Piperazine side chain-containing artemisinin compound and application thereof

Abstract

The invention discloses an artemisinin compound containing a piperazine side chain or a pharmaceutical salt thereof, and the structural general formula is shown in the specification. The artemisinin compound containing the piperazine side chain and the pharmaceutical salt thereof provided by the invention have a brand-new skeleton structure and better anti-malaria and anti-tumor activity, can be used as an anti-tumor drug and an anti-malarial drug, and can be used as an anti-malarial drug. And more choices can be provided for clinical treatment.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a kind of artemisinin compounds containing piperazine side chain and its application. BACKGROUND

[0002] Artemisinin and its derivatives including dihydroartemisinin, artesunate, artemether and lumefantrine are widely used in clinic as antimalarial drugs. In recent years, the resistance of malaria parasites to artemisinin is becoming more and more serious, and it is urgent to develop new antimalarial drugs.

[0003] In addition to the antimalarial application, artemisinin and its derivatives also have broad-spectrum antitumor activity, and the IC 50 are in the μM level. However, there are still many problems to be solved in its antitumor application, such as short half-life, poor solubility and limited bioavailability, which lead to low antitumor activity in vivo and difficulty in direct application in clinical antitumor treatment. The structure of artemisinin is special, and it is too difficult to develop it into an antitumor drug by modifying its parent structure. Previous studies have found that based on the splicing principle, artemisinin derivatives containing other antitumor pharmacophores will exert synergistic antitumor activity of multiple pharmacophores, and further improve the antitumor drug property of artemisinin derivatives.

[0004] In the fields of life sciences and modern medicine, developing efficient and precise treatments is a core objective. Traditional non-covalent drugs rely on weak interactions such as hydrogen bonds and van der Waals forces. While they can alleviate some disease symptoms, they face limitations such as low target selectivity, easy drug resistance, and short-lived efficacy. The emergence of covalent small molecule inhibitors has provided a breakthrough solution to this dilemma: they form irreversible covalent bonds with nucleophilic amino acid residues (such as cysteine ​​and serine) at the active site of the target protein through electrophilic warheads (such as acrylamide), thereby persistently inhibiting the function of the target protein. This mechanism not only endows drugs with long-lasting effects (reducing dosing frequency) and high selectivity (reducing off-target toxicity), but also effectively overcomes the problem of acquired drug resistance caused by tumor target mutations or overexpression. For example, inhibitors targeting KRAS G12C mutations have successfully solved the problem of "undruggable" targets. The application of covalent drugs can be traced back to the accidental discovery of classic drugs. Aspirin blocks prostaglandin synthesis by acetylation of serine residue 529 of cyclooxygenase COX-1; penicillin acylates serine of bacterial penicillin-binding protein, leading to cell wall rupture. It is worth noting that the covalent action modes of these early drugs (including omeprazole and clopidogrel) were mostly discovered retrospectively through mechanistic studies rather than through active design, and some required in vivo metabolic activation to exert their covalent binding ability. With technological advancements, modern covalent drugs are gradually shifting towards rational design. For example, tyrosine kinase inhibitors with α,β-unsaturated amides as targets (such as EGFR and BTK inhibitors) target cysteine ​​residues at the ATP binding site, and eight such drugs have been approved for cancer treatment. KRAS G12C inhibitors have become a milestone in covalent drug design, demonstrating their unique value in tackling complex targets.

[0005] Covalent small molecule inhibitors, with their advantages of high efficacy, long duration of action, and ability to overcome drug resistance, are leading a paradigm shift in drug development. With advancements in new targets, technologies, and combination therapies, covalent drugs are expected to achieve more profound breakthroughs in the treatment of complex diseases such as cancer and infections, paving new paths for precision medicine.

[0006] The prior art does not involve the artemisinin-containing compounds of this invention. Summary of the Invention

[0007] The purpose of this invention is to provide an artemisinin-like compound containing a piperazine side chain.

[0008] Another object of the present invention is to provide the use of the artemisinin-like compound containing a piperazine side chain in the preparation of an antitumor drug.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] In a first aspect, the present invention provides an artemisinin-like compound containing a piperazine side chain or a pharmaceutically acceptable salt thereof, with the following general structural formula:

[0011] R1 is selected from ;

[0012] R2 is selected from hydrogen and C1~C30 alkyl groups;

[0013] R3 is selected from hydrogen;

[0014] R4 is selected from hydrogen, C1~C30 alkyl, C3~C8 cycloalkyl (such as cyclopropyl, cyclobutyl), and -CH2NR5R6;

[0015] R5 is selected from hydrogen and C1~C30 alkyl groups;

[0016] R6 is selected from hydrogen and C1~C30 alkyl groups;

[0017] Alternatively, R5, R6, and the connected N and C form three to six-membered rings.

[0018] Preferably, in the artemisinin compounds containing piperazine side chains,

[0019] R1 is selected from ;

[0020] R2 is selected from hydrogen, methyl, ethyl, and n-propyl;

[0021] R3 is selected from hydrogen;

[0022] R4 is selected from hydrogen, methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl, and -CH2NR5R6;

[0023] R5 is selected from hydrogen, methyl, ethyl, and n-propyl;

[0024] R6 is selected from hydrogen, methyl, ethyl, and n-propyl;

[0025] Alternatively, R5, R6, and the connected N and C form One of them.

[0026] Most preferably, the structure of the artemisinin compound containing the piperazine side chain is selected from one of the following structures:

[0027] In a second aspect, the present invention provides the use of the artemisinin-like compound containing a piperazine side chain or a pharmaceutical salt thereof in the preparation of an antitumor drug.

[0028] The tumors are selected from leukemia, colon cancer, lung cancer, breast cancer, liver cancer, lymphoma, and hematologic malignancies.

[0029] A third aspect of the present invention provides the use of the artemisinin-like compound containing a piperazine side chain or a pharmaceutical salt thereof in the preparation of an antimalarial drug.

[0030] The malaria mentioned is caused by Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, or Plasmodium ovale.

[0031] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0032] The artemisinin compounds containing piperazine side chains and their pharmaceutical salts provided by this invention have novel skeletal structures and superior antimalarial and antitumor activities, and can be used as antitumor and antimalarial drugs, providing more options for clinical treatment.

[0033] The artemisinin compounds containing piperazine side chains and their pharmaceutical salts provided by this invention have a simpler chemical synthesis route, and some derivatives exhibit superior in vitro antitumor and antimalarial activities.

[0034] The synthesis method provided by this invention has a simple synthesis route, readily available raw materials, and is easy to implement.

[0035] This invention introduces an α,β-unsaturated amide Michael receptor side chain into the structure of artemisinin. It is expected that the introduced Michael receptor can form a covalent binding with the binding site of artemisinin target protein, thereby achieving long-term target inhibition by using the covalent binding strategy, further enhancing the antimalarial and antitumor activity of artemisinin, and overcoming the technical problems of low antitumor activity of artemisinin and drug resistance of existing malaria parasites in the prior art.

[0036] The compounds prepared in this invention exhibited broad-spectrum antitumor effects against the HCT116 solid tumor cell line. Compounds 1-3 showed broad-spectrum antitumor effects, with compound 2 showing superior efficacy (IC50). 50 The value was 24.32 μM. In contrast, dihydroartemisinin (DHA) did not show measurable activity (IC50) against solid tumor cell lines. 50 > 50 μM). Notably, compounds 1–4 exhibited excellent antiproliferative activity against both MV-4-11 and HL-60 cells, with an IC50 concentration of > 50 μM against HL-60 cells. 50 Its value ranges from 1.33 μM to 4.36 μM, and its efficacy is superior to DHA (IC50). 50 =5.17 μM); for MV-4-11 cells, IC50 = 5.17 μM; 50 Its value ranges from 0.11 μM to 0.23 μM, and its efficacy is superior to DHA (IC50). 50 = 0.53 μM), with compound 3 showing the best effect, reaching 0.11 μM.

[0037] The compounds prepared in this invention were tested against the EC of Plasmodium falciparum Pf3D7. 50 The compound prepared in this invention was found to have superior antimalarial activity compared to DHA, EC 50 All were within 2 nM. Compounds 1-3 were particularly effective against the tested Plasmodium EC50 cells. 50 All are within 1.3 nM, which is significantly better than DHA. Detailed Implementation

[0038] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0039] Example 1

[0040] Step 1, Preparation of Intermediate III:

[0041] Dihydroartemisinin (DHA) (7 mmol, 2 g) was dissolved in 25 mL of dichloromethane, and 65 μL of DMSO was added. The mixture was stirred for 30 minutes, and then 0.65 mL of oxaloyl chloride was added to the above solution. The mixture was stirred for 10 minutes to obtain a mixed solution. In a separate reaction flask, piperazine, i.e., intermediate II (29 mmol, 2.5 g), was dissolved in 35 mL of dichloromethane, and the above mixed solution was added dropwise. The mixture was stirred overnight. After the reaction was complete, the mixture was purified by column chromatography (dichloromethane:methanol = 100:7) to obtain 1.2 g of intermediate III containing piperazine side chains, a pale yellow powder, with a yield of 48.7%.

[0042] Step 2, preparation of compound 1:

[0043] In 10 mL of dichloromethane, intermediate III (250 mg, 0.88 mmol), 2-butynic acid (intermediate IV, 270 mg, 1.325 mmol), 1-hydroxy-7-azobenzotriazole (HOAt, 180 mg, 1.325 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 200 mg, 1.056 mmol) were added and stirred overnight at room temperature. After the reaction was complete, the mixture was purified by thin-layer chromatography (dichloromethane:methanol = 30:3) to give 233 mg of a yellow-brown solid product, namely compound 1, in a yield of 65%. 1H NMR (400 MHz, DMSO-d6) δ 0.75 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 6.4Hz, 3H), 0.88-0.99 (m, 1H), 1.09-1.17 (m, 1H), 1.23-1.38 (m, 7H), 1.44-1.48(m, 2H), 1.56-1.63 (m, 2H), 1.76-1.82 (m, 1H), 1.98 (t, J = 14.1 Hz, 1H), 2.02 (s, 3H), 2.16 (dt, J = 3.7 Hz, 13.6 Hz, 1H), 2.41 (br, 1H), 2.53-2.64(m, 1H), 2.72-2.86 (m, 2H), 3.45 (br, 2H), 3.58-3.72 (m, 2H), 4.10 (d, J =10.1 Hz, 1H), 5.33 (s, 1H). HRMS (ESI positive) m / z calcd for C 23 H 35 N2O5 (M +H): 419.2546; found 419.2538.

[0044] Example 2

[0045] The compound 2 was prepared according to the method and steps of Example 1, with the first step remaining unchanged, and the raw material in the second step changed to intermediate V, yielding 240 mg of compound 2 as a yellowish-brown solid with a yield of 67%. 1H NMR (400 MHz, DMSO-d6) δ 0.77 (d, J = 7.1Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H), 0.91-1.01 (m, 1H), 1.10-1.18 (m, 1H), 1.25(s, 3H), 1.27-1.63 (m, 16H), 1.78-1.83 (m, 1H), 1.95-2.00 (m, 1H), 2.17 (td,J = 14.0, 3.9 Hz, 1H), 2.37-2.47 (m, 2H), 2.80 (br, 2H), 3.38-3.61 (m, 6H),4.09 (d, J = 10.1 Hz, 1H), 5.34 (s, 1H), 6.57-6.69 (m, 2H). HRMS (ESIpositive) m / z calcd for C 28 H 46 N3O5 (M + H): 504.3437; found 504.3427.

[0046] Example 3

[0047] The compound 3 was prepared according to the method and steps of Example 1, with the first step remaining unchanged, and the raw material in the second step changed to intermediate VI, yielding 235 mg of compound 3 as a yellow-brown solid with a yield of 60%. 1H NMR (400 MHz, DMSO-d6) δ 0.75 (d, J = 7.1Hz, 3H), 0.88 (d, J = 6.3 Hz, 3H), 0.85-0.99 (m, 1H), 1.09-1.17 (m, 1H), 1.24(s, 3H), 1.28-1.38 (m, 2H), 1.46 (br, 2H), 1.60 (br, 2H), 1.75-1.82 (m, 1H), 1.94-2.00 (m, 1H), 2.17 (dt, J = 3.5 Hz, 13.7 Hz, 1H), 2.20 (s, 6H), 2.38-2.45 (m, 2H), 2.78 HRMS (ESIpositive) m / z calcd for C 25 H 42 N3O5 (M + H): 464.3124; found 464.3127.

[0048] Example 4

[0049] The compound 4 was prepared according to the method and steps of Example 1, with the first step remaining unchanged, and the raw material for the second step changed to intermediate VII, yielding 215 mg of compound 4 as a yellow-brown solid with a yield of 62%. 1H NMR (400 MHz, DMSO-d6) δ 0.76 (d, J =7.1 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.91-0.99 (m, 1H), 1.09-1.13 (m, 1H),1.24 (s, 3H), 1.26-1.38 (m, 3H), 1.46 (br, 2H), 1.56-1.62 (m, 2H), 1.76-1.83(m, 1H), 1.96 (d, J = 14.4 Hz, 1H), 2.16 (td, J = 13.9, 3.9 Hz, 1H), 2.42 (m,1H), 2.51-2.55 (m, 2H), 2.79 (br, 2H), 3.43-3.51 (m, 4H), 4.10 (d, J = 10.1Hz, 1H), 5.33 (s, 1H), 5.67 (dd, J = 10.4, 2.4 Hz, 1H), 6.10 (dd, J = 16.7,2.4 Hz, 1H), 6.80 (dd, J = 16.7, 10.4 Hz, 1H). HRMS (ESI positive) m / z calcdfor C 22 H 35 N2O5 (M + H): 407.2546; found 407.2543.

[0050] Example 5

[0051] The compound 5 was prepared according to the method and steps of Example 1, with the first step remaining unchanged, and the raw material for the second step changed to the intermediate crotonic acid VIII, yielding 186 mg of compound 5 as a yellow-brown solid with a yield of 53%. 1H NMR (400 MHz, DMSO-d6) δ 0.78(d, J = 7.1 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.90-0.99 (m, 1H), 1.04-1.15(m, 1H), 1.26 (s, 3H), 1.26-1.35 (m, 3H), 1.48 (br, 2H), 1.55-1.62 (m, 2H), 1.76-1.83 (m, 1H), 1.90 (br, 3H), 1.97 (d, J = 14.2 Hz, 1H), 2.12-2.14 (m,1H), 2.40 (m, 1H), 2.50-2.57 (m, 2H), 2.79 (br, 2H), 3.40-3.51 (m, 4H), 4.11(d, J = 10.3 Hz, 1H), 5.35 (s, 1H), 5.69 (m, 1H), 6.12 (m, 1H), 6.79 (m, 1H).HRMS (ESI positive) m / z calcd for C 23 H 37 N2O5 (M + H): 421.2702; found 421.2705.

[0052] Example 6

[0053] The preparation was carried out according to the method steps of Example 1, with the first step unchanged, and the raw material for the second step changed to intermediate 3-cyclopropylprop-2-enoic acid IX, to obtain 201 mg of compound 6, a yellow-brown solid, with a yield of 62%. 1H NMR (400 MHz, DMSO-d6) δ0.20-0.28 (m, 4H), 0.40-0.49 (m, 4H), 0.77 (d, J = 7.1 Hz, 3H), 0.89 (d, J =6.5 Hz, 3H), 0.89-1.01 (m, 1H), 1.04-1.15 (m, 1H), 1.25 (s, 3H), 1.23-1.39(m, 4H), 1.42-1.49 (br, 2H), 1.55-1.62 (m, 2H), 1.75-1.84 (m, 1H), 1.98 (d, J= 14.2 Hz, 1H), 2.10-2.154 (m, 1H), 2.40 (m, 1H), 2.51-2.59 (m, 2H), 2.80(br, 2H), 3.38-3.52 (m, 4H), 4.13 (d, J = 10.3 Hz, 1H), 5.36 (s, 1H), 5.70(m, 1H), 6.10-6.14 (m, 1H), 6.72-6.77 (m, 1H). HRMS (ESI positive) m / z calcdfor C 25 H 39 N2O5 (M + H): 447.2859; found 447.2856.

[0054] Example 7

[0055] In vitro antitumor activity assay of the compounds prepared in the embodiments of the present invention

[0056] The compounds prepared in Examples 1-6 of this invention were subjected to tumor cell proliferation inhibition assays and proliferation inhibition selectivity assays. The conventional CKK-8 assay was used for solid tumor cells and 293T cells, and the resazurite assay was used for leukemia cells.

[0057] The cell lines used were leukemia MV-4-11 and HL-60, colon cancer HCT116, and human embryonic kidney fibroblast 293T cells, all of which were purchased from the Cell Bank of the Chinese Academy of Sciences.

[0058] The concentration added to each well of the 96-well plate is 8 × 10⁻⁶. 4100 μL of cell suspension (8000 cells / well) was added to each well and incubated at 37°C in a 5% CO2 incubator. After 24 hours, the supernatant was aspirated, and 100 μL of culture medium containing the sample and control solution was added to each well. The well was incubated at 37°C for 72 hours. 10 μL of CKK-8 or resazurin was added to each well and incubated for 1 hour. The OD value at 570 nm was measured using an MK-2 automated microplate reader, and the half-maximal inhibitory concentration (IC50) was calculated. 50 .

[0059] To investigate the effect of α,β-unsaturated amide side chains on activity, this invention synthesized two compounds, 7 and 8, with saturated side chains, as negative controls, with the following structural formulas:

[0060] The antitumor activity and proliferation inhibition selectivity of the compounds are shown in Table 1.

[0061] Table 1. Half-maximal inhibitory concentration (IC50) of the compounds against tumor cells. 50 (Unit: μM)

[0062] Antitumor activity results showed that the compounds of this invention generally exhibited broad-spectrum, moderate in vitro antitumor activity. Against HCT116 solid tumor cells, compounds 1-3, 5, and 6 showed moderate antitumor activity, superior to the marketed drug DHA. Compound 2 showed the best effect, with an IC50 value of [missing value]. 50 The value was 24.32 μM. The compounds prepared in this invention exhibited strong inhibitory activity against hematologic malignancies MV-4-11 and HL-60. Compounds 1-4 showed excellent antiproliferative activity against both MV-4-11 and HL-60 cells, especially compounds 1 and 3, which showed a high IC50 value against MV-4-11 cells. 50 The concentrations were 0.13 μM and 0.11 μM, respectively, which are superior to the marketed drug DHA (IC50). 50 = 0.53 μM), with compound 3 showing the best effect. IC50 values ​​of compounds 1-3 against HL-60. 50 All were below 1.5 μM, exhibiting superior antitumor activity compared to DHA. Analysis of the antitumor activity of MV-4-11, comparing data from compound 5 and negative control compound 7, as well as compound 3 and negative control compound 8, revealed that the unsaturated double bond significantly enhanced the activity compared to the single bond, ranging from 1.36 to 1.78 times, suggesting that the double bond contributes to some of the antitumor effect.

[0063] The proliferation inhibition selectivity assay was performed using human embryonic kidney fibroblasts 293T. The results are shown in Table 1. The compound prepared in this invention showed an inhibitory selectivity (IC50) against 293T cells. 50All are greater than 50 μM, exhibiting excellent antitumor selectivity.

[0064] Example 8

[0065] In vitro antimalarial activity test of the compounds prepared in the embodiments of the present invention

[0066] Malaria strains include wild-type Plasmodium falciparum Pf 3D7. The culture medium was RPMI-1640 complete medium (containing 5% AlbuMAX I, 25 mM HEPES, 25 mM sodium bicarbonate, 2 mM L-glutamine, 0.05 mg / mL hypoxanthine, and 0.05 mg / mL gentamicin), and the culture was carried out in a 37°C incubator (5% CO2, 5% O2, 90% N2).

[0067] In vitro antimalarial activity EC 50 Test: 100 μL of complete culture medium containing different concentrations of compounds was added to each well of a 96-well plate. Dihydroartemisinin was used as the positive control, no drug was added as the negative control, and the group without parasite erythrocytes served as the experimental background. 100 μL of Plasmodium culture (1% circular stage erythrocyte percentage, 4% hematocrit) was added to each well, and the plate was incubated at 37°C for 72 h. 80 μL of supernatant was removed from each well, and 100 μL of lysis buffer (SYBR Green I 3X, 0.12 mg / mL saponin, 1.2% Triton X-100, 30 mM Tris-Cl, and 7.5 mM EDTA) was added. After mixing, the plate was incubated in the dark for 2 h. Values ​​were read using a multi-mode microplate reader (excitation wavelength 485 nm, emission wavelength 535 nm). The inhibition rate was calculated using the formula.

[0068] Inhibition rate = [Negative control - Compound well] / [Negative control - Experimental background] × 100%.

[0069] Data fitting was performed using Graph Pad Prism 8, and EC was calculated. 50 The antimalarial activity data are shown in Table 2:

[0070] Table 2. Effects of the compounds of this invention on Plasmodium falciparum Pf 3D7 half-maximal effective concentration EC 50 (Unit: nM)

[0071] ND Untested

[0072] All compounds prepared in this invention are effective against Plasmodium. Pf 3D7 half-maximal effective concentration EC 50It is comparable to or better than dihydroartemisinin DHA (5.6 nM). Compounds 1-3 of these compounds are effective against Plasmodium parasites. Pf 3D7 half-maximal effective concentration EC 50 Below 1.3 nM, superior to DHA. Comparing the antimalarial activity of compound 3 and the negative control compound 8, it was found that the unsaturated double bond increased the antimalarial activity by 2 times, indicating that the introduction of the unsaturated double bond played a role in increasing the antimalarial activity, further demonstrating the importance of introducing α,β-unsaturated amide side chains.

[0073] In summary, the compounds prepared in this invention, containing artemisinin and α,β-unsaturated amide side chains, possess novel skeletal structures, and key intermediates are constructed using a novel synthetic method. Some of these compounds exhibit significantly superior antitumor and antimalarial activities compared to the marketed drug DHA. Therefore, the compounds prepared in this invention can be used for the development of innovative antitumor and antimalarial drugs.

[0074] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An artemisinin-like compound containing a piperazine side chain or a pharmaceutically acceptable salt thereof, characterized in that, The general structural formula is as follows: ； R1 is selected from ; R2 is selected from hydrogen and C1~C30 alkyl groups; R3 is selected from hydrogen; R4 is selected from hydrogen, C1~C30 alkyl, C3~C8 cycloalkyl, and -CH2NR5R6; R5 is selected from hydrogen and C1~C30 alkyl groups; R6 is selected from hydrogen and C1~C30 alkyl groups; Alternatively, R5, R6, and the connected N and C form three to six-membered rings.

2. The artemisinin compound containing a piperazine side chain or its pharmaceutical salt according to claim 1, characterized in that, Among the artemisinin compounds containing piperazine side chains, R1 is selected from ; R2 is selected from hydrogen, methyl, ethyl, and n-propyl; R3 is selected from hydrogen; R4 is selected from hydrogen, methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl, and -CH2NR5R6; R5 is selected from hydrogen, methyl, ethyl, and n-propyl; R6 is selected from hydrogen, methyl, ethyl, and n-propyl; Alternatively, R5, R6, and the connected N and C form One of them.

3. The artemisinin compound containing a piperazine side chain or its pharmaceutical salt according to claim 2, characterized in that, The structure of the artemisinin-like compound containing the piperazine side chain is selected from one of the following structures: 。 4. The use of an artemisinin compound containing a piperazine side chain, as described in any one of claims 1 to 3, or a pharmaceutical salt thereof, in the preparation of an antitumor drug.

5. The application according to claim 4, characterized in that, The tumors are selected from leukemia, colon cancer, lung cancer, breast cancer, liver cancer, lymphoma, and hematologic malignancies.

6. The use of an artemisinin compound containing a piperazine side chain, as described in any one of claims 1 to 3, or a pharmaceutical salt thereof, in the preparation of an antimalarial drug.

7. The application according to claim 6, characterized in that, The malaria mentioned is caused by Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, or Plasmodium ovale.

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