize and structurally reform natural products more conveniently by chemical methods, so that more lead compounds with excellent activity are discovered and the medicine discovery process is promoted.
In 1937 Birch et al isolated a polyphenol compound Protokosin from Sophora flavescens (Brayera anthelmintica) and performed structural identification, but was limited by too few raw materials to be further derivatization studies. Until 1952, the team obtained enough starting material, and further studies found that Protokosin could be converted to a new natural product derivative, β -kosin, by zinc powder reduction under alkaline conditions, and its chemical structure was determined by spectroscopic, chemical conversion, etc. Since the last 60 years no further studies on β -kosin have been reported until 2014, marwa h. Ahmed et al, university of miscisib, isolated a completely new polyphenol natural product from flowers of one of the north america plants Ivesia gordonii, and identified its chemical structure by means of one-and two-dimensional nuclear magnetism, mass spectrometry, etc., and the authors identified it as Ivesinol in a popular manner, in contrast to the finding that the natural product and β -kosin have the same chemical structure.
Further studies by Ahmed et al have found that Ivesinol has excellent inhibitory effects on Staphylococcus aureus (S.aureus), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus faecium ATCC 700221 (VRE). Wherein, the inhibitory activity of iversinol against MRSA was mic=0.31 ug/mL, the MIC against VRE was 1.25ug/mL, and the inhibitory activity of both positive control ciprofloxacin and vancomycin against both strains of bacteria was weaker than that of iversinol, even without activity (table 1). In addition, ivosinol also showed some inhibitory activity against the fungus m.internellulole (mic=15.67 ug/mL).
TABLE 1 antibacterial Activity data for Ivesinol
The inhibitory activity of the Ivesinol on drug-resistant enterococcus faecium and staphylococcus aureus is far superior to that of the traditional clinical first-line drug, but the researches on safety, stability and the like of the Ivesinol are still missing, the antibacterial mechanism, action targets and the like are not clear, and no related report on the total synthesis of the Ivesinol is so far available, so that the research on the drug formation of the Ivesinol is hindered to a certain extent. Therefore, the total synthesis exploration is completed, a synthetic series compound library is designed, and the method has important significance for further researching the structure-activity relationship of the natural product, researching the antibacterial activity and researching the drug property.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a synthesis method and application of natural product ivosinol and its derivatives, which are used for solving the problem that there is no total synthesis method of ivosinol and its derivatives in the prior art, and laying an important foundation for further antibacterial activity and pharmaceutical research.
To achieve the above and other related objects, a first aspect of the present invention provides a method for synthesizing natural product ivosinol and its derivatives, the method comprising the following synthetic routes:
the method comprises the following steps:
(1) The compound 3 is prepared by methylation and aldehyde reduction reaction of the compound 1, 2,4, 6-trihydroxybenzaldehyde, and the compound 4 is prepared by Friedel-crafts acylation reaction of the compound 3;
(2) The compound 7 is prepared by methylation and Friedel-crafts reaction of the compound 5, aldehyde groups are introduced into the compound 7 through Vilsmeier reaction, and the aldehyde groups are reduced to obtain a compound 9;
(3) The compounds 4 and 9 are subjected to a coupling reaction to obtain compounds IVE-1 and/or IVE-2;
wherein,
R 1 at least one selected from ethyl, isopropyl, n-butyl, n-hexyl and other linear or branched alkane substituents,
R 2 at least one selected from ethyl, isopropyl, n-butyl, n-hexyl and other linear or branched alkane substituents,
R 3 at least one selected from the group consisting of hydroxyl, methoxy, and other linear alkoxy groups,
R 4 at least one selected from the group consisting of hydroxyl, methoxy, and other linear alkoxy groups,
R 5 at least one selected from acetyl, isobutyl, isobutyryl, pivaloyl, n-pentyl, n-pentanoyl and other straight or branched alkyl and acyl groups,
R 6 at least one selected from the group consisting of acetyl, isobutyl, isobutyryl, pivaloyl, n-pentyl, n-pentanoyl, and other linear or branched alkyl and acyl groups.
Further, the synthetic route of the method is as follows:
the method comprises the following steps:
(1) Methylation is carried out on the compound 1, 2,4, 6-trihydroxybenzaldehyde to obtain a compound 2, aldehyde reduction reaction is carried out on the compound 2 to obtain a compound 3, and friedel-crafts acylation reaction is carried out on the compound 3 to obtain a compound 4;
(2) Methylation of the phloroglucinol in the compound 5 to obtain a compound 6, friedel-crafts reaction of the compound 6 to obtain a compound 7, introducing aldehyde groups into the compound 7 through Vilsmeier reaction to obtain a compound 8, and reducing the aldehyde groups in the compound 8 to obtain a compound 9;
(3) Compounds 4 and 9 are coupled to give compounds IVE-1 and/or IVE-2.
Further, in the steps (1) and (2), the methylation reaction is a selective monomethylation reaction, and the adopted methylating agent is any one selected from methyl iodide, dimethyl sulfate and dimethyl carbonate.
Further, in the steps (1) and (2), the methylation reaction is performed at room temperature and 50 to 60 ℃.
Further, in the step (1), the aldehyde group in the compound 2 is reduced to a methyl group by sodium cyanoborohydride under an acidic condition to produce the compound 3.
Further, in the step (1), the aldehyde group reduction reaction is performed at a pH of 2 to 3.
Further, in the step (1), the acylation reagent adopted in the friedel-crafts acylation reaction is acyl chloride, and the chemical structural formula of the acylation reagent is R 1 COCl。
Further, in the step (2), the friedel-crafts reaction comprises acylation reaction and alkylation reaction, wherein an acylation reagent adopted in the acylation reaction is acyl chloride, and the chemical structural formula of the acyl chloride is R 2 COCl；
The alkylating reagent adopted in the alkylation reaction is halogen alkane, and the chemical structural formula of the alkylating reagent is R 5 Cl and/or R 6 Cl。
Further, in the steps (1) and (2), the reaction temperature of the friedel-crafts acylation reaction and the friedel-crafts reaction is 60-70 ℃.
Further, in the step (2), the compound 7 is reacted with oxalyl chloride/N, N-Dimethylformamide (DMF) system to introduce aldehyde groups by Vilsmeier reaction, to prepare compound 8.
Further, in the step (2), in Pd/C/H 2 The aldehyde group is reduced under conditions to give compound 9.
Further, in the step (3), the compound 4, the compound 9 and the TsCl/paraformaldehyde system are subjected to a coupling reaction to obtain the compound IVE-1 and/or IVE-2.
Further, in the step (3), the coupling reaction temperature is 40 to 60 ℃, preferably 45 to 55 ℃.
In a second aspect, the present invention provides a compound synthesized according to the method of the first aspect, wherein the compound has the following structures IVE-1 and IVE-2:
Further, the IVE-1 is selected from at least one of the following structures T-1, T-19, T-21, T-18, T-3, T-4, T-5, T-7, T-10:
further, the IVE-2 is selected from at least one of the following structures T-6, T-8, T-20, T-9, T-11, T-13, T-2, T-12, T-14, T-15, T-16, T-17:
a third aspect of the invention provides the use of the process according to the first aspect for the synthesis of the natural product ivosinol and derivatives thereof.
In a fourth aspect the invention provides the use of a compound according to the second aspect for antibacterial purposes, said compound being selected from at least one of the following structures T-1, T-19, T-21, T-18, T-3, T-4, T-5, T-7, T-10, T-6, T-8, T-20, T-9, T-11, T-13, T-2, T-12, T-14, T-15, T-16, T-17.
Further, the use is to inhibit bacterial or fungal activity, or to treat infectious diseases caused by bacteria or fungi.
In a fifth aspect, the invention provides an antibacterial agent comprising an effective amount of a compound selected from at least one of the following structures T-1, T-19, T-21, T-18, T-3, T-4, T-5, T-7, T-10, T-6, T-8, T-20, T-9, T-11, T-13, T-2, T-12, T-14, T-15, T-16, T-17.
Further, the antibacterial agent is used for inhibiting bacterial or fungal activity or treating infectious diseases caused by bacteria or fungi.
Further, the bacterium is at least one selected from enterococcus faecium (e.faecium), staphylococcus aureus (s.aureus), klebsiella pneumoniae (k.pneumaria), acinetobacter baumannii (a.baumannii), pseudomonas aeruginosa (p.aeromonas), enterobacter sp, methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococcus faecium ATCC 700221 (VRE).
Further, the fungus is selected from the group consisting of the fungi m.
As described above, the synthesis and application of the natural product Ivesinol and the derivatives thereof have the following beneficial effects:
the invention explores and completes the total synthesis route of the natural product Ivesinol and the derivatives thereof by using commercial reagents as initial raw materials through inverse synthetic analysis, builds a series of compound libraries of the Ivesinol derivatives, and lays a foundation for further exploring the structure-activity relationship of the natural product and the derivatives thereof and researching the antibacterial activity and the pharmacy of the compounds. On the basis, the invention verifies that the natural product Ivesinol and partial derivatives thereof have inhibitory activity equivalent to or better than clinical medication on partial bacteria or fungi, which has very important significance for further patent medicine research of the series of compounds and also has important significance for treating infectious diseases caused by drug-resistant bacteria.
Drawings
FIG. 1 is a graph showing the results of an in vitro cytotoxicity test of Ivesinol in example 1 of the present application.
FIG. 2 is a graph showing the concentration-bacterial load in example 1 of the present application.
FIG. 3 is a graph showing the results of an experiment on an anti-biofilm of Ivesinol in example 1 of the present application.
FIG. 4 is a graph showing the results of a drug resistance test of Ivesinol in example 1 of the present application.
FIG. 5 is a graph showing the result of the experiment of the hemolytic toxicity of Ivesinol in example 1 of the present application.
FIG. 6 is a graph showing the results of pharmacokinetic experiments on Ivesinol in example 1 of the present application.
Detailed Description
Other advantages and effects of the present application will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present application with reference to specific examples. The application may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present application. It is also to be understood that the following examples are given solely for the purpose of illustration and are not to be construed as limitations upon the scope of the application, as many insubstantial modifications and variations are within the scope of the application as would be apparent to those skilled in the art in light of the foregoing disclosure. The specific process parameters and the like described below are also merely examples of suitable ranges, i.e., one skilled in the art can make a suitable selection from the description herein and are not intended to be limited to the specific values described below.
Based on the current situation that no total synthesis method of Ivesinol and derivatives thereof exists, one embodiment of the invention provides a synthesis method of a natural product Ivesinol and derivatives thereof, and the synthesis route of the method is as follows:
the method comprises the following steps:
(1) The compound 3 is prepared by methylation and aldehyde reduction reaction of the compound 1, 2,4, 6-trihydroxybenzaldehyde, and the compound 4 is prepared by Friedel-crafts acylation reaction of the compound 3;
(2) The compound 7 is prepared by methylation and Friedel-crafts reaction of the compound 5, aldehyde groups are introduced into the compound 7 through Vilsmeier reaction, and the aldehyde groups are reduced to obtain a compound 9;
(3) The compounds 4 and 9 are subjected to a coupling reaction to obtain compounds IVE-1 and/or IVE-2;
wherein,
R 1 at least one selected from ethyl, isopropyl, n-butyl, n-hexyl and other linear or branched alkane substituents,
R 2 selected from ethyl, isopropyl, n-butyl, n-hexyl and other linear or branched alkane substituentsAt least one of the two or more of the three,
R 3 at least one selected from the group consisting of hydroxyl, methoxy, and other linear alkoxy groups,
R 4 at least one selected from the group consisting of hydroxyl, methoxy, and other linear alkoxy groups,
R 5 at least one selected from acetyl, isobutyl, isobutyryl, pivaloyl, n-pentyl, n-pentanoyl and other straight or branched alkyl and acyl groups,
R 6 At least one selected from the group consisting of acetyl, isobutyl, isobutyryl, pivaloyl, n-pentyl, n-pentanoyl, and other linear or branched alkyl and acyl groups.
In another embodiment of the present invention, a method for synthesizing a natural product, ivosinol and its derivatives is provided, wherein the synthetic route of the method is as follows:
the method comprises the following steps:
(1) Methylation is carried out on the compound 1, 2,4, 6-trihydroxybenzaldehyde to obtain a compound 2, aldehyde reduction reaction is carried out on the compound 2 to obtain a compound 3, and friedel-crafts acylation reaction is carried out on the compound 3 to obtain a compound 4;
(2) Methylation of the phloroglucinol in the compound 5 to obtain a compound 6, friedel-crafts reaction of the compound 6 to obtain a compound 7, introducing aldehyde groups into the compound 7 through Vilsmeier reaction to obtain a compound 8, and reducing the aldehyde groups in the compound 8 to obtain a compound 9;
(3) Compounds 4 and 9 are coupled to give compounds IVE-1 and/or IVE-2.
In some embodiments, in the step (1) and the step (2), the methylation reaction is a selective monomethylation reaction, and the used methylating agent is any one selected from methyl iodide, dimethyl sulfate and dimethyl carbonate.
In some embodiments, in the steps (1) and (2), the methylation reaction is performed at room temperature and 50-60 ℃.
In some embodiments, in step (1), the aldehyde group in compound 2 is reduced to methyl under acidic conditions via sodium cyanoborohydride to produce compound 3.
In some embodiments, in step (1), the aldehyde group reduction reaction is performed at a pH of 2 to 3.
In some embodiments, in step (1), the acylating agent used in the friedel-crafts acylation reaction is an acyl chloride having the chemical formula R 1 COCl。
In some embodiments, in step (2), the friedel-crafts reaction includes acylation and alkylation, wherein the acylating agent used in the acylation reaction is an acyl chloride having a chemical formula of R 2 COCl；
The alkylating reagent adopted in the alkylation reaction is halogen alkane, and the chemical structural formula of the alkylating reagent is R 5 Cl and/or R 6 Cl。
In some embodiments, in the steps (1) and (2), the friedel-crafts acylation reaction is performed at a reaction temperature of 60-70 ℃.
In some embodiments, in step (2), the compound 7 is reacted with oxalyl chloride/N, N-Dimethylformamide (DMF) system to introduce aldehyde groups via Vilsmeier reaction to produce compound 8.
In some embodiments, in step (2), at Pd/C/H 2 The aldehyde group is reduced under conditions to give compound 9.
In some embodiments, in step (3), compound 4, compound 9 and the TsCl/paraformaldehyde system are reacted by coupling to give compounds IVE-1 and/or IVE-2.
In some embodiments, in step (3), the coupling reaction temperature is 40 to 60 ℃, preferably 45 to 55 ℃.
In some embodiments, in the step (1), the synthesis process of the compound 2 includes the steps of:
compound 1, 4, 6-trihydroxybenzaldehyde powder (1.0 equiv), anhydrous K 2 CO 3 (4.0-6.0 equiv) dissolving with mixed solvent (the mixed solvent comprises water and acetone in volume ratio of 1:1), and dropwise adding at room temperatureDimethyl sulfate (1.0-2.0 equiv) dissolved in acetone was added for a period exceeding 2 hours. And reacting for 1.5-3 h after the dripping is finished. After the reaction, ethyl Acetate (EA) is used for extraction, the extracts are combined, the mixture is washed by saturated saline, the water is removed, the dried mixture is concentrated under reduced pressure, and the crude product is separated and purified by a chromatographic silica gel column to obtain a yellowish green solid, namely the compound 2.
In some embodiments, in the step (1), the synthesis process of the compound 3 includes the steps of:
compound 2 (1.0 equiv) was dissolved in THF and NaCNBH was added at 0deg.C 3 (2.0-4.0 equiv), then adjusting the pH with HCl to keep the pH of the reaction solution at about 2-3, and stirring at room temperature for 3-6 h. After the reaction, the solvent was removed under reduced pressure, ethyl Acetate (EA) was used for extraction, the extracts were combined, washed with saturated brine, dried, concentrated under reduced pressure, and purified by chromatography on a silica gel column to give a yellow solid, compound 3.
In some embodiments, in the step (1), the synthesis process of the compound 4 includes the steps of:
compound 3 (1.0 equiv) and AlCl 3 (3.0 to 5.0 equivalents) into a reaction flask, and replacing nitrogen. Adding PhNO 2 Stirring for 20-50 min, then adding acyl chloride (1.0-1.5 equiv) dropwise, transferring the reaction to 60-70 ℃ oil bath, and stirring overnight. After the reaction is completed, H is added 2 The reaction was quenched with O, extracted with Ethyl Acetate (EA), the extracts combined, washed with saturated brine, dried over water, concentrated under reduced pressure, and purified by chromatography on silica gel to give compound 4 as a yellow solid.
In some embodiments, in the step (2), the synthesis process of the compound 6 includes the steps of:
compound 5 phloroglucinol (3.0 equiv), anhydrous K 2 CO 3 (2.0-4.0 equiv) is dissolved by acetone, dimethyl sulfate (1 equiv) is slowly added at room temperature, the dripping time is more than 15min, and after the dripping is finished, the reaction is transferred into an oil bath pot with the temperature of 50-60 ℃ and stirred for overnight. Quenching the reaction with HCl after the reaction, removing the solvent under reduced pressure, extracting with Ethyl Acetate (EA), mixing the extracts, washing with saturated saline, removing water, drying, concentrating under reduced pressureThe crude product is condensed and purified by a chromatographic silica gel column to obtain transparent oily matter, and the solvent is pumped down to obtain white solid, namely the compound 6.
In some embodiments, in the step (2), the synthesis process of the compound 7 includes the steps of:
compound 6 (1.0 equiv) and AlCl 3 (3.0 to 5.0 equiv) is placed in a reaction flask to replace nitrogen. Adding PhNO 2 Stirring for 20-50 min, then adding acyl chloride (1.0-1.5 equiv) dropwise, transferring the reaction to 60-70 ℃ oil bath, and stirring overnight. After the reaction is completed, H is added 2 O quenching, extraction with Ethyl Acetate (EA), combining the extracts, washing with saturated saline, dewatering, drying, concentrating the crude product under reduced pressure, and separating and purifying by a chromatographic silica gel column to obtain an intermediate compound 7.
In some embodiments, in the step (2), the synthesis process of the compound 8 includes the steps of:
putting the compound 7 into a reaction bottle, replacing nitrogen, adding anhydrous MeCN, slowly adding oxalyl chloride (1.0-2.0 equiv) at 0 ℃, reacting anhydrous DMF (0.3-1.0 equiv) for 30min under stirring, then moving to room temperature, reacting for 10-20 h under stirring, filtering the reaction liquid, adding water for 100 ℃ under stirring for 2h, cooling and filtering to obtain the intermediate compound 8.
In some embodiments, in the step (2), the synthesis process of the compound 9 includes the steps of:
dissolving the compound 8 with 10mL of ethanol, adding 10% Pd/C, replacing the reaction system with hydrogen, stirring at room temperature for reaction overnight, filtering with diatomite, and concentrating the filtrate to obtain the target product compound 9.
In one embodiment, the synthetic route for the natural product ivosinol and its derivatives is as follows:
the compounds IVE-1 and IVE-2 according to the embodiments of the present invention are synthesized by a convergent synthesis method, and are obtained by coupling two types of compounds, namely a left fragment compound 4 and a right fragment compound 9, and in some embodiments, the structures of the compounds 4 and 9 are selected from any one of the structures shown below:
compound 4:
compound 9:
in some embodiments, IVE-1 is preferably at least one of the following structures T-1, T-19, T-21, T-18, T-3, T-4, T-5, T-7, T-10 and IVE-2 is preferably at least one of the following structures T-6, T-8, T-20, T-9, T-11, T-13, T-2, T-12, T-14, T-15, T-16, T-17).
The above examples of the present invention explored and completed the total synthetic route of the natural product ivosinol and its derivatives by inverse synthetic analysis using commercial reagents as starting materials, and constructed a series of compound libraries of ivosinol derivatives. Further, the invention also discovers that the compounds shown in the formulas IVE-1 and IVE-2 have the capability of inhibiting the growth of bacteria and/or fungi such as staphylococcus aureus, enterococcus faecium and the like, and can be used for but not limited to treating infectious diseases caused by the two bacteria.
Based on this, an embodiment of the present invention provides the use of a compound according to the above examples selected from at least one of the following structures T-1, T-19, T-21, T-18, T-3, T-4, T-5, T-7, T-10, T-6, T-8, T-20, T-9, T-11, T-13, T-2, T-12, T-14, T-15, T-16, T-17 for antibacterial. Wherein the use is for inhibiting bacterial or fungal activity or for treating an infectious disease caused by a bacterium or fungus.
Another embodiment of the present invention provides an antibacterial agent comprising an effective amount of a compound selected from at least one of the following structures T-1, T-19, T-21, T-18, T-3, T-4, T-5, T-7, T-10, T-6, T-8, T-20, T-9, T-11, T-13, T-2, T-12, T-14, T-15, T-16, T-17. Wherein the antibacterial agent is used for inhibiting bacterial or fungal activity or treating an infectious disease caused by bacteria or fungi. Further, the medicament also comprises pharmaceutically acceptable carriers and/or auxiliary materials; the medicine can be a single-component substance or a multi-component substance; the form of the medicine is not particularly limited, and can be various preparation forms such as solid, liquid, gel, semifluid, aerosol and the like; the medicine is mainly aimed at a mammal, such as rodents, primates and the like; the medicament may be used in combination with other antibacterial agents. In some embodiments, the bacteria are selected from at least one of enterococcus faecium (e.faecium), staphylococcus aureus (s.aureus), klebsiella pneumoniae (k.pneumonia), acinetobacter baumannii (a.baumannii), pseudomonas aeruginosa (p.aerocinosa), enterobacter sp, methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococcus faecium (e.faecium ATCC 700221 (VRE), but are not limited thereto.
In some embodiments, the fungus is selected from the group consisting of, but not limited to, the fungus m.
In one embodiment, the compounds 4-1, 4-2, 4-3 are synthesized as follows:
synthesis of Compound 3:
2,4, 6-Trihydroxybenzaldehyde (Compound 1) powder (1.0 g,6.5mmol,1.0 equiv) was added to a 100mL dry single neck round bottom flask, followed by anhydrous K 2 CO 3 (4.5 g,32.5mmol,5 equiv.) and ultrapure water (32 mL) were added thereto, acetone (32 mL) =1:1 was dissolved, and dimethyl sulfate (1.23 g,9.75mmol,1.5 equiv.) dissolved in acetone (4 mL) was added dropwise at room temperature over 2h. After the completion of the dropwise addition, the reaction was carried out for 2 hours. After the completion of the reaction, the mixture was extracted with EA (3×100 mL), the extracts were combined, washed with saturated brine (3×100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (PE: ea=2:1) to give compound 2 as a yellowish green solid(390mg，35％)。
Compound 2 (2.21 g,13.2mmol,1.0 equiv) was placed in a 250mL dry single neck round bottom flask, and 30mL THF was added to dissolve the mixture, the reaction was placed at 0deg.C, naCNBH was added 3 (2.5 g,39.5mmol,3 equiv.) after which the pH of the reaction mixture was adjusted with 1N HCl to maintain the pH of the reaction mixture at about 4 and stirred at room temperature for 4h. After the completion of the reaction, the solvent was removed under reduced pressure, EA (3X 150 mL) was extracted, and the extracts were combined, washed with saturated brine (3X 100 mL), dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure, and purified by chromatography on a silica gel column (PE: EA=6:1) to give compound 3 (430 mg, 22%) as a yellow solid.
(1) Synthesis of Compound 4-1:
compound 3 (100 mg,0.65mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry single neck round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then isobutyryl chloride (83 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 The reaction was quenched with O (10 mL), extracted with EA (3X 30 mL), and the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by chromatography on a silica gel column (PE: EA=5:1) to give compound 4-1 (110 mg, 76%) as a yellow solid.
(2) Synthesis of Compound 4-2:
compound 3 (100 mg,0.65mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry single neck round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then n-pentanoyl chloride (93.6 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 The reaction was quenched with O (10 mL), extracted with EA (3X 30 mL), and the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by chromatography on a silica gel column (PE: EA=4:1) to give compound 4-2 (96 mg, 62%) as a yellow solid.
(3) Synthesis of Compound 4-3:
the compound is prepared3 (100 mg,0.65mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry single neck round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then n-heptanoyl chloride (115 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 The reaction was quenched with O (10 mL), extracted with EA (3X 30 mL), and the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure and purified by chromatography on a silica gel column (PE: EA=6:1) to give compound 4-3 (94 mg, 54%) as a yellow solid.
In one embodiment, the compounds 9-1, 9-2, 9-3, 9-4, 9-5, 9-6, 9-7 are synthesized as follows:
synthesis of Compound 6:
phloroglucinol (compound 5) (7.0 g,55.5mmol,3.0 equiv) was charged to a 250mL dry single neck round bottom flask followed by anhydrous K 2 CO 3 Dimethyl sulfate (2.334 g,18.5mmol,1 equiv) was slowly added (7.7 g,55.5mmol,3 equiv) to acetone (60 mL) at room temperature over 15min, after which the reaction was transferred to a 55deg.C oil bath and stirred overnight. After completion of the reaction, the reaction mixture was quenched with 1N HCl, the solvent was removed under reduced pressure, extracted with EA (3×150 mL), the extracts were combined, washed with saturated brine (3×100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product, which was separated and purified by column chromatography on silica gel (PE: ea=10:1-2:1) to give a clear oil, which was then extracted with EA to give compound 6 (2.5 g, 32%) as a white solid.
(1) Synthesis of Compound 9-1:
compound 6 (140 mg,1.0mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then acetyl chloride (61 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 O (10 mL) was quenched, EA (3X 30 mL) was extracted, the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure, and the layers were usedSeparating and purifying by silica gel column (PE: EA=5:1) to obtain intermediate compound 7 (56 mg) which is put into a 10mL dry single-neck round bottom flask, adding anhydrous MeCN (8 mL) after nitrogen replacement, slowly adding oxalyl chloride (55 mg,0.43mmol,1.4 equiv), anhydrous DMF (11 mg,0.16mmol,0.5 equiv) at 0 ℃, stirring for 30min, then transferring to room temperature for stirring and reacting for 15h, filtering the reaction solution, adding 5mL water for stirring for 2h at 100 ℃, cooling and filtering, dissolving the obtained intermediate compound 8 by using 10mL ethanol, adding 10% Pd/C, replacing the reaction system with hydrogen, stirring and reacting overnight at room temperature, filtering by using diatomite, and concentrating the filtrate to obtain the target product compound 9-1 (39 mg, 20%).
(2) Synthesis of Compound 9-2:
compound 6 (140 mg,1.0mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then isobutyryl chloride (83 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 O (10 mL) was quenched, EA (3X 30 mL) was extracted, the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (PE: EA=8:1) to give intermediate compound 7 (43 mg) which was placed in a 10mL dry single-port round-bottom flask, nitrogen was replaced, anhydrous MeCN (8 mL) was added slowly at 0℃to oxalyl chloride (55 mg,0.43mmol,1.4 equiv), anhydrous DMF (11 mg,0.16mmol,0.5 equiv) was added dropwise, stirred for 30min and then transferred to room temperature for stirring for 15h, the reaction solution was filtered, after stirring with 5mL of water at 100℃for 2h, cooled and filtered, the intermediate compound 8 obtained was dissolved with 10mL of ethanol, 10% Pd/C was added, the reaction system was replaced with hydrogen, stirred at room temperature for reaction overnight, and then diatomite was filtered, and the filtrate was concentrated to give the objective compound 9-2 (40 mg, 18%).
(3) Synthesis of Compound 9-3:
compound 6 (140 mg,1.0mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, and then pivalol was added dropwiseAcid chloride (94 mg,0.78mmol,1.2 equiv) the reaction was transferred to a 65 ℃ oil bath and stirred overnight. After the reaction is completed, H is added 2 O (10 mL) was quenched, EA (3X 30 mL) was extracted, the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (PE: EA=3:1) to give intermediate compound 7 (61 mg) which was placed in a 10mL dry single-port round-bottom flask, nitrogen was replaced, anhydrous MeCN (8 mL) was added slowly at 0℃to oxalyl chloride (55 mg,0.43mmol,1.4 equiv), anhydrous DMF (11 mg,0.16mmol,0.5 equiv) was added dropwise, stirred for 30min and then transferred to room temperature for stirring for 15h, the reaction solution was filtered, after stirring with 5mL of water at 100℃for 2h, cooled and filtered, the intermediate compound 8 obtained was dissolved with 10mL of ethanol, 10% Pd/C was added, the reaction system was replaced with hydrogen, stirred at room temperature for reaction overnight, and then diatomite was filtered, and the filtrate was concentrated to give the objective compound 9-3 (67 mg, 28%).
(4) Synthesis of Compound 9-4:
compound 6 (140 mg,1.0mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then n-pentanoyl chloride (94 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 O (10 mL) was quenched, EA (3X 30 mL) was extracted, the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (PE: EA=10:1) to give intermediate compound 7 (61 mg) which was placed in a 10mL dry single-port round-bottom flask, nitrogen was replaced, anhydrous MeCN (8 mL) was added slowly at 0℃to oxalyl chloride (55 mg,0.43mmol,1.4 equiv), anhydrous DMF (11 mg,0.16mmol,0.5 equiv) was added dropwise, stirred for 30min and then transferred to room temperature after stirring for 15h, the reaction solution was filtered, after stirring with 5mL of water at 100℃for 2h, cooled and filtered, the intermediate compound 8 obtained was dissolved with 10mL of ethanol, 10% Pd/C was added, the reaction system was replaced with hydrogen, stirred at room temperature for reaction overnight, and then diatomite was filtered, and the filtrate was concentrated to give the objective compound 9-4 (78 mg, 33%).
(5) Synthesis of Compound 9-5:
compound 6 (140 mg,1.0mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then propionyl chloride (72 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 O (10 mL) was quenched, EA (3X 30 mL) was extracted, the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (PE: EA=5:1) to give intermediate compound 7 (56 mg) which was placed in a 10mL dry single-port round-bottom flask, nitrogen was replaced, anhydrous MeCN (8 mL) was added slowly at 0℃to oxalyl chloride (55 mg,0.43mmol,1.4 equiv), anhydrous DMF (11 mg,0.16mmol,0.5 equiv) was added slowly, the reaction was stirred for 30min and then shifted to room temperature after stirring for 15h, the reaction solution was filtered, after stirring for 2h at 5mL of water at 100℃was cooled and filtered, the intermediate compound 8 obtained was dissolved with 10mL ethanol, 10% Pd/C was added, the reaction system was replaced with hydrogen, stirred at room temperature for reaction overnight, celite was filtered, and the filtrate was concentrated to give the target product compound 9-5 (61 mg, 29%).
(6) Synthesis of Compound 9-6:
compound 6 (140 mg,1.0mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then isobutyryl chloride (83 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 O (10 mL) was quenched, EA (3X 30 mL) was extracted, the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, the crude product was concentrated under reduced pressure, and purified by column chromatography on silica gel (PE: EA=8:1) to give intermediate compound 7 (58 mg) which was placed in a 10mL dry single-necked round-bottom flask, after nitrogen substitution, anhydrous MeCN (8 mL) was added, oxalyl chloride (55 mg,0.43mmol,1.4 equiv) was slowly added under 0, anhydrous DMF (11 mg,0.16mmol,0.5 equiv) was stirred for 30min and then transferred to room temperature with stirring for 15h, the reaction solution was filtered, 5mL of water was added and stirred at 100℃for 2h, and after cooling filtration, the intermediate compound was obtainedPlacing the substance 8 in a high-pressure hydrogenation kettle, dissolving with 10mL of ethanol, adding 10% Pd/C, filling the reaction system with hydrogen (0.2 MPa), stirring at room temperature for 3h, filtering with diatomite after the reaction, and concentrating the filtrate to obtain the target product compound 9-6 (44 mg, 21%).
(7) Synthesis of Compounds 9-7:
compound 6 (140 mg,1.0mmol,1.0 equiv) and AlCl 3 (346.34 mg,2.6mmol,4.0 equiv) was placed in a 50mL dry round bottom flask with nitrogen replaced. Adding PhNO 2 (4 mL) was stirred for 30min, then n-pentanoyl chloride (94 mg,0.78mmol,1.2 equiv) was added dropwise, the reaction was moved to 65℃oil bath and stirred overnight. After the reaction is completed, H is added 2 O (10 mL) was quenched, EA (3X 30 mL) was extracted, the extracts were combined, washed with saturated brine (3X 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (PE: EA=10:1) to give intermediate compound 7 (55 mg) which was placed in a 10mL dry single-port round-bottom flask, nitrogen was replaced, anhydrous MeCN (8 mL) was added slowly at 0℃to oxalyl chloride (55 mg,0.43mmol,1.4 eq), anhydrous DMF (11 mg,0.16mmol,0.5 eq) was added, stirred for 30min and then transferred to room temperature with stirring for 15h, the reaction solution was filtered, 5mL of water was added and stirred at 100℃for 2h, cooled and filtered, the obtained intermediate compound 8 was placed in a high pressure hydrogenation vessel, dissolved with 10mL of ethanol, 10% Pd/C was added, the reaction system was filled with hydrogen (0.2 MPa), stirred at room temperature for 3h, and the reaction was completed with celite filtration, and the filtrate was concentrated to give the objective compound 9-7 (72 mg, 21%).
Example 1:
1. synthesis of natural product Ivesinol:
compounds 4-1 (22.4 mg,0.1mmol,1.0 equiv) and 9-2 (22.4 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially followed by CHCl 3 (3 mL) was used as a solvent, and the tube was sealed at 50 and stirred for 2h. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure and purified by column chromatography on silica gel to give Ivesinol (9.7 mg, 21%) as a yellow solid. 1 H NMR(400MHz，CDCl 3 )δ13.54(s，1H)，12.67(s，1H)，8.91(s，1H)，8.78(s，1H)，3.99(d，J＝0.7Hz，3H)，3.96(s，1H)，3.94(d，J＝0.7Hz，3H)，3.71(d，J＝7.5Hz，3H)，2.15-2.10(m，3H)，2.07-2.04(m，3H)，1.15(t，J＝6.8Hz，13H). 13 C NMR(100MHz，CDCl 3 )δ212.12，209.84，163.07，162.08，160.54，159.55，156.10，154.74，110.90，110.38，110.01，107.90，107.84，106.04，65.17，61.93，39.92，38.90，36.30，34.72，19.46，19.18，17.76，8.85，7.99.
After synthesizing the natural product ivosinol, the present example also conducted a study of biological activity on ivosinol, including conducting a wide range of MIC screening, in vitro cytotoxicity assays, sterilization curve assays, anti-biofilm assays, drug resistance assays, minimum Bactericidal Concentration (MBC) assays, cytotoxicity assays, and pharmacokinetic assays for various bacteria, to refine the study data and pave the way for further new drug development.
2. Results and discussion of Ivesinol biological experiments
2.1 Ivesinol minimum inhibitory concentration experiment
The Minimum Inhibitory Concentration (MIC) is an index for quantitatively determining the in-vitro inhibitory activity of a drug, and is also a key index for researching the interaction of bacteria and the drug. The drug should have an effect of killing or inhibiting pathogenic bacteria in vivo, and must be at an effective concentration in the target tissue or organ and be maintained for a certain period of time. The experiments were based on the Ivesinol related bioactivity report, and antibacterial activity screening was performed on methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (E.faecium), and the results are shown in Table 2.
TABLE 2 results of experiments with minimum inhibitory concentration of Ivesinol
Table 3.2 Results of Ivesinol minimum inhibitory concentration experiment
The results of the experiment show that the bactericidal activity of Ivesinol against MRSA is 1-0.5 mug/mL, which is equivalent to Vancomycin, ciprofioxacin activity, and the VER activity is preferably 1 mug/mL (Ef 2006295036), which is not as good as the activity reported in the literature. Gram negative bacteria were then assayed for bactericidal activity, including staphylococcus aureus (SA 1405 and SA 186286), escherichia coli (e.coli 25922) and klebsiella pneumoniae (KPN 3026), and the results are shown in table 3. Unfortunately, however, the experimental results show that there is substantially no bacteriostatic activity against gram-negative bacteria.
TABLE 3 results of experiments with minimum inhibitory concentration of Ivesinol on gram-negative bacteria
Table 3.3 Results of minimal inhibitory concentration of Ivesinol on Gram-negative bacteria
2.2 Ivesinol in vitro cytotoxicity assay
The cytotoxicity test is a simple, efficient and quantitative method for evaluating the safety of the compound in vitro, and the detection principle is that the toxicity of the object to be tested can influence the cell homeostasis, and apoptosis is caused by destroying the integrity and basic functions of the cell. The usual cytotoxicity test methods are: MTT method, CCK-8 method (Cell Counting Kit-8), MEM elution method, direct contact method, etc. The experiment adopts an MTT cytotoxicity test method, and cytotoxicity tests are carried out on 3 cells of L02 (normal liver cells), huvec (human umbilical vein endothelial cells) and 293T (normal kidney cells), and the results are shown in figure 1. With increasing concentration of ivosinol, cytotoxicity increased and viable cells decreased. Calculated L02 cells Ivesinol IC 50 9.7890.5 μg/mL, 293T cell Ivesinol IC 50 IC of Huvec cell Ivesinol = 0.4068 μg/mL 50 =0.351 μg/mL, the data gives greater cytotoxicity, smaller activity window,and does not exhibit the low toxicity reported in the literature.
2.3 Ivesinol sterilization curve experiment
The relationship between the concentration of the antimicrobial agent and the rate and extent of bactericidal activity can be demonstrated by measuring the bactericidal curve of the compound, all of which have a concentration-dependent and non-dependent difference in their concentration-bacterial load curves, which are shown by the slope of the curve, and the non-concentration-dependent agent has a steeper concentration-bacterial load curve than the concentration-dependent agent. MRSA 300 was selected as the experimental strain for this experiment. The bactericidal effect of ivosinol was measured by different concentrations and times and the results are shown in fig. 2. As a result of measuring the sterilization conditions of MIC, 2 xMIC, 4 xMIC, 8 xMIC of Ivesinol at 4 time points with time as the abscissa and 1g CFU/mL as the ordinate, it was found that the sterilization effect was better with the increase of the compound concentration, and Ivesinol belongs to the concentration-dependent compound. 2.4Ivesinol anti-biofilm assay.
There are two main types of anti-biofilm experiments: one is the formation of an anti-biofilm, which is administered prior to the formation of a bacterial biofilm; the second is when a bacterial biofilm has formed, and then administration interferes with the biofilm. This experiment was performed as an experiment in which the first compound affected the formation of the biofilm. From the picture 3, it was observed that 2×mic concentration of iveosin had an inhibitory effect on the biofilm, but was not substantially effective from the MIC value, but positive control ciprofloxacin to 1/2×mic had a certain effect on the biofilm, indicating that the bactericidal effect of iveosin was not caused by the effect on the biofilm.
2.5 Ivesinol resistance test
MIC values of the compounds are increased 1-5 times to low drug resistance; 5-15 is moderate drug resistance; and more than 15 are highly resistant. The drug resistance test of Ivesinol has been carried out for 26 generations (figure 4), and the drug resistance is maintained at low level from the initial 0.5 mug/mL to the rise of the 26 th generation to 2 mug/mL. Whereas the positive control drug ciprofloxacin increased from 0.5 μg/mL to 32 μg/mL for passage 24, a 64-fold increase compared to the initial MIC value, and appeared to be highly resistant. Compared with the positive control, the compound Ivesinol is found to have the characteristic of drug resistance.
2.6 Ivesinol minimum bactericidal concentration experiment
Minimum bactericidal concentration (minimum bactericidal concentration, MBC): the minimum drug concentration required to kill 99.9% (3 orders of magnitude lower) of the test microorganisms was found to better demonstrate the kill of the drug to the bacteria. When the number of colonies on the agar plate was less than 10, the concentration was judged as the minimum bactericidal concentration of the compound, and as shown in Table 4, the minimum bactericidal concentration of Ivesinol was 16. Mu.g/mL, and the minimum bactericidal concentration of ciprofloxacin as a positive control was 1. Mu.g/mL.
TABLE 4 colony count for each concentration of Ivesinol
Table 3.4 Colony count of Ivesinol at each concentration
2.7 Ivesinol hemolytic toxicity experiment
Hemolysis generally refers to the phenomenon that erythrocyte membranes are destroyed, or a plurality of pores appear, or hemoglobin flows out of erythrocytes due to extreme extension, and the erythrocyte free solution gradually increases in transparency and gradually turns dark red, and is one of important indexes of research before medicament marketing. The experiment adopts an enzyme-labeled instrument to carry out OD 600 As a result of measurement and calculation of the measurement result using a hemolysis ratio formula, as shown in FIG. 5, it was found that the concentration of the compound increased from 0.125. Mu.g/mL to 8. Mu.g/mL, the hemolysis ratio was less than 5%, and when the concentration was increased to 16. Mu.g/mL, the concentration increased to 5.8%, and it was found that the compound Ivesinol had no hemolytic toxicity in the active range.
2.8 Ivesinol pharmacokinetic experiments
The pharmacokinetic experiment mainly researches the dynamic change process of the drug in animals, and is an important component of preclinical research of the drug. In this experiment, BALB/c mice were selected as the subjects, the test object was injected via tail vein, blood was collected at the set time point, and the results of the experiment were shown in FIG. 6 by HPLC analysis, with Ivesinol being T in the mice 1/2 Time of ivosinol elimination in mice =4.92 minFast. In example 1, comprehensive biological activity evaluation is carried out on the antibacterial effect of the iversinol, and the antibacterial activity of the compound is found to not reach the level reported in the literature, and further improvement space is provided, and experiments of cytotoxicity, anti-biofilm activity, pharmacokinetics and the like show that indexes such as water solubility, safety and the like of the compound are difficult to reach the requirements of patent medicine. Therefore, the invention carries out structural modification on Ivesinol, carries out further structure-activity relation research, defines a pharmacophore, optimizes the drug property to obtain a more Miao compound with stable structure and simplification, and has important significance for the evaluation of the patent drug property of the compound. Specifically, in the invention of examples 2-22, the compound is still synthesized by dividing the compound into left and right fragments according to the synthesis strategy of Ivesinol, and then the assembly is completed through coupling.
Firstly, the design is kept the left part unchanged, the acyl fragment in the right fragment is changed, whether the alkyl chain in the acyl group has influence on the biological activity is hoped to be clear, and finally, three compounds of T-3/4/5 are successfully obtained. Then, the structure of the left fragment is changed while the right side is kept unchanged, and six compounds of T-6 to T-11 are designed and synthesized through changing phenolic hydroxyl groups on the acyl substrate segment and benzene ring.
Next, another series of analogues were designed with varying substituents on both sides, giving a total of 10 compounds of T-12 to T-21. In the series of compounds, the acyl groups of part of the compounds are directly changed into alkane, or the positions of phenolic hydroxyl groups and methoxy groups of benzene rings at two sides are changed simultaneously, and the acyl form is changed, so that the activity and toxicity can be optimized.
The specific synthesis method of the Ivesinol derivatives T-1 to T-21 is as follows:
example 2:
synthesis of derivative T-1:
compound 4-1 (44.8 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the reaction by TLC, the solvent was removed under reduced pressure and the layer was used The compound T-1 (32.7 mg, 71%) was obtained by separation and purification on a silica gel column. 1 H NMR(400MHz，CDCl 3 )δ12.64(d，J＝1.4Hz，2H)，8.73-8.59(m，3H)，3.93(s，6H)，3.75(q，J＝6.8Hz，2H)，3.69(s，2H)，2.06(s，6H)，1.18(s，6H)，1.16(s，6H). 13 C NMR(100MHz，CDCl 3 )δ210.32，162.06，159.47，154.91，110.70，109.46，106.42，65.13，38.83，29.67，19.68，17.63，7.99.
Example 3:
synthesis of derivative T-2:
compound 4-2 (47.6 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-2 (38.6 mg, 81%). 1 H NMR(400MHz，CDCl 3 )δ13.08(s，2H)，8.68(s，2H)，3.95(s，6H)，3.69(s，2H)，3.04(t，J＝7.5Hz，4H)，2.06(s，6H)，1.64(q，J＝7.6Hz，4H)，1.36(q，J＝7.5Hz，4H)，0.93(t，J＝7.3Hz，6H). 13 C NMR(100MHz，CDCl 3 )δ205.90，162.33，159.65，155.21，110.73，109.55，107.49，64.87，42.31，27.47，22.57，17.56，13.96，7.95.M.p：173-175℃.HRESIMS(m/z)：487.23374[M+H] + (calcd for C 27 H 35 O 8 + ：487.23326).
Example 4:
synthesis of derivative T-3:
compound 4-3 (53.2 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the product was purified by chromatography on a silica gel column to give compound T-3 (41.5 mg, 81%). 1 H NMR(400MHz，CDCl 3 )δ13.09(s，2H)，8.68(s，2H)，3.95(s，6H)，3.69(s，2H)，3.03(d，J＝7.9Hz，4H)，2.06(s，6H)，1.69-1.62(m，4H)，1.32(d，J＝19.5Hz，12H)，0.88(d，J＝6.2Hz，6H). 13 C NMR(100MHz，CDCl 3 )δ205.90，162.35，159.66，155.22，110.73，109.54，107.48，64.88，53.53，42.63，31.71，29.15，25.35，22.49，14.06，7.95.HRESIMS(m/z)：543.29634[M+H] + ，(calcd for C 31 H4 3 O 8 + ：543.29675).
Example 5:
synthesis of derivative T-4:
compound 4-2 (23.8 mg,0.1mmol,1.0 equiv) and compound 9-4 (23.8 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was then added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-4 (8.8 mg, 18%). 1 H NMR(400MHz，CDCl 3 )δ13.69(s，1H)，13.05(s，1H)，8.94(s，1H)，8.76(s，1H)，3.98(s，3H)，3.96(s，3H)，3.69(s，2H)，3.11(t，J＝7.4Hz，2H)，3.03(t，J＝7.5Hz，2H)，2.12(s，3H)，2.05(s，3H)，1.64(q，J＝7.6Hz，5H)，1.38-1.31(m，4H)，0.92(d，J＝7.0Hz，6H). 13 C NMR(100MHz，D 2 O)δ205.34，203.29，160.27，159.72，157.26，156.68，153.99，152.58，108.21，107.64，107.45，105.98，105.13，104.66，62.41，59.41，41.97，39.68，27.13，25.06，24.00，19.90，15.15，11.44，11.27，6.27，5.39.HRESIMS(m/z)：487.23374[M+H] + (calcd for C 27 H 35 O 8 + ：487.23341).
Example 6:
synthesis of derivative T-5:
compound 4-1 (22.4 mg,0.1mmol,1.0 equiv) and compound 9-1 (19.6 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-5 (6.9 mg, 16%). 1 H NMR(500MHz，CDCl 3 )δ9.93(s，1H)，9.93(s，1H)，8.97(s，1H)，8.97(s，1H)，8.51(s，1H)，8.51(s，1H)，5.42(s，1H)，5.42(s，1H)，4.38(hept，J＝12.8Hz，1H)，3.98(s，2H)，3.91(s，3H)，3.77(s，3H)，2.61(s，3H)，2.16(s，6H)，1.16(d，J＝6.4Hz，6H).
Example 7:
synthesis of derivative T-6:
compound 4-1 (22.4 mg,0.1mmol,1.0 equiv) and compound 9-4 (23.8 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-6 (7.1 mg, 15%). 1 H NMR(500MHz，CDCl 3 )δ7.92(s，1H)，5.47(d，J＝26.9Hz，2H)，3.99(s，2H)，3.92(s，3H)，3.78(s，3H)，3.11-2.88(m，3H)，2.16(s，6H)，1.53-1.30(m，4H)，1.16(d，J＝12.8Hz，6H)，1.01-0.82(m，3H).
Example 8:
synthesis of derivative T-7:
compound 4-1 (22.4 mg,0.1mmol,1.0 equiv) and compound 4-3 (26.6 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-7 (9.0 mg, 18%). 1 H NMR(400MHz，CDCl 3 )δ13.67(s，1H)，12.73(s，1H)，8.90(s，1H)，8.77(s，1H)，3.99(s，3H)，3.95(s，3H)，3.78-3.71(m，1H)，3.69(s，2H)，3.08(t，J＝7.4Hz，2H)，2.12(s，3H)，2.06(s，4H)，1.65(p，J＝7.5Hz，3H)，1.41(d，J＝4.9Hz，2H)，1.34-1.27(m，10H)，1.17(d，J＝6.8Hz，9H)，0.90-0.82(m，10H). 13 C NMR(100MHz，CDCl 3 )δ209.85，207.94，162.81，162.14，159.55，159.26，156.56，154.73，110.85，110.21，109.97，108.57，107.70，106.02，65.22，61.98，44.82，38.93，31.66，29.70，29.06，24.48，22.59，19.52，17.72，14.10，8.82，8.01.HRESIMS(m/z)：501.24939[M+H] + (calcd for C 28 H 37 O 8 + ：501.24996)
Example 9:
synthesis of derivative T-8:
compound 4-2 (23.8 mg,0.1mmol,1.0 equiv) and compound 9-2 (22.4 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure, and the product was purified by chromatography on a silica gel column to give compound T-8 (6.6 mg, 14%). 1 H NMR(400MHz，CDCl 3 )δ13.56(s，1H)，13.03(s，1H)，8.97(s，1H)，8.76(s，1H)，3.99(s，3H)，3.96(s，3H)，3.70(s，2H)，3.02(t，J＝7.6Hz，2H)，2.12(s，3H)，2.05(s，3H)，1.65(d，J＝7.5Hz，3H)，1.33(p，J＝7.7Hz，3H)，1.15(d，J＝6.7Hz，6H)，0.90(t，J＝7.4Hz，4H). 13 C NMR(100MHz，CDCl 3 )δ212.21，205.89，163.06，162.28，159.84，159.20，156.08，155.14，110.81，110.38，110.06，107.94，107.84，107.20，64.99，61.97，42.32，39.90，29.70，27.74，22.47，19.23，17.76，13.74，8.90，7.96.HRESIMs(m/z)：473.21809[M+H] + (calcd for C 26 H 33 O 8 + ：473.21865).
Examples: 10:
synthesis of derivative T-9:
compound 4-3 (26.6 mg,0.1mmol,1.0 equiv) and compound 9-2 (22.4 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer and p-fluvium was added sequentially TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv), and CHCl were added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure and purified by chromatography on a silica gel column to give compound T-9 (6.5 mg, 13%). 1 H NMR(500MHz，CDCl 3 )δ9.15(s，1H)，8.63(s，1H)，4.68(s，1H)，4.09(hept，J＝6.4Hz，1H)，3.99(s，2H)，3.92(s，3H)，3.78(s，3H)，2.96(t，J＝7.8Hz，2H)，2.16(s，6H)，1.53(tt，J＝7.8，5.7Hz，2H)，1.38-1.25(m，6H)，1.16(d，J＝6.4Hz，6H)，0.96-0.83(m，3H).
Example 11:
synthesis of derivative T-10:
compound 9-1 (19.6 mg,0.1mmol,1.0 equiv) and compound 9-2 (22.4 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was then added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure and purified by chromatography on a silica gel column to give compound T-10 (6.5 mg, 15%). 1 H NMR(400MHz，CDCl 3 )δ13.66(s，1H)，13.56(s，1H)，9.04(s，1H)，8.94(s，1H)，3.99(s，6H)，4.03-3.96(m，7H)，3.68(s，2H)，2.71(s，3H)，2.12(s，3H)，2.12(s，3H)，1.16(s，3H)，1.14(s，3H). 13 C NMR(100MHz，CDCl 3 )δ212.45，205.34，162.94，162.76，159.70，159.25，157.04，156.22，110.05，109.80，108.76，108.30，108.25，108.03，61.97，39.82，33.78，30.27，29.69，19.27，17.97，8.91，8.77.M.p：152-154℃.HRESIMS(m/z)：431.17114[M+H] + (calcd for C 23 H 27 O 8 + ：431.16965).
Example 12:
synthesis of derivative T-11:
compound 9-3 (23.8 mg,0.1mmol,1.0 equi) and compound 9-2 (22.4 mg,0.1mmol,1.0 equi) were placed in a 20mL dry, sealed tube, and p-TsCl (19 mg,0.1mmol,1.0 equi) was added sequentiallyiv) paraformaldehyde (29 mg,0.2mmol,2.0 equiv), followed by addition of CHCl 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure and purified by chromatography on a silica gel column to give compound T-11 (9.5 mg, 20%). 1 H NMR(400MHz，CDCl 3 )δ13.56(d，J＝1.5Hz，1H)，9.03(s，1H)，8.60(s，1H)，7.57(s，1H)，4.01(td，J＝6.7，1.1Hz，1H)，3.96(d，J＝1.3Hz，3H)，3.95(d，J＝1.2Hz，3H)，3.67(s，2H)，2.12(d，J＝1.3Hz，3H)，2.10(d，J＝1.2Hz，4H)，1.26(d，J＝1.3Hz，10H)，1.17(d，J＝1.2Hz，3H)，1.15(d，J＝1.2Hz，3H). 13 C NMR(100MHz，CDCl 3 )δ216.36，212.47，162.83，159.37，156.26，156.22，151.72，114.14，110.07，110.05，109.48，108.66，108.08，62.07，61.85，45.51，39.79，27.29，19.28，18.16，9.05，8.87.HRESIMS(m/z)：473.21809[M+H] + (calcd for C 26 H 33 O g + ：473.21869).
Example 13:
synthesis of derivative T-12:
compound 9-4 (47.6 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-12 (37.1 mg, 76%). 1 H NMR(400MHz，CDCl 3 )δ13.71(s，2H)，8.99(s，2H)，3.99(s，6H)，3.68(s，2H)，3.13(t，J＝7.3Hz，4H)，2.13(s，6H)，1.68-1.62(m，4H)，1.41-1.33(m，4H)，0.93(t，J＝7.3Hz，6H). 13 C NMR(100MHz，CDCl 3 )δ208.10，162.71，159.32，156.70，109.89，108.70，108.25，61.95，44.56，29.69，26.56，22.46，14.06，8.85.M.p：125-127℃.HRESIMS(m/z)：487.23374[M+H] + (calcd for C 27 H 35 O 8 + ：487.23327).
Example 14:
synthesis of derivative T-13:
compound 9-4 (23.8 mg,0.1mmol,1.0 equiv) and compound 9-2 (22.4 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was then added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure, and the product was purified by chromatography on a silica gel column to give compound T-13 (7.8 mg, 17%). 1 H NMR(500MHz，CDCl 3 )δ9.24(s，1H)，6.05(s，1H)，5.21(s，1H)，4.09-3.86(m，3H)，3.78(s，3H)，3.72(s，3H)，3.12-2.74(m，2H)，2.16(s，3H)，1.54-1.30(m，4H)，1.19(t，J＝26.3Hz，6H)，1.00-0.83(m，3H).
Example 15:
synthesis of derivative T-14:
compound 9-5 (21.0 mg,0.1mmol,1.0 equiv) and compound 9-2 (22.4 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was then added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-14 (7.1 mg, 16%). 1 H NMR(500MHz，CDCl 3 )δ9.13(s，1H)，5.35(d，J＝10.8Hz，2H)，4.06-3.84(m，3H)，3.78(s，6H)，3.54(q，J＝13.4Hz，2H)，2.16(s，6H)，1.22(t，J＝13.4Hz，3H)，1.17(s，3H)，1.15(s，3H).
Example 16:
synthesis of derivative T-15:
compound 9-1 (19.6 mg,0.1mmol,1.0 equiv) and compound 9-3 (23.8 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was then added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of TLC monitoring the reaction, the solvent was removed under reduced pressure, and the mixture was separated and purified by a silica gel column chromatography to give Compound T-15 (9.8 mg, 22%)。 1 H NMR(400MHz，CDCl 3 )δ13.67(s，1H)，9.08(s，1H)，8.58(s，1H)，7.60(s，1H)，3.97(s，3H)，3.96(s，3H)，3.67(s，2H)，2.73(s，3H)，2.12(d，J＝10.2Hz，6H)，1.27(s，10H). 13 C NMR(100MHz，CDCl 3 )δ216.38，205.36，162.70，159.75，157.00，156.27，153.93，151.76，114.02，109.95，109.89，109.51，108.81，108.50，62.07，61.89，45.54，33.79，27.31，18.11，9.09，8.78.M.p：198-200℃.HRESIMS(m/z)：445.18679[M+H] + (calcd for C 24 H 29 O 8 + ：445.18640).
Example 17:
synthesis of derivative T-16:
compound 9-2 (44.8 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give compound T-16 (36.8 mg, 80%). 1 H NMR(400MHz，CDCl 3 )δ13.55(s，2H)，8.98(s，2H)，3.99(s，6H)，3.69(s，2H)，3.72-3.65(m，3H)，2.13(s，6H)，1.16(s，7H)，1.15(s，7H). 13 C NMR(100MHz，CDCl 3 )δ212.44，162.93，159.30，156.25，110.01，108.38，108.09，61.95，39.80，29.67，19.26，8.89.
Example 18:
synthesis of derivative T-17:
Compound 9-6 (42.0 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give compound T-17 (35.4 mg, 82%). 1 H NMR(400MHz，CDCl 3 )δ8.33(s，2H)，4.66(s，2H)，3.90(s，6H)，3.69(s，2H)，2.43(d，J＝7.3Hz，4H)，2.13(s，6H)，0.92(d，J＝6.6Hz，13H). 13 C NMR(100MHz，CDCl 3 )δ152.72，152.33，152.18，112.10，110.52，107.31，61.93，32.92，28.43，22.76，18.96，9.14.M.p：195-197℃.HRESIMS(m/z)：431.24391[M+H] + (calcd for C 25 H 35 O 6 + ：431.24215).
Example 19:
synthesis of derivative T-18:
compound 9-7 (44.8 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the product was purified by chromatography on a silica gel column to give Compound T-18 (35.0 mg, 76%). 1 H NMR(400MHz，CDCl 3 )δ8.36(s，2H)，4.66(s，2H)，3.90(s，6H)，3.69(s，2H)，2.54(t，J＝7.9Hz，4H)，2.12(s，6H)，1.47(q，J＝7.3Hz，4H)，1.37-1.30(m，8H)，0.93-0.82(m，7H). 13 C NMR(100MHz，CDCl 3 )δ152.56，151.95，151.90，113.16，110.60，107.35，61.94，32.20，28.93，23.86，22.66，18.91，14.10，9.07.
Example 20:
synthesis of derivative T-19:
compound 9-1 (19.6 mg,0.1mmol,1.0 equiv) and compound 9-4 (23.8 mg,0.1mmol,1.0 equiv) were placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,1.0 equiv), paraformaldehyde (29 mg,0.2mmol,2.0 equiv) were added sequentially, and CHCl was then added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure and purified by chromatography on a silica gel column to give compound T-19 (7.1 mg, 16%). 1 H NMR(400MHz，CDCl 3 )δ13.72(s，1H)，13.68(s，1H)，9.03(s，1H)，8.96(s，1H)，4.00(s，3H)，3.99(s，3H)，3.68(s，2H)，3.13(t，J＝7.3Hz，2H)，2.72(s，3H)，2.13(d，J＝1.1Hz，7H)，1.65(q，J＝7.4Hz，3H)，1.44-1.33(m，2H)，0.94(t，J＝7.3Hz，3H). 13 C NMR(100MHz，CDCl 3 )δ208.09，205.36，162.78，162.73，159.67，159.27，157.02，156.68，109.92，109.83，108.77，108.68，108.23，108.17，61.98，44.58，33.81，26.55，22.46，17.95，14.09，8.87，8.81.M.p：176-178℃.HRESIMS(m/z)：445.18679[M+H] + (calcd for C 24 H 29 O 8 + ：445.18629).
Example 21:
synthesis of derivative T-20:
compound 9-3 (47.6 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring reaction, the solvent was removed under reduced pressure, and the mixture was purified by chromatography on a silica gel column to give Compound T-20 (35.1 mg, 72%). 1 H NMR(400MHz，CDCl 3 )δ8.63(s，2H)，7.56(s，2H)，3.93(s，6H)，3.66(s，2H)，2.10(s，6H)，1.26(s，19H). 13 C NMR(100MHz，CDCl 3 )δ216.51，156.29，153.63，151.68，114.10，110.30，109.54，61.97，45.53，27.30，18.26.M.p：229-231℃.HRESIMS(m/z)：487.23374[M+H] + (calcd for C 27 H 35 O 8 + ：487.23389).
Example 22:
synthesis of derivative T-21:
compound 9-1 (39.2 mg,0.2mmol,1.0 equiv) was placed in a 20mL dry tube sealer, p-TsCl (19 mg,0.1mmol,0.5 equiv) was added sequentially, paraformaldehyde (29 mg,0.2mmol,1.0 equiv) was added, and CHCl was added 3 (3 mL) was used as a solvent, and the tube was sealed and stirred at 50℃for 2 hours. After completion of the TLC monitoring the reaction, the solvent was removed under reduced pressure and purified by chromatography on a silica gel column to give compound T-21 (33.5 mg, 83%). 1 H NMR(400MHz，CDCl 3 )δ13.64(s，2H)，8.97(s，2H)，3.99(d，J＝1.0Hz，6H)，3.68(s，2H)，2.71(d，J＝1.0Hz，6H)，2.13(d，J＝1.0Hz，6H). 13 C NMR(100MHz，CDCl 3 )δ205.33，162.78，159.64，156.99，109.86，108.76，108.17，61.97，33.77，17.92.
Example 23:
activity of the natural product Ivesinol and its derivatives against Staphylococcus aureus (S.aureus) and enterococcus faecium (E.faecium):
the method for measuring the minimum inhibitory concentration comprises the following steps: MIC of the compounds against Staphylococcus aureus and enterococcus faecium was tested by 96-well dilution for evaluation of their drug-resistant activity. Firstly, dissolving a compound to be tested in DMSO to prepare high-concentration mother liquor, and sequentially carrying out 2-time gradient dilution on the compound mother liquor for 10 times to prepare 11 parts of 10X working solution; the compound gradient dilutions were then transferred to 96-well round bottom plates, wells 1-11 containing 10. Mu.L of the 10 Xworking solution prepared above, and well 12 with 10. Mu.L of water added as solvent control. The fresh monoclonal strain is selected and prepared into bacterial suspension by sterilizing physiological saline, the concentration is regulated to be 0.5 McAb turbidity, the bacterial suspension is diluted by 7H9 culture medium according to the ratio of 1:200, and then 90 mu L of bacterial suspension is sequentially added into the prepared drug-containing 96-well plate. The inoculated 96-well plate was placed in a biochemical incubator (37 ℃) and incubated for 16 hours, and the experimental results were recorded. The clinical first-line drug ciprofloxacin is selected as a positive control. The antibacterial activity is shown in table 5 below:
TABLE 5 results of antibacterial activity of Ivesinol and its derivatives
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As can be seen from the data in Table 5, the antibacterial activity of the compound T-18 was found to be best, and T-18 was different from the natural product in that the acyl side chains of the two fragments were different, the side chain of Ivesinol was isobutyryl group, the number of carbon atoms was 4, and T-18 was n-pentanoyl carbon number was 5. In addition, the antibacterial activity is reduced by changing the symmetrical relation of the left and right fragments or increasing or decreasing the number of the side chain carbon of the acyl, so that the optimal carbon chain length is 5 carbons, and the activity is better when the left and right fragments are asymmetric.
In summary, the examples of the present invention first performed a more comprehensive biological activity assay for Ivesinol, which showed that Ivesinol activity was not as good as that reported in the literature. The design thought of the derivative is carried out, and the derivative structure is finally successfully obtained. Firstly, derivative synthesis is carried out according to the positions of all groups on a benzene ring, the length of an acyl side chain and the existence of an acyl side chain carbonyl group. Under the condition that the left and right fragments are not changed respectively, the other fragment is obtained by changing the number of the carbon of the acyl side chain or reducing the carbonyl on the acyl side chain, and the 9 derivatives are obtained after combined coupling. And 10 derivatives were obtained by random combination of the fragments obtained after the modification. Finally, through antibacterial activity verification, the fact that the symmetrical relation of the left and right fragments is changed or the antibacterial activity of the compound is influenced by increasing or reducing the number of the side chain carbon of the acyl, the optimal carbon chain length is 5 carbons, and the activity is better when the left and right fragments are asymmetrical, namely the antibacterial activity of the compound T-18 is the best.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
Claims (10)
1. A method for synthesizing a natural product Ivesinol and derivatives thereof, which is characterized by comprising the following synthetic route:
the method comprises the following steps:
(1) The compound 3 is prepared by methylation and aldehyde reduction reaction of the compound 1, 2,4, 6-trihydroxybenzaldehyde, and the compound 4 is prepared by Friedel-crafts acylation reaction of the compound 3;
(2) The compound 7 is prepared by methylation and Friedel-crafts reaction of the compound 5, aldehyde groups are introduced into the compound 7 through Vilsmeier reaction, and the aldehyde groups are reduced to obtain a compound 9;
(3) The compounds 4 and 9 are subjected to a coupling reaction to obtain compounds IVE-1 and/or IVE-2;
wherein,
R 1 is selected from at least one of ethyl, isopropyl, n-butyl, n-hexyl and other linear or branched alkane substituents,
R 2 At least one selected from ethyl, isopropyl, n-butyl, n-hexyl and other linear or branched alkane substituents,
R 3 at least one selected from the group consisting of hydroxyl, methoxy, and other linear alkoxy groups,
R 4 at least one selected from the group consisting of hydroxyl, methoxy, and other linear alkoxy groups,
R 5 at least one selected from acetyl, isobutyl, isobutyryl, pivaloyl, n-pentyl, n-pentanoyl and other straight or branched alkyl and acyl groups,
R 6 at least one selected from the group consisting of acetyl, isobutyl, isobutyryl, pivaloyl, n-pentyl, n-pentanoyl, and other linear or branched alkyl and acyl groups.
2. The synthetic method according to claim 1, characterized in that the synthetic route of the method is as follows:
the method comprises the following steps:
(1) Methylation is carried out on the compound 1, 2,4, 6-trihydroxybenzaldehyde to obtain a compound 2, aldehyde reduction reaction is carried out on the compound 2 to obtain a compound 3, and friedel-crafts acylation reaction is carried out on the compound 3 to obtain a compound 4;
(2) Methylation of the phloroglucinol in the compound 5 to obtain a compound 6, friedel-crafts reaction of the compound 6 to obtain a compound 7, introducing aldehyde groups into the compound 7 through Vilsmeier reaction to obtain a compound 8, and reducing the aldehyde groups in the compound 8 to obtain a compound 9;
(3) Compounds 4 and 9 are coupled to give compounds IVE-1 and/or IVE-2.
3. The synthesis method according to claim 2, characterized in that: in the steps (1) and (2), the methylation reaction is a selective monomethylation reaction, and the adopted methylation reagent is any one selected from methyl iodide, dimethyl sulfate and dimethyl carbonate;
and/or, in the steps (1) and (2), the methylation reaction is respectively carried out at room temperature and 50-60 ℃.
4. The synthesis method according to claim 2, characterized in that: in the step (1), under the acidic condition,
reducing aldehyde groups in the compound 2 into methyl groups through sodium cyanoborohydride to prepare a compound 3;
and/or, in the step (1), the aldehyde group reduction reaction is performed under the condition that the pH is 2-3;
and/or, in the step (1), the acylation reagent adopted in the friedel-crafts acylation reaction is acyl chloride, and the chemical structural formula of the acyl chloride is R1COCl;
and/or, in the step (2), the friedel-crafts reaction comprises acylation reaction and alkylation reaction, wherein an acylation reagent adopted in the acylation reaction is acyl chloride, and the chemical structural formula of the acyl chloride is R2COCl; the alkylating reagent adopted in the alkylation reaction is haloalkane, and the chemical structural formula of the alkylating reagent is R5Cl and/or R6Cl.
5. The synthesis method according to claim 2, characterized in that: in the steps (1) and (2), the reaction temperature of the Friedel-crafts acylation reaction is 60-70 ℃;
and/or, in the step (2), introducing aldehyde groups by Vilsmeier reaction between the compound 7 and oxalyl chloride/N, N-Dimethylformamide (DMF) system to prepare a compound 8;
and/or, in the step (2), reducing the aldehyde group under Pd/C/H2 conditions to obtain a compound 9.
And/or, in the step (3), the compound 4, the compound 9 and the TsCl/paraformaldehyde system are subjected to a coupling reaction to obtain compounds IVE-1 and/or IVE-2;
and/or, in the step (3), the coupling reaction temperature is 40-60 ℃.
6. A compound, characterized in that: the compound synthesized according to the method of any one of claims 1 to 5, wherein the structure of the compound is shown as IVE-1 and IVE-2:
7. a compound according to claim 6, characterized in that: the IVE-1 is selected from at least one of the following structures T-1, T-19, T-21, T-18, T-3, T-4, T-5, T-7 and T-10:
and/or, the IVE-2 is selected from at least one of the following structures T-6, T-8, T-20, T-9, T-11, T-13, T-2, T-12, T-14, T-15, T-16, T-17:
8. Use of the method according to any one of claims 1 to 5 for the synthesis of the natural product ivosinol and its derivatives.
9. Use of a compound according to claim 7 in antibacterial, for non-disease therapeutic or diagnostic purposes.
10. An antibacterial agent comprising an effective amount of a compound according to claim 7.
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