Azido tellurium ether derivative, and preparation method and application thereof
The preparation of azidotelluride derivatives by visible light photocatalysis solves the problem of lack of synthetic methods and realizes the application of novel azidotelluride derivatives in the treatment of leishmaniasis, demonstrating good biological activity and pharmaceutical applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NANTONG UNIV
- Filing Date
- 2026-03-09
- Publication Date
- 2026-06-09
AI Technical Summary
The lack of efficient and mild synthetic methods has resulted in a limited variety of azidotelluride compounds, and their potential in medicinal chemistry has not been fully explored, especially in the application research of anti-leishmaniasis.
A visible light-catalyzed reaction system was used to prepare azide telluride derivatives by reacting olefins, trimethylsilane azido, and ditelluride in the presence of a photocatalyst at room temperature. This avoided harsh conditions such as high temperature, strong base, or strong reduction, and simplified the synthesis steps.
This study provides a novel class of azide telluride derivatives that exhibit significant anti-leishmaniasis activity. The synthesis method is mild and efficient, suitable for large-scale preparation, and expands its application in medicinal chemistry and organic synthesis.
Smart Images
Figure SMS_2 
Figure SMS_3 
Figure SMS_4
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthetic chemistry technology, specifically relating to an azide tellurium ether derivative, its preparation method, and its application. Background Technology
[0002] Organotellurium compounds, as an important branch of organochalcogenide chemistry, have received widespread attention in synthetic chemistry, materials science, and medicinal chemistry in recent years. The large atomic radius, low electronegativity, and good polarizability of tellurium atoms endow organotellurium compounds with unique reactivity, such as readily undergoing oxidative addition and reductive elimination reactions, and acting as nucleophiles in various transformations. Significant progress has been made in the study of the bioactivity of organotellurium compounds in recent years. Literature has reported that certain diaryl ditellurium ether derivatives exhibit good antioxidant, antitumor, and antibacterial activities. The nucleophilicity and easy oxidation of tellurium enable it to interfere with the thioredoxin reductase system in pathogens or induce oxidative stress, thereby inhibiting or killing pathogens.
[0003] The azide group, as a highly reactive functional group, plays a crucial role in organic synthesis. It is not only a key player in the renowned click chemistry process but also an important intermediate in the construction of nitrogen-containing heterocyclic compounds and amines. In medicinal chemistry, the azide group is often used as a pharmacophore or precursor group, capable of improving the lipophilicity of molecules or participating in specific bioorthogonal reactions.
[0004] Leishmaniasis is a neglected tropical parasitic disease caused by parasites of the genus *Leishmania*, with hundreds of thousands of new cases reported globally each year. Currently, pentavalent antimony agents remain the first-line treatment in clinical practice, but these drugs have long treatment cycles, significant side effects, and are increasingly showing signs of resistance. Therefore, the development of anti-leishmaniasis drugs with novel mechanisms of action is urgently needed.
[0005] However, due to the lack of efficient and mild synthetic methods, the variety of azidotelluride compounds is limited, and their potential in medicinal chemistry has not been fully explored. In particular, considering the potential inhibitory effect of tellurium atoms on sulfur-containing enzyme systems and the possibility that the azido group may enhance the affinity of molecules for biological targets, research on the application of azidotelluride derivatives in combating parasitic diseases such as Leishmaniasis is still lacking.
[0006] Therefore, developing a method for preparing azide telluride derivatives with mild reaction conditions, simple operation, high yield, and good functional group compatibility, and expanding its application in organic synthesis and biomedicine (especially in the fight against leishmaniasis), is of great theoretical and practical significance. Summary of the Invention
[0007] The purpose of this invention is to provide an azide telluride derivative, its preparation method, and its application.
[0008] In a first aspect, the present invention provides an azide telluride ether derivative, the structural formula of which is as follows: ,
[0009] Ar is a phenyl, naphthyl, furanyl, thiophene, or an aryl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, halogen, ester, cyano, or nitro.
[0010] R is a C1-C10 straight-chain or branched alkyl, benzyl, or phenyl substituted with one or more substituents, wherein the substituents are selected from C1-C10 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, trifluoromethyl, and trifluoromethoxy.
[0011] In a second aspect, the present invention provides a method for preparing an azide tellurium ether derivative, comprising the following steps: in an organic solvent, using an olefin of formula (I), a ditellurium ether of formula (II), and trimethylsilane azide (TMSN3) of formula (III) as raw materials, the reaction is carried out under stirring in the presence of a photocatalyst and under visible light irradiation to obtain the azide tellurium ether derivative of formula (IV), and the reaction equation is shown below:
[0012]
[0013] The compound of formula (I) is an olefin, and Ar is a phenyl, naphthyl, furanyl, thiophene, or an aryl group substituted by one or more substituents, wherein the substituent is an alkoxy, alkyl, halogen, ester, cyano, or nitro group.
[0014] The compound of formula (II) is a ditelluride, where R is a C1-C10 straight-chain or branched alkyl, benzyl, or phenyl substituted with one or more substituents, wherein the substituents are selected from C1-C10 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, trifluoromethyl, and trifluoromethoxy.
[0015] Formula (III) is trimethyl azidosilane.
[0016] Preferably, the photocatalyst is any one of 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate, 2,4,6-triphenylpyranium tetrafluoroborate, and 9-trimethylmethyl-10-methylacridine perchlorate, with 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate being the most preferred.
[0017] Preferably, the light source for the reaction is one of white fluorescent lamp, blue LED, and purple LED, with purple LED being the preferred option.
[0018] Preferably, the organic solvent is at least one of N,N-dimethylformamide, carbon tetrachloride, chloroform, ethyl acetate, and acetonitrile, with acetonitrile being the most preferred.
[0019] Preferably, the molar ratio of the olefin with the structure shown in formula (I), the ditelluride with the structure shown in formula (II), and the TMSN3 with the structure shown in formula (III) is 1:1:2-1:1:4, and more preferably 1:1:3.
[0020] Preferably, the reaction is carried out with stirring at room temperature for 20-30 h.
[0021] Preferably, after the reaction is completed, the reaction solution is concentrated under reduced pressure, and the concentrate is separated by column chromatography with a petroleum ether / ethyl acetate mixed solution as the eluent at a volume ratio of (1-100):1 to obtain the target product.
[0022] A third aspect of the present invention provides a pharmaceutical composition comprising the above-described azide telluride derivative or a medically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
[0023] In a fourth aspect, the present invention provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing leishmaniasis.
[0024] By employing the above technical solutions, the azidotelluride derivatives provided by this invention can be formulated into preparations for drug delivery, either alone or in combination with one or more pharmaceutically acceptable carriers. For example, solvents, diluents, etc., can be used for oral administration, such as tablets, capsules, dispersible powders, granules, etc. Various dosage forms of the pharmaceutical compositions of this invention can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical preparations may contain, for example, 0.05% to 90% by weight of the active ingredient in combination with a carrier, more commonly about 15% to 60% by weight of the active ingredient. The dosage of the compounds of this invention can be 0.005 to 5000 mg / kg / day, and may exceed this range depending on the severity of the disease or the dosage form.
[0025] The beneficial effects of this invention are as follows:
[0026] 1. Novel Compound Structures Provided: This invention discloses for the first time a novel class of azide tellurium ether derivatives. This compound simultaneously introduces an azide functional group and a tellurium ether structure into the same molecule, achieving the integration of two types of active functional groups and providing a new molecular framework for medicinal chemistry and organic synthesis.
[0027] 2. The synthesis method is mild, efficient, and environmentally friendly: This invention employs a visible light-catalyzed reaction system, which can be carried out at room temperature, avoiding harsh conditions such as high temperature, strong base, or strong reduction, effectively protecting the sensitive azide group and tellurium ether structure. The reaction steps are simple, constructing the target molecule in one step, avoiding cumbersome protection and deprotection steps, resulting in high atom economy and suitability for large-scale preparation.
[0028] 3. Significant Bioactivity and Pharmaceutical Uses: This invention is the first to discover the application of azidotellurium ether derivatives in the fight against Leishmaniasis. Utilizing the inhibitory effect of tellurium atoms on the sulfur-containing enzyme system within pathogens (such as thioredoxin reductase), and the improvement of molecular lipophilicity and target affinity by the azido group, these compounds exhibit excellent antiparasitic potential. Detailed Implementation
[0029] Example 1
[0030]
[0031] Styrene (0.2 mmol), diphenyl ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1a in 81% yield.
[0032]
[0033] Example 2
[0034]
[0035] To a 20 mL test tube equipped with a magnetic stirrer, add p-methylstyrene (0.2 mmol), diphenyl ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol), and acetonitrile (2 mL). After addition, place a purple LED 2 cm away from the test tube and react at room temperature for 20 hours under open conditions. After the reaction is complete, remove the solvent from the reaction solution using a rotary evaporator. Purify the residue using a silica gel column (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1b in 80% yield.
[0036]
[0037] Example 3
[0038]
[0039] To a 20 mL test tube equipped with a magnetic stirrer, add p-methoxystyrene (0.2 mmol), diphenyl ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol), and acetonitrile (2 mL). After addition, place a purple LED 2 cm away from the test tube and react at room temperature for 20 hours under open conditions. After the reaction is complete, remove the solvent from the reaction solution using a rotary evaporator. Purify the residue using a silica gel column (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1c in 80% yield.
[0040]
[0041] Example 4
[0042]
[0043] To a 20 mL test tube equipped with a magnetic stir bar, add p-bromostyrene (0.2 mmol), diphenyl ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol), and acetonitrile (2 mL). After addition, place a purple LED 2 cm away from the test tube and react at room temperature for 20 hours under open conditions. After the reaction is complete, remove the solvent from the reaction solution using a rotary evaporator. Purify the residue using a silica gel column (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1d, with a yield of 75%.
[0044]
[0045] Example 5
[0046]
[0047] 4-Vinylphenylacetate (0.2 mmol), diphenylditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1e in 67% yield.
[0048]
[0049] Example 6
[0050]
[0051] 2-Vinylnaphthalene (0.2 mmol), diphenylditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1f in 81% yield.
[0052]
[0053] Example 7
[0054]
[0055] 2-Vinylthiophene (0.2 mmol), diphenylditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain 1 g of the target compound, with a yield of 39%.
[0056]
[0057] Example 8
[0058]
[0059] Styrene (0.2 mmol), dibenzyl ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound in 1 h with a yield of 58%.
[0060]
[0061] Example 9
[0062]
[0063] Styrene (0.2 mmol), di-p-tolyl ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1i in 83% yield.
[0064]
[0065] Example 10
[0066]
[0067] Styrene (0.2 mmol), bis(4-methoxyphenyl)ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1j with a yield of 77%.
[0068]
[0069] Example 11
[0070]
[0071] Styrene (0.2 mmol), di(4-cyanophenyl)ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain the target compound 1k in 70% yield.
[0072]
[0073] Example 12
[0074]
[0075] Styrene (0.2 mmol), di(4-chlorophenyl)ditelluride (0.2 mmol), TMSN3 (0.6 mmol), and 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate (0.01 mmol) and acetonitrile (2 mL) were added to a 20 mL test tube equipped with a magnetic stirrer. After the addition was complete, a purple LED was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 20 hours under open conditions. After the reaction was completed, the solvent was removed from the reaction solution by rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 60 / 1) to obtain 1 L of the target compound, with a yield of 62%.
[0076]
[0077] Example 13
[0078] Investigation of the compound's activity against Leishmania.
[0079] The synthesized compounds and the control drug mitefosine were tested for anti-leishmaniasis activity against the proflagellates of *Leishmania* in Amazonia, using the half-maximal inhibitory concentration (IC50) as the threshold. 50 The cytotoxicity of each compound to the macrophage cell line J774A1 was also determined, expressed as half-maximal cytotoxic concentration (CMC). 50 The selectivity index (SI) of each compound was calculated by dividing the half-maximal cytotoxic concentration (MCC) by the half-maximal inhibitory concentration (HIC) of the promastocytes, thereby assessing the anti-leishmaniasis activity of the tested compounds. Specific experimental results are shown in Table 1 below:
[0080] Table 1
[0081] Based on the in vitro test results of 12 azidotelluride derivatives (1a–1l) and the reference drug mitefoxin in terms of antileishmaniasis activity, cytotoxicity, and selectivity, all target compounds exhibited certain antileishmaniasis activity, IC50, and IL-120. 50 The values ranged from 17.4 to 96.3 μmol / L. Compound 1d exhibited the best inhibitory activity, with an IC50 value of [missing value]. 50 The concentration was 17.4 μmol / L, which was superior to the positive control mitefonine (20.8 μmol / L); followed by 1c (IC50). 50 = 24.3 μmol / L), IC50 of the other compounds 50 All concentrations were above 45 μmol / L, with 1b (96.3 μmol / L) showing the weakest activity. In the cytotoxicity assessment, the CC of each compound... 50 The concentration ranged from 49 to 120 μmol / L. Compounds 1b, 1c, and 1d exhibited relatively high cytotoxicity, while 1h, 1i, and 1l showed superior safety profiles. Further evaluation of the therapeutic window using the SI (selectivity index) revealed that most compounds had SI values below 2, indicating room for improvement in overall selectivity. In summary, compound 1d demonstrated the best anti-leishmaniasis activity and selectivity, superior to the positive control mitefoxin, and possesses the potential for further development as an antiparasitic drug.
[0082] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.
Claims
1. A tellurium azide ether derivative, characterized in that, The structural formula of the azidotelluride derivative is as follows: , Ar is a phenyl, naphthyl, furanyl, thiophene, or an aryl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, halogen, ester, cyano, or nitro. R is a C1-C10 straight-chain or branched alkyl, benzyl, or phenyl substituted with one or more substituents, wherein the substituents are selected from C1-C10 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, trifluoromethyl, and trifluoromethoxy.
2. The method for preparing an azide tellurium ether derivative according to claim 1, characterized in that, The preparation method is as follows: using the olefin shown in formula (I), the ditelluride shown in formula (II), and the trimethylsilane TMSN3 shown in formula (III) as raw materials in an organic solvent, the reaction is carried out under visible light irradiation in the presence of a photocatalyst to obtain the azide telluride ether derivative shown in formula (IV). The reaction equation is as follows: The compound of formula (I) is an alkene, and Ar is phenyl, naphthyl, furanyl, thiophene, or an aryl group substituted by one or more substituents, wherein the substituents are alkoxy, alkyl, halogen, ester, cyano, or nitro. The compound of formula (II) is a ditelluride, where R is a C1-C10 straight-chain or branched alkyl, benzyl, or phenyl substituted with one or more substituents, wherein the substituents are selected from C1-C10 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, trifluoromethyl, and trifluoromethoxy. Formula (III) is trimethyl azidosilane; The photocatalyst is 2,4,6-tris(4-methoxyphenyl)pyranium tetrafluoroborate; the irradiation source for the reaction is a purple LED; and the organic solvent is acetonitrile.
3. The method for preparing an azide tellurium ether derivative according to claim 2, characterized in that, The molar ratio of the olefin with structure (I), the ditelluride with structure (II), and the TMSN3 with structure (III) is 1:1:2-1:1:
4.
4. The method for preparing an azide tellurium ether derivative according to claim 3, characterized in that, The molar ratio of the olefin with structure (I), the ditelluride with structure (II), and the TMSN3 with structure (III) is 1:1:
3.
5. The method for preparing an azide telluride derivative according to claim 2, characterized in that, The reaction was carried out with stirring at room temperature for 20-30 h.
6. The method for preparing an azide tellurium ether derivative according to claim 2, characterized in that, After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated by column chromatography with a petroleum ether / ethyl acetate mixed solution as the eluent at a volume ratio of (1-100):1 to obtain the target product.
7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the azide telluride derivative of claim 1 or a medically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
8. Use of the pharmaceutical composition of claim 7 in the preparation of a medicament for treating leishmaniasis.