CN111494367B - Application of rutaropicrin and derivatives thereof - Google Patents

Application of rutaropicrin and derivatives thereof Download PDF

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CN111494367B
CN111494367B CN202010465753.5A CN202010465753A CN111494367B CN 111494367 B CN111494367 B CN 111494367B CN 202010465753 A CN202010465753 A CN 202010465753A CN 111494367 B CN111494367 B CN 111494367B
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eimeria tenella
rutinoside
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ethk
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CN111494367A (en
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孙铭飞
廖申权
戚南山
吕敏娜
吴彩艳
李娟�
林栩慧
胡俊菁
蔡海明
肖文婉
于林增
张健騑
谢明权
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Abstract

The invention discloses application of rutinoside and derivatives thereof, discloses application of the rutinoside and the derivatives thereof as an EtHK inhibitor, and also discloses that the rutinoside and the derivatives thereof have good effect of resisting Eimeria tenella, can be used for preparing medicines for resisting Eimeria tenella and are beneficial to developing the medicinal value of the rutinoside and the derivatives thereof.

Description

Application of rutaropicrin and derivatives thereof
Technical Field
The invention relates to application of a rutinoside derivative, in particular to application of rutinoside and a derivative thereof used as an EtHK inhibitor and in preparation of a medicine for resisting Eimeria tenella.
Background
Coccidiosis in chickens is a parasitic protozoal disease caused by infection with Eimeria spp. The production performance of sick chicken is seriously reduced, and huge economic loss is brought to the breeding industry. Eimeria tenella (e.tenella) is one of the most virulent pathogens. Can cause the infected chicken to have the adverse symptoms of bloody stool, anorexia, weight gain reduction, laying hen egg reduction and the like. At present, the prevention and control of the coccidiosis of the chicken still depends on the application of the coccidiostat, the side effect is that the coccidiostat resistance of the chicken appears, the effect of most of the original coccidiostat is obviously reduced, and the prevention and control of the coccidiosis of the chicken are seriously challenged.
Eimeria tenella hexokinase (EtHK) phosphorylates glucose to glucose-6-phosphate, requiring Mg for the reaction2+And (4) participating.
Rutachin (Chalepin), belonging to furocoumarin compounds. Is derived from Ruta graveolens L, volatile oil of whole herb, and whole herb of Pinus koraiensis. The existing research shows that the rutinoside has the following functions: 1. has effects of inhibiting and relieving contraction and spasm caused by acetyl-beta-methyl choline; 2. has anticancer effect. The formula of the rutaropicrin is C19H22O4Molecular weight 314.4, CAS accession No.: 13164-04-0.
However, the relationship between the rutinoside and the derivatives thereof and EtHK and Eimeria tenella is not reported at present, and the invention aims to research the relationship between the rutinoside and the derivatives thereof and the EtHK and Eimeria tenella.
Disclosure of Invention
The first object of the present invention is to provide the use of rutinoside and its derivatives as an inhibitor of EtHK.
The second purpose of the invention is to provide the application of the rutinoside and the derivatives thereof in preparing the anti-eimeria tenella drugs.
The rutinoside can effectively inhibit the activity of HK enzyme of the Eimeria tenella in vitro and can effectively inhibit the development of the Eimeria tenella on a cell culture model of the Eimeria tenella, and animal experiments further prove that the rutinoside has good anti-coccidium effect and can be used for developing novel anti-coccidium medicaments.
Research finds that the EtHK is obviously different from host HK, and the EtHK can be used as a potential drug target for developing anticoccidial drugs. Therefore, the inhibitor is searched aiming at the EtHK target, a new coccidiostat is developed, and a new strategy is provided for the effective prevention and treatment of the chicken coccidiosis.
The purpose of the invention is realized by the following technical scheme:
in a first aspect of the invention, the use of rutinoside and its derivatives as an ethhk inhibitor is proposed, said rutinoside derivatives having the following structural formula:
Figure BDA0002512607970000021
wherein R is1Selected from:
Figure BDA0002512607970000022
R2selected from: -H or-COCH3And R is1And R2Not being simultaneously-H. The rutaropicrin and the derivatives thereof can effectively inhibit the activity of HK enzyme, and can search inhibitors aiming at EtHK targets.
According to an embodiment of the invention, the EtHK inhibitor is an EtHK enzyme activity inhibitor.
According to an embodiment of the invention, said rutaropicrin derivative is selected from:
Figure BDA0002512607970000023
according to the rutaropicrin derivatives disclosed by the embodiment of the invention, the rutaropicrin derivatives can effectively inhibit the enzyme activity of EtHK.
In another aspect of the invention, the application of rutinoside and its derivatives in preparing anti-coccidiosis drugs is provided, the formula of the rutinoside derivatives is as follows:
Figure BDA0002512607970000031
wherein R is1A substituent selected from:
Figure BDA0002512607970000032
R2a substituent selected from: -H or-COCH3And R is1And R2Not being simultaneously-H. The rutaecide and the derivatives thereof in the embodiment of the invention have obvious inhibition effect on the propagation of Eimeria tenella, have good Eimeria tenella resistance, and are obviously superior to control drugs of sulfachloropyrazine sodium and diclazuril. Can develop a new anti-coccidiosis drug and provide a new drug for effectively preventing and treating the chicken coccidiosis.
According to an embodiment of the invention, said rutaropicrin derivative is selected from:
Figure BDA0002512607970000033
according to an embodiment of the invention, the chicken coccidia is eimeria tenella.
In another aspect of the invention, the application of rutinoside and derivatives thereof in preparing feed additives for resisting chicken coccidiosis is provided, and the formula of the rutinoside derivatives is as follows:
Figure BDA0002512607970000034
wherein R is1Selected from:
Figure BDA0002512607970000041
R2selected from: -H or-COCH3And R is1And R2Not being simultaneously-H. The rutinoside and the derivatives thereof provided by the invention, as feed additives, have obvious inhibition effects on the propagation of Eimeria tenella, have good Eimeria tenella resistance, and are obviously superior to control drugs sulfachloropyrazine sodium and diclazuril. Can develop a new anti-coccidiosis drug and provide a new drug for effectively preventing and treating the chicken coccidiosis.
According to an embodiment of the invention, said rutaropicrin derivative is selected from:
Figure BDA0002512607970000042
according to an embodiment of the invention, the chicken coccidia is eimeria tenella.
The invention has the beneficial effects that:
the invention discloses that the rutinoside and the derivatives thereof are EtHK inhibitors and are used for treating the infection of Eimeria tenella, the application of the rutinoside and the derivatives thereof is expanded, and simultaneously, a new coccidiostat is developed. The invention analyzes the effect of the rutaropicrin and the derivatives thereof on inhibiting the activity of EtHK enzyme, and the result shows that the rutaropicrin and the derivatives thereof can effectively inhibit the activity of the EtHK enzyme. The invention also carries out cell level tests and animal tests, and the results show that the rutinoside and the derivatives thereof have obvious effect of inhibiting the Eimeria tenella. The compound provided by the invention can be used for preparing an anti-eimeria tenella medicine.
Drawings
FIG. 1 is a graph of the effect of Compound 1 on the reproduction of Eimeria tenella; the abscissa is the compound concentration and the ordinate is the relative activity of Eimeria tenella development.
FIG. 2 is a graph of the effect of Compound 2 on the multiplication of Eimeria tenella; the abscissa is the compound concentration and the ordinate is the relative activity of Eimeria tenella development.
FIG. 3 is a graph of the effect of Compound 3 on the multiplication of Eimeria tenella; the abscissa is the compound concentration and the ordinate is the relative activity of Eimeria tenella development.
FIG. 4 is a graph of the effect of sulfachloropyrazine sodium on the propagation of Eimeria tenella; the abscissa is the compound concentration and the ordinate is the relative activity of Eimeria tenella development.
FIG. 5 is a graph of the effect of diclazuril on the propagation of Eimeria tenella, the compound concentration being plotted on the abscissa and the relative activity of Eimeria tenella development being plotted on the ordinate.
Detailed Description
The present invention will be further described with reference to specific examples, but the present invention is not limited thereto.
Example 1
Experimental materials:
the rutinoside and the derivatives thereof are purchased from Beijing Bailingwei science and technology Limited, and the information is as follows:
table 1 Compounds
Figure BDA0002512607970000051
The experimental method comprises the following steps:
the activity of Eimeria tenella HK enzyme was determined using a coupling reaction, the reaction formula is as follows:
Figure BDA0002512607970000052
the rate of NADPH production was measured by a Varioskan Flash full-wavelength scanning multifunction reader at the relative fluorescence value (RFU) measured at excitation wavelength of 340nm and emission wavelength of 460nm, and the enzymatic activity of the enzyme and the inhibitory effect of the compound on the enzymatic activity were measured.
Wherein the EtHK enzyme kinetic reaction system is 100 mu L, and the reaction system comprises 1mM glucose,2mM ATP and 7mM MgCl2,0.2mM NADP+0.3U G6PDH,100mM Tris-Cl and 10. mu.L EtHK, reaction temperature 36 ℃.
The experimental results are as follows:
according to the experiment, the IC of the compound 150Value 23.5. mu.M, IC of Compound 250The value was 16.3. mu.MIC of Compound 350The value was 18.5. mu.M. The results show that compounds 1, 2 and 3 all inhibit the enzyme activity of EtHK.
Example 2
Experimental materials:
a compound: the compounds 1 to 3 in Table 1 were used.
Control drugs: sulfachloropyrazine sodium, available from Sigma; diclazuril, available from Bailingwei technologies, Beijing.
Coccidian oocysts: eimeria tenella (e.tenella) eurycosporized oocysts, obtained from the institute of animal health, academy of agricultural sciences, guangdong province, were rejuvenated in coccidiless chicks prior to use.
Cell: MDBK cell line, obtained from institute of animal health, college of agricultural sciences, Guangdong province.
The experimental method comprises the following steps:
anticoccidial effect was evaluated in e.tenella MDBK cell culture model: MDBK cells grown to a confluency of 80% or more were digested with 0.25% trypsin digestion solution at 4X 105Cell concentration per well plated 12 well cell culture plates at 37 ℃ with 5% CO2The culture box is used for culturing for 24 hours. When the cells in the 12-well culture plate are grown to a confluent state of 80% or more, 10X 10 cells are inoculated per well4Sporozoites/ml, medium was discarded after 4h, washed 3 times with PBS, suspended sporozoites washed off and 5% fetal bovine serum in MEM medium was added to each well. Adding the drugs to be detected (compound 1-3 and the control drugs sulfachloropyrazine sodium and diclazuril) into each hole, setting 3 times of repetition, and simultaneously setting a blank control and a positive control. Placing at 37 deg.C with 5% CO2The cultivation is continued in the incubator. After 48h of incubation, the medium was discarded, washed 3 times with PBS, and total RNA was extracted from each well sample.
The RT-PCR is used for detecting the influence of each test drug on the growth and development of coccidium, and the primers are as follows:
specific amplification Eimeria tenella actin primer:
EtActin-F:5’-CACCACCGCCGAGAAAGA-3’(SEQ ID NO.1)，
EtActin-R:5’-GAACAACATTG-CCGTAGAGG-3’(SEQ ID NO.2)；
specific amplification host cell actin primers:
Bactin-F:5’-GGATGAGGCTCAGAGCAAGAGA-3’(SEQ ID NO.3)，
Bactin-R:5’-TCGTCCCAGTTGGTG-ACGAT-3’(SEQ ID NO.4)。
by Delta CTThe method calculates the effect of each test drug on coccidian growth and development at the level of cell culture.
The Real-time PCR reaction system is shown in Table 2 and Table 3.
TABLE 2 Real-time RT-PCR reaction System
Figure BDA0002512607970000061
Figure BDA0002512607970000071
Table 3 Real-time PCR reaction procedure is as follows:
Figure BDA0002512607970000072
grouping tests: each drug group (compounds 1-3 and the control drugs sulfachloropyrazine sodium and diclazuril) is respectively provided with 5 drug concentration (0.01 mu M, 0.1 mu M, 1 mu M, 10 mu M and 100 mu M) gradients. 3 replicates per concentration were set and RT-PCR detection was performed in 3 replicates per RNA sample.
Evaluation indexes are as follows: delta C of experimental and control groups was obtained by Real-time RT-PCRT＝CT[Et actin]-CT[Hactin]，ΔΔCT＝ΔCT[exp]-ΔCT[ref]Finally, the anticoccidial effect of the drug to be screened is obtained:
Figure BDA0002512607970000073
Figure BDA0002512607970000074
the experimental results are as follows:
respectively calculating the inhibition effect of each group of medicines on the Eimeria tenella, wherein the compound has obvious inhibition effect on the propagation of the Eimeria tenella, and the MIC of the compounds 1, 2 and 350The values were 16.67. mu.M, 8.60. mu.M, 7.14. mu.M, respectively; the control drugs sulfachloropyrazine sodium and diclazuril both have inhibitory effect on Eimeria tenella, and the MIC of the control drugs sulfachloropyrazine sodium and diclazuril50The values were 26.21. mu.M and 30.39. mu.M, respectively. The results show that the compounds 1, 2 and 3 have good anti-eimeria tenella effect and are obviously superior to the control drugs sulfachloropyrazine sodium and diclazuril.
As can be seen from FIGS. 1 to 5, the effect of inhibiting the propagation of Eimeria tenella is more remarkable with the increase of the concentration of the compound 1 to 3, and the concentration dependence is obtained, so that the compound has a good Eimeria tenella resistant effect, compared with a control drug.
Example 3
Experimental materials:
the preparation of the rutaecarpa powder preparation comprises the following steps: mixing 3g of rutinoside (content not less than 99%) and 97g of starch.
Control drugs: conventional anticoccidial drug, three-character coccidium powder (30% sulfachloropyrazine sodium), was produced by the Shanghai Nowa animal health Limited; diclazuril, produced by Zhejiang Huiwu animal drugs Co.
Coccidian oocysts: eimeria tenella (e.tenella) eurycosporulated oocysts were stored by the institute of animal health, academy of agricultural sciences, guangdong, and rejuvenated in coccidiless chicks before use.
Chicks: lingnan yellow broiler chickens are provided by animal science research institute of Guangdong province academy of agricultural sciences and are raised in a sterilized special animal house; the chicken coop and the utensils are strictly disinfected, and the chicken coop can freely eat and drink purified water; before the test, the chicks are observed to have clinical symptoms and the feces are continuously checked for coccidian oocysts for later use for 2 days.
Feed: the young feed is prepared by Xinnandu feed science and technology Limited company in Guangdong province, and does not contain any anticoccidial drugs.
The experimental method comprises the following steps:
grouping: the 210 south-yellow-meat chickens are raised to 10 days old according to the grouping and processing of the test, the chickens are weighed one by one, weak chicks and the chickens with excessive weight are eliminated, the rest chicks are randomly divided into 7 groups, each group comprises 30 chicks, and the total weight of each group of chicks is approximately equal through proper adjustment.
And (3) treatment: except for group 1 (blank control), group 2-7 chicks were orally administered with E.tenella sporulated oocysts lx 10 at one time5Individuals/feather; on the day of attack, 3 rd to 7 th groups of the chickens were fed with feed containing anticoccidial drugs for 7 days, and the grouping conditions of the test chickens and the usage and dosage of the drugs are shown in table 4.
TABLE 4 Experimental grouping
Figure BDA0002512607970000081
Observing and recording the mental state, feed intake, excrement condition and the like of the chicken flocks every day; weighing dead chicks, performing a autopsy, and if the chicks die due to Eimeria tenella infection, the lesion score is + 4; weighing all chicks one by one on the 7 th day after infection, performing a dissection, and scoring for caecum lesion; and finally, calculating the weight gain and feed reward of each group of chicks.
The efficacy determination method and the standard anticoccidial index (ACI) were calculated according to the formula recommended by Merck, USA: ACI ═ (relative rate of weight gain + survival) - (oocyst value + lesion value); relative gain (test group weight gain ÷ blank control group weight gain) × 100%; survival rate ═ number of surviving chicks per group ÷ total number of chicks per group) × 100%.
Lesions were scored on a five-point scale: firstly, no oocysts exist, and the caecum is normal and is divided into 0 point; secondly, oocysts exist, the mucous membrane of the caecum is slightly thickened, and a small amount of intestinal contents scattered in bleeding or a small amount of blood sample is divided into +1 point; ③ 2 minutes for oocyst, thickening of caecum mucous membrane and obvious bleeding or obvious blood sample intestinal content; fourthly, oocysts exist, mucous membranes of caecum thicken, and a large amount of blood clots or blood sample intestinal cores are present, and the score is + 3; chicks died due to coccidiosis or had a large number of oocysts, the cecum appeared dark reddish brown (or the middle of the small intestine had punctate necrotic foci, the mucous membrane appeared crimson), the intestinal canal was enlarged significantly, and the content formed a significant blood sample intestinal core, which was +4 points. Mean lesion score per group x 10. Oocyst values were converted from the number of cecal contents in grams of fecal Oocysts (OPG). The drug effect judgment standard is that ACI <120 is invalid, 120-160 is weak effect, 160-180 is middle effect, and more than 180 is strong effect.
The experimental results are as follows:
observation of clinical symptoms: on day 2 of the control group (group 2) inoculated with the Eimeria tenella sporulated oocysts, the sick chickens were depressed, calm and anorexia; the control group (group 2) developed a clear bloody stool on day 5 and died, and then gradually decreased in bloody stool.
The anticoccidial index of each group was calculated separately and the results are shown in Table 5. The anti-coccidial indexes of the 5 th, 6 th and 7 th groups are all higher than those of the 3 rd and 4 th groups of the control medicament, and the anti-coccidial indexes (ACI) of the compounds 1, 2 and 3 (the 5 th, 6 th and 7 th groups) can reach more than 165, so that the compound has good anti-eimeria tenella effect and is superior to the conventional anti-coccidial medicament, namely the three-word coccidium powder and the diclazuril.
TABLE 5 anticoccidial index of each group
Figure BDA0002512607970000091
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
SEQUENCE LISTING
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Claims (2)

1. The application of the rutiletin derivative in preparing the anti-coccidiosis drugs is characterized in that the formula of the rutiletin derivative is as follows:
Figure FDA0003139956890000011
the chicken coccidiosis is Eimeria tenella.
2. The application of the rutiletin derivative in preparing the feed additive for resisting chicken coccidiosis is characterized in that the formula of the rutiletin derivative is as follows:
Figure FDA0003139956890000012
the chicken coccidiosis is Eimeria tenella.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105820173A (en) * 2016-04-25 2016-08-03 中山大学 Chalepin acetate compound and application thereof in preparing anti-EBV medicine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105820173A (en) * 2016-04-25 2016-08-03 中山大学 Chalepin acetate compound and application thereof in preparing anti-EBV medicine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
柔嫩艾美耳球虫(Eimeria tenella)已糖激酶(EtHK)的功能研究;孙铭飞 等;《科技成果》;20191231;第1-4页 *
柔嫩艾美耳球虫已糖激酶基因的克隆及体外原核、真核表达;张玉;《中国优秀硕士学位论文全文数据库 农业科技辑》;20140110(第1期);第D050-274页 *

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