Application of usnic acid derivative in preparation of anticoccidial drugs or feed additives
By adding usnic acid-7-(4-chlorobenzoate) as an active ingredient to feed, the problems of high price, large dosage and drug resistance of existing anticoccidial drugs are solved, achieving a highly effective and low-dose anti-coccidiosis effect in chickens.
Patent Information
- Application Number
- CN202511902396.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-16
- Publication Date
- 2026-01-30
AI Technical Summary
Existing anticoccidial drugs are expensive, require large dosages, and some drugs have developed resistance, making it difficult to effectively control coccidiosis in chickens.
Usnea acid derivatives, especially 7-(4-chlorobenzoate), are used as active ingredients in the preparation of anticoccidial drugs or feed additives for chickens. By adding them to the feed, a highly effective anticoccidial effect can be achieved, reducing the dosage required.
It achieves highly effective treatment against chicken coccidiosis, reduces medication costs, and solves the problem of drug resistance in some anticoccidial drugs. Usnea acid-7-(4-chlorobenzoate) has better anticoccidial effects compared to other derivatives.
Smart Images
Figure CN121422005A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically to the application of a usnic acid derivative in the preparation of anticoccidial drugs or feed additives. Background Technology
[0002] Before the 1940s, people used various alchemical methods to control coccidiosis using skim milk, vinegar, and sulfur powder. It wasn't until the early 1940s, with the discovery of sulfonamides' potential anticoccidial activity, that they were used to treat coccidiosis. Commonly used anticoccidial drugs are mainly classified into the following categories: polyether ionocarrier antibiotics; chemically synthesized anticoccidial drugs, including amide anticoccidial drugs, pyridine anticoccidial drugs, quinoline anticoccidial drugs, and plant alkaloid anticoccidial drugs. There are many types of anticoccidial drugs with different mechanisms of action; only by using them appropriately can the effects of each drug be maximized and coccidiosis effectively controlled.
[0003] Usnea acid is the main active ingredient in the medicinal herb Usnea rubra, present in high concentrations. It possesses antibacterial and anticoccidial activities, and its efficacy research primarily focuses on its antibacterial, anti-infective, detoxifying, antitumor, and cosmetic applications. However, its use in the anticoccidial field is relatively expensive, making dosage reduction a research direction. Drug structure optimization is a crucial research direction for lead compounds, enabling the discovery of derivatives with higher efficacy and lower toxicity, and is a core pathway in traditional drug development. Summary of the Invention
[0004] The purpose of this invention is to overcome the problems existing in the prior art and provide an application of a usnic acid derivative in the preparation of anticoccidial drugs or feed additives.
[0005] To achieve the above objectives, the first aspect of the present invention provides the use of a usnic acid derivative in the preparation of anticoccidial drugs or feed additives.
[0006] A second aspect of the present invention provides an anticoccidial drug for chickens, wherein the anticoccidial drug comprises a usnic acid derivative.
[0007] A third aspect of the present invention provides a feed additive for treating coccidiosis in chickens, wherein the feed additive comprises a usnic acid derivative.
[0008] The beneficial technical effects achieved by the present invention through the above technical solution are as follows: (1) This invention provides a new means for treating and preventing coccidiosis in chickens. By adding a usnic acid derivative (especially usnic acid-7-(4-chlorobenzoate)) to the feed, a more effective anti-coccidiosis effect in chickens can be achieved than that of the same dose of usnic acid, reducing the cost of medication, making it more suitable for large-scale promotion, and helping to solve the problem of drug resistance of some clinical anticoccidial drugs.
[0009] (2) The present invention conducted an anticoccidial experiment on usnic acid and several different usnic acid derivatives. The results showed that usnic acid-7-(4-chlorobenzoate) had a better anticoccidial effect than usnic acid and the other two derivatives, significantly improving the anticoccidial effect of usnic acid and reducing the dosage. Attached Figure Description
[0010] Figure 1 The bloody stool of the model group chickens in the test examples of this invention 5 days after infection with sporulated oocysts; Figure 2 This is an example of bloody feces in test chickens 5 days after infection with sporulated oocysts, as described in Example 1 of the present invention. Figure 3 This is the cecal condition of the model group chickens in the test examples of this invention 5 days after infection with sporulated oocysts; Figure 4 This is the cecal condition of test chickens 5 days after infection with sporulated oocysts, as described in Example 1 of the test cases of this invention. Detailed Implementation
[0011] The endpoints and any values of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of the various ranges, the endpoint values of the various ranges and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.
[0012] The first aspect of this invention provides the use of a usnic acid derivative in the preparation of an anticoccidial drug for chickens or in feed additives for treating chicken coccidia.
[0013] In some embodiments of the present invention, the usnic acid derivative is the sole active ingredient.
[0014] In some embodiments of the present invention, the chemical structural formula of the usnic acid derivative is as follows: .
[0015] The molecular formula of the usnic acid derivative is: C 26 H 21 ClO8; its chemical name is 4,8-diacetyl-1,7-dihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-3-yl-4-chlorobenzoate (abbreviated as 7-(4-chlorobenzoate)).
[0016] In some embodiments of the present invention, the chicken coccidia is Eimeria tenella.
[0017] A second aspect of the present invention provides an anticoccidial drug for chickens, wherein the anticoccidial drug comprises a usnic acid derivative.
[0018] In some embodiments of the present invention, the usnic acid derivative is the sole active ingredient in the anticoccidial drug.
[0019] In some embodiments of the present invention, the chemical structural formula of the usnic acid derivative is as follows: .
[0020] A third aspect of the present invention provides a feed additive for treating coccidiosis in chickens, wherein the feed additive comprises a usnic acid derivative.
[0021] In some embodiments of the present invention, the usnic acid derivative is the sole active ingredient in the anticoccidial drug.
[0022] In some embodiments of the present invention, the chemical structural formula of the usnic acid derivative is as follows: .
[0023] In some embodiments of the present invention, the mass of the isoflavone derivative in the feed additive is 5-10 g / 1000 kg, preferably 5 g / 1000 kg.
[0024] The present invention will be described in detail below through embodiments.
[0025] Unless otherwise specified in the following examples and comparative examples, all conditions were performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available products.
[0026] Source of materials: Usnea acid: Hanzhong Natural Valley Biotechnology Co., Ltd., batch number: SL250715.
[0027] Example 1 This example illustrates the preparation of a usnic acid derivative (4,8-diacetyl-1,7-dihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-3-yl-4-chlorobenzoate).
[0028] (1) Preparation of sodium phenolate: Weigh 0.500g of usnic acid into a reaction flask, add 3mL of distilled water, stir under ice bath conditions, slowly add 0.18g / mL NaOH solution until the usnic acid is completely dissolved to form sodium usnicate solution, control the pH of the solution ≥10 to ensure the stability of sodium phenolate.
[0029] (2) Acylation reaction: Dissolve 1.480 mL of p-chlorobenzoyl chloride in 2-3 mL of anhydrous acetone, and slowly add it dropwise to sodium usnic acid solution through a dry dropping funnel. Keep the reaction in an ice bath for 60 min, and monitor the reaction by TLC (developing solvent: petroleum ether: ethyl acetate = 20:1 (volume ratio)).
[0030] (3) Post-processing and purification: After the reaction is completed, the reaction solution is extracted with dichloromethane until the organic phase is neutral and dried with anhydrous sodium sulfate; the crude product is concentrated under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1 (volume ratio)). Then, it is further purified by dextran gel column chromatography (eluent: dichloromethane: methanol = 1:1 (volume ratio)) to obtain the final product.
[0031] Structural verification: through 1 H NMR (CDCl3, 600MHz), 13 The structure was confirmed by C NMR (CDCl3, 150 MHz), with key characteristic peaks including the characteristic hydrogen signals of p-chlorophenyl (δ=7.50, 8.10, d, J=8.6 Hz) and the ester group carbon signal (δ=163.9).
[0032] Comparative Example 1 The method of Example 1 was used to prepare the 4,8-diacetyl-1,7-dihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-3-ylhexanoate, except that in step (2), 1.615 mL of hexanoyl chloride was used instead of 1.480 mL of p-chlorobenzoyl.
[0033] Comparative Example 2 The method of Example 1 was used to prepare the usnic acid derivative (4,8-diacetyl-1,7-dihydroxy-2,9a-dimethyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-3-ylpentanoate), except that in step (2), 1.380 mL of pentanoyl chloride was used instead of 1.480 mL of p-chlorobenzoyl.
[0034] Test case (1) Experimental design One-day-old male laying hens were selected and raised to 12 days of age. Each hen was weighed, and weak or overweight individuals were removed. Healthy hens with a weight difference within 30g were selected and randomly divided into 8 groups of 30 birds each. Five groups were designated as the treatment group, one as the model group, one as the diclazuril group, and one as the control group. Treatment began at 12 days of age in all treatment groups and the diclazuril group. Treatment was administered via feed mixing, while the diclazuril group received treatment via drinking water. At 14 days of age, each hen in the treatment group, diclazuril group, and model group was orally vaccinated with 1.0 × 10¹² ppm. 4The chickens were found to have delicate, sporulated oocysts of Eimeria. All experimental chickens had free access to feed and water until the end of the experiment on the seventh day.
[0035] The experimental design is shown in Table 1.
[0036] Table 1
[0037] (2) Evaluation criteria The criteria for assessing the anticoccidial index (ACI) are as follows: According to the calculation formula of Merck, Inc., that is: ACI is calculated as (relative weight gain rate + survival rate) × 100 - (lesion value + follicle value).
[0038] The relative weight gain rate is calculated as follows: Chickens were weighed at the beginning and end of the experiment, and the average weight gain and relative weight gain rate were calculated. Relative weight gain rate = (weight gain rate of experimental group / weight gain rate of blank control group) × 100%.
[0039] The survival rate is calculated as follows: Record the number of dead chickens in each group, perform necropsy to determine the cause of death, and calculate the survival rate. Survival rate = (number of surviving chickens at the end of the experiment / number of chickens in the experimental group) × 100%.
[0040] The method for calculating lesion values is as follows: Chickens were slaughtered on the 7th day after infection, and the cecum was removed. The intestinal lesion score of each chicken was calculated according to the lesion scoring method designed by John Gon and Reid (1970), and the lesion score was converted into a lesion value. Lesion scoring: (If the lesions on both sides of the cecum are inconsistent, the more severe side shall prevail): 0 points, no visible lesions; 1 point, the cecal wall has a few scattered petechiae, the intestinal wall is not thickened, and the contents are normal; 2 points, numerous lesions, obvious blood in the cecal contents, slightly thickened cecal wall, normal contents; 3 points, the cecum contains a large amount of blood or a cecal core (blood clots or grayish-white, cheese-like banana-shaped masses), the cecal wall is significantly thickened, and the fecal content in the cecum is low; 4 points. Chickens that die from coccidiosis are also given 4 points, as their cecum is swollen due to being filled with a large amount of blood or intestinal contents, and the intestinal contents may or may not contain fecal matter.
[0041] Lesion score (0-40) = Average lesion score (0-4) × 10 for each experimental group.
[0042] The calculation methods for follicle count and relative follicle yield (ROP) are as follows: Collect the chicken feces of each group, and use the McMaster counting method to count the fecal oocysts, and calculate the number of oocysts per gram of feces (OPG) for each group. Calculate the oocyst value according to Table 2.
[0043] Table 2
[0044] Relative oocyst production (ROP) = (average oocyst production of the experimental group / average oocyst production of the model group) × 100%. ROP ≥ 15%, The efficacy judgment criteria are as follows: ACI > 180 belongs to highly effective anti-coccidial drugs; 160 < ACI < 180 belongs to moderately effective anti-coccidial drugs; 120 < ACI < 160 belongs to low-effective anti-coccidial drugs; ACI < 120 is ineffective against coccidia.
[0045] (3)Analysis of test results The test results are shown in Table 3.
[0046] Table 3
[0047] After the experimental chickens in the model group were infected with sporulated oocysts, they gradually showed reactions such as reduced food intake and poor spirit. On the 5th day after infection, the model group had varying degrees of bloody feces discharged ( Figure 1 ), and the food intake decreased, and it was more serious on the 6th day. Some of the experimental chickens in Comparative Example 1 and Comparative Example 2 also had bloody feces.
[0048] Example 1 ( Figure 2 ), the diclazuril group and the blank control group had no bloody feces, and there were no obvious abnormalities in food intake and drinking water.
[0049] The model group ( Figure 3 ), Comparative Example 1 and Comparative Example 2 showed cecal lesions during autopsy, while Example 1 ( Figure 4 ), diclazuril and the blank control group had no obvious changes during autopsy.
[0050] From the analysis of the anti-coccidial index, the anti-coccidial effect of Example 1 is the same as that of diclazuril, belonging to extremely sensitive drugs, and has significantly better effects than Comparative Example 1 and Comparative Example 2. Through drug structure modification, a qualitative breakthrough in drug effects has been achieved, while the effects of the other two derivatives have not been improved, indicating that usnic acid-7-(4-chlorobenzoate) has made outstanding progress compared with other derivatives.
[0051] In addition, although the usnic acid B group also has a highly effective anti-coccidial effect on chickens, its dosage is 10 times that of Example 1. This shows that the specific usnic acid derivative used in this invention can achieve a highly effective anti-coccidial effect at a low dosage.
[0052] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.
Claims
1. Use of a Usnic acid derivative for the preparation of an anticoccidial drug or a feed additive for anticoccidial use.
2. The use according to claim 1, wherein, The Usnic acid derivative is the only active ingredient.
3. Use according to claim 1 or 2, wherein, The Usnic acid derivative has the chemical structure: 。 4. The use according to any one of claims 1 to 3, wherein, The chicken coccidia is Eimeria tenella.
5. An anticoccidial medicament, characterized by comprising the compound of claim 1. The anticoccidial drug comprises a Usnic acid derivative.
6. The anticoccidial drug of claim 5, wherein, The Usnic acid derivative is the only active ingredient in the anticoccidial drug.
7. The anticoccidial drug of claim 5 or 6, wherein, The Usnic acid derivative has the chemical structure: 。 8. A feed additive for use against chicken coccidia, characterized in that, The feed additive comprises a Usnic acid derivative.
9. The feed additive according to claim 8, wherein, The Usnic acid derivative is the only active ingredient in the anticoccidial drug; Preferably, the Usnic acid derivative has the chemical structure: 。 10. The feed additive according to claim 8 or 9, wherein, In the feed additive, the Usnic acid derivative is in a quantity of 5-10 g / 1000 kg, preferably 5 g / 1000 kg.