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CN-122010766-A - Cyclohexene derivative, preparation method and application thereof

CN122010766ACN 122010766 ACN122010766 ACN 122010766ACN-122010766-A

Abstract

The invention relates to the field of chemistry, in particular to a compound shown in a formula (I), a preparation method and application thereof. The compound shown in the formula (I) has obvious biological film inhibition activity, can be used for preparing antibiotics, has good development and application prospects,

Inventors

  • MA ZHIHUI
  • JIANG YONGJUN
  • ZHAO SHUHAN
  • LI XIHUI

Assignees

  • 浙江海洋大学

Dates

Publication Date
20260512
Application Date
20231120

Claims (10)

  1. 1. A compound is characterized by having a structure shown in a formula (I), wherein the compound shown in the formula (I) is colorless blocky crystal, is dissolved in methanol, gives a quasi-ion peak m/z 243.0146[ M+Na ] + by high-resolution mass spectrum, and has a molecular formula of C 7 H 9 ClN 2 O 4,
  2. 2. A process for the preparation of a compound of formula (I) according to claim 1, comprising the steps of: 1) Inoculating Nocardia strain Nocardiopsis sp ZHD to solid culture medium of Gao's first order for activation, inoculating single colony of activated Nocardia strain ZHD to liquid culture medium of Gao's first order, shake culturing to obtain seed liquid, inoculating the seed liquid into rice culture medium, standing culturing, extracting to obtain fermentation broth; 2) Extracting the fermentation broth with ethyl acetate, distilling the obtained ethyl acetate extract under reduced pressure by a rotary evaporator to remove ethyl acetate solvent to obtain concentrated solution, separating the concentrated solution by silica gel column chromatography, collecting eluate, detecting each component by thin layer chromatography, and mixing components containing cyclohexene derivatives; 3) And (3) separating and purifying the component containing the cyclohexene derivative by using a preparative high performance liquid chromatograph to obtain a compound cyclohexene derivative compound (I).
  3. 3. The method for preparing the compound of formula (I) according to claim 2, wherein the nocardia strain Nocardiopsis sp ZHD in step 1) has a preservation number of cctccc No. M2022921.
  4. 4. The preparation method of the compound shown in the formula (I) as claimed in claim 2, wherein the formula ratio of the solid culture medium of the first high-grade used in the step 1) is 20g of soluble starch, 1g of potassium nitrate, 0.5g of dipotassium hydrogen phosphate, 0.5g of magnesium sulfate, 0.01g of ferrous sulfate, 20g of agar, 25g of sea salt and 1L of water, and the formula ratio of the liquid culture medium of the first high-grade used in the step 1) is 20g of soluble starch, 1g of potassium nitrate, 0.5g of dipotassium hydrogen phosphate, 0.5g of magnesium sulfate, 0.01g of ferrous sulfate, 25g of sea salt and 1L of water.
  5. 5. The method for preparing the compound of the formula (I) as claimed in claim 2, wherein the rice culture medium in the step 1) is prepared from rice and sea salt water, the weight-volume ratio of the rice to the sea salt water is 40 g/60 ml, and the formula of the sea salt water is 100 water containing 2.5g of sea salt.
  6. 6. The process for the preparation of a compound of formula (I) according to claim 2, characterized in that the volume ratio of fermentation broth to ethyl acetate in step 2) is 1:1.
  7. 7. The method of claim 2, wherein the silica gel column chromatography conditions in step 2) are CH 2 Cl 2 :CH 3 OH with a gradient of 1:0,100:1,80:1,70:1,60:1,50:1,40:1,30;1,20:1,10:1,5:1,1:1,0:1.
  8. 8. The method for preparing the compound of formula (I) according to claim 2, wherein the high performance liquid chromatograph separation and purification chromatographic column in step 3) is an agilent pursuit C chromatographic column 21.2×250mm,10 μm, the detection wavelength is 210nm, gradient elution is performed for 40 minutes at 10mL/min by using a gradient elution system of 10-100% methanol-0.05% tfa-water, and the eluent is collected for 12.7-14.5 minutes.
  9. 9. A pharmaceutical composition comprising a compound of formula (I), a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, and one or more pharmaceutically acceptable excipients.
  10. 10. Use of a compound of formula (I), a tautomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for the preparation of an antibacterial medicament.

Description

Cyclohexene derivative, preparation method and application thereof Technical Field The invention relates to the technical field of chemistry, in particular to a cyclohexene derivative, a preparation method and application thereof. Background Bacterial resistance to antibiotics has become a global threat, and traditional antibiotic drugs have not been able to perform very good therapeutic actions on resistant bacteria. Antibiotic resistance caused by bacterial biofilm formation is a significant cause of difficult cure of chronic bacterial infections in the clinic. The clinical chronic infection repeatedly attacks due to the formation of the biological film is difficult to radically cure, the treatment cost is greatly increased and the treatment time is prolonged. Therefore, the development of novel antibacterial drugs aiming at bacterial biofilms is expected to alleviate the worldwide problem of bacterial drug resistance. Disclosure of Invention The invention firstly separates the nocardia ZHD001 from the sediment collected in the sea area around the boat and the mountain, and further separates the nocardia ZHD to obtain the cyclohexene derivative of the fermentation product of the nocardia ZHD 001. The chemical structure of the cyclohexene derivative of the novel compound is determined by analyzing the hydrogen spectrum, the carbon spectrum, the COSY spectrum, the HMQC spectrum, the HMBC spectrum and the single crystal diffraction data of the cyclohexene derivative. A series of researches show that the novel natural compound has remarkable biological membrane inhibition activity, can be used for preparing antibiotics, and has good development and application prospects. On one hand, the cyclohexene derivative shown in the formula (I) has remarkable biological membrane inhibition activity, can be used for preparing antibiotics, and has good development and application prospects. Further, the compound of formula (I) is a colorless bulk crystal, dissolved in methanol, and the high-resolution mass spectrum gives a quasi-ion peak m/z 243.0146[ M+Na ] +, with a molecular formula of C 7H9ClN2O4. The specific nuclear magnetic data are shown in the following table 1, 1 H NMR spectrum is shown in FIG. 1, 13 C NMR spectrum is shown in FIG. 2, HSQC spectrum is shown in FIG. 3, HMBC spectrum is shown in FIG. 4, 1H-1 H COSY spectrum is shown in FIG. 5, and X-single crystal diffraction is shown in FIG. 6. TABLE 1 In another aspect, the invention provides a process for the preparation of a cyclohexene derivative as a natural active compound, comprising the steps of: 1) Inoculating Nocardia strain Nocardiopsis sp ZHD to solid culture medium of Gao's first order for activation, inoculating single colony of activated Nocardia strain ZHD to liquid culture medium of Gao's first order, shake culturing to obtain seed liquid, inoculating the seed liquid into rice culture medium, standing culturing, extracting to obtain fermentation broth; 2) Extracting the fermentation broth with ethyl acetate, distilling the obtained ethyl acetate extract under reduced pressure by a rotary evaporator to remove ethyl acetate solvent to obtain concentrated solution, separating the concentrated solution by silica gel column chromatography, collecting eluate, detecting each component by thin layer chromatography, and mixing components containing cyclohexene derivatives; 3) And (3) separating and purifying the component containing the cyclohexene derivative by using a preparative high performance liquid chromatograph to obtain a compound cyclohexene derivative compound (I). Preferably, the nocardia strain Nocardiopsis sp ZHD in the step 1) has a preservation number of cctccc No. M2022921. Preferably, the formula ratio of the solid culture medium No. 1 of Gaoshi used in the step 1) is 20g of soluble starch, 1g of potassium nitrate, 0.5g of dipotassium hydrogen phosphate, 0.5g of magnesium sulfate, 0.01g of ferrous sulfate, 20g of agar, 25g of sea salt and 1L of water. Preferably, the formula ratio of the Gao's first liquid culture medium used in the step 1) is 20g of soluble starch, 1g of potassium nitrate, 0.5g of dipotassium hydrogen phosphate, 0.5g of magnesium sulfate, 0.01g of ferrous sulfate, 25g of sea salt and 1L of water. Preferably, the rice culture medium in the step 1) is prepared from rice and sea salt water, wherein the weight-volume ratio of the rice to the sea salt water is 40 g/60 ml, and the formula of the sea salt water is that 100 water contains 2.5g of sea salt. Preferably, the volume ratio of the fermentation liquor in the step 2) to the ethyl acetate is 1:1. Preferably, the silica gel column chromatography conditions in the step 2) are as follows: the eluent adopted is CH 2Cl2:CH3 OH, the gradients were 1:0,100:1,80:1,70:1,60:1,50:1,40:1,30;1,20:1,10:1,5:1,1:1,0:1. Preferably, the separation and purification chromatographic column of the high performance liquid chromatograph in the step 3) is an Agilent pursuit C chromatographic c