CN113004379B - Norfluxan and preparation method and application thereof - Google Patents

Norfluxan and preparation method and application thereof Download PDF

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CN113004379B
CN113004379B CN202110292043.1A CN202110292043A CN113004379B CN 113004379 B CN113004379 B CN 113004379B CN 202110292043 A CN202110292043 A CN 202110292043A CN 113004379 B CN113004379 B CN 113004379B
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戈惠明
马嘉琪
吴锐
史净
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Abstract

The invention discloses a compound norfloxacin and a preparation method and application thereof, wherein the norfloxacin has the following structure:
Figure DDA0002982586560000011
or

Description

Norfluxan and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological pharmacy, and particularly relates to a compound norfluxanide (daspyromide) and a preparation method and application thereof.
Background
Abundant microbial resources play an important role in national economy and people's life, and are a resource treasury for potential new drug discovery. Of all natural resources capable of producing drugs, microbial resources have become the last, and largest, field of great development potential. In the discovery research of microbial drug lead compounds in the last half century, a plurality of national research institutions and research groups have carried out considerable systematic natural product chemical and biological activity research on microorganisms in China, a large number of novel framework compounds, high-activity lead compounds with new drug development potential and candidate drugs are discovered, and part of components enter the preclinical research process.
Due to the factors such as difficult separation and purification of microbial resources, although some chemical and biological research reports exist in recent years, most of the microbial resources are still in a state of being researched and developed, and the research on various aspects such as microbial species diversity, distribution diversity, biochemical diversity and biological functions is relatively lagged behind at present, and the current situation becomes the bottleneck of the development and utilization of the microbial resources in China. Deep excavation and systematic research on new microbial resources become one of the main ways of researching and developing new drugs with independent intellectual property rights in China.
Disclosure of Invention
The invention discovers two new active substances, namely, the dapyroside A and the dapyroside B, from the liquid fermentation product of Actinokinespora diospora diospyrosa preserved in the biological resource center of Japan technical evaluation research institute for the first time, and an in vitro activity experiment shows that the dapyroside A and the dapyroside B have stronger inhibitory activity to pathogenic bacteria.
The specific technical scheme of the invention is as follows:
a compound having the formula (dapyromide):
Figure BDA0002982586540000011
Figure BDA0002982586540000021
the compound daspyromide is obtained by liquid fermentation and extraction of Actinokinetocpora diospyrosa strain of persimmon tree. The Actinokinetopora diospyrosa strain is a strain deposited in the biological resource center of the Japanese institute for technical evaluation and research, and the deposit number of the strain is NBRC-15665.
The invention also aims to provide a preparation method of the dasyromide, which comprises the following steps:
(1) inoculating Actinokinespora diospyriosa strain of Actinokinensis to F culture medium, fermenting, preferably culturing at 30 deg.C and 150rpm for 7 days; preferably, the Actinokinetopora diospyrosa strain of the persimmon tree can be cultured on a plate ISP2 culture medium at 26-30 ℃ for 7 days, then the culture medium is cut into blocks and put into TSB, and the TSB is cultured at 30 ℃ and 150rpm for 12 hours to obtain a seed solution for large-scale liquid culture.
(2) Adding resin into the fermentation liquor for adsorption, extracting the resin by using an alcohol solvent, carrying out gel column chromatography on the extract liquor or the concentrated solution thereof, and eluting by using the alcohol solvent to obtain 2 elution components;
preferably, the resin is selected from AmberliteTMThe alcohol solvents for extraction and elution of XAD macroporous adsorbent resin can be the same or different, and are selected from one or more of methanol, ethanol, isopropanol, and n-butanol. Preferably, methanol is used for extraction, a gel column is Sephadex LH-20, and elution is carried out by using pure methanol.
(3) And separating and purifying the first elution component by HPLC to obtain the compound shown in the invention.
Preferably, the HPLC chromatographic conditions are: using a reversed phase chromatographic column, and eluting by 30 to 40 percent acetonitrile in water in a gradient manner.
Preferably, a reverse phase chromatography column is used, mobile phase a: acetonitrile, mobile phase B: water, flow rate 2 mL/min.
The gradient elution procedure was:
Figure BDA0002982586540000022
。
in a specific example, in step (3), the HPLC separation and purification process is as follows: semi-preparative reverse phase high performance liquid chromatography by semihplc: ODS-2Hypersil gum, 5 μm, 250 mm. times.10 mm, mobile phase: acetonitrile-water volume ratio ═ 3:7 to 2: 3, elution is carried out with a gradient of 2mL/min for 20 min. The pump may be of the type Hitachi pump L-7100 and the UV lamp may be of the type UV detector L-7400.
The Actinokineospora diospyrosa used in the above preparation method of the present invention is obtained from the biological resource center of the Japanese institute for technical evaluation and research, and is characterized in that: on ISP2 plate, the hypha in the medium is brown yellow at the initial stage of culture, and is easy to generate single colony, and a small amount of aerial hypha begins to generate after one week without producing spores. The strain is preserved in the biological resource center of the Japanese technical evaluation research institute, and the preservation number is as follows: NBRC 15665, class name: actinokineospora diopsoas, address: 2-49-10 of West plain in Tokyo astringency region, 151 Zi code and 0066.
The invention also aims to provide the application of the compound in preparing medicines for inhibiting pathogenic bacteria. The pathogenic bacteria are drug-resistant or drug-intolerant gram-negative bacteria or positive bacteria. For example, Micrococcus luteus (G +), Staphylococcus capitis (G +), Pseudomonas aeruginosa (G-), Staphylococcus aureus (G +), Xanthomonas oryzae pv. oryzae Swings Xanthomonas oryzae (G-), Pseudomonas syringus pv. lachryma-myces melo (G-), Acidovorax avenae subsp. citrulli watermelon bacterial fruit blotch (G +), Bacillus subtilisus (G +), Methiocillin-resisant Staphylococcus aureus (G +), Vancomycin-Resistant Enterococcus enteromyces faecalis (G +).
The compounds of the invention are useful for the preparation of human, veterinary or plant (e.g. crop) antibiotics, particularly for the infection with drug-resistant pathogenic bacteria.
Has the advantages that:
the invention discovers a new compound named as norfloxacin A and norfloxacin B (dapyromide A and B) for the first time from fermentation products of Actinokinespora diospyri obtained from biological resource center of Japanese technical evaluation research institute, and in vitro activity experiments show that the compound has stronger inhibitory activity to pathogenic bacteria and can be further used for preparing medicines for inhibiting the pathogenic bacteria.
Drawings
FIG. 1 is an HPLC chromatogram of dasyromide A and B of the present invention.
FIG. 2 is a mass spectrum of daspyromide A of the present invention.
FIG. 3 is a spectrum of a diospyromin B of the present invention.
FIG. 4 shows dapyromide A1H NMR spectra (in DMSO-d)6 at 800MHz)。
FIG. 5 shows daspyromide A13C NMR spectra (in DMSO-d)6 at 200MHz)。
FIG. 6 is a dappyromide A DEPT 135 map (in DMSO-d)6)。
FIG. 7 shows daspyromide A1H-1H COSY NMR spectrum (in DMSO-d)6)。
FIG. 8 is a DASPYROMIDE A HSQC NMR spectrum (in DMSO-d)6)。
FIG. 9 is a Daspyrolide A HMBC NMR spectrum (in DMSO-d)6)。
FIG. 10 is a dapyrolide A NOESY map (in DMSO-d)6)。
FIG. 11 shows daspyromide B1H NMR spectra (in DMSO-d)6 at 800MHz)。
FIG. 12 shows daspyromide B13C NMR spectra (in DMSO-d)6 at 200MHz)。
FIG. 13 is a dapyrolide B DEPT 135 map (in DMSO-d)6)。
FIG. 14 shows daspyromide B1H-1H COSY NMR spectrum (in DMSO-d)6)。
FIG. 15 is a Daspyrolide B HSQC NMR spectrum (in DMSO-d)6)。
FIG. 16 is a Daspyrolide B HMBC NMR spectrum (in DMSO-d)6)。
FIG. 17 is a dapyrolide B NOESY map (in DMSO-d)6)。
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
Example 1: activation of Actinokineospora diospyrosa.
A freeze-stored dry powder of Actinokineospora diospyrosa, a strain derived from the center of biological resources of the Japan institute of technology evaluation and research, was spread on ISP2 medium (Yeast Extract 4g, Malt Extract 10g, Glucose 4g, agar 20g, distilled water 1L, pH7.4 to 7.6), and cultured in a 28 ℃ incubator to obtain the actinomycetes. On ISP2 plate, the hypha in the medium is brown yellow at the initial stage of culture, and is easy to generate single colony, and a small amount of aerial hypha begins to generate after one week without producing spores. The bacterium is identified as Actinokineospora diospora diospyrosa by the shape and 16S rRNA. The strain is named as Actinokineospora diospyrosa NBRC 15665, is deposited in the biological resource center of the Japanese technical evaluation research institute, and has the deposit number of: NBRC 15665.
Example 2: liquid fermentation of Actinokineospora diospyrosa
The strain Actinokineospora diospyrosa was transferred to TSB medium and fermented at 30 ℃ and 150rpm for 12 hours.
Example 3: 10ml of TSB was inoculated into F medium and cultured at 30 ℃ and 150rpm for 7 days.
Example 4: extraction and isolation of daspyromide
An appropriate amount of resin was added to the medium obtained in example 3, and the resin was extracted with methanol and concentrated to obtain extract F1. And (3) carrying out Sephadex LH-20 gel column chromatography on the extract F1, and eluting by taking MeOH as a mobile phase to obtain 2 peak-appearing components. The first peak-emerging fraction was subjected to semi-HPLC (column: Allsphere ODS-2.5mm column), acetonitrile-water system at a flow rate of 2mL/min in an acetonitrile-water volume ratio of 3:7 to 2: gradient elution is carried out for 20min by 3, and the dasyromide A (10mg) and the dasyromide B (6mg) are prepared. The pump may be of the type Hitachi pump L-7100 and the UV lamp may be of the type UV detector L-7400. The HPLC chromatogram is shown in FIG. 1.
The mass spectrum of daptomide A is shown in FIG. 2, and FIG. 4 shows daptomide A1H NMR spectra (in DMSO-d)6at800 MHz). FIG. 5 shows daspyromide A13C NMR spectra (in DMSO-d)6at 200 MHz). FIG. 6 is a dappyromide A DEPT 135 map (in DMSO-d)6). FIG. 7 shows daspyromide A1H-1H COSY NMR spectrum (in DMSO-d)6). FIG. 8 is a DASPYROMIDE A HSQC NMR spectrum (in DMSO-d)6). FIG. 9 shows dasyromide A HMBC NMR mapping (in DMSO-d)6). FIG. 10 is a dapyrolide A NOESY map (in DMSO-d)6). The data attribution of the hydrogen spectrum and the carbon spectrum are shown in Table 1.
Figure BDA0002982586540000051
TABLE 1
Figure BDA0002982586540000052
Figure BDA0002982586540000061
。
FIG. 3 shows the mass spectrum of daptomide B, and FIG. 11 shows daptomide B1H NMR spectra (in DMSO-d)6at800 MHz). FIG. 12 shows daspyromide B13C NMR spectra (in DMSO-d)6at 200 MHz). FIG. 13 is a dappyromide B DEPT 135 map (in DMSO-d)6). FIG. 14 shows daspyromide B1H-1H COSY NMR spectrum (in DMSO-d)6). FIG. 15 is a Daspyrolide B HSQC NMR spectrum (in DMSO-d)6)。
FIG. 16 is a Daspyrolide B HMBC NMR spectrum (in DMSO-d)6). FIG. 17 is a dapyrolide B NOESY map (in DMSO-d)6). The data attribution of the hydrogen spectrum and the carbon spectrum are shown in Table 2.
Figure BDA0002982586540000071
TABLE 2
Figure BDA0002982586540000072
Figure BDA0002982586540000081
。
Example 5: activity assay
Experimental materials: pathogenic bacteria, LB culture medium, DMSO, dasyromide A and dasyromide B.
The experimental method comprises the following steps:
1) preparation of medium and norfloxacin solution
Dissolving 10g of tryptone, 5g of yeast powder and 10g of sodium chloride in one liter of water, sterilizing at 121 ℃ for half an hour for later use, and adding 2% agar powder if preparing a solid culture medium; the norfloxacin solid was weighed and dissolved in DMSO to make up a 10mM solution.
Minimum inhibitory concentration:
the Minimum Inhibitory Concentration (MIC) is the lowest concentration of a drug that inhibits bacteria in a culture medium after culturing the bacteria in vitro for 18 to 24 hours, and is an index for measuring the magnitude of antibacterial activity of an antibacterial drug.
2) Determination of Activity
The pathogenic bacteria were inoculated into a 20mL tube containing 5mL LB medium and cultured overnight at 30 ℃. 100 mu L of overnight cultured pathogenic bacteria and 50mL of LB culture medium are mixed evenly and are subpackaged in 96-well plates (100 mu L per well), different amounts of norfloxacin solution are added, DMSO with the same volume of the solution is used as a blank control, and the overnight culture is carried out at 30 ℃.
The pathogenic bacteria are selected from Micrococcus luteus (G +), Staphylococcus capitis (G +), Pseudomonas aeruginosa (G-), Staphylococcus aureus (G +), Xanthomonas oryzae pv oryzae (G-), Pseudomonas syringosa (G-), Pseudomonas syringae pv, Lactobacillus macula melo (G-), Acidovorax avenae subsp. The MICs (unit: μ g/ml) of dasyrolide A and dasyrolide B for each pathogenic bacterium are shown in Table 3.
TABLE 3
Figure BDA0002982586540000091
In vitro activity experiments show that the dasyromide has stronger inhibitory activity to gram-negative or gram-positive pathogenic bacteria, and particularly has stronger inhibitory activity to drug-resistant bacteria.

Claims (6)

1. A compound of the formula wherein said formula is:
Figure DEST_PATH_IMAGE002
or
Figure DEST_PATH_IMAGE004
。
2. Process for the preparation of the compounds according to claim 1, characterized in that the persimmon tree is of the genus ActinoplanesActinokineospora diospyrosa The strain is obtained by liquid fermentation and extraction, and comprises the following steps:
(1) actinomyces of persimmon treeActinokineospora diospyrosa Inoculating the strain into an F culture medium for fermentation;
(2) adding resin into fermentation liquor for adsorption, extracting the resin by using an alcohol solvent, carrying out gel column chromatography on extract liquor or concentrated solution of the extract liquor, and eluting by using the alcohol solvent to obtain 2 eluted components, wherein the resin is selected from Amberlite TM XAD macroporous adsorption resin, the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol and n-butyl alcohol, and the gel column is Sephadex LH-20;
(3) separating and purifying the first eluted fraction by HPLC to obtain the compound of claim 1, wherein the HPLC chromatographic conditions are as follows: semi-preparative reverse phase high performance liquid chromatography column by semi-HPLC: ODS-2Hypersil gum, 5 μm, 250mm × 10mm, mobile phase A: acetonitrile, mobile phase B: water, flow rate 2mL/min, gradient elution procedure:
Figure DEST_PATH_IMAGE006
。
3. the method according to claim 2, wherein the culture in step (1) is carried out at 150rpm at 30 ℃ for 7 days.
4. Use of a compound according to claim 1 in the manufacture of a bacteriostatic medicament.
5. Use according to claim 4, characterized in that the pathogenic bacteria are resistant or non-resistant gram-negative or positive bacteria.
6. Use according to claim 5, characterized in that said pathogenic bacteria are selected from Micrococcus luteusMicrococcus luteusStaphylococcus capitisStaphylococcus capitisPseudomonas aeruginosaPseudomonas aeruginosaStaphylococcus aureusStaphylococcus aureusFlavobacterium oryzaeXanthomonas oryzae pv. oryzicola SwingsBacterial leaf spot pathogen of muskmelonPseudomonas syringae pv. LachrymansBacterial fruit blotch of watermelonAcidovorax avenae subsp. citrulliBacillus subtilisBacillus subtilisMethicillin-resistant Staphylococcus aureusMethicillin-resistant Staphylococcus aureusVancomycin-resistant enterococcusVancomycin-Resistant Enterococcus。
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CN113773355A (en) * 2021-08-23 2021-12-10 湖南省微生物研究院 Polyene macrolide compound and preparation method and application thereof

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* Cited by examiner, † Cited by third party
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CN113773355A (en) * 2021-08-23 2021-12-10 湖南省微生物研究院 Polyene macrolide compound and preparation method and application thereof

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