CN114805118A - Perilla aldehyde derivative and preparation method and application thereof - Google Patents

Perilla aldehyde derivative and preparation method and application thereof Download PDF

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CN114805118A
CN114805118A CN202210422849.2A CN202210422849A CN114805118A CN 114805118 A CN114805118 A CN 114805118A CN 202210422849 A CN202210422849 A CN 202210422849A CN 114805118 A CN114805118 A CN 114805118A
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perillaldehyde
derivative
compound
nmr
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CN114805118B (en
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王立升
吴晓琳
李玉芳
刘旭
吴黎川
江俊
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Guangxi University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/82—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses a perillaldehyde derivative and a preparation method and application thereof, and belongs to the technical field of chemical synthesis. According to the invention, the perillaldehyde, the hydrazide, the hydrazine and the bromobenzyl compounds are used as raw materials to synthesize a series of perillaldehyde derivatives, and a new group is introduced while the structure of the perillaldehyde is completely kept, so that the perillaldehyde derivatives with better antibacterial activity are prepared, and a beneficial reference is provided for further developing new medicines for inhibiting candida albicans and propionibacterium acnes.

Description

Perilla aldehyde derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a perillaldehyde derivative and a preparation method and application thereof.
Background
Perilla aldehyde, known as 4-isopropenyl cyclohex-1-ene-1-aldehyde and also known as dihydrocuminaldehyde, exists in perilla, lotus leaf and lemon, is an oily substance with special fragrance, and is often applied to the fields of food, agriculture, medicine and the like due to the special fragrance and the effects of killing insects, inhibiting bacteria, resisting inflammation, resisting tumors, resisting allergy, regulating human body functions and the like. However, since perillaldehyde is low in natural perilla and is easily affected by variety, weather and place of production, the extraction method from natural plants is not easy and economical. Therefore, the synthesis of the perillaldehyde by a chemical method attracts the attention of people, and the total synthesis method is to obtain the perillaldehyde by taking beta pinene as a raw material and performing hydrogen peroxide epoxidation, ring opening synthesis of alcohol and oxidation of alcohol. Perilla aldehyde has a certain bacteriostatic action, but the effect is not strong.
Disclosure of Invention
The invention aims to provide a perillaldehyde derivative, a preparation method and application thereof, and aims to solve the problems in the prior art.
In order to achieve the purpose, the invention provides the following scheme:
one of the technical schemes of the invention is as follows: a perillaldehyde derivative, the structural formula of which is shown as formula (1), formula (2) or formula (3):
Figure BDA0003607204790000011
wherein R is 1 Is composed of
Figure BDA0003607204790000012
Figure BDA0003607204790000013
Any one of the above;
R 2 is composed of
Figure BDA0003607204790000014
R 3 Is composed of
Figure BDA0003607204790000021
Figure BDA0003607204790000022
Any one of them.
The second technical scheme of the invention is as follows: the preparation method of the perillaldehyde derivative with the structure of the formula (1) comprises the following steps: adding an alcohol solvent into perillaldehyde, uniformly mixing, adding sodium bicarbonate and a hydrazide compound, and stirring for reaction to obtain the perillaldehyde derivative.
Further, the molar ratio of the perillaldehyde to the hydrazide compound is 10: 13-15; the molar ratio of the sodium bicarbonate to the hydrazide compound is 1: 1.
Further, the reaction equation of the formula (1) is as follows:
Figure BDA0003607204790000023
wherein R is 1 Is composed of
Figure BDA0003607204790000024
Figure BDA0003607204790000025
Any one of the above;
the third technical scheme of the invention is as follows: the preparation method of the perillaldehyde derivative with the structure of the formula (2) comprises the following steps: adding an alcohol solvent into perillaldehyde, uniformly mixing, adding sodium bicarbonate and a hydrazine compound, and stirring for reaction to obtain the perillaldehyde derivative.
Further, the molar ratio of the perillaldehyde to the hydrazine compound is 10: 13-15; the molar ratio of the sodium bicarbonate to the hydrazine compound is 1: 1.
Further, the reaction equation of the formula (2) is as follows:
Figure BDA0003607204790000031
R 2 is composed of
Figure BDA0003607204790000032
The fourth technical scheme of the invention is as follows: the preparation method of the perillaldehyde derivative with the structure of the formula (3) comprises the following steps:
(1) adding absolute ethyl alcohol into perillaldehyde, uniformly mixing, adding sodium bicarbonate and hydroxylamine hydrochloride for reaction to obtain perillaseed;
(2) weighing NaH, adding anhydrous tetrahydrofuran under the nitrogen protection atmosphere, uniformly mixing, adding a mixed solution of perillaseed and the anhydrous tetrahydrofuran, stirring for reaction, adding a benzyl bromide compound, and continuously stirring for reaction to obtain the perillaldehyde derivative.
Further, the molar ratio of the perillaseed to the bromobenzyl compound is 1: 1; the molar ratio of the NaH to the perillaseed is 2-3: 1.
Further, the reaction equation of the formula (3) is as follows:
Figure BDA0003607204790000033
R 3 is composed of
Figure BDA0003607204790000034
Figure BDA0003607204790000035
Any one of them.
The fifth technical scheme of the invention is as follows: an application of the perillaldehyde derivative in preparing antibacterial drugs.
The invention discloses the following technical effects:
according to the invention, the perillaldehyde, the hydrazide, the hydrazine and the bromobenzyl compounds are used as raw materials to synthesize a series of perillaldehyde derivatives, and a new group is introduced while the structure of the perillaldehyde is completely kept, so that the perillaldehyde derivatives with better antibacterial activity are prepared, and a beneficial reference is provided for further developing new medicines for inhibiting candida albicans and propionibacterium acnes.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
The reaction equation of the acylhydrazone perillaldehyde derivative is as follows:
Figure BDA0003607204790000041
wherein R is 1 Is composed of
Figure BDA0003607204790000042
Figure BDA0003607204790000051
Any one of the above;
the reaction equation of the hydrazone perillaldehyde derivative is as follows:
Figure BDA0003607204790000052
R 2 is composed of
Figure BDA0003607204790000053
The reaction equation of the oxime ether perillaldehyde derivative is as follows:
Figure BDA0003607204790000054
R 3 is composed of
Figure BDA0003607204790000055
Figure BDA0003607204790000056
Any one of them.
Example 1
A method for preparing perillaldehyde derivatives (acylhydrazone perillaldehyde derivatives) comprises:
3.0g (20mmol) of violet was added to a 100mL round-bottomed flaskSulaldehyde, 40mL anhydrous ethanol, stirring well, adding 21.84g (26mmol) sodium bicarbonate, adding 3.54g (26mmol) benzoyl hydrazine, stirring at room temperature for 1h until the reaction is complete (TLC monitoring), removing ethanol, adding 20mL water, extracting with 40mL ethyl acetate for 3 times, combining organic phases, anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, performing silica gel column chromatography (V n-hexane: V ethyl acetate 4:1), purifying, and rotary evaporating to obtain 10- (benzoylhydrazino) perillaldehyde (1A) as white solid powder with yield of 93% and Mp of 134.7-133.5 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,Chloroform-d)δ9.71(s,1H),7.92(s,1H),7.84(d,J＝6Hz,2H),7.50-7.46(m,1H),7.40(d,J＝12Hz,2H),6.11-6.09(m,1H),4.75-4.71(m,2H),2.64(d,J＝18Hz,1H),2.31(d,J＝24Hz,2H),2.22-2.16(m,1H),2.14-2.08(m,1H),1.90-1.85(m,1H),1.74(s,3H),1.48-1.40(m,1H), 13 C NMR(151MHz,CDCl 3 )δ164.28,152.20,149.06,137.46,135.34,133.43,131.78,128.60,127.36,109.09,40.89,31.59,26.80,23.77,20.77,HRMS(ESI+)m/z:calcd for C 17 H 19 N 2 O[M+H + ]:269.16484,found 269.16425。
example 2
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 2-pyridinecarbohydrazide to obtain the compound 10- (2-pyridinecarbohydrazide) perillaldehyde (2A) as a white solid powder with a yield of 92% and Mp of 130.0-131.1 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,Chloroform-d)δ10.76(s,1H),8.56-8.55(m,1H),8.31-8.29(dd,J＝12,1Hz,1H),7.91-7.88(m,2H),7.49-7.46(m,1H),6.21-6.19(m,1H),4.79-4.74(m,2H),2.78-2.73(m,1H),2.42-2.34(m,2H),2.28-2.22(m,1H),2.19-2.12(m,1H),1.97-1.92(m,1H),1.77(s,3H),1.55-1.47(m,1H), 13 C NMR(151MHz,CDCl 3 )δ159.85,152.21,149.31,149.11,147.93,137.62,137.50,135.42,126.57,122.84,109.09,40.94,31.64,26.80,23.91,20.76,HRMS(ESI+)m/z:calcd for C 16 H 19 N 3 O[M+H + ]270.16009,found 270.15942。
example 3
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 3-pyridinecarbohydrazide to obtain the compound 10- (3-pyridinecarbohydrazide) perillaldehyde (3A) as a white solid powder with a yield of 99% and Mp of 149.6-150.8 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,Chloroform-d)δ10.45(s,0.5H),9.94(s,0.5H),9.21(s,0.5H),9.10(s,0.5H),8.70-8.69(t,J＝6Hz,1H),8.27(s,0.5H),7.96(s,0.5H),7.58(s,0.5H),7.40-7.38(m,1H),6.18-6.12(m,1H),4.75-4.71(d,J＝24Hz,2H),2.61-2.57(d,J＝36Hz,1H),2.45-2.30(m,2H),2.23-2.16(m,1H),2.13-2.10(m,1H),1.91-1.84(m,1H),1.74(s,3H),1.47-1.41(m,1H), 13 C NMR(151MHz,CDCl 3 )δ167.97,162.60,153.36,151.95,151.62,151.18,148.93,148.87,148.26,138.29,137.85,137.38,136.08,135.22,134.66,129.44,123.59,122.75,109.16,40.79,31.59,26.72,23.59,20.74,HRMS(ESI + )m/z:calcd for C 16 H 19 N 3 O[M+H + ]270.16009,found 270.15961。
example 4
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 4-pyridinecarbohydrazide to obtain the compound 10- (4-pyridinecarbohydrazide) perillaldehyde (4A) as pale yellow solid powder with a yield of 88%; mp is 141.6-143.1 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.74(s,1H),8.78-8.77(m,2H),8.07(s,1H),7.80-7.79(m,2H),6.25-6.23(m,1H),4.76-4.75(d,J＝6Hz,2H),2.37-2.31(m,1H),2.23-2.17(m,2H),2.15-2.08(m,1H),1.89-1.84(m,1H),1.74(s,3H),1.49-1.40(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ161.80,152.70,150.70,149.17,141.11,137.44,135.28,121.91,109.65,40.77,31.40,26.85,23.82,20.03,HRMS(ESI + )m/z:calcd for C 16 H 19 N 3 O[M+H + ]270.16009,found 270.15955。
example 5
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 2-furoyl hydrazine to obtain the compound 10- (2-furoyl hydrazino) perillaldehyde (5A) as a white solid in 37% yield and Mp of 120.9-122.3 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.48(s,1H),8.05(s,1H),7.90(s,1H),7.24(d,J＝6Hz,1H),6.68-6.67(m,1H),6.18-6.16(m,1H),4.75-4.74(m,2H),2.50-2.47(m,1H),2.35-2.29(m,1H),2.22-2.16(m,2H),2.14-2.07(m,1H),1.87-1.84(m,1H),1.73(s,3H),1.47-1.39(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ154.52,151.65,149.22,147.26,146.02,136.63,135.38,114.95,112.42,109.64,40.79,31.34,26.87,23.86,21.05,HRMS(ESI + )m/z:calcd for C 15 H 18 N 2 O 2 [M+H + ]259.14410,found 259.14349。
example 6
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 2-thiophenecarboxhydrazide to obtain the compound 10- (2-thiophenecarboxhydrazide) perillaldehyde (6A) as a yellow filamentous solid with a yield of 98% and Mp of 140.8-141.5 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,Chloroform-d)δ10.16(s,1H),8.24-8.19(d,J＝6Hz,1H),7.65(d,J＝6Hz,1H),7.59(s,1H),7.14(t,J＝12Hz,1H),6.21-6.20(m,1H),4.78-4.74(m,2H),2.75-2.70(m,1H),2.42-2.34(m,2H),2.24-2.22(m,1H),2.19-2.13(m,1H),2.00-2.16(m,1H),1.78(s,3H),1.59-1.51(m,1H), 13 C NMR(151MHz,CDCl 3 )δ163.14,149.11,148.23,137.09,135.22,135.00,134.47,133.01,126.41,109.12,40.89,31.52,26.95,24.34,20.83,HRMS(ESI + )m/z:calcd for C 15 H 18 N 2 OS[M+H + ]275.12126,found 275.12061。
example 7
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 2-hydroxybenzoyl hydrazine to obtain the compound 10- (2-hydroxybenzoyl hydrazino) perillaldehyde (7A) as a white solid in 24% yield and Mp 209.8-210.9 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.95(s,1H),11.55(s,1H),8.06(s,1H),7.85(dd,J＝6,1Hz,1H),7.44-7.41(m,1H),6.96-6.92(m,2H),6.26-6.24(m,1H),4.75(s,2H),2.51-2.49(m,1H),2.37-2.32(m,1H),2.23-2.17(m,2H),2.16-2.09(m,1H),1.89-1.84(m,1H),1.74(s,3H),1.49-1.41(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ165.25,159.75,152.55,149.20,137.42,135.28,134.18,128.70,119.27,117.74,116.08,109.67,40.76,31.40,26.86,23.84,21.05,HRMS(ESI + )m/z:calcd for C 17 H 20 N 2 O 2 [M-H-]283.14410,found 283.14520。
example 8
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 3-hydroxybenzoyl hydrazine to obtain compound 10- (3-hydroxybenzoyl hydrazino) perillaldehyde (8A) as a white flaky solid in 73% yield; mp is 227.1-228.3 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.41(s,1H),9.75(s,1H),8.03(s,1H),7.29(s,1H),7.28(s,1H),7.24(s,1H),6.97-6.94(m,1H),6.18-6.17(m,1H),4.75(s,2H),2.48(s,1H),2.36-2.30(m,1H),2.22-2.15(m,2H),2.14-2.07(m,1H),1.88-1.85(m,1H),1.74(s,3H),1.48-1.40(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ163.49,157.81,151.51,149.22,136.47,135.48,135.43,118.95,118.45,114.90,109.63,40.81,31.35,26.89,23.86,21.05,HRMS(ESI + )m/z:calcd for C 17 H 20 N 2 O 2 [M-H-]283.14410,found283.14542。
example 9
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 4-hydroxybenzoyl hydrazine to obtain the compound 10- (3-hydroxybenzoyl hydrazino) perillaldehyde (9A) as a white flaky solid with a yield of 16% and Mp of 232.5-233.6 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.28(s,1H),10.09(s,1H),8.02(s,1H),7.81-7.73(d,J＝12Hz,2H),6.84-6.82(d,J＝12Hz,2H),6.16-6.15(m,1H),4.75(s,2H),2.48(s,1H),2.34-2.30(m,1H),2.20-2.17(m,2H),2.14-2.07(m,1H),1.87-1.84(m,1H),1.74(s,3H),1.48-1.40(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ163.06,160.95,150.73,149.27,135.90,135.50,129.97,124.55,115.40,109.64,40.84,31.32,26.91,23.91,21.06,HRMS(ESI + )m/z:calcd for C 17 H 20 N 2 O 2 [M-H-]283.14410,found 283.14523。
example 10
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 4-tert-butylbenzoyl hydrazine to obtain the compound 10- (4-tert-butylbenzoyl hydrazino) perillaldehyde (10A) as a white solid in 84% yield and Mp of 126.0-127.5 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ9.71(s,1H),7.92(s,1H),7.84(d,J＝6Hz,2H),7.50-7.46(m,1H),7.40(d,J＝12Hz,2H),6.11-6.09(m,1H),4.75-4.71(m,2H),2.64(d,J＝18Hz,1H),2.31(d,J＝24Hz,2H),2.22-2.16(m,1H),2.14-2.08(m,1H),1.90-1.85(m,1H),1.74(s,3H),1.48-1.40(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ164.28,152.20,149.06,137.46,135.34,133.43,131.78,128.60,127.36,109.09,40.89,31.59,26.80,23.77,20.77,HRMS(ESI + )m/z:calcd for C 21 H 28 N 2 O[M+H + ]325.22744,found 325.22656。
example 11
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 4-chlorobenzoyl hydrazine to obtain the compound 10- (4-chlorobenzoyl hydrazino) perillaldehyde (11A) as a white solid in a yield of 76% and Mp at 232.5-233.6 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.56(s,1H),8.04(s,1H),7.90-7.89(d,J＝12Hz,2H),7.59-7.58(d,J＝12Hz,2H),6.21-6.20(m,1H),4.75(s,2H),2.49-2.48(m,1H),2.36-2.30(m,1H),2.23-2.17(m,2H),2.14-2.08(m,1H),1.88-1.85(m,1H),1.74(s,3H),1.48-1.40(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ162.28,151.87,149.23,136.82,135.37,132.81,129.91,128.95,109.66,40.80,31.37,26.88,23.87,21.06,HRMS(ESI + )m/z:calcd for C 17 H 19 ClN 2 O[M+H + ]303.12587,found 303.12512。
example 12
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 4-nitrobenzyl hydrazide to obtain the compound 10- (4-nitrobenzoyl hydrazino) perillaldehyde (12A) as a yellow flocculent solid with a yield of 23% and Mp of 189.5-190.6 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,Chloroform-d)δ9.49-9.38(m,1H),8.29-8.27(d,J＝6Hz,2H),8.11-8.09(d,J＝12Hz,1H),8.01-8.00(d,J＝6Hz,1H),7.90(s,0.5H),7.52(s,0.5H),6.20-6.19(m,1H),4.77-4.72(d,J＝30Hz,2H),2.67-2.63(m,1H),2.38-2.34(m,2H),2.23-2.18(m,1H),2.18-2.14(m,1H),1.93-1.90(m,1H),1.75(s,3H),1.50-1.46(m,1H), 13 C NMR(151MHz,CDCl 3 )δ167.83,153.34,148.81,148.71,138.96,137.85,134.45,131.18,128.48,123.93,122.77,109.25,40.78,31.45,26.69,23.70,20.79,HRMS(ESI + )m/z:calcd for C 17 H 19 N 3 O 3 [M+H + ]314.14992,found 314.14917。
example 13
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 4-bromobenzoyl hydrazine to obtain the compound 10- (4-bromobenzoyl hydrazino) perillaldehyde (13A) as a white solid with a yield of 79% and Mp of 189.5-190.6 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.56(s,1H),8.04(s,1H),7.82(d,J＝6Hz,2H),7.72(d,J＝6Hz,2H),6.21(m,1H),4.75(s,2H),2.49-2.48(m,1H),2.36-2.30(m,1H),2.22-2.17(m,2H),2.14-2.08(m,1H),1.88-1.84(m,1H),1.74(s,3H),1.48-1.40(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ162.39,151.89,149.22,136.82,135.38,133.16,131.89,130.08,125.75,40.80,31.37,26.88,23.87,21.06,HRMS(ESI + )m/z:calcd for C 17 H 19 BrN 2 O[M+H + ]349.07331,found 349.07242。
example 14
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 2-methylbenzoyl hydrazine to obtain the compound 10- (2-methylbenzoyl hydrazino) perillaldehyde (14A) as a white solid in 87% yield and Mp 124.4-125.9 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.38(s,1H),7.89(s,1H),7.38-7.35(td,J＝12Hz,2H),7.28-7.24(m,2H),6.15-6.13(m,1H),4.75-4.74(m,2H),2.53-2.50(m,1H),2.34(s,3H),2.32-2.28(m,1H),2.19-2.16(m,2H),2.12-1.98(m,1H),1.88-1.84(m,1H),1.74(s,3H),1.45-1.42(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ167.86,152.52,148.98,137.69,136.19,135.38,134.52,130.50,130.04,127.01,125.45,108.25,40.97,31.31,26.76,23.23,19.58,18.32,HRMS(ESI + )m/z:calcd for C 18 H 22 N 2 O[M+H + ]283.18049,found 283.17981。
example 15
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 3-methylbenzoyl hydrazine to obtain the compound 10- (3-methylbenzoyl hydrazino) perillaldehyde (15A) as a yellow solid in a yield of 98% and Mp of 83.7-84.8 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,Chloroform-d)δ10.13(s,1H),7.97(s,1H),7.82(d,J＝6Hz,2H),7.67-7.64(m,2H),7.30-7.22(m,2H),6.07-6.06(m,1H),4.74-4.70(m,2H),2.62-2.57(m,1H),2.31(s,4H),2.27-2.20(m,1H),2.19-2.14(m,1H),2.11-2.03(m,1H),1.86-1.82(m,1H),1.73(s,3H),1.48-1.37(m,1H), 13 C NMR(151MHz,CDCl 3 )δ164.59,152.22,149.08,138.36,137.18,135.43,133.35,132.46,128.36,128.22,124.42,109.06,40.91,31.59,26.83,23.72,21.28,20.76,HRMS(ESI + )m/z:calcd for C 18 H 22 N 2 O[M+H + ]283.18049,found 283.17984。
example 16
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of pyrazine-2-formhydrazide to obtain the compound 10- (pyrazine-2-formhydrazide) perillaldehyde (16A) as a white solid in 99% yield and Mp 184.7-185.8 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,Chloroform-d)δ10.43(s,1H),9.49(s,1H),8.80-8.79(d,J＝6Hz,1H),8.54-8.53(dd,J＝6,1Hz,1H),7.90(s,1H),6.24-6.22(m,1H),4.79-4.73(m,2H),2.77-2.72(m,1H),2.41-2.34(m,2H),2.28-2.23(m,1H),2.21-2.14(m,1H),1.97-1.92(m,1H),1.77(s,3H),1.56-1.47(m,1H), 13 C NMR(151MHz,CDCl 3 )δ158.59,153.06,148.99,147.67,144.85,144.01,142.38,138.37,135.27,109.17,40.87,31.68,26.74,23.85,20.76,HRMS(ESI + )m/z:calcd for C 17 H 19 N 2 O[M+H + ]:269.16484,found 269.16425。
example 17
The same as example 1 except that 26mmol of benzoyl hydrazine was replaced with 26mmol of 4-methoxybenzoyl hydrazine to obtain the compound 10- (4-methoxybenzoyl hydrazino) perillaldehyde (17A) as a white solid in a yield of 96% and Mp of 119.7-121.5 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ11.37(s,1H),8.05(s,1H),7.88-7.86(m,2H),7.05-7.02(d,J＝12Hz,2H),6.17-6.15(m,1H),4.75-4.74(m,2H),3.34(s,3H),2.50-2.49(m,1H),2.35-2.29(m,1H),2.22-2.15(m,2H),2.14-2.07(m,1H),1.87-1.84(m,1H),1.74(s,3H),1.48-1.39(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ162.79,162.31,150.99,149.26,136.06,135.49,129.85,126.14,114.09,109.63,55.86,40.84,31.34,26.91,23.91,21.06,HRMS(ESI + )m/z:calcd for C 18 H 22 N 2 O 2 [M+H + ]299.17540,found 299.17471。
example 18
A method for preparing perillaldehyde derivatives (hydrazone perillaldehyde derivatives) comprises:
respectively adding 3.0g (20mmol) of perillaldehyde and 40mL of anhydrous ethanol into a 100mL round-bottom flask, uniformly stirring, adding 21.84g (26mmol) of sodium bicarbonate, adding 3.96g (26mmol) of 4-hydrazinobenzoic acid, stirring at normal temperature for 1h till the reaction is complete (TLC monitoring), removing ethanol, adding 20mL of water, slowly dropwise adding NaOH (1M) till all solids are dissolved, dropwise adding HCl (1M) to adjust the pH value to be 7, filtering, washing filter residues with a large amount of water, and drying to obtain 10- (4-carboxyphenylhydrazino) perillaldehyde (1B) which is a yellow solid, wherein the yield is 78%, and the Mp is 178.8-179.9 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,DMSO-d 6 )δ12.23(s,1H),10.44(s,1H),7.78-7.77(m,2H),7.60(s,1H),6.97-6.96(m,2H),6.03-6.01(m,1H),4.74(s,2H),2.58-2.53(m,1H),2.33-2.27(m,1H),2.24-2.16(m,2H),2.12-2.05(m,1H),1.87-1.83(m,1H),1.73(s,3H),1.49-1.40(m,1H), 13 C NMR(151MHz,DMSO-d 6 )δ167.79,149.59,149.40,143.27,135.42,132.08,132.05,131.59,120.12,111.26,109.56,41.05,31.23,27.01,24.05,21.07,HRMS(ESI + )m/z:calcd for C 17 H 20 N 2 O 2 [M-H-]283.14410,found 283.14542。
example 19
A method for preparing perillaldehyde derivatives (oxime ether perillaldehyde derivatives) comprises:
(1) adding absolute ethyl alcohol into perillaldehyde, uniformly mixing, adding sodium bicarbonate and hydroxylamine hydrochloride, and reacting to obtain perillaseed.
(2) Adding 0.96g (40mmol) of NaH into a 100mL clean dry three-necked bottle, protecting with nitrogen, adding 20mL of anhydrous tetrahydrofuran, stirring uniformly, slowly adding a mixed solution of 3.30g (20mmol) of perillaseed and 5mL of anhydrous tetrahydrofuran, stirring at normal temperature for 0.5h, weighing 3.42g (20mmol) of benzyl bromide, adding into the three-necked bottle, stirring for 3h until the reaction is complete (TLC monitoring), slowly dropwise adding 20mL of water after the reaction is finished, quenching, extracting with ethyl acetate for 3 times, mixing organic phases with 40mL of ethyl acetate each time, and adding anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, separating the filtrate by silica gel column chromatography (V n-hexane: V ethyl acetate 100: 1), purifying, concentrating, and drying to obtain 10- (benzyl bromide) perillaseed (1C) as colorless transparent liquid with a yield of 98%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.72(s,1H),7.39-7.36(m,2H),7.35-7.32(m,2H),7.31-7.27(m,2H),5.98-5.96(m,1H),5.09(s,2H),4.77-4.71(m,2H),2.50-2.45(m,1H),2.31-2.25(m,1H),2.25-2.16(m,1H),2.11-2.04(m,1H),1.89-1.85(m,1H),1.74(s,3H),1.50-1.42(m,1H), 13 C NMR(151MHz,CDCl 3 )δ152.03,149.22,137.72,134.94,132.76,128.39,127.85,109.06,76.01,40.94,31.39,26.89,23.95,20.79,HRMS(ESI + )m/z:calcd for[M+H + ]256.16959,found 256.16870。
example 20
The same as in example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 3-methylbenzyl bromide, the compound 10- (3-methylbenzyl bromide) perillartine (2C) was obtained as a colorless transparent liquid in a yield of 63%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.72(s,1H),7.25-7.22(m,1H),7.19-7.16(m,2H),7.11-7.10(d,J＝6Hz,1H),5.98-5.96(m,1H),5.05(s,2H),4.75-4.71(m,2H),2.51-2.46(m,1H),2.35(s,3H),2.32-2.25(m,1H),2.24-2.17(m,2H),2.10-2.06(m,1H),1.89-1.85(m,1H),1.74(s,3H),1.51-1.45(m,1H), 13 C NMR(151MHz,CDCl 3 )δ151.97,149.23,138.00,137.51,134.88,132.77,129.16,128.64,128.31,125.51,109.05,76.11,40.94,31.39,26.90,23.95,21.43,20.79,HRMS(ESI + )m/z:calcd for[M+H + ]270.18524,found 270.18454。
example 21
The same as in example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 4-methylbenzyl bromide, the compound 10- (4-methylbenzyl bromide) perillartine (3C) was obtained as a colorless transparent liquid in a yield of 99%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.71(s,1H),7.27(d,J＝12Hz,2H),7.15(d,J＝12Hz,2H),5.98-5.95(m,1H),5.04(s,2H),4.75-4.71(m,2H),2.51-2.45(m,1H),2.34(s,3H),2.32-2.25(m,1H),2.23-2.16(m,2H),2.11-2.04(m,1H),1.89-1.84(m,1H),1.74(s,3H),1.50-1.42(m,1H), 13 C NMR(151MHz,CDCl 3 )δ151.93,149.25,137.59,134.82,134.61,132.78,129.07,128.55,109.03,75.92,40.94,31.37,26.89,23.94,21.24,20.78；HRMS(ESI + )m/z:calcd for[M+H + ]270.18524,found 270.18457。
example 22
The same as in example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 4-fluorobenzyl bromide to obtain the compound 10- (4-fluorobenzyl bromo) perillartine (4C) as a colorless transparent liquid in 88% yield.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.70(s,1H),7.35-7.32(m,2H),7.04-7.00(m,2H),5.99-5.97(m,1H),5.04(s,2H),4.75-4.71(m,2H),2.48-2.43(m,1H),2.32-2.26(m,1H),2.22-2.16(m,2H),2.11-2.04(m,1H),1.89-1.84(m,1H),1.74(s,3H),1.51-1.43(m,1H), 13 C NMR(151MHz,CDCl 3 )δ163.47,161.51,152.13,149.17,135.13,133.55,133.52,132.67,130.25,130.19,115.30,115.13,109.06,75.19,40.90,31.37,26.85,23.91,20.76,HRMS(ESI + )m/z:calcd for[M+H + ]274.16017,found 274.15936。
example 23
The same as example 19, except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 4-chlorobenzyl bromide to obtain the compound 10- (4-chlorobenzyl bromide) perillartine (5C), which was obtained as a white solid after rotary evaporation in 96% yield. Mp is 38.8-39.9 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.71(s,1H),7.33-7.31(m,2H),7.30-7.29(m,2H),6.00-5.98(m,1H),5.04(s,2H),4.75-4.71(m,2H),2.48-2.42(m,1H),2.32-2.26(m,1H),2.23-2.15(m,2H),2.12-2.05(m,1H),1.89-1.84(m,1H),1.74(s,3H),1.51-1.43(m,1H), 13 C NMR(151MHz,CDCl 3 )δ152.25,149.18,136.33,135.25,133.60.132.63,129.68,128.51,109.05,75.05,40.88,31.36,26.83,23.88,20.75,HRMS(ESI + )m/z:calcd for[M+H + ]290.13062,found 290.12997.
example 24
The same as example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 2-bromobenzyl bromide to give the compound 10- (2-bromobenzyl bromide) perillartine (6C) as a colorless transparent liquid in a yield of 72%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.78(s,1H),7.55-7.53(dd,J＝12,6Hz,1H),7.43-7.41(dd,J＝6,1Hz,1H),7.30-7.27(td,J＝12,6Hz,1H),7.15-7.12(td,J＝6Hz,1H),6.01-5.99(m,1H),5.18(s,2H),4.75-4.71(m,2H),2.48-2.43(m,1H),2.32-2.26(m,1H),2.23-2.16(m,2H),2.12-2.05(m,1H),1.88-1.84(m,1H),1.74(s,3H),1.50-1.42(m,1H), 13 C NMR(151MHz,CDCl3)δ152.33,149.18,137.34,135.23,132.70,132.58,129.81,129.06,127.27,122.99,109.07,75.13,40.90,31.40,26.85,23.91,20.78,HRMS(ESI + )m/z:calcd for[M+H + ]334.08010,found 334.07962。
example 25
The same as in example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 3-bromobenzyl bromide to give the compound 10- (3-bromobenzyl bromide) perillartine (7C) as a colorless transparent liquid in a yield of 76%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.72(s,1H),7.52(t,1H),7.43-7.41(dt,J＝12,6Hz,1H),7.29-7.27(dt,J＝6Hz,1H),722-7.19(t,J＝6Hz,1H),6.01-5.99(m,1H),5.04(s,2H),4.75-4.71(m,2H),2.48-2.42(m,1H),2.33-2.27(m,1H),2.23-2.15(m,2H),2.12-2.05(m,1H),1.89-1.85(m,1H),1.74(s,3H),1.51-1.43(m,1H), 13 CNMR(151MHz,CDCl 3 )δ152.34,149.18,140.21,135.35,132.61,131.17,130.81,129.92,126.70,122.44,109.06,74.97,40.88,31.38,26.83,23.88,20.76,HRMS(ESI + )m/z:calcd for[M+H + ]334.08010,found 334.07959。
example 26
The same as example 19, except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 4-bromobenzyl bromide to obtain the compound 10- (4-bromobenzyl bromo) perillartine (8C), which was obtained as a white solid after rotary evaporation in 68% yield. Mp is 59.1-60.3 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.71(s,1H),7.48-7.45(m,2H),7.25-7.23(m,2H),6.00-5.98(m,1H),5.02(s,2H),4.75-4.71(m,2H),2.47-2.42(m,1H),2.32-2.26(m,1H),2.22-2.14(m,2H),2.12-2.04(m,1H),1.89-1.84(m,1H),1.74(s,3H),1.51-1.42(m,1H), 13 C NMR(151MHz,CDCl 3 )δ152.27,149.18,136.86,135.27,132.62,131.46,129.98,121.75,109.05,75.07,40.88,31.36,26.83,23.88,20.76,HRMS(ESI + )m/z:calcd for[M+H + ]334.08010,found 334.07950.
example 27
The same as in example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 3-nitrobenzyl bromide, the compound 10- (3-nitrobenzyl bromide) perillartine (9C) was obtained as a colorless transparent liquid in a yield of 99%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ8.26-8.23(m,0.5H),8.22-8.19(m,1H),8.16-8.14(m,0.5H),7.77-7.75(m,1H),7.70-7.67(m,0.5H),7.55-7.50(m,1.5H),6.04-6.02(m,1H),5.19-5.17(d,J＝12Hz,2H),4.75-4.72(m,2H),2.45-2.39(m,1H),2.34-2.28(m,1H),2.23-2.15(m,2H),2.14-2.06(m,1H),1.89-1.84(m,1H),1.74(s,3H),1.51-1.42(m,1H), 13 C NMR(151MHz,CDCl 3 )δ152.76,149.10,149.06,145.72,135.87,135.82,133.98,132.48,132.45,129.26,128.35,123.58,122.94,122.68,109.10,109.08,74.38,74.35,40.82,31.38,26.78,26.76,23.83,20.74,HRMS(ESI + )m/z:calcd for[M+H + ]301.15467,found 301.15387。
example 28
The same as example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 4-nitrobenzyl bromide to obtain the compound 10- (4-nitrobenzyl bromide) perillartine (10C), which was obtained as a yellow solid after rotary evaporation in 75% yield. Mp is 62.8-64.3 ℃.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ8.21-8.19(m,2H),7.76(s,1H),7.52-7.50(m,2H),6.04-6.02(m,1H),5.17(s,2H),4.75-4.71(m,2H),2.43-2.38(m,1H),2.33-2.28(m,1H),2.22-2.14(m,2H),2.13-2.06(m,1H),1.89-1.83(m,1H),1.74(s,3H),1.50-1.42(m,1H), 13 C NMR(151MHz,CDCl 3 )δ152.75,149.05,147.41,145.72,135.86,132.45,128.34,123.57,109.10,74.35,40.82,31.38,26.76,23.83,20.74,HRMS(ESI + )m/z:calcd for[M+H + ]301.15467,found 301.15378.
example 29
The same as example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 3-methoxybenzyl bromide to obtain the compound 10- (3-methoxybenzyl bromide) perillartine (11C) as a colorless transparent liquid in a yield of 76%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.73(s,1H),7.27-7.24(m,1H),6.96-6.93(m,2H),6.85-6.82(m,1H),5.99-5.97(m,1H),5.06(s,2H),4.75-4.71(m,2H),3.80(s,3H),2.50-2.45(m,1H),2.32-2.26(m,1H),2.24-2.16(m,2H),2.11-2.04(m,1H),1.89-1.85(m,1H),1.74(s,3H),1.51-1.42(m,1H), 13 C NMR(151MHz,CDCl 3 )δ159.65,152.07,149.21,139.30,134.99,132.73,129.40,120.57,113.66,113.48,109.05,75.87,55.21,40.92,31.37,26.87,23.93,20.77,HRMS(ESI + )m/z:calcd for[M+H + ]286.18016,found 286.17929。
example 30
The same as in example 19 except that 20mmol of benzyl bromide in the step (2) was replaced with 20mmol of 3, 5-dimethoxybenzyl bromide to obtain the compound 10- (3, 5-dimethoxybenzyl bromide) perillartine (12C) as a colorless transparent liquid in a yield of 76%.
The hydrogen, carbon and mass spectra data are as follows: 1 H NMR(500MHz,CDCl 3 )δ7.74(s,1H),6.53(d,2H),6.40(t,J＝6Hz,1H),6.00-6.98(m,1H),5.03(s,2H),4.75-4.71(m,2H),3.79(s,6H),2.50-2.45(m,1H),2.32-2.26(m,1H),2.24-2.16(m,2H),2.12-2.05(m,1H),1.89-1.85(m,1H),1.74(s,3H),1.51-1.43(m,1H), 13 C NMR(151MHz,CDCl 3 )δ160.79,152.13,149.22,140.06,135.05,132.69,109.03,106.02,99.93,75.92,55.34,40.90,31.36,26.85,23.92,20.76,HRMS(ESI + )m/z:calcd for[M+H + ]316.19072,found 316.18982。
the structural formula of the perillaldehyde derivative prepared in example 1-30 is shown in table 1.
TABLE 1 structural formulas of the target compounds
Figure BDA0003607204790000161
Figure BDA0003607204790000171
Figure BDA0003607204790000181
Figure BDA0003607204790000191
Figure BDA0003607204790000201
Effect example 1
The bacteriostatic activity of the perillaldehyde derivatives prepared in examples 1 to 30 was measured.
The experimental method comprises the following steps:
1. preparation of culture Medium
Preparing an LB culture medium: taking a clean 250mL wide-mouth conical flask, respectively adding 1g of peptone, 0.5g of yeast extract powder and 1g of sodium chloride, then measuring 100mL of deionized water, pouring and uniformly stirring, covering the mouth of the conical flask with clean gauze and paper, finally binding with a rubber band to prevent introducing infectious microbes, and putting the conical flask into a sterilization pot at 121 ℃ for 20 min.
Preparing a YM culture medium: taking a clean 250mL wide-mouth conical flask, respectively adding 0.5g of peptone, 1g of glucose, 0.3g of yeast extract powder and 0.3g of maltose, then measuring 100mL of deionized water, pouring and uniformly stirring, covering the mouth of the conical flask with clean gauze and paper, finally binding with a rubber band to prevent introducing infectious microbes, and placing the conical flask into a sterilization pot at 115 ℃ for 20 min.
Preparation of 1053 culture medium: taking a clean 250mL wide-mouth conical flask, respectively adding 1g of peptone, 0.5g of glucose, 0.3g of yeast extract powder, 0.1g of soluble starch, 1g of beef extract, 0.5g of sodium chloride, 0.3g of sodium acetate and 0.05g of L-cysteine hydrochloride, then measuring 100mL of deionized water, pouring and uniformly stirring, covering the mouth of the conical flask with clean gauze and paper, finally binding with a rubber band to prevent introduction of infectious microbes, and putting the conical flask into a sterilization pot at 115 ℃ for 20 min.
2. Preparation of test bacteria
Culturing pseudomonas aeruginosa, staphylococcus aureus and escherichia coli, measuring 50 mu L of strain, inoculating the strain into 15mL of LB broth, placing the broth into a shaker at 37 ℃, culturing for 12h, and determining the OD600 value of the strain to be 0.5-1.
Culturing Candida albicans, inoculating 50 mu L of strain into 15mL of YM broth, placing the culture in a shaking table at 30 ℃, culturing for 24h, and determining the OD600 value of the strain to be 0.5-1.
Culturing propionibacterium acnes, measuring 50 mu L of strain, inoculating the strain into 35mL of 1053 broth, placing the broth into an incubator at 37 ℃, culturing for 48 hours, and measuring the OD600 value of the strain to be 0.5-1.
3. Preparation of test Compound solution
32mg of the drug was weighed, 10. mu.L of DMSO-dissolved drug was measured by using a micropipette gun, and then 990. mu.L of broth was added for dilution.
4. Minimum Inhibitory Concentration (MIC) test
And (3) testing the bacteriostatic activity of the target compound by a double dilution method. Adding broth 100 μ L into each well, sucking 100 μ L of the prepared liquid medicine with a micropipette gun, adding into the well 1 of the microplate, blowing and beating three times, and adding 100 μ L of the liquid medicine in the sucking well 1 into the well 2. After repeating the operation to the well 8, sucking 100. mu.L from the well 8 and discarding, the final concentration of the drug solution is: 16. 8, 4, 2, 1, 0.5, 0.25, 0.125mg/ml, three parallel groups were set up. And adding 5 mu L of cultured bacterial liquid into each hole, placing a 96-enzyme label plate in an incubator for culturing to a logarithmic phase, measuring the OD value of the 96-enzyme label plate at 600nm, and designing a proper concentration gradient to screen MIC. Ceftazidime, penicillin, kanamycin sulfate, fluconazole and doxycycline are respectively used as positive control drugs of pseudomonas aeruginosa, staphylococcus aureus, escherichia coli, candida albicans and propionibacterium acnes, broth is used as negative control, and the experimental result is shown in 2.
TABLE 2 MIC (mg/mL) minimum inhibitory concentration of target Compound
Figure BDA0003607204790000221
Figure BDA0003607204790000231
In the table, A is perillaldehyde, B is 4-hydrazinobenzoic acid, C is perillaseed, P.ae is pseudomonas aeruginosa, S.au is staphylococcus aureus, E.co is escherichia coli, C.al is candida albicans, and P.ac is propionibacterium acnes; the positive control drug of the pseudomonas aeruginosa is ceftazidime; the positive control drug of staphylococcus aureus is penicillin sodium; the positive control drug of the escherichia coli is kanamycin sulfate; the positive control drug of candida albicans is fluconazole; the positive control drug of the propionibacterium acnes is doxycycline hydrochloride; the concentrations of the positive control drugs were 16, 8, 4, 2, 1, 0.5, 0.25, 0.125mg/mL, respectively.
As can be seen from table 2, the bacteriostatic effect of the compound 1B on pseudomonas aeruginosa, staphylococcus aureus and propionibacterium acnes is stronger than that of perillaldehyde, and MICs are respectively 24 mug/mL, 320 mug/mL and 120 mug/mL, wherein the bacteriostatic action of the compound 1B on pseudomonas aeruginosa, candida albicans and propionibacterium acnes is stronger than that of 4-hydrazinobenzoic acid, and the bacteriostatic action of the compound 1B on pseudomonas aeruginosa is better than that of a positive control drug ceftazidime. The bacteriostatic effect of the compound 3C on Candida albicans and Propionibacterium acnes is better than that of perillaldehyde, the MIC is respectively 800 mug/mL and 250 mug/mL, the bacteriostatic action of the compounds 5A, 7A, 8A, 1B, 1C and 6C on Candida albicans is stronger than that of a positive control drug fluconazole, and the bacteriostatic action of the compound 1C on Propionibacterium acnes is close to that of a drug control drug doxycycline hydrochloride. The research result provides beneficial reference for further developing new medicines for inhibiting candida albicans and propionibacterium acnes.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.

Claims (8)

1. A perillaldehyde derivative is characterized in that the structural formula of the perillaldehyde derivative is shown as a formula (1), a formula (2) or a formula (3):
Figure FDA0003607204780000011
wherein R is 1 Is composed of
Figure FDA0003607204780000012
Figure FDA0003607204780000013
Any one of the above;
R 2 is composed of
Figure FDA0003607204780000014
Wherein R is 3 Is composed of
Figure FDA0003607204780000015
Figure FDA0003607204780000016
Any one of them.
2. A method for preparing the perillaldehyde derivative of claim 1, wherein the method for preparing the perillaldehyde derivative having the structure of formula (1) comprises the following steps: adding an alcohol solvent into perillaldehyde, uniformly mixing, adding sodium bicarbonate and a hydrazide compound, and stirring for reaction to obtain the perillaldehyde derivative.
3. The preparation method of claim 2, wherein the molar ratio of the perillaldehyde to the hydrazide compound is 10: 13-15; the molar ratio of the sodium bicarbonate to the hydrazide compound is 1: 1.
4. A method for preparing the perillaldehyde derivative of claim 1, wherein the method for preparing the perillaldehyde derivative having the structure of formula (2) comprises the following steps: adding an alcohol solvent into perillaldehyde, uniformly mixing, adding sodium bicarbonate and a hydrazine compound, and stirring for reaction to obtain the perillaldehyde derivative.
5. The preparation method of claim 4, wherein the molar ratio of the perillaldehyde to the hydrazine compound is 10: 13-15; the molar ratio of the sodium bicarbonate to the hydrazine compound is 1: 1.
6. A method for preparing the perillaldehyde derivative of claim 1, wherein the method for preparing the perillaldehyde derivative having the structure of formula (3) comprises the following steps:
(1) adding absolute ethyl alcohol into perillaldehyde, uniformly mixing, adding sodium bicarbonate and hydroxylamine hydrochloride for reaction to obtain perillaseed;
(2) weighing NaH, adding anhydrous tetrahydrofuran under the nitrogen protection atmosphere, uniformly mixing, adding a mixed solution of perillaseed and the anhydrous tetrahydrofuran, stirring for reaction, adding a benzyl bromide compound, and continuously stirring for reaction to obtain the perillaldehyde derivative.
7. The preparation method of claim 6, wherein the molar ratio of the perillaseed to the bromobenzyl compound is 1: 1; the molar ratio of the NaH to the perillaseed is 2-3: 1.
8. Use of the perillaldehyde derivative of claim 1 in the preparation of a bacteriostatic medicament.
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