Compound containing artemisinin similar structure and preparation method and application thereof

Abstract

The invention provides a compound containing an artemisinin similar structure and a preparation method and application of the compound, the structural formula of the compound is shown in the formula I. The compound has excellent histone deacetylase inhibitory activity and anti-tumor and anti-malarial activity and can be used for preparing anti-tumor and anti-malarial drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of compounds containing artemisinin-like structures, their preparation methods, and applications. Background Technology

[0002] Artemisia annua, a traditional Chinese herbal medicine, is obtained by processing the aerial parts of the Artemisia annua plant (family Asteraceae). It is used to clear internal heat, treat malaria, and improve jaundice. Artemisinin (ART) is a sesquiterpene lactone compound extracted from Artemisia annua. It possesses a unique internal peroxide bridge structure and is currently a first-line drug for treating uncomplicated malaria caused by Plasmodium falciparum. Since its discovery, it has saved hundreds of millions of patients from malaria, becoming one of the most important contributions of Chinese researchers in the medical field. In addition to its antimalarial effects, artemisinin and its derivatives (ARTs) have exhibited a wide range of pharmacological activities. In recent years, due to their broad-spectrum anticancer effects and safety, the potential of ARTs in the field of cancer treatment has attracted considerable attention from researchers. With over ten million deaths from cancer annually, posing a severe challenge to health in countries worldwide, the continuous search for new and more effective anti-tumor drugs is imperative. The anticancer mechanism of artemisinin and its derivatives involves multiple molecular pathways, mainly including the following: First, ARTs can bind to free iron (Fe) in cells. 2+ Artemisinin reacts with tumor cells to generate free radicals, which attack cell membranes and proteins. Because tumor cells have a higher iron content than normal cells, artemisinin can selectively kill tumor cells. Secondly, artemisinin can interfere with the cell cycle of tumor cells, inhibiting their proliferation. Furthermore, artemisinin can inhibit the expression of vascular endothelial growth factor and its receptors, reducing tumor angiogenesis and preventing tumors from receiving sufficient blood supply, thereby inhibiting their growth and metastasis. Finally, artemisinin also produces reactive oxygen species (ROS) in the body, leading to genomic instability in tumor cells and triggering tumor cell death.

[0003] Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups from histones, playing a crucial role in many key biological processes such as cell cycle regulation, apoptosis, and tumor metastasis. Abnormal changes in their activity are often closely related to the occurrence and development of cancer; therefore, histone deacetylase inhibitors have become a hot topic in anticancer drug development. For example, vorinostat, the first HDAC inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of T-cell lymphoma, has a strong inhibitory effect on HDAC activity, affecting gene transcription in tumor cells, thereby blocking tumor cell proliferation and slowing or halting cancer progression.

[0004] Literature (Bioorganic chemistry. 2016 Jun:66:63-71; Pharmaceuticals 2022,15, 333; Bioorganic chemistry. 2025 Feb 25:157:108312.) reports some histone deacetylase inhibitors containing artemisinin structures, but the antitumor activity of these compounds is weaker than that of the marketed drug SAHA. Summary of the Invention

[0005] The purpose of this invention is to provide a class of compounds containing artemisinin-like structures, their preparation methods and applications. These compounds have excellent histone deacetylase inhibitory activity, antitumor and antimalarial activity, and can be used to prepare antitumor and antimalarial drugs.

[0006] This invention is achieved through the following technical solution: In a first aspect, the present invention provides a class of compounds containing artemisinin-like structures, the structural formula of which is shown in Formula I:

[0007] Where X is selected from -CH2- and -C=O; Z is selected from the following groups: .

[0008] In some preferred embodiments of the present invention, X is -CH2-.

[0009] In a further preferred embodiment of the invention, Z is selected from the following groups: .

[0010] Specifically, the compound containing an artemisinin-like structure described in this invention is one of the following compounds: .

[0011] Secondly, the present invention provides a method for preparing the compound containing an artemisinin-like structure, comprising the following steps: S1, Dihydroartemisinin (DHA) was reacted with boron trifluoride diethyl ether (BFE), and the resulting product was recrystallized using a mixed solution of bromine water and carbon tetrachloride. The recrystallized product was then reacted with triethylamine (TEA) to give compounds 1-2. Alternatively, DHA is reacted with BFE, and the resulting product is recrystallized using a mixed solution of bromine water and carbon tetrachloride. The recrystallized product is then reacted with TEA to obtain compound 1-2. Compound 1-2 is then reacted with aminosulfonic acid (ASA) and sodium chlorite to obtain compound 2-1. S2, reacting compound 1-2 with compound 1-3, acetic acid and sodium triacetoxyborohydride (NaHB(OAc)3) to give compound A1 with the X group being methylene-CH2-; Alternatively, compound 2-1 can be reacted with compound 1-3, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and 4-dimethylaminopyridine (DMAP) to give compound A1 with the X group being carbonyl-C=O; S3, react compound A1 with lithium hydroxide (LiOH) to obtain compound A2; S4, compound A2 was reacted with tetrahydropyranylhydroxylamine (THPONH2), N-hydroxy-7-azabenzotriazole (HOAT) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and the crude product was further reacted with benzoyl chloride to obtain a compound containing an artemisinin-like structure. Alternatively, compound A2 can be reacted with methylhydrazine, ethylhydrazine or n-propylhydrazine protected by the Boc group, or o-phenylenediamine or 4-fluoro-1,2-phenylenediamine to obtain a compound containing an artemisinin-like structure. .

[0012] In some preferred embodiments of the present invention, the preparation method of compounds 1-2 in S1 is specifically as follows: dihydroartemisinin is reacted with BFE, then washed with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane (DCM) extractant. The obtained organic phase is dried by evaporating the solvent under reduced pressure, and then the product is purified by column chromatography. The purified product is added to CCl4, and a mixed solution of bromine water and CCl4 is added dropwise at 0 °C. The mixture is stirred, water is added, and stirred again. When a yellow solid precipitates, the solvent is dried under reduced pressure to obtain a yellow solid product. The yellow solid product is added to DCM, and then TEA is added. The mixture is reacted at room temperature. After the reaction is completed, the solvent is evaporated, and the product is purified by column chromatography to obtain compounds 1-2. The specific preparation method of compound 2-1 is as follows: compound 1-2 is added to dioxane, then ASA and water are added, and the reaction is stirred at 0 °C. After the reaction is completed, sodium chlorite (NaClO2) and water are added, and the mixture is stirred at room temperature. Then the solvent is evaporated, the residue is dissolved in DCM, filtered and the filtrate is evaporated, and purified by column chromatography to obtain compound 2-1.

[0013] In some preferred embodiments of the present invention, in step S4, compound A2 is reacted with THPONH2, HOAT, and EDCI, and the resulting crude product is further reacted with benzoyl chloride to obtain a compound containing an artemisinin-like structure, specifically: Compounds A2, THPONH2, HOAT, and EDCI salt were added to DCM and stirred at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. The purified product was added to ethanol with benzoyl chloride and stirred at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a compound containing an artemisinin-like structure.

[0014] Thirdly, the present invention provides the application of the compound containing an artemisinin-like structure in the preparation of antitumor drugs.

[0015] Preferably, the tumor is a solid tumor or a hematologic tumor.

[0016] Furthermore, the solid tumor is selected from lung cancer, colon cancer, and liver cancer.

[0017] Fourthly, the present invention provides the use of the compound containing an artemisinin-like structure in the preparation of antimalarial drugs.

[0018] Preferably, the malaria is caused by Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, or Plasmodium ovale.

[0019] Fifthly, the present invention provides the use of the compound containing an artemisinin-like structure in the preparation of histone deacetylase inhibitors.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The compounds containing artemisinin-like structures provided by this invention exhibited significant inhibitory effects on the proliferation of lung cancer cells A549, colorectal cancer cells HCT116, liver cancer cells HepG2, and leukemia cells MV-4-11 and HL-60. Some compounds showed significantly stronger antitumor activity than the marketed drug SAHA. For example, compound 2 showed an IC50 inhibitory effect on lung cancer cells A549 and liver cancer cells HepG2. 50 The values ​​were 0.44 μM and 0.54 μM, respectively, indicating that its inhibitory activity against these two solid tumor cell lines was superior to that of SAHA. Compound 4 showed IC50 values ​​against all three solid tumor cell lines. 50 The concentrations were 0.56 μM, 0.076 μM, and 0.48 μM, respectively, indicating that compound 1 exhibited significantly better antitumor activity than SAHA, demonstrating exceptionally superior and broad-spectrum antitumor activity. For hematologic malignancies, compound 1 showed IC50 values ​​against HL60 and MV4-11 cells. 50 The values ​​were 0.12 μM and 0.031 μM, respectively, and the IC50 values ​​of compound 4 against HL60 and MV4-11 cells were [values ​​missing]. 50 The values ​​were 0.11±0.06 μM and 0.035±0.01 μM, respectively, significantly superior to the marketed drug SAHA. In summary, the antitumor activity of some compounds synthesized in this invention is significantly superior to the marketed drug SAHA and also superior to the molecules with the best reported activity in the literature (Bioorganicchemistry. 2016 Jun:66:63-71; Pharmaceuticals 2022, 15, 333; Bioorganicchemistry. 2025 Feb 25:157:108312.). Furthermore, the compounds of this invention exhibit stronger inhibitory activity against hematological malignancies and better selectivity for inhibiting different subtypes of human HDAC, holding promise for the successful development of a new generation of HDAC inhibitor antitumor drugs, which can be further studied as candidate antitumor drugs. In vitro antimalarial activity against Plasmodium falciparum revealed that compounds 1 and 3 showed superior antimalarial activity to the marketed drug DHA, EC... 50 All levels are below 4.5 nM, which suggests the potential to develop into a new generation of antimalarial drugs.

[0021] The method for preparing compounds containing artemisinin-like structures provided by this invention has a simple synthetic route, readily available raw materials, and can shorten the reaction time for rapid preparation. Detailed Implementation

[0022] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0023] It should be noted that the process equipment or apparatus not specifically mentioned in the following embodiments are all conventional equipment or apparatus in the art.

[0024] The structural formulas of compounds 1-4 prepared in Examples 1-4 of this invention, 1 H-NMR and HRMS data are shown in Table 1.

[0025] Table 1. Chemical structural formulas of compounds 1-4 1 H-NMR and HRMS data

[0026] Example 1 This embodiment provides the preparation of compound 1, including the following steps:

[0027] Step 1: Take the raw material dihydroartemisinin (850 mg, 3.0 mmol) as shown in Formula 1-1, add it to diethyl ether (10 mL), then control the temperature of the resulting solution at 0 °C, and add BFE (1 mL) dropwise. After reacting for 4 h, wash with a saturated sodium bicarbonate aqueous solution. After washing, extract with DCM extractant. Evaporate the solvent under reduced pressure to obtain the organic phase, and then purify the product by column chromatography to obtain a white solid product. Add 400 mg of the white solid product to 20 mL of CCl4, control the temperature of the resulting solution at 0 °C, and add 2 mL of a mixed solution of bromine water and CCl4 (bromine water to CCl4 volume ratio of 1:20). Stir for 30 min, add 5 mL of water, and stir at room temperature for 1 h. When a yellow solid precipitates, evaporate the solvent under reduced pressure to obtain the yellow solid product. 300 mg of the yellow solid product was added to DCM, followed by 300 μL of TEA. The mixture was reacted overnight at room temperature. After the reaction was complete, the solvent was evaporated, and the product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compounds 1-2 in 53% yield.

[0028]

[0029] Step 2: Compounds 1-2 (120 mg, 0.42 mmol), 1-3 (73.8 mg, 0.28 mmol), acetic acid (77 μL, 1.34 mmol), and sodium triacetoxyborohydride (212 mg, 1.0 mmol) were added to the EDC and stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography (mobile phase was a mixture of dichloromethane and methanol, volume ratio of dichloromethane to methanol was 12:1) to obtain compound 1-4 (73 mg, yield 49%).

[0030]

[0031] Step 3: Compounds 1-4 (60 mg, 0.11 mmol) and lithium hydroxide (11.6 mg, 0.28 mmol) were added to a mixed solution of tetrahydrofuran (THF) and H2O (THF to H2O volume ratio 1:2). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was dissolved in 2 mL of DCM. The resulting solution was acidified with 3 drops of acetic acid. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 8:1) to obtain compounds 1-5 as pale yellow transparent solids (47 mg, yield 85%).

[0032]

[0033] Step 4: Compounds 1-5 (40 mg, 0.08 mmol), tetrahydropyranylhydroxylamine (28.8 mg, 0.23 mmol), N-hydroxy-7-azabenzotriazole (15.8 mg, 0.12 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.3 mg, 0.12 mmol) were added to DCM and stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 30: 1). The obtained product was added to 10 μL of benzoyl chloride in ethanol and stirred for 2 h at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 35: 1) to give compound 1, a pale yellow solid (19.5 mg, yield 47%).

[0034] Example 2 This embodiment provides the preparation of compound 2, including the following steps:

[0035] Step 1: Take compound 1-2 (245 mg, 0.87 mmol), add it to 10 mL of dioxane, then add ASA (340 mg, 3.55 mmol) and water (3.5 mL), control the temperature of the resulting solution at 0 °C, stir and react for 20 h. After the reaction is complete, add NaClO2 (320 mg, 3.55 mmol) and water (2.5 mL), stir at room temperature for 30 min, evaporate the solvent, dissolve the residue with DCM, filter and evaporate the filtrate, separate and purify by column chromatography (dichloromethane:methanol = 100:1), and obtain a white solid which is compound 2-1 (112 mg, yield 43%).

[0036]

[0037] Step 2: Compound 2-1 (100 mg, 0.34 mmol), compound 1-3 (73.8 mg, 0.28 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (96.4 mg, 0.5 mmol), and 4-dimethylaminopyridine (6.8 mg, 0.06 mmol) were added to DCM, and the mixture was stirred at room temperature for 6 h. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound 2-2 as a white solid (96 mg, yield 63%).

[0038]

[0039] Step 3: Compound 2-2 (60 mg, 0.11 mmol) and lithium hydroxide (11.6 mg, 0.28 mmol) were added to a mixed solution of THF and H2O (THF to H2O volume ratio of 1:2). The mixture was stirred at room temperature for 2 h. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was dissolved in 2 mL of DCM. The solution was acidified by adding 3 drops of acetic acid. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 8:1) to obtain compound 2-3 as a yellow solid (51 mg, yield 89%).

[0040]

[0041] Step 4: Compounds 2-3 (40 mg, 0.08 mmol), tetrahydropyranylhydroxylamine (28.8 mg, 0.23 mmol), N-hydroxy-7-azabenzotriazole (15.8 mg, 0.12 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.3 mg, 0.12 mmol) were added to DCM and stirred overnight at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 30: 1). The obtained product was added to 10 μL of benzoyl chloride in ethanol and stirred for 2 h at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 35: 1) to give compound 2, a pale yellow solid (23.5 mg, yield 57%).

[0042] Example 3 This embodiment provides the preparation of compound 3, including the following steps:

[0043] Compounds 1-5 (40 mg, 0.08 mmol), o-phenylenediamine (17.2 mg, 0.08 mmol), EDCI (22.8 mg, 0.12 mmol), and HOAT (16.2 mg, 0.12 mmol) were added to dichloromethane and stirred at room temperature for 15 min. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give compound 3 as a white solid (25 mg, 53% yield).

[0044] Example 4 This embodiment provides the preparation of compound 4, including the following steps:

[0045] Compounds 1-5 (40 mg, 0.08 mmol), 1-propylhydrazine-1-carboxylic acid tert-butyl ester (27.1 mg, 0.16 mmol), HOAT (12.7 mg, 0.09 mmol), and EDCI (17.9 mg, 0.09 mmol) were added to DCM and stirred at room temperature for 6 h. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 50: 1). The resulting product (42 mg, 0.06 mmol) and ZnBr2 (28.2 mg, 0.12 mmol) were added to a mixed solution of DCM and THF (DCM: THF volume ratio 1: 2), and stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH = 35: 1) to give target compound 4, a white solid (13.6 mg, yield 47%).

[0046] Example 5 The compounds prepared in the above embodiments of the present invention were subjected to antitumor activity tests and toxicity tests.

[0047] In the tumor cell proliferation inhibition experiment and in vitro toxicity assay of the compounds of the present invention, lung cancer cells A549, colon cancer cells HCT116, liver cancer cells HepG2 and human kidney epithelial cells 293T were all tested using the CCK8 assay.

[0048] The control drug and the compound of the present invention were each prepared into 10 mM stock solutions using DMSO and stored at -20 °C. Cells in the exponential growth phase (lung cancer cells A549, colon cancer cells HCT116, and liver cancer cells HepG2) were prepared into high-density cell suspensions, and 100 μL of a 1×10⁻⁶ mM stock solution was added to different wells of 96-well plates according to their different cell division and growth rates. 5 Cells were cultured at a concentration of 10 cells / mL. After 24 h of cell culture, the supernatant was aspirated from the wells. 200 μL of culture medium was added to each well in the blank control group, and 200 μL of drug-containing culture medium was added to each well in the experimental group. 200 μL of PBS was added to each well in the outermost wells of the 96-well plate. After incubation for 72 h, the supernatant was aspirated, and 100 μL of CCK8 diluent was added to each well. After incubation for 30 min, the plate was shaken for 20 s using a microplate reader, and the absorbance (OD) was measured at 450 nm to calculate the half-maximal inhibitory concentration (IC50). 50 .

[0049] Table 2. In vitro inhibitory activity of compounds against solid tumor cells (IC50) 50 (μM)

[0050] The results in Table 2 show that the compounds in this invention exhibit excellent antitumor activity, demonstrating superior inhibitory effects on the proliferation of lung cancer cells A549, colon cancer cells HCT116, and liver cancer cells HepG2 (compounds 1, 2, 3, and 4 showed significant inhibitory effects on the proliferation of these three solid tumor cell lines). 50 All values ​​were less than 5 μM. Compound 1 showed an IC50 value for lung cancer cells A549. 50 The value was 0.44±0.12 μM, which was the IC50 value for HepG2 liver cancer cells. 50 The effective value was 0.54 ± 0.18 μM, indicating that its inhibitory activity against both solid tumor cell types was superior to that of SAHA. Furthermore, compound 4 showed an IC50 value of 0.54 ± 0.18 μM against lung cancer cells A549. 50 The value was 0.56 ± 0.13 μM, which was the IC50 value for HCT116 colon cancer cells. 50 The value was 0.076 ± 0.06 μM, which was the IC50 value for HepG2 liver cancer cells. 50 The value was 0.48±0.12μM, and its antitumor activity was significantly better than that of SAHA, demonstrating extremely excellent and broad-spectrum antitumor activity.

[0051] Based on the IC50 of several compounds in solid tumor cells as shown in Table 2 50 In this invention, compounds 1 and 4, which have high antitumor activity, were selected, and their inhibitory activity against leukemia cells and their toxicity to human renal epithelial cells 293T were determined.

[0052] In the in vitro proliferation inhibition experiment of the compounds of this invention on two cell lines, human promyelocytic leukemia HL-60 and human myeloid monocytic leukemia MV4-11, the resazurin indicator method was used. Cells in the exponential growth phase (human promyelocytic leukemia HL-60 and human myeloid monocytic leukemia MV4-11) were prepared into a high-density suspension, and 100 μL of a 1×10⁻⁶ density solution was added to a dedicated black 96-well plate. 5 Cells were cultured at a concentration of 100 μL / mL. After 24 h of cell culture, 100 μL of culture medium was added to each well in the blank control group and 100 μL of drug-containing culture medium was added to each well in the experimental group. 200 μL of PBS was added to each well in the outermost wells of the 96-well plate. After incubation for 72 h, 20 μL of resveratrol dilution was added, and the cells were incubated for another 4 h. The plates were then shaken for 20 s using a microplate reader, and the fluorescence OD value was measured at 450 nm to calculate the half-maximal inhibitory concentration (IC50). 50 The results are shown in Table 3.

[0053] The toxicity of compounds 1 and 4 to human renal epithelial cells 293T was tested using the CCK8 assay, following the same method described above for tumor cell proliferation inhibition experiments on lung cancer cells A549, colon cancer cells HCT116, and liver cancer cells HepG2. The results are shown in Table 3.

[0054] Table 3. In vitro inhibitory activity (IC50) of highly active compounds against leukemia cells and 293T cells. 50 (μM)

[0055] Table 3 shows the results, including the IC50 values ​​of compound 1 for HL60 and MV4-11 cells. 50 The values ​​were 0.12±0.05 μM and 0.031±0.007 μM, respectively, and the IC50 values ​​of compound 4 against HL60 and MV4-11 cells were 0.12±0.05 μM and 0.031±0.007 μM, respectively. 50 The values ​​were 0.11±0.06 μM and 0.035±0.01 μM, respectively, indicating that compounds 1 and 4 showed significantly better in vitro inhibitory activity against leukemia cells than SAHA. Furthermore, cytotoxicity assays showed that compounds 1 and 4 had an IC50 value of 0.11±0.06 μM and 0.035±0.01 μM, respectively. 50 The values ​​were 5.70 μM and 6.23 μM, respectively, which were close to those of SAHA, indicating excellent antitumor selectivity.

[0056] In summary, the four compounds of this invention all possess excellent and broad-spectrum antitumor activity, and have the potential and value for in-depth research and development.

[0057] Example 6 In vitro antimalarial activity test of the compounds prepared in the embodiments of the present invention 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).

[0058] In vitro antimalarial activity EC 50Test: 100 μL of complete culture medium containing different concentrations of compounds was added to each well of a 96-well plate. Dihydroartemisinin and SAHA were used as positive controls, no drugs were used as negative controls, and erythrocytes without malaria parasites and drugs served as the experimental background. 100 μL of malaria parasite culture (1% annular 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 at 37°C in the dark for another 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.

[0059] Inhibition rate = [Positive control - compound well] / [Positive control - experimental background] × 100%.

[0060] Data fitting was performed using Graph Pad Prism 8, and EC was calculated. 50 The antimalarial activity data are shown in Table 4: Table 4. Effects of the compounds of this invention on Plasmodium falciparum Pf 3D7 half-maximal effective concentration EC 50 (Unit: nM)

[0061] All compounds prepared in this invention are effective against Plasmodium. Pf 3D7 half-maximal effective concentration EC 50 It is comparable to or better than dihydroartemisinin DHA (6.2 nM). Compounds 1 and 3 are effective against Plasmodium. Pf 3D7 half-maximal effective concentration EC 50 Below 4.5 nM, it is superior to DHA. The positive-positive HDAC inhibitor SAHA showed poor antimalarial activity, EC50. 50 Greater than 200 nM.

[0062] Example 7 In vitro inhibitory activity assay of highly active compounds against HADC enzyme.

[0063] The enzymes, substrates, drugs, and developing agents required for the experiment were prepared using working solutions at the necessary concentrations. The experiment included a positive control group, a blank control group, an experimental group, and a background group. 25 μL of drug solution and 50 μL of enzyme solution were added sequentially to the experimental and positive control groups; 25 μL of working solution and 50 μL of enzyme solution were added to the blank control group wells; 75 μL of working solution was added to the background group wells, omitting both drug and enzyme solutions. After sample addition, the 96-well plate was placed in a microplate reader and shaken for 30 seconds to ensure thorough mixing, then incubated at 37 ℃ for 10 min. 25 μL of substrate solution was added to each well, mixed, and incubated at 37 ℃ for 60 min. Finally, 10 μL of developing agent was added to each well, mixed, and incubated at 37 ℃ for 5 min. The fluorescence OD value was then detected using a microplate reader at 380 / 500 nm wavelengths.

[0064] Table 5. Enzyme inhibitory activities of compound 1 and SAHA against different isoforms of HDACs (IC50) 50 , nM)

[0065] The in vitro half-maximal inhibitory concentrations (IC50) of compound 1 and the positive control drug SAHA against several different isotypes of HADC enzymes are shown in Table 5. The IC50 of compound 1 against HDAC6 is also shown in Table 5. 50 The value is 20±6 nM for the HDAC8 IC. 50 The value was 26±8 nM, significantly higher than the inhibitory activity against several other HDAC enzymes, indicating it is a dual-target selective inhibitor of HDAC6 / HDAC8. Notably, its inhibitory activity against HDAC8 is similar to that of SAHA (IC50). 50 = 1574±484 nM) is 60 times higher than that of SAHA. In addition, compound 1, like SAHA, has no inhibitory effect on SIRT2.

[0066] In summary, the compounds containing artemisinin-like structures prepared in this invention possess novel skeletal structures, and key intermediates are constructed using a novel synthetic method. Some compounds exhibit significantly superior antitumor and antimalarial activities compared to marketed drugs DHA and SAHA. Therefore, the compounds prepared in this invention can be used for the development of innovative antitumor and antimalarial drugs.

[0067] 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. A class of compounds containing an artemisinin-like structure, characterized in that, The structural formula of the compound is shown in Formula I: Where X is selected from -CH2- and -C=O; Z is selected from the following groups: 。 2. The compound containing an artemisinin-like structure according to claim 1, characterized in that, X is -CH2-.

3. The compound containing an artemisinin-like structure according to claim 2, characterized in that, Z is selected from the following groups: 。 4. The compound containing an artemisinin-like structure according to claim 1, characterized in that, The compound is one of the following compounds: 。 5. A method for preparing a compound containing an artemisinin-like structure as described in any one of claims 1 to 4, characterized in that, Includes the following steps: S1, dihydroartemisinin was reacted with boron trifluoride diethyl ether, and the product was recrystallized with a mixed solution of bromine water and carbon tetrachloride. The recrystallized product was reacted with triethylamine to give compounds 1-2. Alternatively, dihydroartemisinin is reacted with boron trifluoride diethyl ether, and the resulting product is recrystallized using a mixed solution of bromine water and carbon tetrachloride. The recrystallized product is then reacted with triethylamine to give compound 1-2. Compound 1-2 is then reacted with aminosulfonic acid and sodium chlorite to give compound 2-1. S2, reacting compound 1-2 with compound 1-3, acetic acid and sodium triacetoxyborohydride to give compound A1 with the X group being -CH2-; Alternatively, compound 2-1 can be reacted with compound 1-3, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine to give compound A1 with the X group being -C=O; S3, react compound A1 with lithium hydroxide to obtain compound A2; S4, compound A2 is reacted with tetrahydropyranylhydroxylamine, N-hydroxy-7-azabenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the product is further reacted with benzoyl chloride to give a compound containing an artemisinin-like structure. Alternatively, compound A2 can be reacted with methylhydrazine, ethylhydrazine or n-propylhydrazine protected by the Boc group, or o-phenylenediamine or 4-fluoro-1,2-phenylenediamine to obtain a compound containing an artemisinin-like structure. 。 6. The use of the compound containing an artemisinin-like structure as described in any one of claims 1 to 4 in the preparation of antitumor drugs.

7. The application according to claim 6, characterized in that, The tumor is a solid tumor or a hematologic tumor; the solid tumor is selected from lung cancer, colon cancer, and liver cancer.

8. The use of the compound containing an artemisinin-like structure as described in any one of claims 1 to 5 in the preparation of antimalarial drugs.

9. The application according to claim 8, characterized in that, The malaria mentioned is caused by Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, or Plasmodium ovale.

10. The use of the compound containing an artemisinin-like structure as described in any one of claims 1 to 5 in the preparation of histone deacetylase inhibitors.

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