Use of curcumin compounds in the preparation of a medicine for treating schistosomiasis, pharmaceutical composition

Abstract

This invention relates to the field of biopharmaceutical technology, and more particularly to the application of curcuminoid compounds in the preparation of drugs for treating schistosomiasis, and pharmaceutical compositions thereof. The curcuminoid compounds used in this invention contain different substituents on their benzene rings, which can effectively regulate the electrophilic and lipophilic properties of the compounds, making them easier to enter the schistosomiasis cell. They interact with redox enzymes within the schistosomiasis cell, disrupting the redox balance and promoting schistosomiasis death. Therefore, they exhibit highly effective therapeutic activity against schistosomiasis and show great promise for application in the preparation of drugs for treating schistosomiasis.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical technology, and in particular to the application of curcumin compounds in the preparation of drugs for treating schistosomiasis and pharmaceutical compositions thereof. Background Technology

[0002] Schistosomiasis has a complex life cycle and developmental morphology, consisting of seven stages: egg, miracidia, maternal sporocyst, daughter sporocyst, cercaria, juvenile worm, and adult worm. The internal control stage is one of the main pathways for controlling the spread of schistosomiasis. Praziquantel is the only drug recommended by the World Health Organization for the current treatment of schistosomiasis, boasting advantages such as high efficacy, short treatment course, few adverse reactions, convenient oral administration, low price, and safety for children and pregnant women. However, with the widespread use of praziquantel, there have been reports of decreased cure rates and treatment failures, and the risk of reinfection remains even after treatment. These situations urge researchers to find alternative drugs to praziquantel. Furthermore, compared to the rapid development of new drugs for other diseases, the research and development of new drugs for schistosomiasis treatment has lagged significantly, and no new clinical drugs have yet been developed. Therefore, the development of effective and safe new drugs for the treatment of schistosomiasis is of paramount practical importance for the prevention and control of schistosomiasis. Wang Huigang (Wang Huigang. New progress in the application of curcumin in the prevention and control of parasitic diseases [J]. Tianjin Pharmaceutical Journal, 2019, 31(06):64-68.) disclosed the application of curcumin in the prevention and control of parasitic diseases (such as Plasmodium, Leishmania, Trypanosomiasis, and Schistosomiasis). However, there are no reports of other curcumin compounds with anti-schistosomiasis properties. Summary of the Invention

[0003] The purpose of this invention is to provide the application of curcuminoid compounds in the preparation of drugs for treating schistosomiasis, and pharmaceutical compositions thereof. The curcuminoid compounds having the structure shown in Formula I provided by this invention exhibit highly effective therapeutic activity against schistosomiasis.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides the application of curcuminoid compounds in the preparation of drugs for treating schistosomiasis, wherein the curcuminoid compounds have the structure shown in Formula I:

[0006]

[0007] In formula I, R 1 ~R 5 Independently includes -H, -OH, -NH2, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, C1-C4 alkyl or ether groups; said ether group includes methyl ether, diethyl ether, trifluoromethyl ether, or propenyl ether; when R 1 -H, R 4 -H, R5 -H, R 2 When it is -OCH3, R 3 Not -OH; when R 1 -H, R 2 -H, R 5 -H, R 4 When it is -OCH3, R 3 It is not -OH.

[0008] Preferably, the in vitro concentration of the curcumin compounds is 10–40 μM.

[0009] Preferably, the in vivo concentration of the curcumin-like compound is 100–1000 mg / kg.

[0010] Preferably, the curcuminoid compounds include:

[0011]

[0012] Preferably, the method for preparing the curcumin-like compounds includes the following steps:

[0013] A mixture of substituted benzaldehyde having the structure shown in Formula II, boron oxide, tributyl borate, acetylacetone, n-butylamine and an organic solvent were subjected to a condensation reaction to obtain curcumin-like compounds.

[0014]

[0015] In formula II, R 1 ~R 5 With R in Equation I 1 ~R 5 same.

[0016] Preferably, the molar ratio of boron oxide to tributyl borate is 1:1 to 6;

[0017] The molar ratio of boron oxide to acetylacetone is 1:1 to 2.5;

[0018] The molar ratio of boron oxide to substituted benzaldehyde is 1:1 to 5;

[0019] The molar ratio of the substituted benzaldehyde and n-butylamine is 1:0.25 to 4.

[0020] Preferably, the organic solvent includes one or more of ethyl acetate, ethanol, methanol, and toluene.

[0021] Preferably, the condensation reaction is carried out at a temperature of 0–100°C for a time of 0.5–10 h.

[0022] This invention provides a pharmaceutical composition comprising a curcuminoid compound and pharmaceutically acceptable excipients; said curcuminoid compound having the structure shown in Formula I:

[0023]

[0024] In formula I, R 1 ~R 5 Independently includes -H, -OH, -NH2, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, C1 to C4 alkyl or ether groups; the ether group includes methyl ether, diethyl ether, trifluoromethyl ether, or propenyl ether.

[0025] The curcumin-like compounds with the structure shown in Formula I proposed in this invention contain different substituents on the benzene ring, which can effectively regulate the electrophilic and lipophilic properties of the compounds, making them easier to enter the schistosome body. They interact with the redox balance enzymes in the schistosome body, disrupting the redox balance and promoting the death of schistosomes. Therefore, they have highly effective therapeutic activity against schistosomiasis and have great application prospects in the preparation of drugs for treating schistosomiasis. Detailed Implementation

[0026] This invention provides the application of curcuminoid compounds in the preparation of drugs for treating schistosomiasis, wherein the curcuminoid compounds have the structure shown in Formula I:

[0027]

[0028] In formula I, R 1 ~R 5 Independently includes -H, -OH, -NH2, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, C1-C4 alkyl or ether groups; said ether group includes methyl ether (-OCH3), diethyl ether, trifluoromethyl ether, or propenyl ether; when R 1 -H, R 4 -H, R 5 -H, R 2 When it is -OCH3, R 3 Not -OH; when R 1 -H, R 2 -H, R 5 -H, R 4 When it is -OCH3, R 3 Not -OH. In this invention, the C1-C4 alkyl group preferably includes methyl, ethyl, propyl, or butyl.

[0029] In this invention, the curcumin-like compounds preferably include:

[0030]

[0031] In this invention, the preparation method of the curcumin-like compounds preferably includes the following steps:

[0032] A mixture of substituted benzaldehyde having the structure shown in Formula II, boron oxide, tributyl borate, acetylacetone, n-butylamine and an organic solvent were subjected to a condensation reaction to obtain curcumin-like compounds.

[0033]

[0034] In formula II, R 1 ~R 5 With R in Equation I 1 ~R 5 same.

[0035] In this invention, unless otherwise specified, the raw materials and solvents required for preparation are all commercially available products well known to those skilled in the art.

[0036] In this invention, the molar ratio of boron oxide to tributyl borate is preferably 1:1 to 6, more preferably 1:2 to 5, and even more preferably 1:3 to 4.

[0037] In this invention, the molar ratio of boron oxide to acetylacetone is preferably 1:1 to 2.5, more preferably 1:1.2 to 2.2, and even more preferably 1:1.5 to 2.

[0038] In this invention, the molar ratio of boron oxide to substituted benzaldehyde is preferably 1:1 to 5, more preferably 1:2 to 4, and even more preferably 1:3. This invention does not specifically limit the source of the substituted benzaldehyde; it can be prepared using commercially available products well known to those skilled in the art or by methods well known in the art.

[0039] In this invention, the molar ratio of the substituted benzaldehyde and n-butylamine is preferably 1:0.25 to 4, more preferably 1:0.4 to 3, and even more preferably 1:0.5 to 2.

[0040] In this invention, the organic solvent preferably includes one or more of ethyl acetate, ethanol, methanol, and toluene. There is no particular limitation on the amount of the organic solvent used, as long as it is sufficient to ensure the smooth progress of the condensation reaction.

[0041] This invention does not impose any particular limitation on the mixing method; any mixing method well-known to those skilled in the art that can ensure uniform mixing of the raw materials is acceptable, such as stirring. In this invention, the preferred mixing sequence is: completely dissolving boron oxide and tributyl borate in an organic solvent, then adding acetylacetone and substituted benzaldehyde, followed by the dropwise addition of n-butylamine.

[0042] In this invention, the temperature of the condensation reaction is preferably 0–100°C, more preferably 50–70°C; the time of the condensation reaction is preferably 0.5–10 h, more preferably 4–6 h; the reaction formula of the condensation reaction is as follows:

[0043]

[0044] Following the condensation reaction, the present invention preferably includes post-treatment, which preferably includes: adjusting the obtained condensation reaction solution to neutral, then performing dichloromethane extraction, drying with anhydrous sodium sulfate, solid-liquid separation, concentrating the obtained liquid component, and purifying it by column chromatography to obtain curcumin-like compounds. In the present invention, adjusting to neutral is preferably achieved by sequentially adding dilute hydrochloric acid aqueous solution and sodium hydroxide aqueous solution; the concentration of the dilute hydrochloric acid aqueous solution is preferably 0.5–2.0 mol / L, more preferably 1 mol / L; the concentration of the sodium hydroxide aqueous solution is preferably 0.5–2.0 mol / L, more preferably 0.5–1 mol / L. The present invention does not have any particular limitation on the solid-liquid separation; any solid-liquid separation method well known to those skilled in the art can be used, such as filtration, vacuum filtration, or centrifugation. In this invention, the eluent used for column chromatography purification preferably includes a petroleum ether-ethyl acetate mixed solvent, and the volume ratio of petroleum ether to ethyl acetate in the eluent is preferably 3 to 20:1, more preferably 3 to 16:1, and specifically preferably 3:1, 15:1, 16:1 or 20:1.

[0045] In this invention, the in vitro concentration of the curcumin compounds is preferably 10-40 μM, more preferably 20-30 μM.

[0046] In this invention, the in vivo concentration of the curcumin compounds is preferably 100-1000 mg / kg, more preferably 300-800 mg / kg.

[0047] This invention provides a pharmaceutical composition comprising a curcuminoid compound and pharmaceutically acceptable excipients; said curcuminoid compound having the structure shown in Formula I:

[0048]

[0049] In Equation I, R 1 ~R 5 Independently comprising -H, -OH, -NH2, -F, -Cl, -Br, -I, -CN, -NO2, -CF3, C1-C4 alkyl or ether groups; wherein the C1-C4 alkyl groups preferably include methyl, ethyl, propyl or butyl; wherein the ether groups include methyl ether, diethyl ether, trifluoromethyl ether, and propenyl ether. In this invention, when R 1 -H, R 4-H, R 5 -H, R 2 When it is -OCH3, R 3 Preferred to be non-OH; when R 1 -H, R 2 -H, R 5 -H, R 4 When it is -OCH3, R 3 It is preferred that it is not -OH.

[0050] This invention does not impose any particular limitation on the pharmaceutically acceptable excipients; any pharmaceutically acceptable excipient well known to those skilled in the art can be used. This invention also does not impose any particular limitation on the dosage form of the pharmaceutical composition; any dosage form well known to those skilled in the art can be used.

[0051] The following examples illustrate the application of curcumin compounds provided by this invention in the preparation of drugs for treating schistosomiasis and the pharmaceutical compositions thereof, but these should not be construed as limiting the scope of protection of this invention.

[0052] Comparative Example 1

[0053] Synthesis of (curcumin, compound 1):

[0054] 1.2 mmol boron oxide, 4.8 mmol tributyl borate, 2 mmol acetylacetone, and 4 mmol 4-hydroxy-3-methoxybenzaldehyde were dissolved in 25 mL ethyl acetate. Then, 4 mmol n-butylamine was slowly added dropwise. After reacting at 50 °C for 6 h, the pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 1.2 mol / L dilute sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1) to give a yellow solid (curcumin, compound 1, yield 65.7%). 1 H NMR (400MHz, DMSO-d6) δ9.64 (s, 2H), 7.57 (d, J = 16.0Hz, 2H), 7.32 (d, J = 2.0Hz, 2H), 7.1 6(dd,J=8.3,1.9Hz,2H),6.84(s,2H),6.77(d,J=16.0Hz,2H),6.06(s,1H),3.84(s,6H). 13 C NMR (101MHz, DMSO-d6) δ183.61,149.76,148.40,141.10,126.75,123.51,121.51,116.12,111.78,101.21,56.10.

[0055] Example 1

[0056] Synthesis of Compound 2

[0057] 6 mmol boron oxide, 24 mmol tributyl borate, 10 mmol acetylacetone, and 20 mmol benzaldehyde were dissolved in 50 mL ethyl acetate. Then, 20 mmol n-butylamine was slowly added dropwise. After reacting at 50 °C for 8 h, the pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 1.5 mol / L dilute sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1) to give a yellow solid (compound 2, yield 54.7%). 1 H NMR (400MHz, DMSO-d6) δ7.74(dd,J=7.5,2.1Hz,4H),7.68(d,J=16.0Hz,2H),7.45-7.43(m,6H),6.98(d,J=16.0Hz,2H),6.21(s,1H). 13 C NMR (101MHz, DMSO-d6) δ = 183.19, 140.35, 134.63, 130.29, 128.96, 128.31, 124.29, 101.78.

[0058] Example 2

[0059] Synthesis of Compound 3

[0060] 5 mmol boron oxide, 25 mmol tributyl borate, 25 mmol acetylacetone, and 20 mmol 4-hydroxybenzaldehyde were dissolved in 40 mL ethyl acetate. Then, 20 mmol n-butylamine was slowly added dropwise. After reacting at 50 °C for 4 h, the pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 0.6 mol / L dilute sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 15:1) to give a pale yellow solid (compound 3, yield 49.3%). 1 H NMR (400MHz, DMSO-d6) δ10.06 (s, 2H), 7.57-7.53 (m, 6H), 6.84 (d, J = 8.5Hz, 4H), 6.70 (d, J = 15.9Hz, 2H), 6.03 (s, 1H). 13C NMR (101MHz, DMSO-d6) δ183.21,159.82,140.39,130.34,125.86,120.80,115.95,101.02,48.64.

[0061] Example 3

[0062] Synthesis of Compound 4

[0063] 10 mmol boron oxide, 24 mmol tributyl borate, 10 mmol acetylacetone, and 20 mmol anisaldehyde were dissolved in 30 mL ethyl acetate. Then, 20 mmol n-butylamine was slowly added dropwise. After reacting at 50 °C for 2 h, the pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 2.0 mol / L dilute sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1) to give a pale yellow solid (compound 4, yield 48.5%). 1 H NMR (400MHz, DMSO-d6) δ7.70-7.66(m,4H),7.62(d,J=16.0Hz,2H),7.01-6.99(m,4H),6.70(d,J=16.0Hz,2H),6.09(s,1H),3.81(s,6H). 13 C NMR (101MHz, DMSO-d6) δ183.37,161.26,140.19,130.30,127.53,122.02,114.69,101.37,55.54.

[0064] Example 4

[0065] Synthesis of Compound 5

[0066] 4 mmol boron oxide, 20 mmol tributyl borate, 10 mmol acetylacetone, and 20 mmol 4-fluorobenzaldehyde were dissolved in 25 mL ethyl acetate. Then, 5 mmol n-butylamine was slowly added dropwise. After reacting at 60 °C for 5 h, the pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 1.5 mol / L dilute sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1) to give a pale yellow solid (compound 5, yield 48.2%). 1H NMR (400MHz, DMSO-d6) δ7.83-7.79(m,4H),7.67(d,J=16.0Hz,2H),7.31(t,J=8.8Hz,4H),6.94(d,J=16.0Hz,2H),6.16(s,1H). 13 C NMR (101MHz, DMSO-d6) δ183.12,164.41,161.93,139.12,131.33,131.30,130.65,130.57,124.15,124.13,116.09,115.87,101.76.

[0067] Example 5

[0068] Synthesis of Compound 6

[0069] 5 mmol boron oxide, 6 mmol tributyl borate, 10 mmol acetylacetone, and 20 mmol 4-chlorobenzaldehyde were dissolved in 50 mL ethyl acetate. Then, 20 mmol n-butylamine was slowly added dropwise. The mixture was reacted at 55 °C for 6 h. The pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 1.2 mol / L dilute sodium hydroxide aqueous solution sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1) to give a pale yellow solid (compound 6, yield 42.5%). 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=8.5Hz,4H),7.65(d,J=16.0Hz,2H),7.51(d,J=8.4Hz,4H),7.00(d,J=16.0Hz,2H),6.18(s,1H). 13 C NMR (101MHz, DMSO-d6) δ183.03,138.99,134.77,133.59,130.00,129.00,125.01,102.11.

[0070] Example 6

[0071] Synthesis of Compound 7

[0072] 5 mmol boron oxide, 6 mmol tributyl borate, 20 mmol acetylacetone, and 10 mmol 2-methoxybenzaldehyde were dissolved in 50 mL ethyl acetate. Then, 20 mmol n-butylamine was slowly added dropwise. The mixture was reacted at 55 °C for 5 h. The pH was then adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 1.0 mol / L dilute sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 16:1) to give a pale yellow solid (compound 7, yield 42.5%). 1 H NMR(400MHz,DMSO-d6)δ7.91(d,J=16.0Hz,2H),7.74(dd,J=7.7,1.5Hz,2H),7.44–7.40(m,2H), 7.11(d,J=8.0Hz,2H),7.03(t,J=8.0Hz,2H),6.96(d,J=16.0Hz,2H),6.13(s,1H),3.89(s,6H). 13 C NMR (101MHz, DMSO-d6) δ183.33,157.92,134.86,131.88,128.24,124.33,122.94,120.75,111.80,101.92,55.66.

[0073] Example 7

[0074] Synthesis of Compound 8

[0075] 10 mmol boron oxide, 24 mmol tributyl borate, 10 mmol acetylacetone, and 20 mmol 3,4-dimethoxybenzaldehyde were dissolved in 35 mL ethyl acetate, followed by the slow addition of 10 mmol n-butylamine. After reacting at 50 °C for 4 h, the pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 1.5 mol / L dilute sodium hydroxide aqueous solution sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1) to give a pale yellow solid (compound 8, yield 52.5%). 1 H NMR (400MHz, DMSO-d6) δ7.61(d,J=16.0Hz,2H),7.35(d,J=1.8Hz,2H),7.28(dd,J=8.3,1.9H z,2H),7.02(d,J=8.0Hz,2H),6.85(d,J=16.0Hz,2H),6.11(s,1H),3.83(s,6H),3.81(s,6H). 13C NMR (101MHz, DMSO-d6) δ183.19,150.96,149.02,140.40,127.56,111.68,110.48,100.98.

[0076] Example 8

[0077] Synthesis of Compound 9

[0078] 6 mmol boron oxide, 12 mmol tributyl borate, 8 mmol acetylacetone, and 10 mmol 3,4,5-trimethoxybenzaldehyde were dissolved in 60 mL ethyl acetate. Then, 40 mmol n-butylamine was slowly added dropwise. The mixture was reacted at 70 °C for 5 h. The pH was adjusted to neutral by adding 1 mol / L hydrochloric acid aqueous solution and 1.8 mol / L dilute sodium hydroxide aqueous solution sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1) to give a pale yellow solid (compound 9, yield 55.7%). 1 HNMR (400MHz, DMSO-d6) δ7.64(d,J=15.9Hz,2H),7.10(s,4H),6.97(d,J=16.0Hz,2H),6.20(s,1H),3.86(s,12H),3.72(s,6H). 13 C NMR (101MHz, DMSO-d6) δ183.19,153.12,140.56,139.52,130.25,123.70,105.94,101.23,60.13,56.02.

[0079] Test Example 1

[0080] In vitro anti-schistosomiasis activity tests of compounds 1-9

[0081] 1980 μL of culture medium containing 10% newborn calf serum was pre-added to 24-well plates and incubated at 37°C with 5% CO2 for 30 min. Five pairs of active adult worms with intact body membranes were picked into each well, and then different concentrations of compound solutions (20 μL) were added. Changes in the worms were observed at regular intervals, such as whether the body membrane swelled, whether the worms were curved, and the degree of decrease in activity frequency. Simultaneously, RPMI 1640 medium containing only 10% newborn calf serum served as a blank control; RPMI 1640 medium containing 2% (v / v) DMSO and 10% newborn calf serum served as a negative control; and 10 μM praziquantel served as a positive control. Each experiment was repeated twice.

[0082] Curcumin-like compounds were used in the culture medium at concentrations ranging from 10 to 40 μM. The results are shown in Table 1. Furthermore, the results indicated no schistosomiasis mortality in the blank control group and the negative control group, meaning the mortality rate was 0%.

[0083] Table 1. Antischistosomiasis activity (%) of curcuminoids

[0084]

[0085] Table 1 shows that curcumin (1) at a concentration of 40 μM can cause 100% death of schistosomiasis after 72 hours.

[0086] A 40 μM concentration of the compound caused 80% mortality of schistosomiasis worms after 272 hours.

[0087] A 40 μM concentration of the compound caused 100% mortality of schistosomiasis worms after 372 hours.

[0088] A 40 μM concentration of the compound caused 70% mortality of schistosomiasis worms after 472 hours.

[0089] A 40 μM concentration of the compound caused 100% mortality of schistosomiasis worms after 572 hours.

[0090] A 40 μM concentration of the compound caused 45% mortality of schistosomiasis worms after 672 hours.

[0091] A 40 μM concentration of the compound caused 100% mortality of schistosomiasis worms after 772 hours.

[0092] A 40 μM concentration of the compound caused 100% mortality of schistosomiasis worms after 872 hours.

[0093] A 40 μM concentration of the compound caused 80% mortality of schistosomiasis 9 after 72 hours.

[0094] Curcumin compounds can effectively induce the death of schistosomes in the range of 10–40 μM. Among them, curcumin compounds 1, 3, 5, 7, 8 and 9 have excellent anti-schistosome activity.

[0095] Test Example 2

[0096] Mice infected with Schistosoma cercariae were randomly divided into groups of five. After 28 days of routine feeding, they were administered the drug via gavage. The mice were fasted for 24 hours the day before gavage and then fed for 2 hours after gavage. Gavage continued for 5 days. The cycle began on the last day of gavage, and mice were dissected 14 days after routine feeding. Mice were anesthetized and 10% chloral hydrate solution was injected intraperitoneally (0.1 mL / 10 g based on body weight). The number of worms collected from the porta hepatis-mesenteric veins was recorded, and the worm reduction rate was calculated. The control group (no drug administration) consisted of mice given praziquantel, the positive control group (giving praziquantel), and the experimental group (giving curcumin-like compounds). The in vivo concentrations of curcumin-like compounds 8 and 9, and praziquantel, were 500 mg / kg. The experimental results are shown in Table 2.

[0097] Table 2. In vivo killing effects of curcumin compounds 8 and 9 and praziquantel on 28-day-old adults.

[0098]

[0099] Note: "-" indicates that the test compound has no in vivo killing activity against 28-day-old adults.

[0100] As shown in Table 2, compounds 8 and 9 of the curcumin family exhibited greater than 75% activity in killing schistosomiasis in vivo at 500 mg / kg, which was significantly better than compound 1 (curcumin) and close to the positive control praziquantel.

[0101] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The application of curcuminoids in the preparation of drugs for treating schistosomiasis, wherein the curcuminoids have the structure shown in Formula I: Equation I.

2. The application according to claim 1, characterized in that, The in vitro concentration of the curcumin compounds is 10~40 μM.

3. The application according to claim 1, characterized in that, The in vivo concentration of the curcumin compounds is 100~1000 mg / kg.

4. The application according to any one of claims 1 to 3, characterized in that, The preparation method of the curcumin-like compounds includes the following steps: A condensation reaction was carried out by mixing substituted benzaldehyde, boron oxide, tributyl borate, acetylacetone, n-butylamine and an organic solvent to obtain curcumin-like compounds; the substituted benzaldehyde was 3,4-dimethoxybenzaldehyde.

5. The application according to claim 4, characterized in that, The molar ratio of boron oxide to tributyl borate is 1:1~6; The molar ratio of boron oxide to acetylacetone is 1:1 to 2.5; The molar ratio of boron oxide to substituted benzaldehyde is 1:1~5; The molar ratio of the substituted benzaldehyde and n-butylamine is 1:0.25~4.

6. The application according to claim 4, characterized in that, The organic solvent includes one or more of ethyl acetate, ethanol, methanol, and toluene.

7. The application according to claim 4, characterized in that, The condensation reaction is carried out at a temperature of 0~100℃ for a time of 0.5~10h.

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