CN116606283A - Rumbrin compounds with anti-HIV activity - Google Patents

Rumbrin compounds with anti-HIV activity Download PDF

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CN116606283A
CN116606283A CN202210119647.0A CN202210119647A CN116606283A CN 116606283 A CN116606283 A CN 116606283A CN 202210119647 A CN202210119647 A CN 202210119647A CN 116606283 A CN116606283 A CN 116606283A
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unsubstituted
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alkoxy
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胡友财
岑山
钟贝芬
商昌辉
王宇佳
温佳佳
柏健
刘冰语
魏茜
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Institute of Materia Medica of CAMS
Institute of Medicinal Biotechnology of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention belongs to the field of biological medicine, relates to a Rumbrin compound with anti-HIV activity, and in particular relates to a Rumbrin compound shown in a general formula (I) and pharmaceutically acceptable salts thereof, a pharmaceutical composition and application of the Rumbrin compound in preparation of anti-HIV medicines.

Description

Rumbrin compounds with anti-HIV activity
Technical Field
The invention relates to the field of biological medicine, in particular to application of a rumbrin compound or pharmaceutically acceptable salt thereof and a medicinal composition containing the compound in preparation of anti-HIV (human immunodeficiency Virus) medicaments.
Background
AIDS (AIDS), also known as acquired immunodeficiency syndrome, is an infectious disease caused by specific infection of Human Immunodeficiency Virus (HIV) and killing of main lymphocytes of human body, after infection of an individual, due to destruction of immune system, easy occurrence of sexual infection and malignant tumor, high death rate, and no thorough cure method at present [1] . The first anti-HIV drug in 1987 was marketed [2] However, with the rapid increase of the number of people infected by AIDS for many years, a great deal of manpower and financial resources are put into the field of anti-HIV medicines worldwide, and the field is always one of hot spots for medicine development.
AIDS seriously jeopardizes the health of human beings and the stability of society, and no effective cure method exists until now. High-potency antiretroviral therapy (highly active antiretroviral therapy, HAART) is currently the primary treatment for AIDS, requiring a lifetime medication. Currently, AIDS therapeutic drugs are mainly directed to the 3 key enzymes IN the HIV life cycle, namely reverse transcriptase (reverse transcriptase, RT), protease, integrase (IN), and HIV invasion process [3] . According to different action targets, anti-HIV drugs can be classified into six categories, namely nucleoside reverse transcriptase inhibitors (nucleoside reverse transcriptase inhibitors, NRTI), non-nucleoside reverse transcriptase inhibitors (nonnucleoside reverse transcriptase inhibitors, NNRTI), protease inhibitors (protease inhibitors, PI), fusion inhibitors (fusion inhibitors), entry inhibitors (entry inhibitors) or co-receptor antagonists (CCR 5 co-receptor antagonist), and integrase inhibitors (HIV integrasestrand transfer inhibitors) [4] 。
Rumbrin was at the earliest the compound identified by isolation from Australian soil fungus Auxarthron umbrinum DSM3193 [5] Is a secondary metabolite of fungi catalyzed by polyketide synthase. At present, the research on the rumbrin is not more, and the existing research results show that the rumbrin compounds are used for brain cells Has good activity in protecting and tumor cytotoxicity. For example, rumberin can alleviate tissue injury by preventing cell membrane lipid peroxidation and antagonizing intracellular overload calcium ions, has cytoprotective activity (1.3-40 μg/mL, more than 50% of cells are viable) comparable to that of commercially available medicine flunarizine, and shows more remarkable effect (IC) 50 ＝0.47μg/mL vs 11.5μg/mL) [6] . Furthermore, the toxicity test results show that the aqueous solution of the crude methanol extract has no obvious toxicity to mice administered at a dose of 200mg/kg for three consecutive days [7] . On the other hand, the rumbrin structural analogues show remarkable cytotoxic activity on cancer cells [8][9][10] But has no cytotoxic activity to human normal lung cells, and the cellular activity is basically maintained at 90-100% [11] . So far, no report on anti-HIV activity is known.
The inventors of the present invention found that 12E-rumberin has significant anti-HIV activity. On the basis, a series of rumbrin novel compounds are prepared by the methods of wild strain culture, substrate feeding, precursor-directed biosynthesis and the like. The literature search shows that the structure and anti-HIV activity of the compounds are not reported in the literature, and the compounds are anti-HIV compounds with novel structures and have potential application value as anti-HIV candidate drug development.
Reference is made to:
[1] wang Xia, ma Hongtao, wen Ruixing, anti-HIV drugs and research on their targets [ J ]. J.Chinese J.traditional Chinese medicine, 2009,34 (11): 1454-1459.
[2] Feng, zhang Qingwen, xu Yungen New development of anti-HIV-1 drugs and compound preparations thereof [ J ]. Pharmaceutical development, 2012,36 (12): 539-546.
[3] Yang Wensai, wang Yang HIV inhibitor mechanism of action, and research progress [ J ]. Modern biomedical progress, 2012,12 (23): 4560-4565.
[4]Mehellou Y,De Clercq E.Twenty-six years of anti-HIV drug discovery:where do we stand and where do we go[J].J Med Chem,2010,53(2):521-538.
[5]Yamagishi Y,Shindo K,Kawai H.Rumbrin.a New Cytoprotective Substance Produced by Auxarthron umbrinum.II.Physico-Chemical Properties and Structure Determination[J].The Journal of Antibiotics,1993,46(6):888–891.
[6]Erik B,Jacqueline H,Walter J,et al.New Anti-Ischaemic Drugs:Cytoprotective Action with No Primary Haemodynamic Effects[J].Trends in Pharacological Sciences 1989,10(10):397–400.
[7]Yamagishi Y,Matsuoka M,Odagawa A,et al.Rumbrin,a New Cytoprotective Substance Produced by Auxarthron umbrinum.I.Taxonomy,Production,Isolation and Biological Activities[J].The Journal of Antibiotics,1993,466(6):884–887.
[8]Benjamin R C,Robert J C,Ernest L,et al.Polyenylpyrroles and Polyenylfurans from an Australian Isolate of the Soil Ascomycete Gymnoascus reessii[J].Organic Letters,2006,8(4):701–704.
[9]Robert S C,Matthew C W.Total Synthesis of Gymnoconjugatins Aand B[J].Journal of Chemistry,2006,71(26):9841–9846.
[10]Benjamin R C,Ernest L,Jennifer H G,et al.The Effect of Halide Salts on the Production of Gymnoascus Reessii Polyenylpyrroles[J].The Journal of Natural Products,2007,70(4):665–667.
[11]Fang Z,Liao P C,Yang Y L,et al.Synthesis and Biological Evaluation of Polyenylpyrrole Derivatives as Anticancer Agents Acting through Caspases-Dependent Apoptosis[J].Journal of Medicinal Chemistry,2010,53(22):7967–7978.
Disclosure of Invention
The invention solves the technical problem of providing a rumbrin compound and pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and application of the compound in preparation of anti-HIV drugs.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides a rumbrin compound and pharmaceutically acceptable salt thereof, and the structural formula of the rumbrin compound is shown as a general formula (I):
wherein ,
n=0, 1, 2,3, 4, the double bonds are each independently selected from cis or/and trans configurations;
R 2 and R3 Each independently selected from halogen such as hydrogen, F, cl, br, I, etc.;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution being monosubstitutedDi-, tri-, tetra-substituted, each substituent being independently selected from hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
Preferably, the compound is represented by formula (IA)
wherein ,
R 2 and R3 Each independently selected from halogen such as hydrogen, F, cl, br, I, etc.;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution being monosubstitutedDi-, tri-, tetra-substituted, each substituent being independently selected from hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
Preferably, the compound is represented by formula (IA 1)
wherein ,
R 3 halogen selected from hydrogen, F, cl, br, I, etc.;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitutionSubstituted, each substituent being independently selected from hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
Preferably, the compound is represented by formula (IA 2)
wherein ,
R 2 halogen selected from hydrogen, F, cl, br, I, etc.;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are independentIs selected from hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
Preferably, the compound is represented by formula (IA 3)
wherein ,
R 2 halogen selected from hydrogen, F, cl, br, I, etc.;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitro and cyanoRadicals, amino radicals, carboxyl radicals, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
Preferably, the compound is represented by formula (IA 4)
wherein ,
R 3 halogen selected from hydrogen, F, cl, br, I, etc.;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
Preferably, the compound is represented by formula (IB)
wherein ,
R 2 halogen selected from hydrogen, F, cl, br, I, etc.;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
Specifically, the rumbrin compounds represented by general formulas (I), (IA 1), (IA 2), (IA 3), (IA 4), and (IB) and pharmaceutically acceptable salts thereof, wherein the compounds are selected from the following groups (the compound numbers correspond to the compound numbers in the examples):
in a second aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to each of formulae (I), (IA 1), (IA 2), (IA 3), (IA 4) and (IB) and a pharmaceutically acceptable carrier.
According to the present invention, the compound of the present invention may exist in the form of an isomer, and the general term "compound of the present invention" includes the isomer of the compound.
According to an embodiment of the invention, the compounds of the invention also include pharmaceutically acceptable salts, hydrates of salts or prodrugs thereof.
The invention also relates to pharmaceutical compositions containing as active ingredient a compound according to the invention and conventional pharmaceutical excipients or auxiliaries. Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of the compound of the present invention. The compounds of the invention are generally present in unit dosage forms in amounts of from 0.1 to 100mg, with preferred unit dosage forms containing from 4 to 50mg.
Pharmaceutical compositions of the compounds of the present invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention may, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or auxiliaries, in any suitable form or dosage form for use as a human or veterinary drug.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intramuscular, subcutaneous, nasal, oral, dermal, peritoneal or rectal, etc. The route of administration of the compounds of the invention or pharmaceutical compositions containing them may be by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.
The administration dosage form may be liquid dosage form or solid dosage form. For example, the liquid dosage form may be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The compound of the invention can be prepared into common preparations, and can also be sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For example, in order to prepare a unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, and the like; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
For example, carriers well known in the art may be widely used for the purpose of making the dosage unit into a pill. Examples of carriers include diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, glycerol monostearate, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.
For example, in order to capsule the administration unit, the compounds of the invention are mixed with the various carriers described above, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredient of the compound can be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, or can be filled into hard capsules or prepared into injection for application.
For example, the compounds of the present invention may be formulated as injectable formulations, such as solutions, suspension solutions, emulsions, lyophilized powder for injection, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxyl isostearyl alcohol, polyoxyethylene sorbitol ester, fatty acids, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of the present invention depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, character and individual response of the patient or animal, the route of administration, the number of times of administration, the purpose of treatment, and thus the therapeutic dosage of the present invention may vary widely. Generally, the dosages of pharmaceutical ingredients used in the present invention are well known to those skilled in the art. The amount of the actual drug contained in the final formulation of the compound composition of the present invention may be appropriately adjusted to achieve the therapeutically effective amount thereof, thereby achieving the preventive or therapeutic object of the present invention. Daily suitable dosage range of the compounds of the invention: the compounds of the present invention are used in an amount of 0.001 to 150mg/kg body weight, preferably 0.1 to 100mg/kg body weight, more preferably 1 to 60mg/kg body weight, most preferably 2 to 30mg/kg body weight. The compound of the invention is taken by adult patients at a daily dose of 10-500 mg, preferably 10-100 mg, and can be taken once or 2-3 times; the dose taken by children is 5-30 mg, preferably 10-20 mg/kg body weight per kg body weight. The above-mentioned dosages may be administered in a single dosage form or in divided dosage forms, for example, two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the administration regimen of the therapeutic means. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.
According to a third aspect of the technical scheme, the application provides application of the compound in the first aspect and pharmaceutically acceptable salts thereof and the pharmaceutical composition in the second aspect in preparation of anti-HIV drugs. Detailed description of the application:
various terms and phrases used herein have the ordinary and customary meaning as understood by those skilled in the art, and even though they are still intended to be more fully described and explained herein, the terms and phrases used herein are to be understood and to have a meaning inconsistent with the ordinary and customary meaning as set forth herein. The following are definitions of various terms used in the present application, which are applicable to terms used throughout the specification of the present application unless otherwise specified in the specific context.
As referred to herein, the terms "halogen", "halogen atom", "halo", and the like, denote fluorine, chlorine, bromine, or iodine, preferably chlorine or fluorine.
The term "C" as referred to in the present application 1-6 The "hydrocarbon group" of (C) refers to a straight-chain or branched hydrocarbon group having 1, 2, 3, 4, 5, 6 carbon atoms, and may include C 1-5 C is a hydrocarbon group of (C) 1-4 C is a hydrocarbon group of (C) 2-5 C is a hydrocarbon group of (C) 2-4 C is a hydrocarbon group of (C) 2-3 C is a hydrocarbon group of (C) 3-5 A hydrocarbon group, etc., and preferably specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.
The term "alkyl" as referred to herein means an alkyl group having the indicated number of carbon atoms, which may be a straight or branched chain alkyl group, e.g. "C" as referred to 3-6 Cycloalkyl "of (C) refers to a substituted or unsubstituted cycloalkyl group having 3, 4, 5, 6 carbon atoms, and may include C 3-5 Cycloalkyl, C 3-4 Cycloalkyl, C 4-6 Cycloalkyl, C 4-5 Cycloalkyl, C 5-6 Cycloalkyl groups, and the like, and preferred specific groups such as cyclopropane, cyclopentane, and cyclohexane.
The term "C" as referred to in the present invention 1-6 Alkoxy "of (C) refers to an alkoxy group having 1, 2, 3, 4, 5, 6 carbon atoms, including C 1-5 Alkoxy, C 1-2 Alkoxy, C 2-4 Alkoxy, C 2-3 Alkoxy, C 3-4 Alkoxy, etc., and preferred specific groups such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, etc.
The term "C" as referred to in the present invention 2-6 The term "unsaturated hydrocarbon group" as used herein means an unsaturated hydrocarbon group having 2, 3, 4, 5, 6 carbon atoms, and may include C 2-5 Unsaturated hydrocarbon group, C 2-4 Sub-ranges of groups represented by unsaturated hydrocarbon groups and the like, and preferably specific groups such as vinyl groups Acetylene, isopropenyl, isobutenyl, isopentenyl, 1, 4-dibutenyl.
The term "C" as referred to in the present invention 1-6 The "acyl" refers to an acyl group having 1, 2, 3, 4, 5, and 6 carbon atoms, and may include C 1-5 Acyl group, C 1-3 Acyl group, C 2-5 Acyl group, C 2-3 Acyl group, C 3-4 Acyl groups, etc., and preferred specific groups, such as formyl, acetyl, propionyl, etc.
Reference to "C" in the present invention 1-6 The "acyloxy group" of (C) refers to a straight-chain or branched acyloxy group having 1, 2, 3, 4, 5, 6 carbon atoms and may include C 1-5 Acyl group C of (2) 1-3 Acyl group C of (2) 2-5 Acyl group C of (2) 2-3 Acyl group C of (2) 3-4 The acyl group and the like, and preferably specific groups such as formyloxy, acetoxy, propionyloxy and the like.
Reference to "C" in the present invention 1-6 Alkoxyacyl "of (C) is an alkanoyl group having 1, 2, 3, 4, 5, 6 carbon atoms and may include C 1-5 Alkoxyacyl radicals C 1-3 Alkoxyacyl radicals C 2-5 Alkoxyacyl radicals C 2-3 Alkoxyacyl radicals C 3-4 A sub-range group represented by an alkanoyl group or the like, and preferably a specific group such as a methoxyacyl group, an ethoxyacyl group or the like;
the term "C" as referred to in the present invention 1-6 Alkylthio "of (C) refers to straight-chain or branched alkylthio of 1, 2, 3, 4, 5, 6 carbon atoms, and may include C 1-5 Alkylthio, C 1-3 Alkylthio, C 2-5 Alkylthio, C 2-3 Alkylthio, C 3-4 Alkylthio groups, etc., and preferably specific groups, such as methylthio, ethylthio, etc.
The beneficial technical effects are as follows:
the inventors of the present invention have obtained significant results in the investigation of the secondary metabolite active ingredient of the fungus a. Umbrinum by means of heterologous expression and precursor directed biosynthesisanti-HIV active rumbrin compounds. Further evaluation of antiviral activity of the compounds proves that the compounds have anti-HIV-1 virus effect, and the compounds have strong inhibitory activity on HIV-1 virus replication. IC of compound with highest inhibitory activity on HIV-1 virus 50 The value can reach 24.85+/-0.86 nM.
Detailed Description
The following examples further illustrate the invention but do not limit it in any way.
Example 1: feeding different precursors to the wild strain, and extracting and separating the fermentation liquor to obtain the compounds 1-12, wherein the specific operation process is as follows:
commercial strains Auxarthron umbrinum DSM3193 were cultivated in 3 groups in cottonseed meal-rich medium and 3 days later fed 3 different substrates: pyrrole-2-carboxylic acid, 3-fluoro-pyrrole-2-carboxylic acid ethyl ester and 4-fluoro-pyrrole-2-carboxylic acid. After 7 days, mycelia were collected, and extracted with an appropriate amount of EtOAc (1 h/3 times) by sonication, and rotary evaporation to give a crude extract, 3 strains of 3 groups gave 3 crude extracts of M1, M2 and M3, respectively. And (3) performing medium-pressure separation and High Performance Liquid Chromatography (HPLC) purification on each crude extract to obtain the compounds 1-12.
The crude extract M1 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gave 15 fractions Fr.1-Fr.15. HPLC purification of Fr.5 fraction with 68% MeOH-H as mobile phase system 2 O, to give Compound 1 (2.3 mg), 2 (1.2 mg), 3 (5.3 mg), respectively; HPLC purification of Fr.6 fraction with mobile phase system of 72% MeOH-H 2 O, to give Compound 4 (1.8 mg); HPLC purification of Fr.9 fraction with mobile phase system of 53% MeCN-H 2 O, to give Compound 5 (2.8 mg); HPLC purification of Fr.11 fraction with mobile phase system of 75% MeCN-H 2 O, compound 12 (6.8 mg) was obtained.
The crude extract M2 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gave 7 fractions Fr.1-Fr.7. HPLC purification of Fr.3 fraction with mobile phase system of 65%MeOH-H 2 O, to give Compound 6 (2.5 mg), respectively; HPLC purification of Fr.4 fraction with mobile phase system of 75% MeOH-H 2 O, compounds 7 (2.3 mg) and 8 (4.5 mg) were obtained.
The crude extract M3 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gives 8 fractions Fr.1-Fr.8. HPLC purification of Fr.4 fraction with 70% MeOH-H as mobile phase system 2 O, compounds 9 (3.2 mg), 10 (1.5 mg) and 11 (4.1 mg) were obtained, respectively.
Example 2: compounds 1-11 can be obtained by precursor-directed biosynthesis:
gene function analysis and annotation of the gene cluster rum for the synthesis of rumbrin in fungi A. Umbrinum, which contains 5 genes, encoding a coenzyme A ligase (RumA, SEQ ID NO.1 for the gene sequence encoding the protein), a polyketide synthase (RumB, SEQ ID NO.2 for the gene sequence encoding the protein), a free thioesterase (RumC, SEQ ID NO.3 for the gene sequence encoding the protein), a methyltransferase (RumD, SEQ ID NO.4 for the gene sequence encoding the protein) and a chloroenzyme (RumE, SEQ ID NO. 5) were carried out. The method comprises the steps of using a strategy of precursor-directed biosynthesis to introduce biosynthesis genes of the rumbrin compounds into a heterologous expression host of aspergillus nidulans in different combination modes, fermenting the obtained mutant strain to obtain a fermentation product, and obtaining a metabolite through various column chromatography and purification means. Firstly, respectively transferring rumABC, rumABCD, rumABE, rumABCDE recombinant plasmids into aspergillus nidulans to construct 4 heterologous expression mutant strains, respectively feeding pyrrole-2-carboxylic acid, 3-fluoro-pyrrole-2-carboxylic acid ethyl ester and 4-fluoro-pyrrole-2-carboxylic acid serving as precursor substrates into different mutant strains to obtain 6 different seed combinations (table 1), respectively culturing at 28 ℃ for 7-10 days, collecting a culture medium, adding a proper amount of EtOAc (1 h/3 times), performing ultrasonic extraction, performing rotary evaporation to obtain crude pastes, and respectively obtaining 6 crude pastes of the total of 6 different combinations of F1, F2, F3, F4, F5 and F6. Compounds 1-11 were obtained by medium pressure separation and HPLC purification of the respective crude extracts.
Table 1: information of 6 different combinations of coarse pastes
The separation and purification process of each crude extract is as follows:
the crude extract F1 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gave 4 fractions Fr.1-Fr.4. HPLC purification of Fr.3 fraction with 68% MeOH-H as mobile phase system 2 O, compounds 1 (1.2 mg), 2 (0.8 mg) and 3 (7.0 mg) were obtained, respectively.
The crude extract F2 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gave 6 fractions Fr.1-Fr.6. HPLC purification of Fr.4 fraction with mobile phase system of 72% MeOH-H 2 O, compound 4 (1.0 mg) was obtained.
The crude extract F3 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gives 8 fractions Fr.1-Fr.8. HPLC purification of Fr.4 fraction with mobile phase system of 53% MeCN-H 2 O, compound 5 (5.8 mg) was obtained.
The crude extract F4 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gave 22 fractions Fr.1-Fr.22. The fractions Fr.13-Fr.19 were combined and purified by HPLC with a mobile phase system of 53% MeCN-H 2 O, compound 6 (5.9 mg) was obtained.
The crude extract F5 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gives 8 fractions Fr.1-Fr.8. HPLC purification of Fr.6 fraction with mobile phase system of 60% MeCN-H 2 O, compound 7 (1.3 mg) was obtained. HPLC purification of Fr.4 fraction with mobile phase system of 65% MeCN-H 2 O, compound 8 (1.2 mg) was obtained.
The crude extract F6 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gives 10 fractions Fr.1-Fr.10. HPLC purification of Fr.8 fraction with mobile phase system of 65% MeCN-H 2 O, compound 10 (23.5 mg) was obtained. HPLC purification of Fr.6 fraction with mobile phase system of 53% MeCN-H 2 O gave compounds 10 (1.5 mg) and 11 (11.4 mg), respectively.
The crude extract F7 is prepared by passing through ODS chromatographic column under medium pressure, meOH-H 2 O gradient elution (30:70, 100:0, v/v) gave 12 fractions Fr.1-Fr.12. HPLC purification of Fr.11 fraction with mobile phase system of 75% MeCN-H 2 O, compound 12 (6.3 mg) was obtained.
The spectral data for compounds 1-12 are as follows:
compound 1: red amorphous powder; UV (MeCN) lambda max (logε)267(4.22),318(4.13),334(4.28),434(4.75)nm；IRν max 3429,2960,2919,2851,1722,1621,1566,1543,1468,1432,1415,1261,1097,1035,863,802,720cm -1 ；HRESIMS:282.11185[M+H] + ,Calcd.for C 17 H 16 O 3 N,282.11247； 1H and 13 The C NMR data are shown in Table 2 and Table 6.
Compound 2: red amorphous powder; UV (CHCl) 3 )λ max (logε)267(4.35),318(4.17),334(4.20),434(4.92)nm；IRν max 3417,2962,2918,2851,1724,1600,1563,1468,1445,1407,1261,1092,1038,863,802,705cm -1 ；HRESIMS:296.12759[M+H] + ,Calcd.for C 19 H 19 O 3 NCl,296.12812； 1H and 13 the C NMR data are shown in Table 2 and Table 6.
Compound 3: red amorphous powder; UV (CHCl) 3 )λ max (logε)268(3.75),319(3.60),334(3.84),434(4.28)nm；IRν max 3371,3207,2961,2923,2853,1634,1584,1554,1474,1405,1374,1262,1155,1096,1029,981,800,724cm -1 ；HRESIMS:310.14252[M+H] + ,Calcd.for C 19 H 19 O 3 NCl,310.14377； 1H and 13 the C NMR data are shown in Table 2 and Table 6.
Compound 4: red amorphous powder; UV (MeCN) lambda max (logε)269(3.99),338(3.84),454(4.42)nm；IR ν max 3340,2962,2920,2852,1712,1661,1628,1538,1412,1261,1095,1037,863,801,705cm -1 ；HRESIMS:310.14328[M+H] + ,Calcd.for C 19 H 20 O 3 N,310.14377； 1H and 13 the C NMR data are shown in Table 3 and Table 6.
Compound 5: red amorphous powder; UV (MeCN) lambda max :269,322,339,430nm；HR-ESI-MS:342.09036[M-H] - ；Calcd.for C 19 H 17 ClNO 3 ,342.09024； 1H and 13 the C NMR data are shown in Table 3 and Table 6.
Compound 6: red amorphous powder; UV (MeCN) lambda max :266,320,332,430nm.HRESIMS:328.1339[M+H] + ,Calcd.for C 19 H 19 FNO 3 ,328.1343. 1H and 13 the C NMR data are shown in Table 3 and Table 6.
Compound 7: red amorphous powder; UV (MeCN) lambda max :270,322,338,437nm.HRESIMS:[M+H] + ,m/z 342.1495；Calcd.for C 20 H 21 FNO 3 ,342.1500； 1H and 13 the C NMR data are shown in Table 4 and Table 7.
Compound 8: red amorphous powder; UV (MeCN) lambda max :261,312,329,435nm；HRESIMS:[M+H] + ,m/z 314.1185；Calcd.for C 18 H 17 FNO 3 ,314.1187； 1H and 13 the C NMR data are shown in Table 4 and Table 7.
Compound 9: red amorphous powder; UV (MeCN) lambda max :261,325,339,430nm；HRESIMS:376.1108[M+H] + ,calcd for C 20 H 20 ClFNO 3 ,376.111； 1H and 13 the C NMR data are shown in Table 4 and Table 7.
Compound 10: red amorphous powder; UV (MeCN) lambda max :267,324,339,432nm；HRESIMS:362.0955[M+H] + ；Calcd.for C 19 H 18 ClFNO 3 ,362.0954； 1H and 13 the C NMR data are shown in Table 5 and Table 7.
Chemical combinationArticle 11: red amorphous powder; UV (MeCN) lambda max :262,315,330,426nm；HRESIMS:348.0795[M+H] + ,Calcd.for C 18 H 16 ClFNO 3 ,348.0797； 1H and 13 the C NMR data are shown in Table 5 and Table 7.
Compound 12: red amorphous powder; UV (MeCN) lambda max :268,329,341,440nm；HRESIMS:C 20 H 21 ClNO 3 [M+H] + ,m/z 358.1205；Calcd.for C 20 H 21 ClNO 3 ,358.1204； 1H and 13 the C NMR data are shown in Table 5 and Table 7.
Table 2: compounds 1 to 3 1 H NMR data
a 1-3 were tested on a 500MHz nuclear magnetic resonance spectrometer with DMSO-d as solvent 6 。
Table 3: compounds 4 to 6 1 H NMR data
a 4 testing on 500MHz nuclear magnetic resonance spectrometer, the solvent is DMSO-d 6 ； b 5 testing on 800MHz nuclear magnetic resonance spectrometer, the solvent is DMSO-d 6 ； c 6 testing on 700MHz nuclear magnetic resonance spectrometer, the solvent is DMSO-d 6 。
Table 4: compounds 7 to 9 1 H NMR data
a 9 testing on 500MHz nuclear magnetic resonance spectrometer, the solvent is DMSO-d 6 ； c 7-8 was tested on a 700MHz nuclear magnetic resonance spectrometer with DMSO-d as solvent 6 。
Table 5: compounds 10 to 12 1 H NMR data
a 10-12 were tested on a 500MHz nuclear magnetic resonance spectrometer with DMSO-d as solvent 6 。
Table 6: compounds 1 to 6 13 C NMR data
a 1-4 was tested on a 125MHz NMR spectrometer with DMSO-d as solvent 6 ； b 5 testing on 200MHz nuclear magnetic resonance spectrometer, the solvent is DMSO-d 6 ； c 6 testing on 175MHz nuclear magnetic resonance spectrometer, the solvent is DMSO-d 6 。
Table 7: compounds 7 to 12 13 C NMR data
a 9-12 were tested on a 125MHz NMR spectrometer with DMSO-d as solvent 6 ； c 7-8 was tested on a 175MHz nuclear magnetic resonance spectrometer with DMSO-d as solvent 6 。
Example 3: evaluation of anti-HIV Activity of Compounds
(1) Experimental method
293T cells (cell concentration 2X 10) 5 Individual/mL) was co-transfected with pHIT/G (0.4. Mu.g) and pNL4-3.Luc.R-E- (0.6. Mu.g). After 48h, HIV-1 pseudoviruses were collected by filtration and then the viral capsid proteins were quantified by p24 antigen capture ELISA. The resulting virus was used to infect SupT1 cells (moi=1) at a cell concentration of 2×10 5 And (3) per mL, then adding the serial dilutions of the compound to be detected (efavirenz as positive control). At 37℃with 5% CO 2 After a further 48 hours incubation under the conditions of (a) the inhibition was determined using a firefly luciferase assay system. Cells were lysed with cell culture lysis buffer (Promega) and treated at 37℃for 20 min. 10 mu L of cell lysate is added into 40 mu L of luciferase substrate, and the mixture is uniformly mixed, and the activity of luciferase is measured by a 960 enzyme-labeled instrument, and the activity of the luciferase is reflected in HIV replication level, and the result is shown in Table 5.
(2) Experimental results
The present invention investigated the anti-HIV-1 activity of the compounds 1-12 of the examples and found that these compounds have various degrees of inhibition of HIV-1 at a concentration of 10. Mu.M. The inhibition rates of other compounds than compound 2 were all more than 50% (Table 5), with ICs of compounds 3, 4, 5, 7, 8, 10 and 11 50 At 4.25+ -0.62 μM, 376.66 + -5.46 nM, 24.85+ -0.86 nM, 79.29 + -1.98 nM, 251.61 + -3.77 nM, 311.8+ -7.29 nM and 32.73+ -0.98 nM, respectively.
TABLE 5 evaluation of anti-HIV-1 Activity of partial Compounds
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Sequence listing
<110> national academy of medical science, pharmaceutical and biotechnology institute of national academy of medical sciences
<120> Rumbrin compounds with anti-HIV activity
<160> 5
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1816
<212> DNA
<213> Auxarthron umbrinum DSM3193
<400> 1
atgatttgcc ccagccatgg caacatttcc accgatttgg tgacttttac ctttagcgga 60
cccgcgaagc acaccgagcg gccgcttttt atcgacgcgg aaaacccgtc gcgggcattg 120
aacgcagccg agttcaggct cttggttcgg acgttgatcg caggtcttca agctcagggt 180
gttcagcggg gagattgcgt gctggtacat tcgaaaaata atgtacgttt ctgcatgctt 240
ccgagaactt ttttatgaag cctgacatat gtggcgttcg gatcataggt gatctatcca 300
gctctgttcc tcgccatcgt tggagccggt ggtgtccata tggggtctaa tccaaatagt 360
cgggccttcg agctggagca tacgttggac ctcgcggagc ctcggataat tatcacctgc 420
gctgagtctc ttgacacagt ccttgcggtt tcttcgggga aaggcatcga cccaaaacag 480
attttcctgc ttgacgattc cgggattggc gatgttgtca gttttgtaaa taatcgggac 540
gaaacagctt cggtatcttc gacaaactct gaggaaccgt atatgaatat tatgcatctt 600
ctttcgcatg gagaaaacga ctggcgcacc attggcgatg agaaaacctc caagggaacg 660
ccagccgcca tgtttcccac gagtggcacg accgggcttt ccaaggcagc gattatgtcg 720
catcattccc tcatctcatg gcatatgagc atctgttacg aagtcccgta cgacgtgtcc 780
cggctgatcg ctatccctat gtttcataac tttagttcga cctttaccca tttcttctca 840
gtccgctaca gtcacccgtt atatatcctg cccgagttta acctatcgca ggttctcaaa 900
gcagcatcca agtaccaaat ctccgaaatg tttctggttc cagtcatgat ccagatgata 960
agtcaatcgt ctctgccagt aaaggaatct ttgtcctcca tccgctatgt tggtgtagcc 1020
ggggcaccca tcgatggaga gtccatgaag aaattccagg agctactcca tggcgacgcc 1080
cgtgcttcac agatgtgggg aatgactgaa gttggagtgg caatgcagaa ccggtacagt 1140
ctctcaaata cgggctatga aatggggagt attggaaagc tgtctccagg atatgaaacc 1200
cgcttgattg accctgaaag cggaaaaatc atagtcgacg acaactgtcc gggccagttg 1260
tatatccgcg gtcccggcct gctcctgacc tacaaaggtc gcagcaatgc caaggacgac 1320
gatggatggt ttgacactgg agatgtcgcg tataccaagg atgggtacta tttcatcttt 1380
ggtcggacga aagagatcat caaagtgcga gggtaagtgc tatgatgcgg ttatctccct 1440
tcttcgcccc ttctgcagac ttatactgaa ctctggtgtc cctagatatc aagtcgcgcc 1500
cgcggagatc gaagccgtcc tattaaccca tcctcaaatc cgagatgcgg gcgtcattgg 1560
cgtgatgtct gccgatgaaa gcacggaggt cccttgtgcc tatatcgtac ctgtgtcgcc 1620
cacaaccaag cccacagcgc gggaagtgta cgaatttgca gggcagcggt tggcaggcta 1680
caaagccttg gatggaggcg taatcatggt agaccagatc ccacggtcaa cgattggcaa 1740
gatccagcgg ttcaagttgt tgcacatgca ttcgcagcgg gagcgaatgg caaaacttct 1800
ggctcgtgga aagtag 1816
<210> 2
<211> 7475
<212> DNA
<213> Auxarthron umbrinum DSM3193
<400> 2
atggctgaaa tggagcccat cgccatcata ggcagtgggt gtaaatttcc tgggtcatct 60
tcctccccgt cacgcctatg ggatctcgtc cgcgaccctc aagatgtagc ctcagcaacc 120
ccgcgtaaac ggttcaatat ggatgggttc taccatccga actgggatca gcatgggaca 180
accaattccg ccgagagcta ttacctccag gaggatatcc gcgcatttga cgctcagttc 240
ttcaatatct cacctgccga ggcggcatca atggatcctc agcagcgact ccttctagaa 300
acagtgtacg aatcactaga tacggcaggc ctgcgactag atctcctaca agggtcttcc 360
accggagtgt attgtggcat catgaacatc gactatacgc gaattgttgc agcggatatc 420
gaagcgctgc ctccttatat ggcgccgggg atcgcgagct ccatcttgtc caatcgtcta 480
tcatacttct ttgattggca cggcccgtct atgacacttg atacagcatg ctccgggagt 540
ctggtctctc ttcaccttgc agtagaagca ttacgaaaac gcgactgctc cctcgcggtc 600
gcggccggta gcaacctaat tctcgtacca gacacctgcg tttccgacac aaaaatgcag 660
atgctgtccc cgacgggccg gagcagaatg tgggatgaga aagccgacgg ctatgcgcgc 720
ggggaaggcg tgggagccgt catcttaaag cgcttgagcg atgcagttag agatggagac 780
agaattgaat ctgtcatccg tgcctcaggg gtcaattcag atggccgcac aacgggtctc 840
actatgccaa gtagcgaggc acaacaagca ctcatccgtt ccacgtatgc gcaagcgggt 900
ctcaacccag atgatccgaa agatcgatgc caatacttcg aggcccatgg tactgggact 960
ccagcaggcg atcccaaaga agctgcggct atctacaacg cgtttttcca agagcctgga 1020
gacgatatgc tctatgttgg atcgataaaa accatcatcg gtcacacgga atccgcagca 1080
ggtattgcgg gtatcctcaa agcctccctg gctttgcaga acaagctcat tccgccgaat 1140
ctgcatttcg acactttcaa tccagatata gcgccatttt cctctcgttt gcgaattccc 1200
ctggcggccg taccgtggcc agaacttccc gccggcacac cccggcgagt atcggtgaac 1260
tcgttcggat tcgggggcac taatgcgcat gttattctcg agagcttcga taaatcaact 1320
ccggagcctt ctcctcggtc gacgccgtca gtgcccgtgc tcccattcgt tttctccgcg 1380
gtgtcagagg cttctttggg tgctgtgcta gagcagtacg gccagttcct ccgagaacac 1440
cccgatattg atttacttga tctcgcttcg tccttgatga cccgaagatc cgccttcagc 1500
aaccggatag tcctgacagc cccatgccgc gatagcctac tccagaagat ccaggaggag 1560
cttaaccaga gaagtgccaa aaacccatca acaattgtat cgcggactag tcctggcccc 1620
aagagaatcc ttggagtttt cacgggacag ggtgcgcagt gggctcaaat ggggttggat 1680
ctcattcaga cctgcccgga agctaaatcg tggctcgatg agttgcaaaa atctctagac 1740
gagctaccta gcgaatggcg acccgacttc tcccttctcg atgaactgtc tgtcccagct 1800
gcctcttctc ggattggtac cagcgaactt tctctcactc ttcgaacggc gttacaaata 1860
attcaggtca attatttgag gtcgctaggg attacattcg ccgctgttgt tggccattct 1920
tccggtgaaa tttccgccgc atatgctgcc ggaattctaa gtgcgtctga taccatccga 1980
acagcatatc tccggggtgt ggcttctaag gaagcaggag ccaatggcaa acctggaggg 2040
atgttggctg tcggaatttc ctcaagccag gctcaggctc ttttggagga tgccccctac 2100
gccggtaacg ttaccattgc tgccatgaac tctccgtcaa atgtgaccct ttccggagat 2160
gcagatcttc tccaggagct agggtggctg ctcaagagct tggacctttc tccgcgccat 2220
cttcgagtag acaccgcata ccattcccac cacatgcaac cctgtgcgga gccatacatc 2280
cgcgctctgg aagcctgcca gatccaggtg aatcctccga caacgaaatg gtattcaagt 2340
gtttatgacg gccagctcgt tgagaacgtt gaggacctgc gctcagaata ctggaaagaa 2400
aacatgcttc gtccggtgat gttctcgcag gcgataacgt cagccattga gcatgtccaa 2460
gatgtggatt tgattgttga ggttggccca caagctgctc tcaggggtcc gacgcttcag 2520
actatttcaa caatttcccc tgataacgct gatgttcctt acgtcggatt agcagaccga 2580
aatgcgagtg gtgttgaggc tatggccaag gcgatcggct ccttttggac ttacctaggc 2640
tctaacagtg tcgacattgc tcggtatacc tcactgttca atccatccaa acagcttgct 2700
ttcgtcaaca acctcccgac atatccattt gaccatacca aaacatactg ggccgaatct 2760
cgcctgtcaa aagctcgcct ccatcgccct cgaccgaatg ctctcttagg agtcatcagc 2820
cctgaagctg gggagggtga atatcgctgg cgcaattatc tgcggcgcga agagttagca 2880
tggctaaacg atcataagat ccaatctcaa agtgtgttcc ccggtaccgg ctacatggtc 2940
atggtcctcg aagctgctac tataattgct ggccaaaggt ctctgagcct tgtcgatatt 3000
cagaacctgg ctgtcgaccg tgccatcgcc atttcagacg acgtagcggg gatagagact 3060
ctgttcaagg tcgagcagat acacgacgac gggaacacac tatcggcggc ctttgactgc 3120
caggcgagct ttgacggaag cttgaaatcc tgtgcctctg ggcagatgat catcacattt 3180
ggagaacaag acacggagat tttgccaacg agatcctcag cgaagggcga actgcaaccc 3240
gtggacatgg ccgaatttta cggggaactc gaggagctgg gatatgggta tacaggactg 3300
ttcaaagctc tcaccaacct ctctcggaaa aaaaatgtgg ctcgtggcat catccccgtc 3360
gcaaagcaga cagatccaca ttatcccctc cttttccacc cggccactat tgacactggg 3420
ctacatgctc tttttgctgc gatcggcgct cctagagacg gccaactgac taccttgctt 3480
cttccgacaa aaattgagcg catgacaatc aatccggcat tttgcagaaa cggagcagcg 3540
ggtgtgctcg acagcatttc tgtggatgcc actatcacga atattggtcc gatccagggt 3600
gatgtcgacc tcttcgacca gcatggccgg ggtattatcc agatagaggg agtccacgta 3660
tctccgctca tgacatcccc agatcacaac cccccaatct tctccgaaac tacttggggt 3720
ccgttggaac tggacgcttc gcgggcaact tccatcggca cctcggtctg ctggagtaat 3780
cgatacttag gagaccgggt cgcattgctc tacctgcggg atgtcagtac ccaagtcacc 3840
tcctcagacc gcgagggtat ggactggaat cgtggccgct atgcggcatg gatggactgg 3900
actctcgcaa gtgttcgcga cgggacccac cccattcatg gacccgaagc cctggaaggt 3960
agtgtcgaag aggtcgcaaa gattataccc aaggaatcgg agactatgct acatactata 4020
cggagggttg gggagaactt gttagccttc ctccgggggg agacaagtat cctggaagcg 4080
ctacgacagg atgacatact cactcggttt tacgaaaata cgcacgagct ttcggtgtcg 4140
actcgaaact tagcgtcttt tgtcagtcag attgcattcc gatatccgcg catgaagata 4200
ctcgagatcg gtgctggtat tggatctgcc acccgggaag tgcttaaacg ggtcgggaga 4260
gactaccatt cgtacaccta cactgatatt tcagccgcct tcttcgagga tgcccaggcc 4320
ttattttcgg agcatgagga ccgattcgtg tatgaagtcc tagatattga cgccgaccct 4380
acgaagcagg gttttgctat gcacagctat gacttggtca ttgccaacaa tgttctccat 4440
gctacccgat ccttaagtca gactctaaag cacgctcgga agctgttgaa accgggcggc 4500
aagctcgctg tgatggaaat tactactccc gacgctccga ctttctcgtt catattcggt 4560
ggctgcgaag gatggtggca cggagaaaac gatggccgta ctcgggggcc cttggtcaac 4620
tgcgaagaat gggacaggct gctcaggacc actggcttcg gcgggttcga ggcggcatca 4680
ctaaaggagg aagcagaaat tttggggatt acagttttcg tatcggaggc agtagacgac 4740
accgtgaaac tgctgcgtaa cccgttgacg gtttcagatc ccgtgcgata taatgatctg 4800
ttcctggtgg gcggtgcaac ggaggccacg tcgagtctgg tcccagcctt gaacgaaatt 4860
ctgaaacctc atttccaccg cattttcgaa gtacggaacc tcaatacctt tgtcgcaccc 4920
gaggattcct cattggcaac catcctcacc gtatcagaca tggactggcc ctgcctgaag 4980
gaccttaccg aaagtcgttt caagggcctt aaaaccctaa taggagtaac gggcaaactg 5040
ctctgggtcg caaccaatcc ggatggcaag gacccataca tgaccatgag caagggtttg 5100
cttcaaagca tagcttacga gaacacccat ggcctgttcc agcacctcac catcgcagac 5160
ccatcggcgg ttaccgcaga gcttctcgcg acaactctga tgcgattagt gcataccgat 5220
tttgacaatg attataacat gccaaactgc gtcgggaaca cggagacaga actcgtgttc 5280
gaagatggcg tcatgaaaat cccccgtatc catgccaact cacccatgaa ccagcgtttc 5340
tttgccagtc gggggacccg ggccggggag gtcgacgttc gagaaacacc tgtccaggcc 5400
gtcgctccga cacaagatcg ccccgggttt agccttgtcc ccatacccca acagcaatgc 5460
gcccggattc aagatacaaa gactgtcgaa tcttccacgc gtatatgtgt ccgctattcg 5520
acacttagcg ccgtgcgtat cgacgggctc ggcttcttgc acatagttat cggtcacgat 5580
ataggttctc agcggcgcaa gctagcatta tctgtggagc acgcttctct catctccact 5640
ccttcctctt ggtgctggga cgttcctagt gtgctactcg agagcgaaga acctgcttac 5700
ttgaaagata tcgctgctac actatcggca atatacctag tcaacaaggt acctcctagt 5760
acgactctcc tggtccatga agcggatgat gtgagccgta cattgcgggt tgcaatatcg 5820
agcctggcat ctctgcgggg aatttccaca gtgttcacga gtagcaacaa ggccctcgaa 5880
cacgagcagg gagtacgttt tgttcatccg agacactcca aacgcatggt ctccaacgtc 5940
ataccagcag atgtttcggt cgctgccaaa ctctgtaaag ctccgcatgg aacgtatgat 6000
cgaatcgagt caattatgtc ggaaaatgtg gctcgatatg atgttgggag cttctaccaa 6060
ccgactgctt cgctcgaaaa gacccatggg ctccatcctg tcgcagaagc cctctcaaca 6120
gcttgtatga tcgcaattca aactgctggg caacgtcaaa ccattcccac gatccagctg 6180
caagatcttc caaaatctag ggcgactggg ttggagatcc tggattggac aagccccaac 6240
ccggttccgg tagagatcca atccgccagt tctcaggtga cgttctctgc aaacaagaca 6300
tacctcttga tcggccttac tggggatttg ggtcgatcag tgtgtcactg gatgattacc 6360
agaggtgcac agcacgtggt attgaccagt cggtcaccga agatcaaccc tcggtggatc 6420
gatgagatgg caaccctagg aggccgagta attcctatgt caatgtaagc tcagcgaatc 6480
actccaaccg agtattttaa gtaacggaca ttctaactaa ctttaatagg gatgttacga 6540
gcagcgattc gattcgcaac gtagacagca ctatcagaaa ggagctgcct ccaatcggcg 6600
gtgttgtgaa cggggccatg gtaatgaacg acattctttt cgccgacata tcgctagagg 6660
ccacgctccg taccttcgcg cccaaggttc aaggaagtct tttgctagat gagctctacc 6720
gcgacgtgga tttcttcata cttttcggtt ctctttcggg agtcattgga aacttcaacc 6780
aggcagccta tggtgctgcc aatgcattca tgactggcct tgtacagcgg cgccgacgtg 6840
aaaatttgcc ggctagtatc atcaatccag gcgagattcg cggccttgga tacgtatccc 6900
gcatgggcag tggactttca gaccttatgg cagaaactct aggattgacc tactcatctg 6960
agcgggatct gcacgaattg ttcgccgaag gcatcctggc gagccctcat aactctggtc 7020
ggaaccccga gattgtctgc ggcgtgcgga aaacagaccc cgtcaaacgc cccaacgtca 7080
tctggtacag aagcccaaaa atgtggccat ttatcgacta cgccctccaa tccaacgtga 7140
catcgtccag cggccaagcc gcaccggtca aagtccagct cgaagccgca accagcgttc 7200
cggaggctgc aggaatcatc accacaaact tcatggtgaa gattcgcaat aagctgaacc 7260
tcgccggcga tacaccgctt acaggaaagt tcctgttaag tgagttggga atagactccc 7320
ttgtggcggt ggacttgcgt ctctggtttg taaaggagct gggcgtggat ataccggtcc 7380
tccgtctact tggcggctct agcatcgaca atgtagccag tgaggctgcc acaaagctcg 7440
atgccagcct gattcccctt gtcaagttag catag 7475
<210> 3
<211> 894
<212> DNA
<213> Auxarthron umbrinum DSM3193
<400> 3
atggacaaaa atctttgtga gatccagtcg gggcctccag gcgaatgtgc tgtcccgctt 60
atcctgtttc acgatggcgg gggaaccgtg ttcccgtact tttgtctagg ggacttgcaa 120
cggccggtct atggcatggc gaatatacgt tttgactcgg gtgggggttg ggaacacggg 180
attcgcgaga tgggcgtggt ttatgcgcat agagtcagat ctaccatcaa gtcaggcaaa 240
gttctccttg gaggtctgat tcagcccccc agtccaaata acacctgaca tgcaaggctg 300
acctattttc cgattgcgta ggatggtccc tcggtggctc tatagcgctt gaggttgcat 360
cccgcctggc tcagcttcca aattttaccg tggaaggggt gatcatgatt gacagcgtct 420
ttccattcaa agagagcacg gaccgttatc cccgcagcct cgaacaggtg gaggctgcct 480
gccctcttcc cacggacttg gcggacgacc tccgggcaca gtcgctatct tgccttttgc 540
agagtcacaa catgcttcgg gagtggatcc cgccatcgtt tgcacccccg ccagctgtga 600
tgctgcgagc gactgggaaa gtgaatggcg acgatacgaa ttcgatccat tatttcgacc 660
ttgtcagaga ctcggcagat cttggctggc aagagtatag gcaagaccta ttcatagttt 720
ccctggagat acccggtcat catttcagcg tgttcgacga gcctcacgta agacaatccc 780
ggcatttact tcatagcttc ttgatcagag ccacacgcta atgccttcaa gtcccaggat 840
gtgacgcaac agctgcgtca agcatgtttc tctttgctag agaggaagaa gtaa 894
<210> 4
<211> 723
<212> DNA
<213> Auxarthron umbrinum DSM3193
<400> 4
atggctcaag gacaacccaa atcggttacg gggggggaat cgtactcgaa cctcagcctc 60
aaaatttacg actatctcgt cctgacgttc aacacgaact gcctgtggaa atgctcttgc 120
aagaacgtgc tcgttccttt ctttggagcc aacgcgagtc cttgccacct ggatattggc 180
gtgggcaatg gttatttccc tgcaaccctg aaggaaaaag agaaactggc aaatcggtcc 240
tggccagaga aattgactct aatcgacgtg aatcccgcgt gcctcgaaac cgcctccaga 300
agggtgggcc taccggaacg aacaacctgt ttgcaagccg atattctcaa accaatcgtc 360
attccctccg atacttccga tccaaagaat atcccccaat tcgactccat ttcgcttatg 420
tacgtcttcc actgcttacc ggttccgaca cagaggaaga cccacgtgtt tgcagacgtc 480
aagaaatacc tcgcgcccaa gggaaccctg ttcggtgcga ccatcttggg caggggtgtt 540
ccgattagcc tgcctggtcg gatgggactg tggttcctga actacaaggg tgtgttttgg 600
aaccgagagg atgggccaga agaatttgtg caggcgctgg aggctgaatt tgacgaggtc 660
gagaccacgg tggttggatg cgttttactt tttcgcgcac agaaacctaa gcaggccatc 720
tga 723
<210> 5
<211> 1980
<212> DNA
<213> Auxarthron umbrinum DSM3193
<400> 5
atggcgttga aaggaccctc tccaaagcat acatttacac aacgtgccgc ggcaggcaac 60
ctgaatgaca gcgagatcct taactccaac aaccctgctg gagcagacct ccctagtgag 120
tcggacgtgg tggtcgctgg gggtggtatc catggcctta tatacgcaat tcacgcagcc 180
aagtacaaac ccggcgactt gaagatatct ctaatcgaga agaacaccaa gcccggatac 240
aaaattggcg agagtactct acctctcttt gccgcgtggt gcaagacaca tgggctcaca 300
gccgaatatc ttttacgact ctttggcctt aaggagggac tcgctttcta cttcctcgac 360
cgggaaaacc cagacaatta cactgatttc tgcagcaccg gcacgcccgg ctttatagcg 420
agcgcttttc aagtcgagcg gtcgattagc gaactccttt ttaccctgct tgcgcagcga 480
cagggcgtca acgtatatca tggcagacag gtcgacttta gagccacagc ggttgaagga 540
ggggtcaaaa gcaacaaaat tgctattgcc cctggcaaac atgacggcaa gccggcggca 600
acaatcggct cttccctctt agtcgatgct acggggcgct tccgccagct tgcctccaaa 660
aaggcttctc tgcaccgctt tgaaggattc aactacgacg ccttctgggg atatttcact 720
gcgccaaaag acgagagcaa aattcccttc cgcttctacg agggcaccaa caccaaccac 780
atatgcttcc ccgagggctg ggcctgggtt atccgtttgc cttcctggga aggtagcccc 840
attcccaatc tgatggatat gatttcctat ctactggatt gtgccgaagc tcgtgttccc 900
aacgaccaaa ttccctgctc cgaagaactc gcaaagatgt ttgacctcaa gttccaatgg 960
gtgaccagca tcggcttcgc agtgcggaac gatgtcaagt acccggagga catgtctgca 1020
tacggcaatc gggaagcaga gcgcaaattc aacttcattg tcgaaaagta cccaatcgtc 1080
aaggaattca tgaccaattt tgagcttatt gaaaatcttt acggccccgg aacgacgtgg 1140
tatatccgca aatctctgtc gtaccagtcg ccagtggtgt ctgggccggg atggttggcc 1200
atcggcgatg catgtggttt caccacacct cttttctccc ccggtatcac agccgccatg 1260
tctacttcaa cgttcgcggc agaactcaca catcaagcac tcgagaaagc aaaaaaggat 1320
cgcaattcaa aggccgcaga aatttccatt cgcaagacat tcgcaccata tgacgaattc 1380
gccaagcgcc tggtcaccgc ccttaaccag atgaatcggt tcaattatct ttgcttccgt 1440
gaacctcgtc tcggcccaca ggtgtcatgt ctctggcaat tctatgccgg aacggagcaa 1500
aatgtcgcga aggttacctt ccagacgtac gtcaaacact cgaccaattg gggttgggga 1560
tccatgaacc cagcatacga cacagtcgcg cgaaaagcaa tcgagctgct tgcccctatc 1620
cccctagaag agacaatccc cgacgcgact gtccgcgaat tgattgactt ttccaacggt 1680
attaaaaagg ctaccgtgga agcgaatccg tcgtacttcc gctgggacgg ttttctgcga 1740
tattacgaca agatgctcaa ttacaatgta gaagatacta ccagggatag tctttcgagg 1800
cagtgctctg cttgcggttc ctgggtagtt ctccgtccag actggaggaa gtgctattcg 1860
tgtggccagg tgcggactgc agaggagtcg gttatcggtt ggaacccccc gttgagtgag 1920
attcagatta cgaatttaac taagtcactg gcggccgtcg gaatccatct atcaccctaa 1980

Claims (12)

1. A compound of formula (I) and pharmaceutically acceptable salts thereof:
wherein ,
n=0, 1, 2, 3, 4, the double bonds are each independently selected from cis or/and trans configurations;
R 2 and R3 Each independently selected from hydrogen or F, cl, br, I;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
2. The compound according to claim 1, wherein the compound is represented by the formula (IA)
wherein ,
R 2 and R3 Each independently selected from hydrogen or F, cl, br, I;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstitutedC of (2) 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
3. The compound according to claim 2, wherein the compound is represented by the formula (IA 1)
wherein ,
R 3 selected from hydrogen or F, cl, br, I;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
4. The compound according to claim 2, wherein the compound is represented by the formula (IA 2)
wherein ,
R 2 selected from hydrogen or F, cl, br, I;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted Or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
5. The compound according to claim 2, wherein the compound is represented by the formula (IA 3)
wherein ,
R 2 selected from hydrogen or F, cl, br, I;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
6. The compound according to claim 2, wherein the compound is represented by the formula (IA 4)
wherein ,
R 3 selected from hydrogen or F, cl, br, I;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
7. The compound according to claim 1, wherein the compound is represented by the formula (IB)
wherein ,
R 2 selected from hydrogen or F, cl, br, I;
R 1 ，R 4 ，R 5 and R7 Each independently selected from hydrogen, hydroxy, nitro, cyano, carboxy, phenyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted C 1-6 Amino, substituted or unsubstituted C 1-6 Alkylthio, substituted or unsubstituted C 1-6 Alkyl sulfoxide group, substituted or unsubstituted C 1-6 Alkyl sulfonyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Cyclic alkoxy, beta-D glucopyranosyloxy, sulfonyloxy, phosphoryloxy, F, cl, br, I; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Is an alkane of (2)Oxy, F, cl, br, I;
R 6 selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 3-6 Cycloalkyl, beta-D glucopyranosyl, sulfonyl, phosphoryl; the substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituents are respectively and independently selected from hydroxyl, nitryl, cyano, amino, carboxyl and C 1-6 Alkyl, C of (2) 1-6 Alkoxy, F, cl, br, I.
8. The compound according to claim 1, wherein said compound is selected from the group consisting of:
9. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 8, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, and injections.
11. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is selected from the group consisting of a sustained release formulation, a controlled release formulation and a particulate delivery system.
12. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 9 to 11 for the manufacture of a medicament for the prevention, alleviation and/or treatment of HIV infection.
CN202210119647.0A 2022-02-08 2022-02-08 Rumbrin compounds with anti-HIV activity Pending CN116606283A (en)

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