Novel harmine derivative, synthetic method and application thereof in resisting toxoplasma gondii diseases

Abstract

The invention relates to the technical field of medicinal chemistry and parasitic disease prevention and treatment, and particularly discloses a novel harmine derivative, a synthesis method and application of the novel harmine derivative to toxoplasma gondii disease resistance. The structural general formula of the derivative is shown in the specification. Wherein R1 is selected from one of hydrogen, C1-4 alkyl, substituted or non-substituted five-membered aryl or six-membered aryl, and substituted or non-substituted five-membered heteroaryl or six-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S; r9 is selected from one of hydrogen, substituted or unsubstituted five-membered aryl or six-membered aryl; and R7 is selected from hydrogen, C1-4 alkyl, substituted or unsubstituted five-membered aryl or six-membered aryl. Preferably, the compound is 1-methyl-9-(3-methylpyridine)-beta-carboline-7-ol, and the formula is shown in the description. The novel harmine derivative provided by the invention shows high-efficiency and low-toxicity anti-toxoplasma gondii activity, the synthesis method is simple, and an excellent candidate compound is provided for developing novel anti-toxoplasma gondii drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry and prevention and treatment of parasitic diseases, and particularly relates to a novel dehydropegoine derivative, a synthesis method and application thereof in anti-Toxoplasma gondii disease. BACKGROUND

[0002] Toxoplasma gondii is a widespread zoonotic parasitic disease caused by Toxoplasma gondii, which can infect mammals and birds, invade their nucleated cells and proliferate. Most Toxoplasma gondii patients are caused by eating food, water, infected meat or contacting oocysts in cat feces. In addition, Toxoplasma gondii infection has vertical transmission characteristics. For hosts with normal immune function, Toxoplasma gondii infection rarely requires drug treatment, and the most common severe clinical manifestation in patients with low immunity is toxoplasmosis encephalitis, which usually includes multiple discontinuous brain lesions. Ocular and pulmonary diseases are the most common extracranial infection sites, and congenital infection can also cause severe toxoplasmosis, and up to half of the affected newborns have extracranial lesions.

[0003] At present, the clinical treatment of Toxoplasma gondii mainly relies on classic drug combinations such as pyrimethamine and sulfonamides. However, the existing treatment has obvious limitations: first, these drugs have large toxic and side effects, and long-term use may cause bone marrow suppression, liver and kidney function damage, etc.; second, the emergence of drug-resistant strains makes the efficacy of traditional drugs gradually decrease. Therefore, the development of highly efficient, low-toxicity and novel mechanism of action anti-Toxoplasma gondii drugs has become an urgent need for current research.

[0004] β-carboline alkaloids are an important class of alkaloids widely existing in marine organisms, terrestrial plants and higher fungi, and their molecular structure is a tricyclic system constructed by indole and pyridine. They have the characteristics of simple structure, easy synthesis and easy modification. Studies have shown that β-carboline alkaloids have rich biological activities, such as anti-tumor, anti-malaria, hypoglycemic, anti-viral and anti-fungal activities. However, in the prior art, the systematic research and development of β-carboline alkaloids, especially their structural modification products, in the aspect of anti-Toxoplasma gondii are still insufficient, the structure-activity relationship is not clear, and there is a lack of preferred compounds with strong anti-parasite activity and low cytotoxicity. SUMMARY

[0005] The present application aims to provide a novel dehydropegoine derivative, a synthesis method and application thereof in anti-Toxoplasma gondii disease. The derivative has the significant advantages of high anti-parasite activity and low cytotoxicity, providing a potential drug treatment option with high efficiency and low toxicity for clinical use; at the same time, the synthesis route is simple and efficient, and is suitable for industrial production.

[0006] To achieve the above object, in one aspect, the present application provides a novel dehydropegoenine derivative, the structural general formula of which is as follows: ; wherein R 1 is selected from hydrogen, C 1-4 alkyl, substituted or unsubstituted five-membered or six-membered aryl, substituted or unsubstituted five-membered or six-membered heteroaryl containing 1 to 4 heteroatoms selected from N or O or S; R 9 is selected from hydrogen, substituted or unsubstituted five-membered or six-membered aryl; R 7 is selected from hydrogen, C 1-4 alkyl, substituted or unsubstituted five-membered or six-membered aryl.

[0007] Further, the dehydropegoenine derivative has a chemical name of 1-methyl-9-(3-methylpyridine)-beta-carboline-7-ol and a structural formula as follows: .

[0008] In another aspect, the present application further provides a synthesis method of the dehydropegoenine derivative, comprising the following steps: S1, dehydropegoenine is used as a starting material and is added to N,N-dimethylformamide solvent, stirred at room temperature, then sodium hydride and 3-(bromomethyl)pyridine hydrobromide are added and the stirring reaction is continued at room temperature. After the reaction is completed, the reaction liquid is poured into water, and the reaction liquid is extracted with ethyl acetate. The organic phases are combined, and the organic phase is washed with water and saturated brine respectively, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained oily substance is recrystallized with diethyl ether, and solid is precipitated, filtered, and dried to obtain white solid; S2, the white solid is added to hydrobromic acid and glacial acetic acid, and the reaction mixture is then heated to reflux. After the reaction is completed, the mixture is first cooled to room temperature, then poured into cold water, and the pH is adjusted with sodium hydroxide solution. The precipitated solid is filtered with a Buchner funnel, washed with water, and dried to obtain the final target product.

[0009] Further, in S1, the amount of dehydropegoenine is 1.1-2.3 g, and the amount of N,N-dimethylformamide is 25-75 mL; the room temperature is 23-27°C, and the stirring time of the mixture of dehydropegoenine and N,N-dimethylformamide is 0.5-0.8 h.

[0010] Further, in S1, the amount of NaH is 1.5-3.5 g, and the amount of 3-(bromomethyl)pyridine hydrobromide is 3.1-4.0 g. After addition, the reaction time of continued stirring at room temperature is 24-30 h.

[0011] Further, in S1, the amount of ethyl acetate is 200-500 mL, the extraction times are 3-6 times; the amount of water is 300-600 mL, the amount of saturated brine is 200-300 mL, and the amount of anhydrous sodium sulfate is 100-300 g; and the amount of diethyl ether is 200-400 mL.

[0012] Further, in S2, the amount of hydrobromic acid is 20-50 mL, the amount of glacial acetic acid is 10-20 mL, and the reaction time of heating reflux is 8-10 h.

[0013] On the other hand, the application also discloses an application of the dehydropeydonine derivative in preparation of an anti-Toxoplasma drug.

[0014] Further, the administration mode of the drug is intravenous injection or intraperitoneal administration.

[0015] Further, the application also provides an anti-Toxoplasma drug, and the effective component comprises the dehydropeydonine derivative.

[0016] The novel dehydropeydonine derivative, the synthesis method and the application of the novel dehydropeydonine derivative in anti-Toxoplasma disease have the following beneficial effects: The application provides a novel dehydropeydonine derivative, and the preferred compound is 1-methyl-9-(3-methylpyridine)-beta-carboline-7-ol. The compound is prepared by a simple and efficient two-step synthesis method, has significant anti-Toxoplasma activity and excellent safety. Experimental results show that the compound has a strong inhibitory effect on Toxoplasma in vitro, and the survival rate of host cells is still more than 90% at a concentration of 1000 muM, which shows an excellent safety window. Animal experiments further prove that the compound can significantly prolong the survival time of mice infected with Toxoplasma. Compared with the parent compound dehydropeydonine, the compound has significantly improved anti-parasite activity while maintaining low toxicity, and provides a new solution to overcome the problems of large toxic and side effects and easy drug resistance of existing anti-Toxoplasma drugs, and has important development value and clinical application prospect.

[0017] The technical solutions of the application are further described in detail below with reference to the drawings and examples. DESCRIPTION OF DRAWINGS

[0018] Figure 1 The high-resolution spectrum of 1-methyl-9-(3-methylpyridine)-beta-carboline-7-ol synthesized in the embodiment 1 of the application is shown in the figure; Figure 2 The hydrogen spectrum of 1-methyl-9-(3-methylpyridine)-beta-carboline-7-ol synthesized in the embodiment 1 of the application is shown in the figure; Figure 3Cell toxicity of different concentrations of Derivative 1 to Vero cells; Figure 4 Inhibition effect of different concentrations of Derivative 1 on proliferation of Toxoplasma after 48h; Figure 5 Half inhibitory concentration of Derivative 1 to Toxoplasma; Figure 6 Dose-effect relationship of Derivative 1 and Harmine on Toxoplasma, wherein A is Derivative 1 and B is Harmine; Figure 7 Comparison chart of Derivative 1 and Harmine on Toxoplasma; Figure 8 Changes of body weight of mice; Figure 9 Survival time curve of mice. DETAILED DESCRIPTION

[0019] The technical solutions of the present application are further described below by means of the accompanying drawings and examples.

[0020] Based on the examples in the present application, all other examples obtained by those of ordinary skill in the art without creative work fall within the scope of protection of the present application. The experimental methods not specified in the following examples are generally determined according to national standards. The experimental instruments, equipment and reagents not specified in the following examples are all commercially available raw materials.

[0021] Unless otherwise defined or specified, all professional and scientific terms used in the present application have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to those described can be applied to the method of the present application.

[0022] Example 1: The synthesis method of the novel compound 1-methyl-9-(3-methylpyridine)-β-carboline-7-ol is as follows: ; S1, Synthesis of 7-methoxy-1-methyl-9-(pyridine-3-methyl)-beta-carboline: In a round bottom flask, add raw dehydrogenated acacia alkaloids (2.12 g, 10 mmol), N, N-dimethylformamide (50 mL), stir at room temperature for 0.5 hours, then add NaH (1.72 g, 43 mmol, 4.3 eq), 3-(bromomethyl)pyridine hydrobromide (3.5 g, 14 mmol, 1.4 eq) continue to stir at room temperature. Reaction process TLC tracking detection, reaction is completed, the reaction liquid is poured into water, the reaction liquid is extracted with ethyl acetate. Extract 3 times, combine the organic phase, the organic phase is washed with water, saturated brine, dry over anhydrous sodium sulfate, concentrated to dryness under reduced pressure. The obtained oil is recrystallized with diethyl ether, and the solid is separated, filtered and dried to obtain a white solid.

[0023] S2, Synthesis of 1-methyl-9-(3-methylpyridine)-beta-carboline-7-ol: In a 100 ml round bottom flask, add 7-methoxy-1-methyl-9-(pyridine-3-methyl)-beta-carboline (7.5 mmol), hydrobromic acid (30 ml), glacial acetic acid (10 ml), then heat the reaction mixture to reflux for 10 h, and track the detection by TLC. After the reaction is completed, the mixture is first cooled to room temperature, then poured into 200 ml of cold water, and the pH is adjusted to 6-7 with NaOH solution, a large amount of solid is precipitated, the precipitated solid is filtered with a separatory funnel, the solid is washed with water, and the solid is placed in an oven to dry, and finally a white solid is obtained.

[0024] The mass spectrum and nuclear magnetic resonance data of the compound are as follows: ESI: [M+1]=290.1297, 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1 H), 8.81 (d, 1 H), 8.71 (d, 1 H), 8.58 (d, 1 H), 8.49 (d, 1 H), 8.41 (d, 1 H), 7.99 (d, 1 H), 7.85 (dd, 1 H), 7.07-7.00 (m, 2 H), 6.11 (s, 2 H), 3.00 (s, 3 H).

[0025] 13C NMR (101 MHz, DMSO-d6) δ 162.11, 146.55, 143.55, 142.06, 140.57, 136.78, 136.22, 134.08, 133.72, 129.82, 126.42, 125.07, 114.20, 113.35, 112.42, 95.56, 45.14, 17.50. (As Figure 1 and Figure 2 shown).

[0026] The following is a specific pharmacological experiment of the application of the above-mentioned derivative of dehydropegerine as a drug for preparing an anti-toxoplasmosis drug according to the above-mentioned embodiment of the present application: Derivative 1 is [1-methyl-9-(3-methylpyridine)-β-carboline-7-ol] in the experiment.

[0027] I. Anti-toxoplasma efficacy test: 1. MTT method for detecting the cytotoxicity of Derivative 1: The cytotoxicity of Derivative 1 on Vero cells was determined by MTT experiment, and a blank group and a Derivative 1 drug group were set up. The Derivative 1 drug group was diluted by 5 times to form 5 gradient concentrations, and the blank group only contained DMEM medium. Each group had 3 parallel control wells to increase the accuracy of the experiment. The specific experimental method is as follows: the monolayer Vero cells were digested with 0.25% trypsin for 1-3 min, and then the digestion was terminated by adding DMEM medium containing 3% FBS when the cells became single round and flowed, and then the cells were uniformly blown. The cells were counted with a hemocytometer, and the cell concentration was adjusted to 1×10 5 / mL. After the cells were uniformly blown, 100 μL / well was added to the 96-well plate, and the information, time, and experimental object were marked on the cover, and then the plate was placed in a 37°C, 5% CO2 incubator for static culture. When the cells were more than 90% full, the supernatant was removed, and 100 μL / well of DMEM medium containing different concentrations of drugs was added, and incubated at 37°C for 24 h. 10 μL (5 mg / mL) of MTT solution was added to each well, and incubated at 37°C in the dark for 3 h. After the end, the supernatant was removed, 100 μL of Formazan dissolving solution was added to each well, and mixed well. Then it was dissolved at 37°C in the cell culture box for 4 h. The OD value of each well was detected at 570 nm by full-wavelength enzyme-labeled instrument. The concentration of half of the Vero cell growth was calculated (CC 50 ). The results showed that the cell survival rate of Derivative 1 was about 90% at the measured concentration (0.1-1000 μM) and the difference was not significant. Even at the maximum concentration, the cell survival rate still reached 93%, so the CC 50 value of Derivative 1 on cells could not be obtained (asFigure 3 The results are shown in FIG. 1.

[0028] II. Derivative 1 inhibits the growth of Toxoplasma in vitro: The RH-RFP strain has red fluorescence, and the change in the proliferation of Toxoplasma is evaluated by measuring the fluorescence intensity of Toxoplasma. In this experiment, the positive drug control is ethylamino pyrimidine (5 μM), and seven different concentration groups of Derivative 1 (1000 μM, 250 μM, 62.5 μM, 16 μM, 4 μM, 1 μM, and 0.25 μM) are set. By comparing the differences in the fluorescence intensity of RH-RFP after 24 h and 48 h of treatment with different concentrations of drugs, the ability of the drug to inhibit the proliferation of Toxoplasma is evaluated. The results show that after 24 h and 48 h of treatment, Derivative 1 shows a significant inhibitory effect on the proliferation of Toxoplasma, and the effect is more obvious after 48 h. The results are shown in FIG. 2 (48 h): Derivative 1 shows an inhibitory effect on the proliferation of Toxoplasma at a concentration of 1 μM, and the inhibitory effect is dose-dependent with the change in concentration. When the concentration is 16-62.5 μM, there is no significant difference in the efficiency of the drug in inhibiting the proliferation of Toxoplasma compared with the positive drug control group of ethylamino pyrimidine (5 μM). Figure 4

[0029] III. The concentration of Derivative 1 that inhibits the growth of half of the Toxoplasma: Derivative 1 (12.0 mg) was weighed, 100 μL of dimethyl sulfoxide was added, and a stock solution of 20 mg / mL was prepared, and then diluted with DMSO to 10, 5, 2.5, 1.25, 0.625, 0.3125, and 0.156 mg / mL solutions, respectively, and stored in a 4°C refrigerator. When used, it was placed at room temperature until dissolved and mixed. Parasites with a survival rate of more than 95% were mixed with the culture medium, and then evenly added to a 96-well culture plate, 198 μL per well. It was divided into a negative group, a solvent control (1% DMSO) group, and a Derivative 1 group. The negative group was added with 2 μL of normal saline, the solvent control group was added with 2 μL of DMSO, and the drug intervention group was added with different concentrations (5, 2.5, 1.25, 0.625, 0.3125, 0.156 mg / mL) of Derivative 1 solution in each well, and then mixed with a pipette gun. The well plate was moved into a CO2 incubator at 37°C for constant temperature culture. After 48 h, the parasites were aspirated, stained with eosin, smeared, and photographed for counting, the effects of the drug on the parasites at different times were observed, the mortality rate was calculated, and the experiment was repeated three times. According to the mortality rate at different concentrations, SPSS 20 software was used for statistical processing, and the LC 50 ​The experiment was conducted to determine the growth of T. gondii under different concentrations of Derivative 1 within 24 hours. According to the results of the previous study, the concentration of Derivative 1 was not significantly different in inhibiting the proliferation of T. gondii at 62.5-1000 μM. Therefore, the highest concentration of 100 μM was selected, and seven gradient concentrations were set according to the two-fold dilution method. The group infected with T. gondii without treatment was the blank control group. The concentration of Derivative 1 that inhibited the growth of T. gondii by 50% within 24 hours (IC 50 ) was about 34.52 μM (as shown in Figure 5 ).

[0030] Four, the dose-effect relationship of Derivative 1 on the inhibition of T. gondii tachyzoites: The experiment was conducted to evaluate the anti-T. gondii ability of Derivative 1 by comparing the number of red fluorescent tachyzoites (RH-RFP) treated with different concentrations of Derivative 1 for 48 hours. The highest concentration of 100 μM was selected, and seven gradient concentrations were set according to the two-fold dilution method. The group infected with T. gondii without treatment was the blank control group. The results showed that the effect of inhibiting T. gondii was significantly enhanced with the increase of the dose of Derivative 1. Compared with the group infected with T. gondii without treatment, Derivative 1 showed extremely significant inhibitory activity against T. gondii with the increase of the dose. The proliferation efficiency of T. gondii was similar to that of the positive drug control group of pyrimethamine (1 mM) at a concentration of 12.5-25 μM. The anti-T. gondii efficacy of different concentrations of Harmine was also determined. The results showed that the effect of inhibiting T. gondii was significantly enhanced with the increase of the dose of Harmine. Compared with the group infected with T. gondii without treatment, Harmine showed extremely significant inhibitory activity against T. gondii with the increase of the dose. The proliferation efficiency of T. gondii was similar to that of the positive drug control group of pyrimethamine (1 mM) at a concentration of 50-100 μM (as shown in Figure 6 ). By comparing the anti-T. gondii efficacy of Derivative 1 and Harmine, the results showed that the anti-T. gondii efficacy of Derivative 1 was stronger than that of Harmine at a concentration of 3.1-100 μM (as shown in Figure 7 ).

[0031] Five, in vivo T. gondii efficacy: The experiment uses 6-8 weeks old, body weight about 25-30g ICR male mice (SPF), all mice are adaptively fed for 1 week. Experimental animals are raised in 12 hours day-night alternating environment, and sufficient water and food are provided. Mice are infected with Cryptosporidium by intraperitoneal injection (200 / each), and drug treatment is started 4 hours after infection. Each mouse is injected once a day for 5 consecutive days, and the drug dose is 80mg / kg, which is Derivative 1, Harmine drug group (Table 1). During the experiment, the clinical symptoms of mice are observed regularly, including body weight change, activity, hair condition, etc., and body weight and mortality are recorded daily.

[0032] Table 1 Infection and treatment grouping of mice

[0033] Six, mental state and body weight change of mice: Six days before the start of the experiment, the mice in each group showed good mental state and normal behavior. The activity level of the mice was active, and they could move freely and exhibit normal social behavior with their peers, showing good exploratory and adaptive behavior, and responding normally to external stimuli (such as light touch or environmental changes).

[0034] Their appetite and water drinking habits remained stable, and there was no refusal to eat or drink water, smooth and neat hair, clear eyes, and overall good health, and no abnormal performance or adverse reactions were observed, fully meeting the health standards. However, around the 7th day, as the infection continued to develop, the mice in the negative untreated group began to show significant signs of illness, including hair loss, lethargy, reduced activity, and weight loss. At the same time, some mice in the Derivative 1 and Harmine drug groups also showed similar clinical symptoms, but the symptoms were relatively mild, showing mild lethargy and reduced activity. These changes mean the beginning of the infection symptoms, and also lay the foundation for the subsequent evaluation of the effect of drug treatment. In terms of body weight change, the body weight of the mice in the blank group always increased smoothly, and there was no abnormal body weight fluctuation Figure 8The body weight of the mice in the negative untreated group also kept a rising trend before the onset of the disease, indicating that no obvious health changes occurred in the early stage of infection. Unlike this, the body weight of the mice in the two drug groups changed relatively smoothly before the onset of the disease, and no obvious fluctuation in increase or decrease occurred, which suggested that the drug treatment did not cause a significant impact on the body weight of the mice at this stage. However, after the 6th to 7th day, the body weight of the mice in all the infection groups decreased significantly, except for the blank group, and this change was basically consistent with the time of clinical onset. In particular, in the negative untreated group and the drug groups, the decrease in body weight almost occurred at the same time as the onset of the symptoms (such as hair loss, listlessness, etc.), which showed the systemic reaction caused by the infection. The significant decrease in body weight was a key indicator of the onset, and provided an important basis for the subsequent evaluation of the drug efficacy.

[0035] Seven, survival rate of mice: The test results showed that in the negative untreated group, one mouse died on the 9th day after challenge, and three mice died on the 10th day; after the 13th day, all the mice died. In contrast, the survival of the mice in the drug groups was different. In Derivative 1, one mouse died on the 9th day, two mice died on the 10th day, and one mouse died on the 17th day; while in the Harmine group, one mouse died on the 10th day, one mouse died on the 11th day, one mouse died on the 15th day, and one mouse died on the 16th day. Until the 23rd day after challenge, there was only one surviving mouse left in both the Derivative 1 and Harmine groups (as shown in Table 2). Figure 9 Compared with the untreated group, the survival time of the mice in the drug groups was prolonged by 4 days, indicating that the drug treatment significantly improved the survival of the mice and exhibited obvious anti-Toxoplasma effect.

[0036] Therefore, the present application successfully provides a novel dehydropegerine derivative, especially the preferred compound 1-methyl-9-(3-methylpyridine)-β-carboline-7-ol, which has a simple synthetic route, mild conditions, good yield, and is suitable for large-scale preparation. This compound exhibits significantly better anti-Toxoplasma activity than the parent compound Harmine in in vitro and in vivo experiments, and has extremely low cytotoxicity and an excellent safety window. The present application provides a new solution to overcome the problems of existing anti-Toxoplasma drugs, such as large toxic and side effects and easy drug resistance, and has important application value and broad market prospects in the development of highly efficient and low-toxic anti-Toxoplasma drugs.

[0037] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application rather than limit them, and although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can still be modified or replaced by equivalents, and these modifications or equivalent replacements cannot make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present application.

Claims

1. A novel dehydropegoamine derivative, characterized in that, The structural general formula is: ； wherein R is selected from hydrogen, C 1 alkyl, substituted or unsubstituted five-membered aryl or six-membered aryl, substituted or unsubstituted five-membered heteroaryl or six-membered heteroaryl containing one to four heteroatoms selected from N or O or S; and 1-4 alkyl, substituted or unsubstituted five-membered aryl or six-membered aryl, substituted or unsubstituted five-membered heteroaryl or six-membered heteroaryl containing one to four heteroatoms selected from N or O or S; and R 9 is selected from one of hydrogen, a substituted or non-substituted five-membered aryl group or a six-membered aryl group; R 7 is selected from hydrogen, C 1-4 alkyl, substituted or unsubstituted five-membered aryl or six-membered aryl.

2. The dehydropegerine derivative according to claim 1, characterized in that, The chemical name is 1-methyl-9-(3-methylpyridine)-β-carboline-7-ol, and the structural formula is: 。 3. A process for the synthesis of a dehydropegoine derivative according to claim 2, characterized in that, The method comprises the following steps: S1, dehydropeimine is used as a starting material and is added to N,N-dimethylformamide solvent, stirred at room temperature, then NaH and 3-(bromomethyl)pyridine hydrobromide are added, and stirring at room temperature is continued, after the reaction is completed, the reaction liquid is poured into water, the reaction liquid is extracted with ethyl acetate, the organic phases are combined, the organic phases are washed with water and saturated brine respectively, dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, the obtained oily substance is recrystallized with diethyl ether, solid is precipitated, filtered, and dried to obtain a white solid; S2, the white solid is added to hydrobromic acid and glacial acetic acid, the reaction mixture is then heated to reflux, after the reaction is completed, the mixture is first cooled to room temperature, then poured into cold water, and the pH is adjusted with a sodium hydroxide solution, the precipitated solid is filtered with a Buchner funnel, washed with water, and the obtained solid is dried to obtain the final target product.

4. The method of synthesis of claim 3, wherein, In S1, the amount of dehydropeimine is 1.1-2.3 g, and the amount of N,N-dimethylformamide is 25-75 mL; the room temperature is 23-27°C, and the stirring time of the mixture of dehydropeimine and N,N-dimethylformamide is 0.5-0.8 h.

5. The method of synthesis of claim 3, wherein, In S1, the amount of NaH is 1.5-3.5 g, and the amount of 3-(bromomethyl)pyridine hydrobromide is 3.1-4.0 g, and the reaction time of continued stirring at room temperature after addition is 24-30 h.

6. The method of synthesis of claim 3, wherein, In S1, the amount of ethyl acetate is 200-500 mL, and the extraction times are 3-6 times; the amount of water is 300-600 mL, the amount of saturated brine is 200-300 mL, and the amount of anhydrous sodium sulfate is 100-300 g; the amount of diethyl ether is 200-400 mL.

7. The method of synthesis of claim 3, wherein, In S2, the amount of hydrobromic acid is 20-50 mL, the amount of glacial acetic acid is 10-20 mL, and the reaction time of heating to reflux is 8-10 h.

8. Use of the dehydropeimine derivative of claim 1 in the preparation of an anti-Toxoplasma drug.

9. Use according to claim 8, characterized in that, The administration mode of the drug is intravenous injection or intraperitoneal administration.

10. A medicine against Toxoplasma gondii, characterized in that, The effective component comprises the dehydropeimine derivative of claim 1.

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