A selenium-based indoloquinazoline derivative, and a preparation method and application thereof

Abstract

This invention belongs to the field of organic synthetic chemistry technology, specifically relating to a selenium-based indoloquinazoline derivative, its preparation method, and its application, comprising: in an organic solvent, using aromatic amine compounds, malononitrile, and diselenoether as raw materials, in the presence of a palladium catalyst and an organic base, at 90°C... o The reaction was carried out under C conditions with stirring to obtain a selenyl indoline quinazoline derivative. This method features mild reaction conditions, simple operation, high yield, and good functional group compatibility, conforming to the principles of green chemistry. Furthermore, the selenyl indoline quinazoline derivative provided by this invention exhibits good inhibitory activity against Plasmodium, providing a drug lead compound for the development of novel antimalarial drugs and holding significant importance for the prevention and / or treatment of malaria.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, specifically relating to a selenium-based indoline quinazoline derivative, its preparation method, and its application. Background Technology

[0002] Malaria is a mosquito-borne parasitic disease caused by Plasmodium parasites. Globally, especially in tropical and subtropical regions, it remains a leading cause of disease burden and death. While artemisinin-based combination therapy is currently the first-line treatment for malaria, the emergence and spread of resistance to artemisinin and its derivatives in Plasmodium parasites pose a serious challenge to the global fight against malaria. Therefore, the development of novel antimalarial drugs with novel mechanisms of action, high activity, and no cross-resistance with existing drugs has become an urgent need in the global public health field.

[0003] Indophylloquinazoline compounds are an important class of nitrogen-containing heterocyclic compounds, playing a vital role in medicinal chemistry. Studies have shown that this class of skeletal structures possesses diverse biological activities, including antitumor, anti-inflammatory, and antibacterial effects. In recent years, some indophylloquinazoline derivatives have also been reported to exhibit certain inhibitory activity against Plasmodium, but their antimalarial activity still has considerable room for improvement, and the mechanism of action remains unclear. Therefore, structural modification and optimization of this class of skeletal structures to obtain highly effective and low-toxicity antimalarial candidate compounds is of significant research value.

[0004] Selenium is an essential trace element for the human body, existing in the form of selenocysteine ​​in various selenoproteins, participating in important physiological processes such as antioxidant defense and immune regulation. Introducing selenium atoms into organic molecules can significantly alter their redox properties, lipophilicity, and interaction patterns with biological targets. In recent years, selenium-containing heterocyclic compounds have attracted attention due to their unique chemical properties and potential antiparasitic activities. Previous studies have shown that some selenium-containing compounds exert antimalarial effects through mechanisms such as inducing oxidative stress, interfering with thioredoxin reductase, or inhibiting heme polymerization. However, compounds with selenium atoms directly constructed in the indole-quinazoline core structure, and their applications in the field of antimalarial therapy, have not yet been reported.

[0005] Existing synthetic methods for indo-quinazoline derivatives typically suffer from drawbacks such as cumbersome steps, the use of precious metal catalysts, harsh reaction conditions, or limited substrate applicability. In particular, a universal synthetic strategy for efficiently and concisely constructing selenium-containing indo-quinazoline skeletons is lacking. Furthermore, existing antimalarial drugs face the problem of drug resistance, necessitating the development of novel compounds with unique structures and mechanisms of action.

[0006] Therefore, designing and synthesizing a class of novel selenium-based indoloquinazoline derivatives, developing simple and efficient preparation methods, and exploring their application in the preparation of antimalarial drugs are of great scientific significance and clinical application prospects for overcoming drug resistance of existing antimalarial drugs, enriching the antimalarial compound library, and promoting the research and development of new antimalarial drugs. Summary of the Invention

[0007] This invention provides a selenium-based indolequinazolin derivative, its preparation method, and its application.

[0008] One objective of this invention is to provide a selenium-based indoline-quinazoline derivative, the structural formula of which is:

[0009]

[0010] R 1 Hydrogen atom, C1-C 10 Alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, acyl, cyano, nitro.

[0011] R 2 Hydrogen atom, C1-C 10 Alkyl, C1-C4 alkoxy, halogen.

[0012] R 3 It is aryl or alkyl.

[0013] The second objective of this invention is to provide a method for preparing a selenium-based indoloquinazoline derivative, comprising the following steps: in an organic solvent, using an aromatic amine compound of formula (I), malononitrile of formula (II), and diselenoether of formula (III) as raw materials, in the presence of a palladium catalyst and an organic base, at 90 °C... o The reaction was stirred under C conditions to obtain the selenyl indoline quinazoline derivative shown in formula (IV), and the reaction equation is shown below:

[0014]

[0015] Compound of formula (I) is an aromatic amine compound, R 1 The radicals are methoxy, methyl, halogen, trifluoromethyl, acetoxy, cyano, and nitro. R 2 For methoxy, methyl, halogen, R 3 It is aryl or alkyl.

[0016] The compound of formula (II) is malononitrile.

[0017] The compound of formula (III) is a diaryl diselenide or a dialkyl diselenide.

[0018] Preferably, the palladium catalyst is at least one of bis(benzonitrile)palladium dichloride, palladium trifluoroacetate, bis(triphenylphosphine)palladium dichloride and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and more preferably bis(benzonitrile)palladium dichloride.

[0019] Preferably, the organic solvent is at least one of carbon tetrachloride, chloroform, dichloroethane, and toluene, with toluene being the most preferred.

[0020] Preferably, the base is at least one of pyridine, diisopropylethylamine, and triethylamine, and more preferably triethylamine.

[0021] Preferably, the molar ratio of the aromatic amine compound with the structure shown in formula (I), the malononitrile with the structure shown in formula (II), and the diselenide with the structure shown in formula (III) is 1:(1-3):1, and more preferably 1:2:1.

[0022] Preferably, the reaction occurs at 90°C. o The reaction was carried out under stirring at C for 16 hours.

[0023] 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.

[0024] A third aspect of the present invention provides a pharmaceutical composition comprising the above-described selenyl indoquinazoline derivative or a medically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0025] In a fourth aspect, the present invention provides the use of the above-described pharmaceutical composition in the preparation of an antimalarial disease drug for the treatment and / or prevention of malaria.

[0026] By employing the above technical solutions, the selenium-based indoline quinazoline 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.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] 1. This invention is the first to directly construct selenium atoms in the core structure of indo-quinazoline, obtaining a series of selenium-based indo-quinazoline derivatives, enriching the library of selenium-containing heterocyclic compounds.

[0029] 2. The synthesis method of this invention has the advantages of mild conditions, simple operation, high yield, and good functional group compatibility, which conforms to the principles of green chemistry.

[0030] 3. The compounds synthesized in this invention exhibit good inhibitory activity against both the chloroquine-sensitive D6 strain and the chloroquine-resistant W2 strain. This provides novel candidate compounds with potentially different mechanisms of action for overcoming the drug resistance problem of existing antimalarial drugs (such as artemisinin), and has important scientific significance and application prospects for the development of new antimalarial drugs. Detailed Implementation

[0031] Example 1

[0032]

[0033] Add 1 mmol of 2-bromo-N-(2-bromobenzyl)aniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas at 90 °C. o After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. 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 70% yield.

[0034]

[0035] Example 2

[0036]

[0037] Add 1 mmol of 2-bromo-N-(2-bromobenzyl)-4-methoxyaniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas and heat to 90 °C. O After reaction C for 16 hours, the organic phase was removed by rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 50:1) to obtain target compound 1b in 73% yield.

[0038]

[0039] Example 3

[0040]

[0041] Add 1 mmol of 2-bromo-N-(2-bromobenzyl)-5-chloroaniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas and heat to 90 °C. O After reaction C for 16 hours, the organic phase was subjected to a rotary evaporator to remove the solvent. 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 1c in 59% yield.

[0042]

[0043] Example 4

[0044]

[0045] Add 1 mmol of 2-bromo-N-(2-bromobenzyl)-4-(trifluoromethyl)aniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas and heat to 90 °C. O After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 40:1) to obtain the target compound 1d, with a yield of 63%.

[0046]

[0047] Example 5

[0048]

[0049] Add methyl 3-bromo-4-[(2-bromobenzyl)amino]benzoate (1 mmol), malononitrile (2 mmol), diphenyldiselenoether (1 mmol), and triethylamine (3 mmol), and toluene (2 mL) to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas. O After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 30:1) to obtain the target compound 1e in 80% yield.

[0050]

[0051] Example 6

[0052]

[0053] Add 1 mmol of 3-bromo-4-[(2-bromobenzyl)amino]benzonitrile, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stir bar. After addition, purge the tube with nitrogen gas and heat to 90 °C. O After the reaction was completed at C for 16 hours, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 30:1) to obtain the target compound 1f in 73% yield.

[0054]

[0055] Example 7

[0056]

[0057] Add 1 mmol of 2-bromo-N-(2-bromobenzyl)-5-nitroaniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas and heat to 90 °C. O After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 40:1) to obtain 1 g of the target compound, with a yield of 65%.

[0058]

[0059] Example 8

[0060]

[0061] Add 1 mmol of 2-bromo-N-(2-bromo-4-methylbenzyl)aniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas. OAfter the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 50:1) to obtain the target compound in 1 hour with a yield of 68%.

[0062]

[0063] Example 9

[0064]

[0065] Add 1 mmol of 2-bromo-N-(2-bromo-4,5-dimethoxybenzyl)aniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas and heat to 90 °C. O After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 30:1) to obtain the target compound 1i in 65% yield.

[0066]

[0067] Example 10

[0068]

[0069] Add 1 mmol of 2-bromo-N-(2-bromo-5-fluorobenzyl)aniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After the addition is complete, purge the tube with nitrogen gas. O After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. 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 74%.

[0070]

[0071] Example 11

[0072]

[0073] Add 1 mmol of 2-bromo-N-[(3-bromopyridin-4-yl)methyl]aniline, 2 mmol of malononitrile, 1 mmol of diphenyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas and bring the temperature to 90 °C. O After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 30:1) to obtain the target compound 1k in 50% yield.

[0074]

[0075] Example 12

[0076]

[0077] Add 1 mmol of 2-bromo-N-(2-bromobenzyl)aniline, 2 mmol of malononitrile, 1 mmol of dimethyl diselenyl ether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas at 90 °C. o After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 40:1) to obtain 1 liter of the target compound with a yield of 72%.

[0078]

[0079] Example 13

[0080]

[0081] Add 1 mmol of 2-bromo-N-(2-bromobenzyl)aniline, 2 mmol of malononitrile, 1 mmol of diethyldiselenoether, and 3 mmol of triethylamine, along with 2 mL of toluene, to a 20 mL Schlenk tube equipped with a magnetic stirrer. After addition, purge the tube with nitrogen gas at 90 °C. o After the reaction was completed, the organic phase was removed by a rotary evaporator to remove the solvent. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 50:1) to obtain the target compound 1m, with a yield of 74%.

[0082]

[0083] Example 14

[0084] Investigation of the antimalarial activity of the compound.

[0085] The synthesized compounds and the control drug quinine were subjected to drug susceptibility testing against two Plasmodium falciparum clones: the Sierra Leone strain (D6) and the Indochina strain (W2). The antimalarial activity of the compounds was evaluated in vitro using the SYBR Green I method. Plasmodium was cultured in RPMI 1640 medium with a human hematocrit of 2% at 37°C and a CO2 concentration of 5%. The Plasmodium was synchronized to the cyclic stage with 5% sorbitol, resulting in a final infection rate of 1% and a hematocrit of 2%. The cyclic Plasmodium and the tested compounds were co-cultured in 96-well plates for 72 hours, followed by the addition of the fluorescent dye SYBR Green I. Finally, the growth of the Plasmodium was detected by measuring the fluorescence values ​​(excitation: 485 nm, emission: 535 nm) using a microplate reader. The half-maximal inhibitory concentration (IC50) was used to determine the growth of the Plasmodium. 50 This indicates that the antimalarial activity of the test compound was evaluated. Specific experimental results are shown in Table 1 below:

[0086]

[0087] In vitro antimalarial activity tests of 13 selenyl indoline quinazoline derivatives (1a-1m) and the clinical antimalarial drug quinine against Plasmodium falciparum showed that most compounds exhibited good to excellent inhibitory activity on the chloroquine-sensitive D6 strain, with IC50 values ​​of [missing information]. 50 The concentration ranged from 4.3 to 75.4 ng / mL, with the highest activity at 1f and 1h, and an IC50 concentration of [missing value]. 50 The concentrations were as low as 4.3 ng / mL and 8.1 ng / mL, respectively, demonstrating the overall high inhibitory potential of this type of backbone against the D6 strain. In stark contrast, 1c and 1f showed relatively better inhibitory effects on the chloroquine-resistant W2 strain. Overall, selenyl indoline quinazoline derivatives have strong antimalarial potential against the sensitive D6 strain, and 1c, 1f, and 1h, in particular, can be used as lead compounds for further research.

[0088] 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 selenyl indoloquinazoline derivative, characterized in that, The structural formula of the selenyl indoline quinazoline derivative is: R 1 Hydrogen atom, C1-C 10 Alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, acyl, cyano, nitro; R 2 Hydrogen atom, C1-C 10 Alkyl, C1-C4 alkoxy, halogen; R 3 It is aryl or alkyl.

2. The method for preparing a selenium-based indoloquinazoline derivative according to claim 1, characterized in that, The preparation method is as follows: In an organic solvent, using an aromatic amine compound of formula (I), malononitrile of formula (II), and diselenoether of formula (III) as raw materials, the mixture is heated and stirred under nitrogen protection in the presence of a palladium catalyst and an organic base to obtain a selenium-based indoloquinazoline derivative of formula (IV). The reaction equation is shown below: R 1 Hydrogen atom, C1-C 10 Alkyl, C1-C4 alkoxy, halogen, trifluoromethyl, acyl, cyano, nitro; R 2 Hydrogen atom, C1-C 10 Alkyl, C1-C4 alkoxy, halogen; R 3 It is aryl or alkyl; The palladium catalyst is palladium di(benzonitrile)dichloride; the base is triethylamine; and the organic solvent is toluene.

3. The method for preparing a selenium-based indoloquinazoline derivative according to claim 2, characterized in that, The molar ratio of the aromatic amine compound with structure (I), the malononitrile with structure (II), and the diselenide with structure (III) is 1:(1~3):

1.

4. The method for preparing a selenium-based indoloquinazoline derivative according to claim 3, characterized in that, The molar ratio of the aromatic amine compound with structure (I), the malononitrile with structure (II), and the diselenide with structure (III) is 1:2:

1.

5. The method for preparing a selenium-based indoloquinazoline derivative according to claim 2, characterized in that, The reaction was at 90 o The reaction was carried out under stirring at C for 16 hours.

6. The method for preparing a selenium-based indoloquinazoline 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 selenium-indoquinazoline derivative of claim 1 or a medically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

8. The use of the pharmaceutical composition of claim 7 in the preparation of an antimalarial disease drug.

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