CN107955057B - Fusidic acid chemical modifier and preparation method and application thereof - Google Patents

Fusidic acid chemical modifier and preparation method and application thereof Download PDF

Info

Publication number
CN107955057B
CN107955057B CN201711032579.XA CN201711032579A CN107955057B CN 107955057 B CN107955057 B CN 107955057B CN 201711032579 A CN201711032579 A CN 201711032579A CN 107955057 B CN107955057 B CN 107955057B
Authority
CN
China
Prior art keywords
fusidic acid
nitrogen
chemical modification
preparation
dichloromethane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201711032579.XA
Other languages
Chinese (zh)
Other versions
CN107955057A (en
Inventor
赵肃清
张炳杰
吴盼盼
钟颖颖
梁汉英
张春国
江政云
方颖林
高美婷
杨洋
朱秋雁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong University of Technology
Original Assignee
Guangdong University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong University of Technology filed Critical Guangdong University of Technology
Priority to CN201711032579.XA priority Critical patent/CN107955057B/en
Publication of CN107955057A publication Critical patent/CN107955057A/en
Application granted granted Critical
Publication of CN107955057B publication Critical patent/CN107955057B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/10—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with sulfur as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N45/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds having three or more carbocyclic rings condensed among themselves, at least one ring not being a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/002—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical chemistry small molecular structure modified medicines, and discloses a fusidic acid chemical modifier, and a preparation method and application thereof. The chemical structural formula of the fusidic acid chemical modifier is shown as follows:
Figure DDA0001449584780000011
wherein R is a mono-substituted or poly-substituted aromatic ring group. The aromatic ring group is an aromatic ring group containing a benzene ring and/or a thiophene ring, or an aromatic ring group containing a furan ring. The invention carries out chemical modification on the structure of the natural product extract fusidic acid to obtain the fusidic acid chemical modifier substituted by the aromatic ring group. The fusidic acid chemical modifier is applied to the preparation of the pharmaceutical preparation and the antibacterial activity to bacteria, and also has application in the preparation of preventing, inhibiting, controlling and/or treating bacterial infection. In addition, the chemical modification of fusidic acid can also be applied to the safety aspect of food and drink and/or the field of disinfection of instruments.

Description

Fusidic acid chemical modifier and preparation method and application thereof
Technical Field
The invention belongs to the field of modification of medicinal chemical small molecular structures, and particularly relates to a fusidic acid chemical modifier and a preparation method and application thereof.
Background
Fusidic acid cream or sodium fusidate and the like prepared from fusidic acid are natural antibacterial drugs widely used in the market, and the chemical structural formula of fusidic acid is shown as formula 2:
Figure RE-GDA0001577361150000011
the main common pharmaceutical dosage forms of fusidic acid are antibacterial creams, tablets, ophthalmic solutions, injections and the like. Fusidic acid is an antibiotic with a steroid skeleton structure, which was first extracted from fungi in 1962 by pharmaceutical company, australia, daneli, and has a chemical structure similar to that of sporin P, and mainly exerts an antibacterial effect by inhibiting the synthesis of bacterial proteins. Fusidic acid has a strong antibacterial effect on a series of gram-positive bacteria, particularly has high antibacterial activity on strains of staphylococcus aureus (resistant to penicillin, streptomycin, erythromycin and chloramphenicol), and multiple strains of staphylococcus are highly sensitive to the product. In clinical use, there is no cross-resistance between fusidic acid and other antibacterial drugs. Furthermore, fusidic acid has excellent tissue penetration ability and can be widely distributed in the body. Clinically significant attention has been paid not only to the high concentration of fusidic acid present in tissues with abundant blood supply, but also to the concentration of drug in less vascularised tissues. It is known that fusidic acid can be present in human tissues such as blood, pus, brain abscess and eyes at concentrations greater than the minimum inhibitory concentration for staphylococci; meanwhile, the medicine is metabolized by the liver in vivo, and is basically not discharged through the bile mainly through the kidney. Fusidic acid has very low toxicity in terms of toxicity and is not cross-allergenic when used with other antibacterial drugs, and therefore the drug can be used normally by patients with allergic contraindications for other antibiotics, such as those sensitive to penicillin or other antibiotics.
Furthermore, it should be noted that the phenomenon of hypersensitivity, which may be caused by intravenous injection of fusidic acid, is very rare. There have been some reports of reversible jaundice in patients after intravenous injection of large doses, and serum bilirubin returns to normal when administration is stopped.
At present, various types of antibacterial antibiotic drugs exist in markets at home and abroad, but simultaneously, due to abuse of the antibiotic drugs, a plurality of super bacteria with drug resistance appear, various inflammation infection and other problems caused by various bacterial infections are solved, and the health safety of human beings is seriously influenced. Based on the above, the research and development of fusidic acid and derivatives thereof have high-efficiency bacteria inhibition, and particularly can solve the urgent health problems of a plurality of known drug-resistant super bacteria, such as a broader-spectrum antibacterial drug and a plurality of inflammations caused by bacterial infection, and the like, and have a relevant important breakthrough. Therefore, such fusidic acid drugs based on market applications have a good development prospect.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a chemical modification compound of fusidic acid. The chemical modification of fusidic acid has antibacterial activity with higher efficiency and great potential value.
Another object of the present invention is to provide a process for the preparation of the above chemical modifications of fusidic acid. The method takes fusidic acid as a raw material, modifies hydroxyl on C-3 with bioactivity of the fusidic acid, and mainly adopts a ring-substituted fusidic acid derivative, wherein the ring-substituted fusidic acid derivative comprises a benzene ring with a single-substituted group or a plurality of substituent groups, a thiophene ring with the single-substituted group or the plurality of substituent groups and a furan ring with the single-substituted group or the plurality of substituent groups.
It is a further object of the present invention to provide the use of the above chemical modifications of fusidic acid.
The above purpose of the invention is realized by the following technical scheme:
a chemical modification of fusidic acid is shown in formula 1:
Figure RE-GDA0001577361150000021
wherein R is a mono-substituted or poly-substituted aromatic ring group.
Preferably, the aromatic ring group is an aromatic ring group containing a benzene ring and/or a thiophene ring, or an aromatic ring group containing a furan ring.
More preferably, the molecular structural formula of the aromatic ring group containing benzene ring and/or thiophene ring is:
Figure RE-GDA0001577361150000031
more preferably, the molecular structural formula of the aromatic ring group containing furan ring is
Figure RE-GDA0001577361150000032
The preparation method of the fusidic acid chemical modifier comprises the following specific steps:
s1, mixing fusidic acid and 4-dimethylaminopyridine, and introducing nitrogen to remove air;
s2, under the protection of nitrogen, adding anhydrous dichloromethane into the mixture obtained in the step S1, stirring until the anhydrous dichloromethane is completely dissolved, adding dried pyridine, stirring, adding cyclic formyl chloride, and carrying out esterification reaction for 2-3 hours;
s3, detecting the reaction end point by TLC, washing, extracting and drying after the reaction is finished to obtain a crude product of the fusidic acid chemical modifier, and purifying by silica gel column chromatography to obtain the fusidic acid chemical modifier.
Preferably, the mass ratio of fusidic acid and 4-dimethylaminopyridine in step S1 is 1: (1-3).
Preferably, the mass ratio of fusidic acid, 4-dimethylaminopyridine and pyridine in step S2 is 1: (1-3): (1-3), wherein the mass ratio of the fusidic acid to the cyclic formyl chloride is 1: (1-3).
Preferably, the stirring in the step S2 is carried out for 15-60 min.
The use of the chemical modification of fusidic acid in the field of the preparation of bacterial inhibitors.
Preferably, the bacteria in the bacterial inhibitor are gram positive and/or gram negative bacteria.
In addition, the use of said chemical modifications of fusidic acid for the preparation of a medicament for the prevention, inhibition, control and/or treatment of bacterial infections.
Furthermore, the use of said chemical modification of fusidic acid in the area of food and beverage safety and/or disinfection of instruments.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention carries out chemical modification on the natural product fusidic acid to obtain a series of fusidic acid chemical modifiers, and has the advantages of simple preparation method, high synthesis yield and wide application range of the obtained fusidic acid for carrying out chemical modification. Pharmacological experiments of antibacterial property show that most of cyclic substituent fusidic acid derivatives have excellent effect of inhibiting bacterial activity (such as staphylococcus aureus, staphylococcus albus and staphylococcus epidermidis), especially part of fusidic acid aryl cyclic derivatives have antibacterial activity equal to or higher than that of fusidic acid raw materials, and the fusidic acid derivatives can be applied to preparation of medicines for preventing, controlling and treating bacterial infection; thus, it can be shown that fusidic acid modifications containing thiophene structures may have significant potential antibacterial activity value. The antibacterial activity of the site-modified chemical modifier is higher than that of the fusidic acid parent.
2. The antibacterial activity experiment of the chemical modification compound of fusidic acid proves that modification and modification of hydroxyl on fusidic acid C-3 are facilitated, the biological activity of the medicine is changed and improved, and the antibacterial activity of the chemical modification compound of fusidic acid is equal to or higher than that of fusidic acid.
Drawings
FIG. 1 is the molecular structural formula of fusidic acid chemical modification FA-E-01.
FIG. 2 is the molecular structural formula of fusidic acid chemical modification FA-E-02.
FIG. 3 is the molecular structural formula of fusidic acid chemical modification FA-E-03.
FIG. 4 is the molecular structural formula of fusidic acid chemical modification FA-E-04.
FIG. 5 is the molecular structural formula of fusidic acid chemical modification FA-E-05.
FIG. 6 is the molecular structural formula of fusidic acid chemical modification FA-E-06.
FIG. 7 is the molecular structural formula of fusidic acid chemical modification FA-E-07.
FIG. 8 is the molecular structural formula of fusidic acid chemical modification FA-E-08.
FIG. 9 is the molecular structural formula of fusidic acid chemical modification FA-E-09.
FIG. 10 is the molecular structural formula of fusidic acid chemical modification FA-E-10.
FIG. 11 is the molecular structural formula of fusidic acid chemical modification FA-E-11.
FIG. 12 is the molecular structural formula of fusidic acid chemical modification FA-E-12.
FIG. 13 is the molecular structural formula of fusidic acid chemical modification FA-E-13.
FIG. 14 is the molecular structural formula of fusidic acid chemical modification FA-E-14.
FIG. 15 is the molecular structural formula of fusidic acid chemical modification FA-E-15.
FIG. 16 is the molecular structural formula of fusidic acid chemical modification FA-E-16.
FIG. 17 is the molecular structural formula of fusidic acid chemical modification FA-E-17.
FIG. 18 is the molecular structural formula of fusidic acid chemical modification FA-E-18.
FIG. 19 is the molecular structural formula of fusidic acid chemical modification FA-E-19.
FIG. 20 is the molecular structural formula of fusidic acid chemical modification FA-E-20.
FIG. 21 is the molecular structural formula of the chemical modification of fusidic acid.
Detailed Description
The following examples are presented to further illustrate the present invention and should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
EXAMPLE 1 preparation of chemical modification of fusidic acid (FA-E-01)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 0.20mL (1.743mmol) of benzoyl chloride in three times is added, and the reaction is stirred for 2h under the protection of nitrogen at room temperature. The end of the reaction was checked by TLC (developer: dichloromethane: ethyl acetate ═3: 1, the color developing agent is methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio) 85: 10: 5: 0.5), and the reaction is completed, a crude product of the compound FA-E-01 is obtained by washing, extraction, drying and the like, and purified by silica gel column chromatography (eluent: dichloromethane: ethyl acetate ═ 6: 1) to obtain compound FA-E-01, whose molecular structural formula is shown in figure 1, white solid, Rf0.45 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 76 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 85-86 ℃;1H NMR(400MHz,Chloroform-d)8.05-7.97(m,2H), 7.67-7.58(m,1H),7.47(t,J＝7.8Hz,2H),5.86(d,J＝8.4Hz,1H),5.18-5.08(m, 1H),4.37(q,J＝2.7Hz,1H),3.74(q,J＝2.7Hz,1H),3.12(dd,J＝12.6,3.2Hz, 1H),2.64-2.46(m,2H),2.35(dt,J＝13.1,3.2Hz,1H),2.32-2.07(m,5H),2.02(s, 3H),1.97-1.80(m,4H),1.74(dtt,J＝10.0,7.6,4.0Hz,2H),1.68-1.64(m,3H), 1.63-1.58(m,4H),1.58-1.54(m,2H),1.54-1.47(m,1H),1.39(s,3H),1.36-1.19(m, 3H),1.18-1.04(m,2H),0.98(s,3H),0.95(s,3H),0.91(d,J＝6.8Hz,3H)；13C NMR(101MHz,CDCl3)171.06,164.99,162.49,153.26,134.41,133.08,130.54, 129.09,129.06,128.86,122.91,74.32,71.52,68.31,49.44,48.90,44.80,39.63,39.19, 37.10,36.49,36.10,35.55,32.29,30.33,30.02,29.05,28.84,25.86,24.17,23.12, 21.17,20.95,18.06,17.97, 16.07; high resolution mass spectrum HRMS (ESI): C38H52NaO7(643.3605) [M+Na]+643.3608. As can be seen from Table 1 below, the antimicrobial activity of the chemical modification of fusidic acid (FA-E-01) was higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 2 preparation of chemical modification of fusidic acid (FA-E-02)
First, 300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL round bottom flask containing magnetons, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, and after the mixture is completely dissolved under the conditions of room temperature and nitrogen protection and stirred for about 15min, 0.94mL (1.161mmol) of pyridine is added by a syringe and the mixture is stirred into the flaskStirring for about 20min at room temperature under nitrogen, finally adding 0.23mL (1.743mmol) of p-methylbenzoyl chloride in an amount which is three times that of the p-methylbenzoyl chloride, and stirring for reaction for 2h at room temperature under nitrogen protection. Detecting the reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-02, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain crude product of compound FA-E-02, the molecular structural formula of which is shown in figure 2, white solid, Rf0.42 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 78 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 92-93 ℃;1H NMR(400MHz, Chloroform-d)NMR(400MJ＝8.2Hz,2H),7.27(d,J＝8.3Hz,2H),5.86(d,J＝ 8.4Hz,1H),5.19-5.09(m,1H),4.38(q,J＝2.6Hz,1H),3.75(q,J＝2.7Hz,1H), 3.13(dd,J＝12.5,3.2Hz,1H),2.63-2.49(m,2H),2.43(s,3H),2.34(s,1H), 2.32-2.09(m,5H),2.03(s,4H),1.94-1.80(m,2H),1.79-1.70(m,2H),1.69-1.65 (m,3H),1.64-1.55(m,6H),1.54-1.48(m,1H),1.40(s,3H),1.36-1.25(m,2H), 1.19-1.05(m,2H),0.99(s,3H),0.95(s,3H),0.92(d,J＝6.8Hz,3H)；13C NMR (101MHz,CDCl3) z, CDCl1MHz, CDCl (s,3H),0.95(s,3H),0.92(d, 129.09,129.06,128.86,122.91,74.32,71.52,68.31,49.44,48.90,44.80,39.63,39.19, 37.10,36.49,36.10,35.55,32.29,30.33,30.02,29.05,28.84,25.86,24.17,23.12, 21.17,20.95,18.06,17.97, 98,17.95, 16.06. High resolution mass spectrum HRMS (ESI): C39H54NaO7 (657.3762)[M+Na]+657.3767. As can be seen from Table 1 below, the antimicrobial activity of the chemical modification of fusidic acid (FA-E-02) against Staphylococcus aureus is higher than that of the parent fusidic acid.
EXAMPLE 3 preparation of chemical modification of fusidic acid (FA-E-03)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are first weighed into a 50mL magneton-containing round-bottomed flask under nitrogenUnder the protection condition, 10mL of ultra-dry anhydrous dichloromethane is measured into a flask, the mixture is stirred for about 15min under the room temperature and nitrogen protection condition until the mixture is completely dissolved, 0.94mL (1.161mmol) of pyridine is added by a syringe, the mixture is stirred for about 20min under the room temperature and nitrogen protection condition, finally, 0.23mL (1.743mmol) of m-methylbenzoyl chloride which is three times the amount of the mixture is added, and the mixture is stirred and reacted for 2h under the room temperature and nitrogen protection condition. Detecting the reaction endpoint by TLC (developer: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), after the reaction is finished, washing, extracting and drying to obtain a crude product of the compound FA-E-03, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain the compound FA-E-03, wherein the molecular structural formula is shown in figure 3, the white solid is shown, and Rf is 0.42 (developer: dichloromethane: ethyl acetate: 3: 1), and the yield is as follows: 71 percent. And carrying out structural identification through nuclear magnetic resonance 1H NMR, 13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 88 to 89 ℃; 1H NMR (400MHz, Chloroform-d)7.81(d, J ═ 9.0Hz,2H),7.42(d, J ═ 7.6Hz,1H),7.35(t, J ═ 7.6Hz,1H), 5.85(d, J ═ 8.4Hz,1H),5.18-5.08(m,1H),4.37(q, J ═ 2.6Hz,1H),3.74(d, J ═ 2.7Hz,1H),3.12(dd, J ═ 12.4,3.2Hz,1H),2.55(dt, J ═ 14.7,7.1Hz,2H),2.40 (s,3H),2.35(d, J ═ 13.2Hz,1H),2.30-2.07 (m), 2.91.7 (m), 3.1.1H), 3.54-54 (m), 3.3.35 (d, J ═ 13.2.2H, 1H, 3.3.3.3.3H, 3.3.3.3H, 3.3.3.3.3.3H, 3.3.3H, 3.3.3.3.3H, 3H, 1H, 3.3.3.3.3.3.3.3.3.3H, 1H, 3, 3H) 1.32(d, J ═ 14.3Hz,1H),1.12(tq, J ═ 11.4,5.6Hz, 2H),0.98(s,3H),0.94(s,3H),0.91(d, J ═ 6.7Hz, 3H); 13C NMR (101MHz, CDCl3)171.09,165.10,162.65,153.15,138.75,135.24,133.04,131.03,129.07, 128.97,128.73,127.70,122.93,74.31,71.52,68.30,49.43,48.86,44.78,39.61,39.17, 37.05,36.50,36.04,35.53,32.22,30.29,29.99,29.06,28.84,25.85,24.12,23.15, 21.36,21.18,20.96,18.03,17.97, 16.07. High resolution mass spectrum HRMS (ESI): C39H54NaO7 (657.3762)[M+Na]And 657.3773. It can be seen from table 1 below that the chemical modification of fusidic acid (FA-E-03) has higher antibacterial activity against staphylococcus aureus and staphylococcus albus than the parent fusidic acid.
EXAMPLE 4 preparation of chemical modification of fusidic acid (FA-E-04)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 0.23mL (1.743mmol) of three-fold amount of o-methylbenzoyl chloride is added, and the reaction is stirred for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-04, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-04 with molecular structural formula shown in figure 4, white solid, and Rf0.43 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 73 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 84-85 ℃;1H NMR(400MHz, Chloroform-d)7.93-7.85(m,1H),7.48(td,J＝7.5,1.5Hz,1H),7.33-7.27(m, 2H),5.88(d,J＝8.3Hz,1H),5.19-5.09(m,1H),4.39(d,J＝2.5Hz,1H),3.76(q, J＝2.7Hz,1H),3.13(dd,J＝12.5,3.2Hz,1H),2.65(s,3H),2.62-2.49(m,2H), 2.37(dt,J＝13.3,3.4Hz,1H),2.20(ddtd,J＝30.0,16.8,12.8,11.1,6.0Hz,5H), 2.05(s,3H),1.90(td,J＝12.8,3.0Hz,4H),1.78(s,2H),1.68(s,3H),1.60(d,J＝ 8.8Hz,6H),1.53(dt,J＝12.2,3.6Hz,1H),1.40(s,3H),1.37-1.26(m,2H),1.15 (tq,J＝12.1,5.6Hz,2H),1.00(s,3H),0.97(s,3H),0.93(d,J＝6.7Hz,3H)；13C NMR(101MHz,CDCl3)171.09,165.31,162.52,152.98,142.62,133.56,133.03, 132.24,131.36,129.19,127.89,126.07,122.94,74.31,71.51,68.33,49.43,48.88, 44.78,39.62,39.22,37.12,36.46,36.14,35.58,32.33,30.35,30.04,29.02,28.82, 25.85,24.19,23.07,21.99,21.28,20.94,18.07,17.96,16.07. High resolution mass spectrum HRMS (ESI): C39H54NaO7(657.3762)[M+Na]+657.3764. As can be seen from Table 1 below, the chemical modification of fusidic acid (FA-E-04) has higher antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis than the parent fusidic acid.
EXAMPLE 5 preparation of chemical modification of fusidic acid (FA-E-05)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.743mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally, 0.26mL (1.743mmol) of three times of p-ethylbenzoyl chloride is added, and the reaction is stirred for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-05, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-05 with molecular structural formula shown in figure 5, white solid, and Rf0.45 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 75 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 84-85 ℃;1H NMR(400MHz, Chloroform-d)7.92(d,J＝8.2Hz,2H),7.28(d,J＝8.1Hz,2H),5.85(d,J＝8.4 Hz,1H),5.18-5.07(m,1H),4.37(q,J＝2.6Hz,1H),3.74(q,J＝2.7Hz,1H),2.71 (q,J＝7.6Hz,2H),2.55(dt,J＝14.3,7.1Hz,2H),2.35(dt,J＝13.1,3.2Hz,1H), 2.30-2.07(m,5H),2.02(s,3H),1.96-1.80(m,4H),1.73(ddd,J＝15.3,8.0,4.5Hz, 2H),1.66(s,3H),1.63-1.54(m,6H),1.54-1.47(m,1H),1.38(s,3H),1.32(d,J＝ 14.3Hz,1H),1.25(t,J＝7.6Hz,4H),1.12(tq,J＝11.6,5.6Hz,2H),0.98(s,3H), 0.94(s,3H),0.91(d,J＝6.8Hz,3H)；13C NMR(101MHz,CDCl3)171.08,165.20, 162.52,152.92,151.60,133.03,130.75,129.18,128.42,126.51,122.96,74.32,71.51, 68.32,49.44,48.88,44.74,39.62,39.19,37.09,36.49,36.11,35.56,32.29,30.33, 30.03,29.19,29.07,28.83,25.86,24.16,23.11,21.18,20.96,18.05,17.98,16.07, 15.20; high resolution mass spectrum HRMS (ESI): C40H56NaO7(671.3918)[M+Na]+671.3923. It can be seen from table 1 below that the chemical modification of fusidic acid (FA-E-05) has higher antibacterial activity against staphylococcus aureus and staphylococcus albus than the parent fusidic acid.
EXAMPLE 6 preparation of chemical modification of fusidic acid (FA-E-06)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.743mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally, three times of p-tert-butylbenzoyl chloride (1.743mmol) is added, and the reaction is stirred for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-06, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-06 with molecular structural formula shown in figure 6, white solid, Rf0.45 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 67%. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 100-101 ℃;1H NMR(400MHz, Chloroform-d)7.94(d,J＝8.2Hz,2H),7.47(d,J＝8.2Hz,2H),5.86(d,J＝8.4 Hz,1H),5.13(t,J＝7.3Hz,1H),4.41-4.30(m,1H),3.74(q,J＝2.6Hz,1H), 3.16-3.05(m,1H),2.54(h,J＝7.0Hz,2H),2.35(dt,J＝13.1,3.2Hz,1H), 2.29-2.08(m,6H),2.02(s,4H),1.93-1.79(m,2H),1.78-1.69(m,2H),1.66(s,3H), 1.58(d,J＝10.0Hz,6H),1.51(dt,J＝11.3,3.2Hz,1H),1.38(s,3H),1.36-1.24(m, 11H),1.12(tq,J＝11.5,5.9Hz,2H),0.98(s,3H),0.94(s,3H),0.91(d,J＝6.7Hz, 3H)；13C NMR(101MHz,CDCl3)171.10,165.23,162.49,158.37,152.86,133.01, 130.50,129.20,126.24,125.88,122.97,74.33,71.52,68.31,49.45,48.88,44.73, 39.62,39.19,37.09,36.50,36.10,35.56,35.38,32.28,31.16,30.33,30.03,29.08, 28.83,25.87,24.15,23.12,21.18,20.96,18.04,17.98,16.07. High resolution mass spectrum HRMS (ESI): C39H54NaO7(699.4231)[M+Na]+699.4232. From the data in Table 1 below, it can be seen that the chemical modification of fusidic acid (FA-E-06) is more active against Staphylococcus aureus and Staphylococcus albus than the parent fusidic acid against Staphylococcus aureus and Staphylococcus albus.
EXAMPLE 7 preparation of chemical modification of fusidic acid (FA-E-07)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.743mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally, 0.29mL (1.743mmol) of 2,4, 6-trimethylbenzoyl chloride in three times is added, and the reaction is carried out for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-07, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-07 with molecular structural formula shown in figure 7, white solid, and Rf0.49 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 68 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting Point：90-91℃；1H NMR(400MHz, Chloroform-d)6.85(s,2H),5.13-4.99(m,1H),4.34(q,J＝2.6Hz,1H),3.74(t,J ＝2.8Hz,1H),3.06(dd,J＝12.6,3.2Hz,1H),2.48(dt,J＝14.2,7.0Hz,2H),2.37 (s,6H),2.28(s,4H),2.24-2.05(m,5H),2.02(s,3H),1.85(td,J＝12.9,3.0Hz, 2H),1.79-1.67(m,4H),1.63(s,3H),1.49(dd,J＝12.2,3.7Hz,1H),1.36(s,3H), 1.35-1.24(m,2H),1.11(tq,J＝13.2,7.9,6.8Hz,2H),0.97(s,3H),0.91(d,J＝6.2 Hz,6H)；13C NMR(101MHz,CDCl3)171.02,165.48,164.96,153.33,140.83, 136.70,133.03,129.03,128.95,122.82,74.29,71.50,68.32,49.35,48.85,44.79, 39.58,39.18,37.16,36.38,36.22,35.53,32.44,30.39,30.04,28.95,28.74,25.81, 24.28,22.97,21.33,21.24,20.89,20.27,18.08,17.86, 16.07; high resolution mass spectrum HRMS (ESI): C41H58NaO7(685.4075)[M+Na]+685.4071. From the data in Table 1 below, it can be seen that the antimicrobial activity of the chemical modification of fusidic acid (FA-E-07) against three staphylococci is lower than that of the parent fusidic acid.
EXAMPLE 8 preparation of chemical modification of fusidic acid (FA-E-08)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 0.25mL (1.743mmol) of three-fold 4-chloromethylbenzoyl chloride is added, and the reaction is stirred for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-08 after reaction, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-08, the molecular structural formula of which is shown in figure 8, white solid, Rf0.43 (developing solvent: dichloromethane: ethyl acetate)Ester 3: 1) yield, yield: and 63 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 84-85 ℃;1H NMR(400MHz, Chloroform-d)8.01(d,J＝8.1Hz,2H),7.49(d,J＝8.0Hz,2H),5.85(d,J＝8.4 Hz,1H),5.12(t,J＝7.3Hz,1H),4.61(s,2H),4.37(q,J＝2.6Hz,1H),3.75(q,J＝ 2.7Hz,1H),3.18-3.03(m,1H),2.55(dp,J＝16.1,7.5Hz,2H),2.35(dt,J＝13.2, 3.2Hz,1H),2.31-2.08(m,5H),2.02(s,3H),1.94-1.72(m,6H),1.66(s,3H),1.57 (s,5H),1.51(d,J＝12.4Hz,1H),1.38(s,3H),1.28(d,J＝18.1Hz,2H),1.13(ddt, J＝17.7,12.1,5.8Hz,2H),0.98(s,3H),0.95(s,3H),0.91(d,J＝6.7Hz,3H)；13C NMR(101MHz,CDCl3)171.06,164.84,161.99,153.48,143.83,133.14,130.95, 129.00,128.94,122.87,74.32,71.50,68.33,49.41,48.92,45.26,44.85,39.63,39.21, 37.17,36.41,36.21,35.54,32.42,30.40,30.05,29.08,28.83,25.88,24.29,23.01, 21.18,20.90,18.11,18.00, 16.07; high resolution mass spectrum HRMS (ESI): C39H53ClNaO7 (671.3918)[M+Na]+671.3923. From the data in Table 1 below, it can be seen that the antimicrobial activity of the chemical modification of fusidic acid (FA-E-08) is higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 9 preparation of chemical modification of fusidic acid (FA-E-09)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally, 0.24mL (1.743mmol) of p-methoxybenzoyl chloride in three times is added, and the reaction is stirred for 2h under the protection of nitrogen at room temperature. Detecting the reaction end point by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain the crude product of the compound FA-E-09Purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate ═ 6: 1) to obtain compound FA-E-09 with molecular structure formula shown in figure 9, white solid, and Rf0.42 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 78 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 91-92 ℃;1H NMR(400MHz, Chloroform-d)7.99-7.91(m,2H),6.99-6.86(m,2H),5.84(d,J＝8.4Hz,1H), 5.18-5.06(m,1H),4.36(q,J＝2.7Hz,1H),3.86(s,3H),3.74(q,J＝2.7Hz,1H), 3.11(dd,J＝12.4,3.3Hz,1H),2.54(q,J＝7.7,7.1Hz,2H),2.35(dt,J＝13.0,3.1 Hz,1H),2.30-2.24(m,1H),2.23-2.14(m,4H),2.12(d,J＝5.2Hz,1H),2.01(s, 3H),1.86(qd,J＝14.2,13.4,6.3Hz,2H),1.74(dd,J＝11.4,5.5Hz,2H),1.65(s, 3H),1.55(s,5H),1.53-1.47(m,1H),1.38(s,3H),1.35-1.23(m,2H),1.20(t,J＝ 7.0Hz,1H),1.12(ddt,J＝16.0,10.9,5.5Hz,2H),0.97(s,3H),0.94(s,3H),0.90 (d,J＝6.8Hz,3H)；13C NMR(101MHz,CDCl3)171.12,165.33,164.61,162.11, 152.68,132.99,132.84,129.21,122.96,121.28,114.18,74.31,71.53,68.29,55.67, 49.44,48.85,44.70,39.60,39.16,37.03,36.52,36.01,35.54,32.17,30.27,29.98, 29.07,28.84,25.86,24.06,23.18,21.18,20.98,17.99,17.97, 16.06; high resolution mass spectrum HRMS (ESI): C39H54NaO8(673.3711)[M+Na]+673.3709. From the data in Table 1 below, it can be seen that the antimicrobial activity of the chemical modification of fusidic acid (FA-E-09) is higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 10 preparation of chemical modification of fusidic acid (FA-E-10)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL round bottom flask containing magnetons, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, 0.24mL (1.743) of m-methoxybenzoyl chloride is added under the protection of nitrogen for about 20min, and finally three times of m-methoxybenzoyl chloride is addedmmol) and stirring the mixture for reaction for 2 hours at room temperature under the protection of nitrogen. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-10, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-10 with molecular structural formula shown in figure 10, white solid, and Rf0.36 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 74 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 81-82 ℃;1H NMR(400MHz, Chloroform-d)7.60(d,J＝7.7Hz,1H),7.36(t,J＝8.0Hz,1H),7.15(dd,J＝8.2, 2.6Hz,1H),5.85(d,J＝8.4Hz,1H),5.12(t,J＝7.3Hz,1H),4.36(q,J＝2.6Hz, 1H),3.85(s,3H),3.74(q,J＝2.7Hz,1H),3.11(dd,J＝12.3,3.2Hz,1H),2.54(q, J＝8.7,8.2Hz,2H),2.35(dt,J＝13.1,3.2Hz,1H),2.30-2.24(m,1H),2.24-2.07 (m,5H),2.02(s,4H),1.87(qd,J＝14.4,13.5,6.4Hz,2H),1.78-1.69(m,2H),1.65 (s,3H),1.55(d,J＝2.9Hz,6H),1.50(dt,J＝12.6,3.5Hz,1H),1.38(s,3H),1.32 (d,J＝14.3Hz,1H),1.18-1.04(m,2H),0.98(s,3H),0.94(s,3H),0.91(d,J＝6.7 Hz,3H)；13C NMR(101MHz,CDCl3)171.05,164.98,162.43,159.89,153.27, 133.10,130.31,129.85,129.02,122.92,122.89,121.06,114.81,74.31,71.52,68.30, 55.64,49.43,48.89,44.79,39.62,39.17,37.08,36.49,36.08,35.54,32.26,30.32, 30.01,29.06,28.83,25.85,24.15,23.12,21.16,20.95,18.04,17.97, 16.06; high resolution mass spectrum HRMS (ESI): C39H54NaO8(673.3711)[M+Na]+673.3720. As can be derived from the data in Table 1 below, the antimicrobial activity of the chemical modification of fusidic acid (FA-E-10) was higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 11 preparation of chemical modification of fusidic acid (FA-E-11)
First 300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) were weighed into a 50mL magneton-containing round-bottomed flaskUnder the protection of nitrogen, 10mL of ultra-dry anhydrous dichloromethane is measured into a flask, the mixture is stirred for about 15min under the conditions of room temperature and nitrogen protection until the mixture is completely dissolved, 0.94mL (1.161mmol) of pyridine is added by a syringe, the mixture is stirred for about 20min under the conditions of room temperature and nitrogen, finally 0.26mL (1.743mmol) of three times of o-methoxybenzoyl chloride is added, and the mixture is stirred and reacted for 2h under the conditions of room temperature and nitrogen protection. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-11, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-11 with molecular structural formula shown in figure 11, white solid, and Rf0.40 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 71 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 82-83 ℃;1H NMR(400MHz, Chloroform-d)7.81(dd,J＝7.9,1.7Hz,1H),7.53(td,J＝7.9,1.9Hz,1H),6.98(t, J＝7.8Hz,2H),5.86(d,J＝8.3Hz,1H),5.12(t,J＝7.4Hz,1H),4.35(p,J＝4.7, 3.7Hz,1H),3.88(s,3H),3.75(q,J＝2.7Hz,1H),3.09(dd,J＝12.4,3.2Hz,1H), 2.53(t,J＝8.0Hz,2H),2.35(dt,J＝13.1,3.2Hz,1H),2.31-2.24(m,1H), 2.24-2.06(m,5H),2.03(s,3H),1.86(qd,J＝14.5,13.5,3.1Hz,2H),1.79-1.69(m, 2H),1.66(s,3H),1.57(d,J＝7.2Hz,5H),1.54-1.47(m,1H),1.37(s,3H), 1.36-1.25(m,2H),1.11(dp,J＝19.9,7.5,6.6Hz,2H),0.97(s,3H),0.95-0.88(m, 6H)；13C NMR(101MHz,CDCl3)171.13,165.12,161.50,160.37,153.06,135.33, 132.87,129.21,123.11,120.37,118.47,112.26,74.27,71.50,68.37,56.05,49.37, 48.88,44.77,39.60,39.19,37.15,36.39,36.22,35.59,32.43,30.38,30.05,28.97, 28.86,25.85,24.27,22.98,21.22,20.90,18.10,17.96, 16.07; high resolution mass spectrum HRMS (ESI): C40H57NNaO7(686.4027)[M+Na]+686.4033. As can be seen from the data in Table 1 below, the antibacterial activity of the chemical modification of fusidic acid (FA-E-11) against three staphylococci is higher than that of fusidic motherAntibacterial activity against three staphylococci.
EXAMPLE 12 preparation of chemical modification of fusidic acid (FA-E-12)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 0.28mL (1.743mmol) of 2, 4-dimethoxybenzoyl chloride in three times is added, and the reaction is carried out for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-12, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-12 with molecular structural formula shown in figure 12, white solid, and Rf0.38 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 75 percent. And by nuclear magnetic resonance1HNMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 85-86 ℃;1HNMR(400MHz,Chloroform-d) 7.82(d,J＝8.8Hz,1H),6.55-6.40(m,2H),5.86(t,J＝7.9Hz,1H),5.17-5.06 (m,1H),4.35(q,J＝2.7Hz,1H),3.86(d,J＝2.5Hz,6H),3.74(q,J＝2.7Hz,1H), 3.09(dd,J＝12.4,3.1Hz,1H),2.52(t,J＝8.1Hz,2H),2.35(dt,J＝13.6,3.6Hz, 1H),2.31-2.25(m,1H),2.24-2.06(m,5H),2.03(s,3H),1.94-1.79(m,3H),1.75 (dt,J＝10.3,6.2Hz,2H),1.66(s,3H),1.59(s,5H),1.54-1.47(m,1H),1.37(s, 3H),1.29(dd,J＝27.7,12.0Hz,2H),1.12(ddt,J＝18.2,12.3,5.5Hz,2H),0.97(d, J＝3.5Hz,3H),0.95-0.87(m,6H)；13C NMR(101MHz,CDCl3)171.21,165.84, 165.60,162.82,160.69,152.45,135.31,132.78,129.42,123.19,110.75,105.18, 98.98,74.26,71.51,68.38,56.05,55.74,49.37,48.85,44.68,39.59,39.18,37.13, 36.40,36.19,35.60,32.39,30.36,30.03,29.03,28.90,25.87,24.23,23.00,21.27, 20.92,18.07,17.99, 16.07; high resolution mass spectrum HRMS (ESI): C40H56NaO9(649.3169) [M+Na]+649.3170. From the data in Table 1 below, it can be seen that the chemical modification of fusidic acid (FA-E-12) has greater antibacterial activity against Staphylococcus aureus than the parent fusidic acid.
EXAMPLE 13 preparation of chemical modification of fusidic acid (FA-E-13)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally, 0.28mL (1.743mmol) of 3, 5-dimethoxybenzoyl chloride in three times is added, and the reaction is carried out for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-13, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-13 with molecular structural formula shown in figure 13, white solid, and Rf0.40 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 76 percent. And by nuclear magnetic resonance1HNMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 88 to 89 ℃;1HNMR(400MHz,Chloroform-d) 7.15(d,J＝2.3Hz,2H),6.69(t,J＝2.4Hz,1H),5.85(d,J＝8.4Hz,1H),5.12(t, J＝7.3Hz,1H),4.37(d,J＝2.5Hz,1H),3.83(s,6H),3.76(q,J＝2.7Hz,1H), 3.15-3.06(m,1H),2.63-2.44(m,2H),2.35(dt,J＝13.1,3.3Hz,1H),2.30-2.24(m, 1H),2.24-2.07(m,4H),2.03(s,3H),1.94-1.81(m,3H),1.75(dd,J＝10.4,4.1Hz, 2H),1.66(s,3H),1.57(s,5H),1.52(d,J＝12.1Hz,1H),1.39(s,3H),1.33(d,J＝ 14.3Hz,2H),1.12(ddt,J＝20.0,13.2,6.7Hz,2H),0.98(s,3H),0.96-0.89(m,6H)；13C NMR(101MHz,CDCl3)171.02,164.99,162.39,160.97,153.22,133.15, 130.83,129.06,122.88,108.11,107.13,74.30,71.50,68.36,55.79,49.39,48.92, 44.78,39.63,39.20,37.21,36.36,36.30,35.56,32.52,30.43,30.08,29.11,28.81, 25.85,24.36,22.94,21.17,20.89,18.13,17.99, 16.07; high resolution mass spectrum HRMS (ESI): C40H56NaO9(647.3554)[M+Na]+647.3556. As can be derived from the data in Table 1 below, the antimicrobial activity of the chemical modification of fusidic acid (FA-E-13) was higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 14 preparation of chemical modification of fusidic acid (FA-E-14)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 320mg (1.743mmol) of p-dimethylaminobenzoyl chloride in three times is added, and the reaction is carried out for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-14, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-14 with molecular structural formula shown in FIG. 14, white solid, and Rf0.35 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 70 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 105-106 ℃;1H NMR(400MHz, Chloroform-d)7.99-7.92(m,1H),7.89-7.81(m,1H),6.64(dd,J＝13.3,8.9Hz, 2H),5.87(dd,J＝16.1,8.4Hz,1H),5.12(dt,J＝15.1,7.4Hz,1H),4.36(p,J＝3.2, 2.8Hz,1H),3.75(d,J＝2.9Hz,1H),3.06(d,J＝1.8Hz,8H),2.59-2.43(m,2H), 2.34(td,J＝14.1,13.6,5.1Hz,1H),2.29-2.07(m,4H),2.03(s,2H),1.86(ddd,J＝ 16.9,12.0,3.0Hz,2H),1.76(dd,J＝11.6,6.2Hz,2H),1.67(s,3H),1.56(d,J＝3.1 Hz,5H),1.55-1.48(m,1H),1.38(d,J＝2.1Hz,3H),1.36-1.24(m,2H),1.11(dq,J ＝16.1,9.0Hz,2H),0.97(d,J＝3.1Hz,3H),0.95-0.87(m,6H)；13C NMR(101 MHz,CDCl3)171.22,166.04,162.63,154.29,151.57,132.87,132.76,132.15, 129.66,123.14,115.17,110.96,110.86,74.33,71.55,68.41,49.39,48.85,44.52, 40.22,40.15,39.61,39.20,37.16,36.40,36.26,35.60,32.45,30.39,30.05,29.15, 28.82,25.90,24.27,22.98,21.26,20.92,18.06,18.02, 16.07; high resolution mass spectrum HRMS (ESI): C40H57NNaO7(686.4027)[M+Na]+686.4033. From the data in Table 1 below, it can be seen that the chemical modification of fusidic acid (FA-E-14) has higher antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis than the parent fusidic acid.
EXAMPLE 15 preparation of chemical modification of fusidic acid (FA-E-15)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally three times of biphenyl 4-formyl chloride 377mg (1.743mmol) is added, and the reaction is carried out for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-15, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-15 with molecular structural formula shown in FIG. 15, white solid, and Rf0.44 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 78 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 90-91 ℃;1H NMR(400MHz,Chloroform-d)8.08 (d,J＝8.2Hz,2H),7.69(d,J＝8.1Hz,2H),7.62(d,J＝7.2Hz,2H),7.48(dd,J＝ 8.4,6.5Hz,2H),7.41(dd,J＝8.4,6.0Hz,1H),5.15(t,J＝7.3Hz,1H),4.38(q,J＝ 2.7Hz,1H),3.76(q,J＝2.7Hz,1H),2.57(tq,J＝14.1,7.2,6.8Hz,2H),2.37(dt,J ＝13.9,3.6Hz,1H),2.29(dd,J＝13.8,5.4Hz,1H),2.26-2.08(m,4H),2.05(s,3H), 1.95-1.81(m,2H),1.80-1.70(m,4H),1.68(s,3H),1.64-1.57(m,6H),1.52(dd,J＝ 12.3,3.6Hz,1H),1.40(s,3H),1.34(d,J＝14.3Hz,1H),1.19-1.06(m,2H),0.99 (s,3H),0.96(s,3H),0.92(d,J＝6.7Hz,3H)；13C NMR(101MHz,CDCl3) 171.11,165.08,162.40,153.16,147.20,139.77,133.12,131.11,129.16,129.13, 128.60,127.72,127.54,127.47,122.94,74.35,71.50,68.36,49.40,48.93,44.81, 39.63,39.23,37.19,36.38,36.26,35.57,32.49,30.42,30.07,29.12,28.85,25.90, 24.34,22.98,21.23,20.90,18.13,18.03, 16.08; high resolution mass spectrum HRMS (ESI): C44H56NaO7(719.3918)[M+Na]+719.3920. From the data in Table 1 below, it can be seen that the antimicrobial activity of the chemical modification of fusidic acid (FA-E-15) is higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 16 preparation of chemical modification of fusidic acid (FA-E-16)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL round bottom flask containing magnetons, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 0.24mL (1.743mmol) of benzothiophene-2-carbonyl chloride in three times is added, and the reaction is carried out for 2h under the protection of nitrogen at room temperature. Detecting the end point of the reaction by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying after the reaction is finished to obtain the compound FA-E-16The crude product was purified by silica gel column chromatography (eluent: dichloromethane: ethyl acetate ═ 6: 1) to give compound FA-E-16, whose molecular structure is shown in fig. 16, as a white solid, Rf0.37 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 68 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 101-102 ℃;1H NMR(400MHz, Chloroform-d)8.11(s,1H),7.89(dd,J＝12.8,8.0Hz,2H),7.52-7.46(m,1H), 7.43(t,J＝7.5Hz,1H),5.90(d,J＝8.4Hz,1H),4.38(q,J＝2.6Hz,1H),3.75(q,J ＝2.7Hz,1H),3.14(dd,J＝12.5,3.2Hz,1H),2.58(dt,J＝15.2,7.3Hz,2H),2.37 (dt,J＝13.4,3.3Hz,1H),2.33-2.27(m,1H),2.17(dtd,J＝34.9,12.7,11.2,5.3Hz, 4H),2.04(s,5H),1.95-1.81(m,2H),1.80-1.71(m,2H),1.68(s,3H),1.59(d,J＝ 7.3Hz,5H),1.52(dt,J＝10.1,2.7Hz,1H),1.40(s,3H),1.32(s,1H),1.13(ddt,J ＝17.8,12.1,5.6Hz,2H),0.98(s,3H),0.95(s,3H),0.92(d,J＝6.7Hz,3H)；13C NMR(101MHz,CDCl3)171.07,164.23,158.29,153.85,143.23,138.62,133.19, 133.01,132.36,128.71,127.94,126.19,125.38,122.99,122.89,74.36,71.53,68.32, 49.42,48.93,44.88,39.63,39.19,37.13,36.44,36.16,35.54,32.35,30.37,30.02, 29.05,28.85,25.90,24.24,23.07,21.18,20.93,18.10,18.05, 16.07; high resolution mass spectrum HRMS (ESI): C40H52NaO7S(699.3326)[M+Na]+699.3329. As can be derived from the data in Table 1 below, the antimicrobial activity of the chemical modification of fusidic acid (FA-E-16) was higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 17 preparation of chemical modification of fusidic acid (FA-E-17)
Firstly, 300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL round-bottom flask containing magnetons, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, after the mixture is completely dissolved under the conditions of room temperature and nitrogen protection, 0.94mL (1.161mmol) of pyridine is added by a syringe, the mixture is stirred for about 20min under the conditions of room temperature and nitrogen, and finally, three times of 2-thiophenecarbonyl chloride is added0.19mL (1.743mmol) was stirred at room temperature under nitrogen for 2 h. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-17, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-17 with molecular structural formula shown in FIG. 17, white solid, and Rf0.39 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 73 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 85-86 ℃;1H NMR(400MHz,Chloroform-d) 7.88-7.81(m,1H),7.68(d,J＝4.9Hz,1H),7.14(t,J＝4.4Hz,1H),5.85(d,J＝8.5 Hz,1H),5.13(t,J＝7.3Hz,1H),4.42-4.29(m,1H),3.79-3.68(m,1H),3.11(dd,J ＝12.6,3.2Hz,1H),2.54(q,J＝8.5,8.0Hz,2H),2.34(dt,J＝13.1,3.2Hz,1H), 2.29-2.21(m,2H),2.14(qd,J＝16.2,15.0,8.3Hz,5H),2.03(s,3H),1.86(qd,J＝ 15.3,13.9,3.2Hz,2H),1.74(dd,J＝11.2,5.1Hz,2H),1.66(s,3H),1.57(s,5H), 1.51(dt,J＝12.5,3.4Hz,1H),1.38(s,3H),1.32(d,J＝14.3Hz,1H),1.12(tq,J＝ 11.7,5.5Hz,2H),0.98(s,3H),0.95-0.89(m,6H)；13C NMR(101MHz,CDCl3)171.08,164.51,157.49,153.39,135.80,135.10,133.09,132.67,128.78,128.48, 122.90,74.32,71.53,68.30,49.42,48.88,44.79,39.60,39.16,37.08,36.48,36.10, 35.52,32.28,30.32,30.00,29.03,28.80,25.87,24.17,23.12,21.16,20.95,18.04, 18.01, 16.07; high resolution mass spectrum HRMS (ESI): C36H50NaO7S(649.3169)[M+Na]+649.3170. From the data in Table 1 below, it can be seen that the antimicrobial activity of the chemical modification of fusidic acid (FA-E-17) is higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 18 preparation of chemical modification of fusidic acid (FA-E-18)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are first weighed into a 50mL magneton-containing round-bottomed flask under nitrogen protectionThen, 10mL of ultra-dry anhydrous dichloromethane was taken into the flask, stirred for about 15min under the conditions of room temperature and nitrogen protection until the anhydrous dichloromethane was completely dissolved, 0.94mL (1.161mmol) of pyridine was added by a syringe, stirred for about 20min under the conditions of room temperature and nitrogen protection, and finally 0.20mL (1.743mmol) of three times of 5-chloro-2-thiophenecarbonyl chloride was added, and stirred for reaction for 2h under the conditions of room temperature and nitrogen protection. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-18, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-18 with molecular structural formula shown in FIG. 18, white solid, and Rf0.46 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 80 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 85-86 ℃;1H NMR(400MHz, Chloroform-d)7.63(dd,J＝11.3,4.1Hz,1H),6.96(dd,J＝12.7,4.1Hz,1H), 5.83(d,J＝8.4Hz,1H),5.18-5.05(m,1H),4.37(q,J＝2.7Hz,1H),3.76(q,J＝ 2.7Hz,1H),3.11(dd,J＝12.5,3.2Hz,1H),2.61-2.44(m,2H),2.34(dt,J＝13.0, 3.3Hz,1H),2.28-2.22(m,2H),2.21-2.07(m,5H),2.02(s,3H),1.93-1.80(m,2H), 1.74(dt,J＝16.4,6.2Hz,2H),1.67(s,3H),1.57(d,J＝6.8Hz,5H),1.54-1.48(m, 1H),1.39(s,3H),1.32(d,J＝14.4Hz,1H),1.13(tq,J＝12.0,5.5Hz,2H),0.98(s, 3H),0.95-0.88(m,6H)；13C NMR(101MHz,CDCl3)171.06,164.12,156.49, 153.84,140.31,135.42,133.22,130.76,128.59,128.09,122.80,74.31,71.54,68.31, 49.39,48.91,44.88,39.61,39.18,37.14,36.41,36.19,35.50,32.38,30.37,30.01, 29.02,28.78,25.89,24.26,23.04,21.16,20.91,18.08,18.03, 16.07; high resolution mass spectrum HRMS (ESI): C36H49ClNaO7S(683.2780)[M+Na]+683.2784. As can be derived from the data in Table 1 below, the antimicrobial activity of the chemical modification of fusidic acid (FA-E-18) was higher for three staphylococci than for the parent fusidic acid.
EXAMPLE 19 preparation of chemical modification of fusidic acid (FA-E-19)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 0.17mL (1.743mmol) of three-fold 2-furoyl chloride is added, and the reaction is stirred for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-19, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-19 with molecular structural formula shown in FIG. 19, white solid, and Rf0.43 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 76 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 77-78 ℃;1H NMR(400MHz,Chloroform-d) 7.67-7.61(m,1H),7.29(d,J＝3.6Hz,1H),6.58-6.53(m,1H),5.84(d,J＝8.4Hz, 1H),5.12(t,J＝7.4Hz,1H),4.37(q,J＝2.7Hz,1H),3.75(q,J＝2.7Hz,1H), 3.11(dd,J＝12.5,3.2Hz,1H),2.53(dh,J＝14.0,7.1Hz,4H),2.34(dt,J＝13.2, 3.2Hz,1H),2.29-2.07(m,5H),2.02(s,3H),1.93-1.80(m,2H),1.75(dd,J＝11.2, 5.1Hz,2H),1.66(s,3H),1.58(d,J＝14.9Hz,5H),1.54-1.47(m,1H),1.38(s, 3H),1.32(d,J＝14.4Hz,1H),1.13(tq,J＝11.9,5.5Hz,2H),0.98(s,3H), 0.95-0.89(m,6H)；13C NMR(101MHz,CDCl3)171.11,164.59,153.76,153.51, 148.31,143.60,133.10,128.69,122.91,121.27,112.66,74.33,71.57,68.31,49.41, 48.88,44.81,39.61,39.15,37.10,36.45,36.14,35.51,32.31,30.34,29.99,29.06, 28.78,25.86,24.19,23.09,21.13,20.94,18.05,17.95,16.06；HRMS(ESI): C36H50NaO8(633.3398)[M+Na]+633.3401. As can be seen from the data in Table 1 below, thisThe chemical modification of fusidic acid (FA-E-19) has higher antibacterial activity against Staphylococcus aureus than the parent fusidic acid.
EXAMPLE 20 preparation of chemical modification of fusidic acid (FA-E-20)
300mg (0.581mmol) of fusidic acid and 142mg (1.161mmol) of 4-Dimethylaminopyridine (DMAP) are weighed into a 50mL magneton-containing round-bottom flask, 10mL of ultra-dry anhydrous dichloromethane is weighed into the flask under the protection of nitrogen, 0.94mL (1.161mmol) of pyridine is added by a syringe after the complete dissolution under the protection of nitrogen at room temperature, the stirring is carried out for about 20min under the protection of nitrogen, finally 0.20mL (1.743mmol) of three times of 5-methyl-2-furoyl chloride is added, and the reaction is carried out for 2h under the protection of nitrogen at room temperature. Detecting reaction endpoint by TLC (developing agent: dichloromethane: ethyl acetate: 3: 1, developer: methanol: acetic acid: concentrated sulfuric acid: anisaldehyde (volume ratio): 85: 10: 5: 0.5), washing, extracting and drying to obtain crude product of compound FA-E-20, purifying by silica gel column chromatography (eluent: dichloromethane: ethyl acetate: 6: 1) to obtain compound FA-E-20 with molecular structural formula shown in figure 20, white solid, and Rf0.38 (developing solvent: dichloromethane: ethyl acetate: 3: 1), yield: 89 percent. And by nuclear magnetic resonance1H NMR、13C NMR analysis, high-resolution mass spectrum, melting point and the like. Melting point: 93-94 ℃;1H NMR(400MHz,Chloroform-d)7.18(d,J ＝3.5Hz,1H),6.17(d,J＝3.4Hz,1H),5.82(d,J＝8.4Hz,1H),5.16-5.07(m,1H), 4.36(q,J＝2.6Hz,1H),3.74(q,J＝2.7Hz,1H),3.09(dd,J＝12.5,3.2Hz,1H), 2.59-2.44(m,2H),2.39(s,3H),2.33(dt,J＝13.0,3.2Hz,1H),2.28-2.06(m,5H), 2.02(s,3H),1.94(s,2H),1.91-1.79(m,2H),1.78-1.69(m,2H),1.66(s,3H),1.56(t, J＝3.6Hz,5H),1.50(dt,J＝12.1,3.5Hz,1H),1.38(s,3H),1.32(d,J＝14.3Hz, 1H),1.12(ddt,J＝16.4,11.2,5.5Hz,2H),0.97(s,3H),0.94-0.86(m,6H)；13C NMR (101MHz,CDCl3)171.13,164.98,159.96,153.71,153.01,141.97,133.01,128.80, 123.11,122.96,109.46,74.29,71.52,68.30,49.41,48.85,44.72,39.60,39.14,37.07, 36.48,36.08,35.53,32.25,30.31,30.00,29.06,28.74,25.86,24.14,23.12,21.15,20.95, 18.01,17.97,16.07, 14.28; high resolution mass spectrum HRMS (ESI): C37H52NaO8(647.3554) [M+Na]+647.3556. From the data in Table 1 below, it can be seen that the chemical modification of fusidic acid (FA-E-20) is more active against Staphylococcus aureus and Staphylococcus epidermidis than the parent fusidic acid.
Example 21
Experimental tests and results of minimum inhibitory concentration and minimum bactericidal concentration of fusidic acid and the ring-based substituted chemical modification of fusidic acid are shown in table 1 below. Wherein R is a mono-substituted or multi-substituted aromatic ring group, and specifically, R is an aromatic ring group containing a benzene ring and/or a thiophene ring, or an aromatic ring group containing a furan ring. The molecular structural formula of the chemical modification of fusidic acid is shown in figure 21.
Minimum inhibitory and bactericidal concentration test: in the experiment, the minimum inhibitory concentration and the minimum bactericidal concentration of the fusidic acid and the chemical modifier thereof are tested by a sterile 96-well plate; in the experiment, 10 gradients of diluted sample compounds are obtained by using a dimethyl sulfoxide (DMSO) solvent by a two-fold dilution method, then 5 mu L of sample is removed in a 96-well plate each time by using a pipette gun, and 5 mu L of dimethyl sulfoxide (DMSO) is taken in a micropore plate in a negative control group; configuring the concentration of 1.5 multiplied by 10 under the condition of 610nm wavelength by a multifunctional microplate reader5CFU/mL bacterial suspension provides activity test research, 195 μ L of bacterial suspension is taken in a 96-well plate by a discharge gun, wherein a blank control group is added with a pure liquid culture medium; finally, covering a prepared 96-well plate with a cover, placing the 96-well plate into a constant-temperature bacteria incubator at 37 ℃, after overnight culture, testing the absorbance of the 96-well plate by using a multifunctional microplate reader under the condition of a wavelength of 610nm, and respectively obtaining the minimum inhibitory concentration and the minimum bactericidal concentration of the compound after 24h and 48h intervals; and counting the size range values of the inhibition zones of the fusidic acid and three fusidic acid chemical modifiers containing thiophene rings of the fusidic acid, which are shown in the table 1.
TABLE 1 minimal inhibitory experiments on 5 bacteria by fusidic acid and chemical modifications of fusidic acid
Figure RE-GDA0001577361150000241
Figure RE-GDA0001577361150000251
Note: MIC (nmol/mL), minimum inhibitory concentration, minimum concentration capable of completely inhibiting bacterial growth; MBC (nmol/mL), minimum bactericidal concentration, minimum concentration capable of completely killing bacterial growth; ND, not detected; in the table, A is 0.1-1 nmol/mL, B is 1-3 nmol/mL, C is 3-5 nmol/mL, and D is not less than 5nmol/mL (maximum value in MIC & MBC). ATCC 6538: staphylococcus aureus bacteria; ATCC 29213: staphylococcus albus; ATCC 12228: staphylococcus epidermidis; CMCC 44102: e.coli; CMCC 50115: salmonella typhimurium.
Experimental determination and results of minimum inhibitory concentration and minimum bactericidal concentration prove that fusidic acid and a chemical modification compound containing cyclic group substitution shows excellent biological activity of an inhibitory zone on three gram-positive bacteria (staphylococcus aureus, staphylococcus albus and staphylococcus epidermidis), the bacteriostatic activity of the chemical modification compound of fusidic acid with partial aryl ring substitution on three staphylococci is equal to or higher than that of fusidic acid, but the action effect of fusidic acid and the chemical modification compound of fusidic acid on gram-negative bacteria is general.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations and simplifications are intended to be included in the scope of the present invention.

Claims (5)

1. A chemical modification of fusidic acid, wherein the chemical modification of fusidic acid is represented by the chemical formula 1:
Figure FDA0002568827330000011
wherein R is a mono-substituted or poly-substituted aromatic ring group; the aromatic ring group is an aromatic ring group containing a benzene ring and/or a thiophene ring, or an aromatic ring group containing a furan ring;
the molecular structural formula of the aromatic ring group containing benzene ring and/or thiophene ring is as follows:
Figure FDA0002568827330000012
the molecular structural formula of the aromatic ring group containing furan ring is as follows:
Figure FDA0002568827330000013
2. a process for the preparation of chemical modifications of fusidic acid as claimed in claim 1, characterised by the specific steps of:
s1, mixing fusidic acid and 4-dimethylaminopyridine, and introducing nitrogen to remove air;
s2, under the protection of nitrogen, adding anhydrous dichloromethane into the mixture obtained in the step S1, stirring until the anhydrous dichloromethane is completely dissolved, adding dried pyridine, stirring, adding cyclic formyl chloride, and carrying out esterification reaction for 2-3 hours;
s3, detecting the reaction end point by TLC, washing, extracting and drying after the reaction is finished to obtain a crude product of the fusidic acid chemical modifier, and purifying by silica gel column chromatography to obtain the fusidic acid chemical modifier.
3. A process for the preparation of chemical modifications of fusidic acid as claimed in claim 2, wherein the mass ratio of fusidic acid and 4-dimethylaminopyridine in step S1 is 1: (1-3).
4. A process for the preparation of chemical modifications of fusidic acid as claimed in claim 2, wherein the mass ratio of fusidic acid, 4-dimethylaminopyridine and pyridine in step S2 is 1: (1-3): (1-3), wherein the mass ratio of the fusidic acid to the cyclic formyl chloride is 1: (1-3), wherein the stirring time is 15-60 min.
5. Use of fusidic acid chemical modification according to claim 1 for the manufacture of a medicament for the prevention, inhibition, control and/or treatment of bacterial infections.
CN201711032579.XA 2017-10-30 2017-10-30 Fusidic acid chemical modifier and preparation method and application thereof Active CN107955057B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201711032579.XA CN107955057B (en) 2017-10-30 2017-10-30 Fusidic acid chemical modifier and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201711032579.XA CN107955057B (en) 2017-10-30 2017-10-30 Fusidic acid chemical modifier and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN107955057A CN107955057A (en) 2018-04-24
CN107955057B true CN107955057B (en) 2020-11-17

Family

ID=61964242

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711032579.XA Active CN107955057B (en) 2017-10-30 2017-10-30 Fusidic acid chemical modifier and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN107955057B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115505018B (en) * 2022-09-30 2023-10-24 烟台大学 Fusidic acid derivative with anti-inflammatory activity and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004004A (en) * 1974-09-12 1977-01-18 Leo Pharmaceutical Products Ltd. A/S Fusidic acid derivatives
US6103884A (en) * 1996-03-27 2000-08-15 The University Of Michigan Glycosylated analogs of fusidic acid
CN102140125A (en) * 2010-01-28 2011-08-03 北京润德康医药技术有限公司 Novel fusidic acid derivative, preparation method and medical application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004004A (en) * 1974-09-12 1977-01-18 Leo Pharmaceutical Products Ltd. A/S Fusidic acid derivatives
US6103884A (en) * 1996-03-27 2000-08-15 The University Of Michigan Glycosylated analogs of fusidic acid
CN102140125A (en) * 2010-01-28 2011-08-03 北京润德康医药技术有限公司 Novel fusidic acid derivative, preparation method and medical application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Synthesis and Conformational Analysis of Fusidic Acid Side Chain Derivatives in Relation to Antibacterial Activity;Tore Duvold 等;《Journal of Medicinal Chemistry》;20010821;第44卷(第19期);第3125-3131页 *

Also Published As

Publication number Publication date
CN107955057A (en) 2018-04-24

Similar Documents

Publication Publication Date Title
Jin et al. Synthesis and antimicrobial evaluation of L-phenylalanine-derived C5-substituted rhodanine and chalcone derivatives containing thiobarbituric acid or 2-thioxo-4-thiazolidinone
CN113666824B (en) Cannabidiol-2-propionate and application thereof
CN113735709B (en) Cannabidiol-2-butyrate and application thereof
JP6975487B2 (en) Crotyl alcohol casic acid ester with antibacterial activity and its preparation method
CN114230519A (en) Pleuromutilin cinnamate compounds with drug-resistant bacterium resisting activity and synthesis method and application thereof
CN107955057B (en) Fusidic acid chemical modifier and preparation method and application thereof
CN111410643B (en) Preparation and application of novel cinnamoyl ester catechin and four novel phenylpropanoid flavan alkaloids
CN114507158B (en) Pleuromutilin alpha-cyano cinnamic acid ester compounds with drug-resistant bacteria resisting activity and preparation method and application thereof
CN109206469B (en) Glycyrrhetinic acid derivative and preparation method and application thereof
EP0259496B1 (en) Derivatives of cervinomycin antibiotics and process for their preparation
US5990322A (en) Alpha-tocopherol cyclopropylates, the new vitamin E derivatives and method for producing the same
CN109111397B (en) Quinoline aromatic ethylene derivative and preparation method and application thereof
AU2006319748B2 (en) Biologically active compounds
US20070155830A1 (en) Concentricolide and its derivatives, process for preparing them, pharmaceutical composition comprising the same and its use
CN109111396B (en) Quinoline aromatic vinyl derivative and preparation method and application thereof
CN107746423B (en) Ergosta-7, 22-diene-3-ketoxime, preparation method thereof and application thereof in preparation of antibacterial drugs
CN110437177A (en) A kind of pleuromutilin derivative and its preparation method and application
CN107746422B (en) Ergosta-7, 22-diene-3-ketaminothiohydrazone, preparation method thereof and application thereof in preparation of antibacterial drugs
CN110437157A (en) A kind of arylpyrimidines pleuromutilin derivative and its preparation method and application
CN106432153B (en) A kind of sulfur-bearing andrographolidume derivative, its pharmaceutical composition, synthetic method, the application in preparation treatment prostate cancer drug
Masood-ur-Rahman et al. Synthesis and antimicrobial activity of triazolyl analogs of diosgenin
CN112645964B (en) Tyrosol-biotin small-molecule probe and preparation method and application thereof
CN114426538B (en) Berberine canagliflozin derivative and preparation method and application thereof
CN116253736B (en) Pyrazole beta-lactam derivative and preparation method and application thereof
CN111018780B (en) N-carbonyl-9, 10-dihydroacridine compound and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant