阅读说明：本技术 蒽醌类化合物及其在制备抗寨卡或登革病毒药物中的应用 (Anthraquinone compound and application thereof in preparation of anti-Zika or dengue virus drugs ) 是由 黎孟枫 龙玉华 袁洁 于暕辰 陈涛 涂松源 罗佳 于 2020-12-31 设计创作，主要内容包括：本发明提供了蒽醌类化合物及其在制备抗寨卡或登革病毒药物中的应用,本发明提供了一种蒽醌类化合物,实验证明该蒽醌类化合物对于寨卡病毒以及登革病毒具有很好的抑制作用,其抑制EC-(50)为0.5～100μM,且对宿主细胞安全、无毒副作用,可用于寨卡病毒或登革病毒的防治中,为研究开发抗寨卡或登革病毒药物提供了新的选择和途径。(The invention provides an anthraquinone compound and application thereof in preparation of medicaments for resisting Zika virus or dengue virus, and experiments prove that the anthraquinone compound has good inhibition effect on Zika virus and dengue virus and inhibits EC (infectious EC) 50 The composition is 0.5-100 mu M, is safe to host cells, has no toxic or side effect, can be used for preventing and treating Zika virus or dengue virus, and provides a new choice and approach for researching and developing Zika or dengue virus resistant medicaments.)

1. An anthraquinone compound, which is characterized in that the chemical structural formula is as follows:

wherein the substituent R is selected from the following structures:

2. the use of an anthraquinone compound of claim 1, or a pharmaceutically acceptable salt, or a stereoisomer, or a prodrug thereof, for the preparation of an antiviral medicament.

3. The use according to claim 2, wherein the virus is Zika virus and/or dengue virus.

4. The use according to claim 2, wherein the pharmaceutically acceptable salt of the anthraquinone compound is an inorganic acid salt, an inorganic base salt or a double salt thereof.

5. Use according to claim 4, wherein the inorganic acid salt is hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid or silicic acid.

6. The use according to claim 4, wherein the inorganic base is sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, ammonium hydroxide or lithium hydroxide.

7. The use according to claim 2, wherein the anthraquinone compound prodrug is a substance which can be converted into the anthraquinone compound or a salt thereof in vivo.

8. An anti-dengue virus drug comprising the anthraquinone compound of claim 1, or a pharmaceutically acceptable salt, or a stereoisomer, or a prodrug thereof.

9. A pharmaceutical agent against Zika virus, which comprises the anthraquinone compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug thereof.

10. The medicament according to claim 8 or 9, further comprising a pharmaceutically acceptable carrier and/or excipient, and is prepared into different dosage forms.

Technical Field

The invention relates to the technical field of medicines, in particular to anthraquinone compounds and application thereof in preparation of anti-Zika or dengue virus medicines.

Background

Zika Virus (ZIKV) is a positive single-stranded RNA Virus, a flavivirus Virus of the Flaviviridae family, that is transmitted primarily by mosquito bites and also by sexual contact. ZIKV-infected persons may develop fever, arthritis, guillain-barre syndrome, etc., and newborn-infected persons may develop congenital microcephaly. Dengue Virus (Dengue Virus, DENV) belongs to the flaviviridae genus of flaviviridae family, is RNA positive strand Virus, can cause symptoms such as systemic fever, eruption, arthritis and the like through mosquito transmission, and can cause shock death in severe cases. At present, no safe and effective vaccine exists for Zika virus or dengue virus, and no clinically approved specific effective medicament for resisting Zika virus and dengue virus exists, so that the search for medicaments capable of effectively resisting Zika virus and dengue virus is of great significance.

Anthraquinone (Anthraquinone, chemical formula: C)₁₄H₈O₂) The product is a quinone chemical, and the anthraquinone compound naturally exists or can be artificially synthesized, and the anthraquinone includes products and dimers with different reduction degrees, such as anthraphenol, oxidized anthraphenol, anthrone, and glycosides of the compounds. In natural products, anthraquinone often exists in metabolites of lichens and fungi of higher plants and lower plants, and researches show that anthraquinone compounds have the effects of stopping bleeding, resisting bacteria, purging and promoting urination, for example, patent CN107412227B provides an anthraquinone compound which has good antifungal effect on various clinical true strains. However, no research on the antiviral aspect of the anthraquinone compounds exists at present.

Disclosure of Invention

Aiming at the defects of anthraquinone compounds in antiviral research in the prior art, the invention provides the anthraquinone compounds and the application thereof in preparing medicaments for resisting Zika virus or dengue virus₅₀0.5-100 mu M, is safe to host cells, has no toxic or side effect, and can be used for preventing and treating Zika virus or dengue virus.

The invention aims to provide an anthraquinone compound.

The invention also aims to provide application of the anthraquinone compound or the pharmaceutically acceptable salt or the stereoisomer or the prodrug thereof in preparing antiviral drugs.

It is still another object of the present invention to provide a pharmaceutical composition against dengue virus.

It is still another object of the present invention to provide a pharmaceutical composition against Zika virus.

The above object of the present invention is achieved by the following technical solutions:

the invention provides an anthraquinone compound, which has a chemical structural formula as follows:

wherein R is selected from the following substituents:

in addition, the substituent R can also be other amino substituent, including fatty amine, aryl amine and the like.

The research of the invention finds that the anthraquinone compound has good inhibition effect on Zika virus and dengue virus, and has half antiviral effective dose EC₅₀In the range of 0.5-100 mu M, is safe and nontoxic to host cells, and can be used for preventing and treating Zika virus and/or dengue virus.

Preferably, antiviral activity is strongest when R is selected from the following substituents:

therefore, the application of the anthraquinone compound or the pharmaceutically acceptable salt or the stereoisomer or the prodrug thereof in preparing antiviral drugs is also within the protection scope of the invention.

Preferably, the virus is Zika virus and/or dengue virus.

The pharmaceutically acceptable salt of the anthraquinone compound is an inorganic acid salt, an inorganic alkali salt or a complex salt thereof.

The inorganic acid salt is hydrochloric acid, hydroiodic acid, hydrobromic acid, nitric acid, boric acid, carbonic acid, sulfuric acid, phosphoric acid or silicic acid.

The inorganic base is sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, ammonium hydroxide or lithium hydroxide.

The anthraquinone prodrug is a substance which can be converted into the anthraquinone compound or the salt thereof in vivo.

The invention also provides an anti-dengue virus drug which comprises the anthraquinone compound or the pharmaceutically acceptable salt or the stereoisomer or the prodrug thereof.

The invention also provides an anti-Zika virus medicament, which comprises the anthraquinone compound, or pharmaceutically acceptable salt, stereoisomer or prodrug thereof.

Preferably, the medicine also comprises a medicinal carrier and/or an excipient, and is prepared into different dosage forms.

The medicament dosage form is powder, tablets, granules, capsules, solutions, syrups, suspensions, injections, powder injections, water injections, aerosols, ointments, eye drops or suppositories.

The administration mode of the medicine is gastrointestinal tract administration, injection administration, respiratory tract administration, skin administration, mucosa administration or cavity administration.

As a preferred method, the compounds of the present invention can be synthesized by:

(1) dissolving 10mmol of naphthazarin in 80mL of AcOH solution, adding 50mmol of 2, 3-dimethyl-1, 3-butadiene (5equiv), refluxing and reacting for 6h under the protection of nitrogen, and detecting by TLC to complete the reaction; cooling, distilling under reduced pressure to remove the reaction solvent, completely dissolving the crude product with 50ml of 2M NaOH solution, and rapidly stirring at normal temperature for 1 h; and under the condition of ice water cooling, adding diluted hydrochloric acid to acidify until the pH value of the solution is 6-7, and performing vacuum filtration to obtain a filter cake. The crude product was subjected to column chromatography using EA (ethyl acetate): PE (petroleum ether) ═ 1: elution with 80(v/v) eluent gave compound 4 b.

(2) 5mmol of the compound 4b was dissolved in 50mL of chloroform, and then 1.38g of m-chloroperoxybenzoic acid (m-CPBA) (8mmol, 1.6equiv) was added and reacted at room temperature for 1 hour, and a saturated sodium thiosulfate solution was added, stirred for 30 minutes and then extracted, and the organic phase was dried over anhydrous magnesium sulfate and rotary-evaporated to give a crude product (5 b). The crude product was subjected to silica gel column chromatography and purified with EA: PE ═ 1: elution with 20(v/v) eluent gave compound 5 b.

(3) Take 286mg of compound 5b (1mmol), tert-butanol: water 1: 1(V/V) is used as a solvent, Amberlyst-15 is used as a catalyst, and the reaction is carried out for 2 hours under ultrasonic wave;adding a small amount of saturated saline solution, and extracting with ethyl acetate; adding anhydrous MgSO₄Drying, distilling under reduced pressure to remove the solvent, and separating the crude product by silica gel column chromatography using EA: PE ═ 1: elution with 15(v/v) eluent gave compound 6 b.

(4) 30.4mg of compound 6b (0.1mmol) was dissolved in 3ml of anhydrous methanol, 0.5mmol of amine (5equiv) was added, stirring was carried out at room temperature, TLC was used to monitor completion of the reaction, the solvent was distilled off under reduced pressure, washed with water, extracted with ethyl acetate, dried, and concentrated to give a crude product, which was subjected to silica gel column chromatography using EA: PE ═ 1: 15(v/v) -1: 2(v/v) eluent to obtain the anthraquinone compound.

Compared with the prior art, the invention has the beneficial effects that:

the anthraquinone compound provided by the invention has good inhibition effect on Zika virus and dengue virus, and inhibits EC₅₀In the range of 0.5-100 mu M, the polypeptide is safe to host cells, can be used for preventing and treating Zika virus and/or dengue virus, provides a new choice and approach for researching and developing new medicaments for resisting Zika virus or dengue virus, and has good application prospect.

Drawings

FIG. 1 is a scheme showing the synthesis of anthraquinones.

Detailed Description

The present invention will be further described with reference to specific embodiments, but the present invention is not limited to the examples in any way. The starting reagents employed in the examples of the present invention are, unless otherwise specified, those that are conventionally purchased.

The following examples relate to compounds of the following series of anthraquinones:

EXAMPLE 1 Synthesis and characterization of anthraquinones

The synthetic route of the anthraquinone compound is shown in figure 1.

1. Synthesis of Compounds

(1) 10mmol of naphthazarin is added into a 250 mL round-bottom flask, dissolved in 80mL of AcOH solution, added with 2, 3-dimethyl-1, 3-butadiene (50mmol, 5equiv), refluxed for 6h under the protection of nitrogen, and checked by TLC to be complete. Cooling, distilling under reduced pressure to remove the reaction solvent, completely dissolving the crude product with 50ml of 2M NaOH solution, and rapidly stirring at normal temperature for 1 h; adding dilute hydrochloric acid to acidify until the pH value of the solution is 6-7 under the condition of ice water cooling, and performing vacuum filtration to obtain a filter cake; the crude product was subjected to column chromatography using EA (ethyl acetate): PE (petroleum ether) ═ 1: elution with 80(v/v) eluent gave compound 4 b.

(2) Adding compound 4b (5mmol) into a 25mL round-bottom flask, dissolving in 50mL chloroform, adding 1.38g m-chloroperoxybenzoic acid (m-CPBA) (8mmol, 1.6equiv), reacting at room temperature for 1h, adding saturated sodium thiosulfate solution, stirring for 30 min, extracting, drying the organic phase with anhydrous magnesium sulfate, and rotary evaporating to obtain crude product (5 b); the crude product was subjected to silica gel column chromatography and purified with EA: PE ═ 1: elution with 20(v/v) eluent gave compound 5 b.

(3) In a 25ml flask was added 286mg of compound 5b (1mmol), tert-butanol: water 1: 1(V/V) is used as a solvent, Amberlyst-15 is used as a catalyst, and the reaction is carried out for 2 hours under ultrasonic wave; adding a small amount of saturated saline solution, and extracting with ethyl acetate; adding anhydrous MgSO₄Drying, distilling under reduced pressure to remove the solvent, and separating the crude product by silica gel column chromatography using EA: PE ═ 1: elution with 15(v/v) eluent gave compound 6 b.

(4) To a 10ml round bottom flask was added compound 6b (30.4mg, 0.1mmol), dissolved in 3ml of anhydrous methanol, added the corresponding amine (0.5mmol, 5equiv), stirred at room temperature, TLC monitored for reaction completion, distilled under reduced pressure to remove the solvent, washed with water, extracted with ethyl acetate, dried, concentrated to give crude product, which was chromatographed on silica gel using EA: PE ═ 1: 15(v/v) -1: 2(v/v) eluent to obtain anthraquinone compounds 7 b-27 b.

2. Identification of Compounds

(1) Identification method

The structure of each anthraquinone compound was confirmed by MS/HR-ESI-MS and NMR.

(2) Identification results

Compound 4 b: a red solid; melting point: 173.2-174.5 ℃;¹H NMR(400MHz，CDC_l3)δ12.54(s，2H)，7.20(s，2H)，3.15(s，4H)，1.77(s，6H)；ESI-MS m/z 269.47[M-H]^-. The structural formula is as follows:

compound 5 b: a red-brown solid; melting point: 158.0-158.8 ℃;¹H NMR(400MHz，CDC_l3)δ12.38(s，2H)，7.12(s，2H)，3.33(s，1H)，3.28(s，1H)，2.67(s，1H)，2.62(s，1H)，1.49(s，6H)；¹³C NMR(101MHz，CDCl3)δ185.73，158.57，141.39，129.57，111.39，60.51，30.03，19.24；HR-ESI-MS m/z[M–H]^-calcd for C₁₆H₁₃O₅285.0769, found 285.0767. The structural formula is as follows:

compound 6 b: a red solid; melting point: 182.6-183.5 ℃;¹H NMR(400MHz，DMSO)δ12.42(s，2H)，7.33(s，2H)，4.64(s，2H)，2.50(s，4H)，1.23(s，6H)；¹³C NMR(101MHz，DMSO)δ186.54，157.28，143.79，129.42，111.31，70.32，35.23，22.81；HRESIMS m/z[M–H]^-calcd for C₁₆H₁₅O₆303.0874, found 303.0872. The structural formula is as follows:

compound 7 b: a red solid; melting point: 170 ℃ and 171 ℃;¹H NMR(500MHz，DMSO)δ14.10(s，1H)，12.42(s，1H)，8.23(s，1H)，7.61(s，1H)，6.41(s，2H)，5.77(s，1H)，4.69-4.37(m，4H)，2.79-2.58(m，4H)，1.24(s，6H)；¹³C NMR(126MHz，DMSO)δ186.12(s)，182.77(s)，156.37(s)，154.55(s)，150.04(s)，149.39(s)，142.68(s)，139.81(s)，133.42(s)，110.49(s)，108.26(d，J＝12.8Hz)，106.85(s)，99.85(s)，70.14(s)，38.74(s)，35.85(s)，35.17(s)，23.06(s).ESI-MS m/z：399.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 8 b: red solid (39.3% yield); melting point: 140 ℃ and 142 ℃;¹H NMR(500MHz，DMSO)δ14.18(s，1H)，12.40(s，1H)，7.81(s，1H)，7.53(d，J＝0.9Hz，1H)，6.47-6.19(m，2H)，5.65(s，1H)，4.53(d，J＝3.7Hz，2H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ186.01(s)，182.74(s)，156.27(s)，154.41(s)，152.38(s)，149.37(s)，141.74(s)，139.86(s)，133.17(s)，129.58(s)，110.44(s)，108.29(s)，106.40(s)，98.85(s)，70.13(s)，40.73(s)，35.85(s)，35.14(s)，26.09(s)，23.02(s)；ESI-MS m/z：413.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 9 b: red solid (yield 46%); melting point: 130 ℃ to 132 ℃;¹H NMR(500MHz，DMSO)δ14.23(s，1H)，12.43(s，1H)，7.37(d，J＝8.3Hz，1H)，5.70(s，1H)，4.52(d，J＝3.6Hz，2H)，4.22(t，J＝6.4Hz，1H)，2.80-2.65(m，4H)，2.04-1.81(m，5H)，1.78-1.61(m，5H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ186.96(s)，184.00(s)，157.26(s)，155.32(s)，149.34(s)，140.89(s)，133.99(s)，130.56(s)，109.37(s)，107.86(s)，99.66(s)，71.14(s)，65.95(s)，52.03(s)，36.88(s)，36.12(s)，31.96(s)，27.51(s)，26.01(s)，25.35(s)，24.02(s)，23.03(s)；ESI-MS m/z：401.2[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 10 b: red solid (92.8% yield); melting point: 190 ℃ and 192 ℃;¹H NMR(500MHz，DMSO)δ14.14(s，1H)，12.46(s，1H)，7.98(s，1H)，5.87(s，1H)，4.53(d，J＝4.0Hz，2H)，3.31(s，2H)，2.79-2.62(m，4H)，1.25(s，10H)，0.82(dd，J＝6.8，2.0Hz，2H)，0.74-0.66(m，2H)；¹³C NMR(126MHz，DMSO)δ186.92(s)，183.68(s)，157.39(s)，155.59(s)，152.11(s)，140.69(s)，134.31(s)，109.35(s)，107.98(s)，101.60(s)，71.14(s)，36.83(s)，36.13(s)，25.43(s)，24.02(s)，7.38(s)；ESI-MS m/z：359.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 11 b: red solid (89.8% yield); melting point: 198-200 ℃;¹H NMR(500MHz，DMSO)δ14.24(s，1H)，12.43(s，1H)，7.86(d，J＝5.8Hz，1H)，5.64(s，1H)，4.52(d，J＝4.1Hz，2H)，3.17(dd，J＝13.9，6.6Hz，2H)，2.76-2.62(m，4H)，1.65-1.56(m，2H)，1.25(s，6H)，0.91(t，J＝7.4Hz，3H)；¹³C NMR(126MHz，DMSO)δ185.89(s)，182.95(s)，156.21(s)，154.31(s)，149.65(s)，139.82(s)，132.98(s)，108.36(s)，106.94(s)，98.44(s)，70.13(s)，43.72(s)，35.86(s)，35.13(s)，23.03(s)，20.70(s)，11.30(s)；ESI-MS m/z：361.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 12 b: red solid (88.5% yield); melting point: 188-190 ℃;¹H NMR(500MHz，DMSO)δ14.22(s，1H)，12.39(s，1H)，7.64(t，J＝5.9Hz，1H)，5.62(s，1H)，5.46(s，1H)，4.52(d，J＝4.1Hz，2H)，3.30-3.22(m，2H)，2.75-2.62(m，4H)，2.22(t，J＝6.9Hz，2H)，1.94(d，J＝5.8Hz，4H)，1.56(dd，J＝10.3，4.6Hz，2H)，1.52-1.45(m，2H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ186.86(s)，183.79(s)，157.23(s)，155.36(s)，150.38(s)，140.88(s)，135.42(s)，134.05(s)，123.62(s)，109.30(s)，107.90(s)，99.61(s)，71.13(s)，36.86(s)，36.53(s)，36.13(s)，28.58(s)，25.67(s)，24.02(s)，23.34(s)，22.80(s)；ESI-MS m/z：427.2[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 13 b: red solid (56.7% yield); melting point: 162 ℃ and 163 ℃;¹H NMR(500MHz，DMSO)δ14.09(s，1H)，12.45(s，1H)，8.44(t，J＝6.5Hz，1H)，7.34(d，J＝4.3Hz，5H)，5.54(s，1H)，4.53(d，J＝1.8Hz，2H)，4.47(d，J＝6.5Hz，2H)，2.76-2.63(m，4H)，1.25(d，J＝3.9Hz，6H)；¹³C NMR(126MHz，DMSO)δ185.91(s)，182.84(s)，156.35(s)，154.49(s)，149.56(s)，139.80(s)，137.14(s)，133.29(s)，128.48(s)，127.11(s)，108.35(s)，106.87(s)，99.69(s)，70.13(s)，45.24(s)，35.83(s)，35.16(s)，23.03(s)；ESI-MS m/z：409.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 14 b: red solid (yield 99%); melting point: 166-168 ℃;¹H NMR(500MHz，DMSO)δ14.08(s，1H)，12.43(s，1H)，8.39(t，J＝6.3Hz，1H)，7.43(dd，J＝5.1，1.0Hz，1H)，7.12(d，J＝3.3Hz，1H)，6.99(dd，J＝5.0，3.5Hz，1H)，5.73(s，1H)，4.66(d，J＝6.3Hz，2H)，4.53(d，J＝2.9Hz，2H)，2.76-2.63(m，4H)，1.25(d，J＝2.1Hz，6H)；¹³C NMR(126MHz，DMSO)δ186.52(s)，183.24(s)，156.94(s)，155.12(s)，149.65(s)，140.56(s)，140.37(s)，133.97(s)，131.97(s)，130.12(s)，129.13(s)，127.29(s)，126.78(s)，125.98(s)，108.82(s)，107.33(s)，100.50(s)，70.65(s)，36.35(s)，35.68(s)，23.55(s)；ESI-MS m/z：415.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 15 b: red solid (yield 99%); melting point: 157 ℃ and 159 ℃;¹H NMR(500MHz，DMSO)δ14.18(s，1H)，12.40(s，1H)，7.83(s，1H)，7.34(dd，J＝4.5，1.7Hz，1H)，7.00-6.94(m，2H)，5.68(s，1H)，4.53(d，J＝3.8Hz，2H)，3.49(dd，J＝13.4，6.8Hz，2H)，3.14(t，J＝7.0Hz，2H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ186.00(s)，182.73(s)，156.27(s)，154.41(s)，149.37(s)，140.69(s)，139.87(s)，133.18(s)，126.98(s)，125.58(s)，124.30(s)，108.29(s)，106.88(s)，98.97(s)，70.13(s)，43.48(s)，35.85(s)，35.15(s)，27.58(s)，23.03(s)；ESI-MS m/z：429.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 16 b: red solid (33% yield); melting point: 149-150 ℃;¹H NMR(500MHz，DMSO)δ14.21(s，1H)，12.45(s，1H)，7.49(d，J＝5.9Hz，1H)，5.66(s，1H)，4.52(s，2H)，3.84(s，1H)，3.05-2.55(m，4H)，1.97(s，2H)，1.62(d，J＝62.0Hz，6H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ186.84(s)，183.94(s)，157.24(s)，155.35(s)，150.14(s)，140.80(s)，134.06(s)，109.33(s)，107.93(s)，100.41(s)，71.13(s)，54.63(s)，36.86(s)，36.12(s)，32.45(s)，24.86(s)，24.03(s)；ESI-MS m/z：387.2[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 17 b: red solid (58.2% yield); melting point: 157 ℃ and 159 ℃;¹H NMR(500MHz，DMSO)δ14.32(s，1H)，12.70(s，1H)，5.57(s，1H)，4.50(d，J＝3.8Hz，2H)，3.30(s，4H)，2.69(d，J＝18.7Hz，4H)，1.90(t，J＝6.3Hz，4H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ184.79(s)，156.15(s)，153.71(s)，149.26(s)，138.84(s)，133.07(s)，109.24(s)，107.14(s)，103.07(s)，70.17(d，J＝3.8Hz)，51.36(s)，35.79(s)，35.27(s)，23.05(s)；ESI-MS m/z：373.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 19 b: red solid (48.4% yield); melting point: 149-150 ℃;¹H NMR(500MHz，DMSO)δ14.21(s，1H)，12.39(s，1H)，7.78(s，1H)，7.29(q，J＝7.9Hz，4H)，7.23-7.18(m，1H)，5.68(s，1H)，4.53(d，J＝4.0Hz，2H)，3.47(dd，J＝13.9，6.7Hz，2H)，2.91(t，J＝7.3Hz，2H)，2.76-2.62(m，4H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ186.95(s)，183.77(s)，157.26(s)，155.40(s)，150.37(s)，140.86(s)，139.75(s)，134.12(s)，129.70(s)，129.35(s)，127.26(s)，109.31(s)，107.91(s)，99.85(s)，71.15(s)，44.39(s)，36.86(s)，36.15(s)，34.35(s)，24.03(s)；ESI-MS m/z：423.2[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 21 b: red solid (39.6% yield); melting point: 165-167 ℃;¹H NMR(500MHz，DMSO)δ14.24(s，1H)，12.43(s，1H)，7.81(d，J＝6.2Hz，1H)，5.63(s，1H)，4.52(d，J＝3.5Hz，2H)，3.25(dd，J＝13.4，6.7Hz，2H)，2.80–2.61(m，4H)，1.25(s，6H)，1.17(t，J＝7.1Hz，3H)；¹³C NMR(126MHz，DMSO)δ186.90(s)，183.96(s)，157.21(s)，155.33(s)，150.39(s)，140.82(s)，133.99(s)，109.36(s)，107.94(s)，99.39(s)，71.14(s)，37.86(s)，36.86(s)，36.12(s)，24.03(s)，13.92(s)；ESI-MS m/z：347.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 23 b: red solid (product of)99.7% yield); melting point: 160-162 ℃;¹H NMR(500MHz，DMSO)δ14.21(s，1H)，12.41(s，1H)，7.62(s，1H)，5.70(s，1H)，4.88(t，J＝5.5Hz，1H)，4.53(d，J＝3.8Hz，2H)，3.61(dd，J＝11.1，5.5Hz，2H)，3.30-3.15(m，2H)，2.76-2.61(m，4H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ187.01(s)，183.82(s)，157.26(s)，155.38(s)，150.84(s)，140.88(s)，134.08(s)，109.29(s)，107.93(s)，99.86(s)，71.13(s)，59.43(s)，45.81(s)，36.86(s)，36.13(s)，24.03(s)；ESI-MS m/z：363.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 24 b: red solid (yield 65.3%); melting point: 168-170 ℃;¹H NMR(500MHz，DMSO)δ14.20(s，1H)，12.36(s，1H)，7.51(s，1H)，5.67(s，1H)，4.53(d，J＝3.8Hz，2H)，3.64-3.53(m，4H)，3.32(s，2H)，2.71(dd，J＝19.3，14.4Hz，4H)，2.57(t，J＝6.2Hz，2H)，2.44(s，4H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ186.97(s)，183.65(s)，157.27(s)，155.43(s)，150.36(s)，140.91(s)，134.15(s)，107.92(s)，71.13(s)，67.16(s)，56.28(s)，54.00(s)，36.86(s)，36.15(s)，24.02(s)；ESI-MS m/z：432.2[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 25 b: red solid (yield 55.5%); melting point: 185-187 deg.C;¹H NMR(500MHz，DMSO)δ14.19(s，1H)，12.39(s，1H)，7.60(t，J＝6.1Hz，1H)，5.75(s，1H)，4.53(d，J＝3.7Hz，2H)，4.12-4.05(m，1H)，3.71(ddd，J＝66.2，14.4，7.6Hz，2H)，3.38-3.31(m，1H)，3.25(dd，J＝13.7，6.8Hz，1H)，2.77-2.62(m，4H)，1.96(ddd，J＝15.3，10.2，6.9Hz，1H)，1.89-1.76(m，2H)，1.60(dt，J＝12.0，7.6Hz，1H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ187.05(s)，183.71(s)，157.30(s)，155.41(s)，150.69(s)，140.90(s)，134.15(s)，109.26(s)，107.89(s)，100.10(s)，77.15(s)，71.13(s)，68.22(s)，47.15(s)，36.86(s)，36.13(s)，29.64(s)，26.05(s)，24.03(s)；ESI-MS m/z：403.2[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 26 b: red solid (yield 46%); melting point: 210 ℃ and 212 ℃;¹H NMR(500MHz，DMSO)δ14.18(s，1H)，12.47(s，1H)，7.97(d，J＝6.6Hz，1H)，5.53(s，1H)，4.57(s，2H)，3.99(dd，J＝15.2，7.6Hz，1H)，2.78-2.60(m，4H)，2.37-2.09(m，4H)，1.79-1.66(m，2H)，1.24(s，6H)；¹³C NMR(126MHz，DMSO)δ186.00(s)，183.01(s)，156.27(s)，154.41(s)，148.45(s)，139.79(s)，133.21(s)，108.43(s)，107.02(s)，99.53(s)，70.19(d，J＝1.6Hz)，47.28(s)，35.89(s)，35.19(s)，28.98(s)，23.11(d，J＝1.6Hz)，15.07(s)；ESI-MS m/z：373.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

compound 27 b: red solid (62% yield); melting point: 160-162 ℃;¹H NMR(500MHz，DMSO)δ13.74(s，1H)，12.79(s，1H)，6.06(s，1H)，4.53(d，J＝3.6Hz，2H)，3.78-3.70(m，4H)，3.61-3.51(m，4H)，2.70(t，J＝8.7Hz，4H)，1.25(s，6H)；¹³C NMR(126MHz，DMSO)δ184.34(s)，182.30(s)，158.67(s)，156.46(s)，153.47(s)，138.95(s)，135.15(s)，110.55(s)，109.70(s)，106.94(s)，70.14(d，J＝5.9Hz)，65.70(s)，49.42(s)，35.93–35.74(m)，35.51(d，J＝35.3Hz)，23.00(s)；ESI-MS m/z：389.1[M-H]^-. The structural formula is as follows:

wherein the content of the first and second substances,

example 2 measurement of the antiviral Activity of anthraquinones at the cellular level and the half-cytotoxicity concentration measurement

Detection of anti-Zika virus activity of anthraquinone compound at cellular level

1. Test virus strains: zika virus ZIKV (Z16019)

Cell line: a549

2. The detection method comprises the following steps:

antiviral half Effective dose (EC) of anthraquinone compound₅₀): DMSO with concentration of 0.5, 1, 2.5, 5, 10, 25, 50, 100 μ M corresponding compound is saturated cells 1h in advance, and virus-free culture medium containing corresponding concentration of drug is replaced for 48h after virus infection for 1 h; cell supernatants were collected and tested for plaque formation inhibition by plaque assay against solvent (DMSO) for different dose groups of compounds after viral infection.

The inhibition ratio (%) (number of viral plaque formation in 1-administration group/number of plaque formation in solvent control group) × 100%, calculated using the Forecast formula of EXCEL 2013, when the inhibition ratio is 50%, the concentration of the corresponding anthraquinone compound is EC₅₀. Three replicates were averaged.

Secondly, the anti-dengue virus activity detection of anthraquinone compounds at the cellular level

1. Test virus strains: dengue virus DENV2(NGC)

Cell line: a549

2. The detection method comprises the following steps:

antiviral half Effective dose (EC) of anthraquinone compound₅₀): DMSO with concentration of 0.5, 1, 2.5, 5, 10, 25, 50, 100 μ M corresponding compound is saturated cells 1h in advance, and virus-free culture medium containing corresponding concentration of drug is replaced for 48h after virus infection for 1 h; cell supernatants were collected and tested for dengue virus RNA level inhibition by RT-qPCR assay against solvent group (DMSO) for different dose groups of compounds after viral infection.

The inhibition ratio (%) (1-number of copies of dengue virus RNA in the administration group/number of copies of dengue virus RNA in the solvent control group) × 100%, calculated using the Forecast formula of EXCEL 2013, when the inhibition ratio is 50%, the concentration of the corresponding anthraquinone compound is regarded as EC₅₀. Three replicates were averaged.

Third, detection of half cytotoxic concentration of anthraquinone compounds

And (3) testing by using an MTT method, adding the gradient dose of the anthraquinone compound into the supernatant of the A549 cells, maintaining for 48 hours, adding MTT, incubating for 4 hours, sucking out the culture medium, adding DMSO (dimethyl sulfoxide) to detect the absorbance value at 490nm, comparing with a DMSO solvent control group, and calculating the inhibition rate.

The inhibition (%) was 100% (1-490 nm absorbance value of drug administration/490 nm absorbance value of solvent control), and the concentration of the corresponding compound when the inhibition was 50% was calculated by Forecast's equation of EXCEL 2013 as CC₅₀. Three replicates were averaged.

Fourth, the detection result

Anthraquinone compounds inhibit EC of ZIKV and DENV2 in a549 cells₅₀And half the cytotoxic concentration CC₅₀The test results are shown in table 1.

TABLE 1 anthraquinones inhibit EC of ZIKV and DENV2 in A549 cells₅₀And CC₅₀

As can be seen from the results in Table 1, the anthraquinones have a very good inhibitory effect on Zika virus and dengue virus, and particularly the anthraquinones of series I have the strongest antiviral activity. Meanwhile, the anthraquinone compound has better safety to host cells under effective antiviral dose, has certain specificity to target viruses, can be prepared into anti-Zika virus and anti-dengue virus medicaments for application, and has important significance for preventing and treating Zika virus and dengue virus.

It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.