CN110818613A - Carbazole compound, preparation method thereof and application thereof in anti-HIV (human immunodeficiency virus) medicines - Google Patents

Carbazole compound, preparation method thereof and application thereof in anti-HIV (human immunodeficiency virus) medicines Download PDF

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CN110818613A
CN110818613A CN201910975721.7A CN201910975721A CN110818613A CN 110818613 A CN110818613 A CN 110818613A CN 201910975721 A CN201910975721 A CN 201910975721A CN 110818613 A CN110818613 A CN 110818613A
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petroleum ether
ethyl acetate
carbazole
dichloromethane
extract
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CN110818613B (en
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汪云松
汪欣怡
扬靖华
卢溶
白逸欣
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Yunnan University YNU
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56Ring systems containing three or more rings
    • C07D209/80[b, c]- or [b, d]-condensed
    • C07D209/82Carbazoles; Hydrogenated carbazoles
    • C07D209/88Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV

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  • Tropical Medicine & Parasitology (AREA)
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  • AIDS & HIV (AREA)
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Abstract

The invention discloses a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, belonging to the technical field of drugs. The carbazole compound has the chemical structural formula
Figure DDA0002233550340000011
Named as carbazole compound Clauolenzoles A. The carbazole compound Clauolenzoles A has the inhibitory activity on HIV, EC50The value was 2.4. mu.g/mL; the carbazole compound Clauolenzoles A and a medicinal carrier and/or an excipient can be prepared into an anti-HIV medicinal composition, and the anti-HIV medicinal composition is in the dosage form of injection, tablets, pills, capsules, solution, suspending agent or emulsion.

Description

Carbazole compound, preparation method thereof and application thereof in anti-HIV (human immunodeficiency virus) medicines
Technical Field
The invention relates to a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, belonging to the technical field of drugs.
Background
Current aids treatment regimens rely on a series of drugs, known as combined antiretroviral therapy (cART), which can improve the quality of life of HIV positive patients (Trends in pharmaceutical Sciences2011,32(12), 715.); another is the development of molecules capable of interacting with multiple targets simultaneously (drug discov. today, 2004, 9, 641.; med. chem., 2014, 22, 4658.); however, due to increasing drug resistance and side effects of current drugs, new anti-HIV drug molecules are constantly being discovered (clin. trials, 2005, 6, 5.; bmbrep.2015,48,121.); therefore, the search and development of highly effective and low-toxic anti-HIV drugs have become one of the most important research subjects in the world medical field.
Disclosure of Invention
Aiming at the problem of toxic and side effects of anti-HIV drugs in the prior art, provides a carbazole compound, a preparation method thereof and application thereof in anti-HIV drugs, wherein the carbazole compound Clauolenzoles A is extracted and separated from Clausena anium-olens Merr, has an inhibitory activity on HIV, and has EC50The value is 2.4 mu g/mL, and can be used for preparing anti-HIV pharmaceutical compositions.
A carbazole compound with the following chemical structural formula
Figure BDA0002233550330000011
Named as carbazole compound Clauolenzoles A.
An anti-HIV pharmaceutical composition comprises a medicinal carrier and/or an excipient, and the carbazole compound Clauolenzoles A.
The anti-HIV pharmaceutical composition is in the dosage form of injection, tablet, pill, capsule, solution, suspension or emulsion.
The extraction method of the carbazole compound comprises the following specific steps:
(1) percolating and extracting Clausena ansum-olens Merr dry powder of the flaccid Clausena by adopting ethanol to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;
(2) suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction aqueous phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction aqueous phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;
(3) performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed solution system and a dichloromethane/methanol mixed solution system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H;
(4) performing gel column chromatography on the component B in the step (3), eluting by adopting dichloromethane, and merging similar fractions according to thin-layer chromatography inspection to obtain 6 components, namely a, B, c, d, e and f;
(5) and (4) performing silica gel column chromatography on the component c, and eluting and purifying by adopting dichloromethane/methanol mixed solution to obtain the carbazole compound Clauolenzoles A.
Further, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution in the step (3) is 8:2, 2:1, 5:5, 4:6 and 0:1 in sequence, and the component B is an elution part with the volume ratio of petroleum ether to ethyl acetate of 2: 1.
Further, the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution for gradient elution in the step (3) is 8:2, 7:3, 6:4, 1:1 and 0:1 in sequence.
Further, the volume ratio of the dichloromethane to the methanol in the dichloromethane/methanol mixed solution in the step (5) is 50: 1.
Further, the mass percentage content of the carbazole compound Clauolenzoles A in the clausena lansium extract is 0.05%;
the pharmaceutically acceptable carrier and/or excipient is non-toxic to both humans and animals and is inert;
the medicinal carrier is one or more of solid diluent, semisolid diluent, liquid diluent, filler and pharmaceutical product adjuvant;
the pharmaceutical composition is administered in the form of an amount administered per unit body weight;
the medicine can be administered by injection (intravenous injection, intramuscular injection), oral administration or skin administration.
The invention has the beneficial effects that:
(1) the carbazole compound Clauo of the inventionLenzoles A have HIV inhibiting activity, EC50The value was 2.4. mu.g/mL; the carbazole compound Clauolenzoles A and a medicinal carrier and/or an excipient can be prepared into an anti-HIV medicinal composition;
(2) the carbazole compound Clauolenzoles A is derived from edible natural plant components, and the anti-HIV medicinal composition prepared from the carbazole compound Clauolenzoles A is non-toxic or low-toxic.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments, but the scope of the present invention is not limited to the description.
Example 1: the extraction method of the carbazole compound comprises the following specific steps:
(1) percolating and extracting Clausena ansum-olens Merr dry powder of the flaccid Clausena by adopting ethanol to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;
(2) suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction aqueous phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction aqueous phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;
(3) performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed solution system and a dichloromethane/methanol mixed solution system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H; wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixed solution for gradient elution is 8:2, 2:1, 5:5, 4:6 and 0:1 in sequence, and the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution for gradient elution is 8:2, 7:3, 6:4, 1:1 and 0:1 in sequence; the component B is an elution part with the volume ratio of petroleum ether to ethyl acetate of 2: 1;
(4) subjecting the component B in the step (3) to Sephadex LH-20 gel column chromatography, eluting with dichloromethane, and checking and combining similar fractions according to thin-layer chromatography to obtain 6 components, namely a, B, c, d, e and f; wherein the diameter of the gel column is 3cm, the length is 160cm, and the dry weight of Sephadex LH-20 gel is 150 g;
(5) performing silica gel column chromatography on the component c in the step (4), eluting and purifying by adopting a dichloromethane/methanol mixed solution to obtain a carbazole compound Clauolenzoles A, wherein the volume ratio of dichloromethane to methanol in the dichloromethane/methanol mixed solution is 50: 1;
the carbazole compound of the embodiment has the following chemical structural formula
Figure BDA0002233550330000031
Named as carbazole compound Clauolenzoles A;
preparation of carbazole-based Compound of the present example1H-NMR data (600MHz) (delta in ppm, J in Hz) and13c NMR data (. delta.in ppm, J in Hz) are shown in Table 1,
TABLE 1 preparation of carbazole-based compounds1H-NMR data and13c NMR data
Figure BDA0002233550330000041
The carbazole compound Clauolenzoles A is a white solid, and the molecular formula is C15H13NO2High resolution mass spectrum HRESIMS262.0839[ M + Na ]]+(calcd.262.0838)。
Example 2: in vitro anti-HIV activity assay of the carbazole compounds claulolenzoles a of example 1;
anti-HIV-1 activity of carbazole compound Clauolenzoles A, MT4 cells (1 x 10) in 96-well plate5cells/mL) at 50TCID in the presence of various concentrations of each test compound50Dose per well was infected with HIV-1NL4-3 Nonoluc-sec; on day 3 post-infection, supernatants were collected and assayed for luciferase activity using the Nano-Glo luciferase assay System (Promega); antiviral efficacy is defined as the concentration of compound that reduces luciferase activity by 50% (EC)50);
The result of the inhibitory activity test is as follows: EC (EC)50The (. mu.g/mL) values were: 2.4. + -. 0.53, CC50The (. mu.g/mL) values were: 17 plus or minus 2.5;
through molecular biological tests, it can be seen that the carbazole compound Clauolenzoles A shows anti-HIV activity and can act with HIV, so that the carbazole compound Clauolenzoles A can be used for preparing anti-HIV drugs and can be prepared into anti-HIV drug compositions with other drugs;
taking carbazole compound Clauolenzoles A as a raw material, and adding a medicinal carrier and/or an excipient to obtain a pharmaceutical composition containing the carbazole compound Clauolenzoles A;
the carbazole compound Clauolenzoles A is derived from edible natural plant components, and the anti-HIV medicinal composition prepared from the carbazole compound Clauolenzoles A is non-toxic or low-toxic;
the pharmaceutically acceptable carrier and/or excipient is non-toxic to both humans and animals and is inert;
the medicinal carrier is one or more of solid diluent, semisolid diluent, liquid diluent, filler and pharmaceutical product adjuvant;
the pharmaceutical composition is administered in the form of an amount administered per unit body weight;
the medicine can be administered by injection (intravenous injection, intramuscular injection), oral administration or skin administration.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (7)

1. A carbazole-based compound characterized in that: has the following chemical structural formula
Figure FDA0002233550320000011
Named as carbazole compound Clauolenzoles A.
2. An anti-HIV pharmaceutical composition characterized by: comprising a pharmaceutically acceptable carrier and/or excipient, and the carbazole-based compound according to claim 1.
3. The anti-HIV pharmaceutical composition of claim 2, in the form of injection, tablet, pill, capsule, solution, suspension or emulsion.
4. The extraction method of the carbazole-based compound according to claim 1, comprising the following steps:
(1) percolating and extracting Clausena ansum-olens Merr dry powder of the flaccid Clausena by adopting ethanol to obtain an extracting solution, and concentrating under reduced pressure to obtain a crude extract;
(2) suspending the crude extract obtained in the step (1) in water to obtain a suspension, extracting the suspension with petroleum ether to obtain a petroleum ether extract and a petroleum ether extraction aqueous phase, concentrating the petroleum ether extract to obtain a petroleum ether extraction extract, extracting the petroleum ether extraction aqueous phase with ethyl acetate to obtain an ethyl acetate extract, and concentrating the ethyl acetate extract to obtain an ethyl acetate extraction extract;
(3) performing silica gel column chromatography on the ethyl acetate extract obtained in the step (2), performing gradient elution by sequentially adopting a petroleum ether/ethyl acetate mixed solution system and a dichloromethane/methanol mixed solution system, and checking and merging similar fractions according to thin-layer chromatography to obtain 8 components, namely A, B, C, D, E, F, G and H;
(4) performing gel column chromatography on the component B in the step (3), eluting by adopting dichloromethane, and merging similar fractions according to thin-layer chromatography inspection to obtain 6 components, namely a, B, c, d, e and f;
(5) and (4) performing silica gel column chromatography on the component c, and eluting and purifying by adopting dichloromethane/methanol mixed solution to obtain the carbazole compound Clauolenzoles A.
5. The method for extracting carbazole-based compounds according to claim 4, wherein: and (3) carrying out gradient elution by sequentially using petroleum ether/ethyl acetate mixed liquor with the volume ratio of 8:2, 2:1, 5:5, 4:6 and 0:1, wherein the component B is an elution part with the volume ratio of petroleum ether to ethyl acetate of 2: 1.
6. The method for extracting carbazole-based compounds according to claim 4, wherein: and (3) carrying out gradient elution by sequentially using dichloromethane/methanol mixed solution to obtain dichloromethane/methanol mixed solution with the volume ratio of 8:2, 7:3, 6:4, 1:1 and 0: 1.
7. The method for extracting carbazole-based compounds according to claim 4, wherein: and (5) the volume ratio of the dichloromethane to the methanol in the dichloromethane/methanol mixed solution is 50: 1.
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Cited By (1)

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CN115385883A (en) * 2022-07-08 2022-11-25 云南大学 Preparation method of coumarin compound and application of coumarin compound in monoamine oxidase B inhibition resisting medicine

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Cited By (1)

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