3-Spirocyclic indole ketone derivatives and their preparation method and application

Abstract

The present invention relates to the field of chemical synthesis, and more specifically to a 3-spiroindolone derivative, its preparation method, and application. This application prepares a 3-spiroindolone derivative and applies it to combat forest-derived fungi. It is found that compared with the prior art, the synthesized derivative has moderate inhibitory effects against Rhizoctonia solani, Solanum solani, and Aspergillus pinecone, providing a new direction for the prevention and control of forest pests and diseases.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a 3-spirocyclic indole one derivative, a preparation method and an application thereof. Background Art

[0002] Plant diseases, primarily caused by fungal pathogens, have long impacted forestry, agricultural, and horticultural crop production worldwide. For example, Rhizoctonia solani is best known for causing diseases such as damping-off, root rot, damping-off, and silk stem disease. Some of the consequences include major yield losses (ranging from 25% to 100%), increased soil weight (due to soil adhesion to fungal mycelium), and reduced industrial quality of crops due to increased sodium, potassium, and nitrogen levels. Some of these diseases are primarily caused by Rhizoctonia solani. These devastating diseases also pose a threat to global food security. Furthermore, post-harvest losses of fruits and vegetables due to decay caused by fungal pathogens can also produce mycotoxins that harm animal and human health.

[0003] The indolinone skeleton is a common scaffold found in many natural products, such as spiroprostaglandins, rhynchophylline, and rhynchophylline. Indolinone derivatives play an important role in medicinal chemistry and agrochemicals. Spiroindolone derivatives have been reported to exhibit a variety of biological activities, including progesterone receptor modulators, anti-HIV, anti-cancer, anti-tuberculosis, anti-malarial, and antifungal activities. Over the past decade, 3-spiroindolone derivatives have garnered significant interest among researchers worldwide in synthetic organic chemistry and medicinal chemistry, with the development of new synthetic methods and improvements to existing ones. While the construction of 3-spiroindolones using isatin as a starting material via a 1,3-dipolar cycloaddition reaction is generally convenient, it also presents challenges such as difficulty in subsequent modification and cumbersome post-processing. Furthermore, bioactivity testing of 3-spiroindolone derivatives has primarily focused on agricultural crop pathogens, with limited research on forest pathogens.

[0004] Therefore, we designed and synthesized 15 hydrazone-containing 3-spiroindolinone derivatives using isatin and its derivatives as starting materials and investigated their antifungal activities against three plant pathogenic fungi. The synthesis and antifungal activities of all these compounds are reported for the first time. Summary of the Invention

[0005] Based on the above objectives, the first objective of the present application is to provide a 3-spirocyclic indole ketone derivative having the general structural formula shown in I:

[0006]

[0007] Among them, R1 is one of hydrogen, methyl, and halogen, R2 is one of hydrogen, methyl, and benzyl, and R3 is one of p-toluenesulfonyl and benzenesulfonyl.

[0008] The second object of the present application is to provide a method for preparing the above-mentioned 3-spirocyclic indole one derivatives, which comprises the following steps:

[0009] S1. dispersing an isatin derivative, proline, and naphthoquinone in a solvent to undergo a 1,3 dipolar cycloaddition reaction to obtain an intermediate;

[0010] S2. Adding an acylhydrazine derivative to the intermediate to react to obtain a 3-spirocyclic indole derivative having the general structure as shown in claim 1;

[0011] Wherein, the indigo derivative has the structural formula shown in II:

[0012]

[0013] Wherein, R1 is one of hydrogen, methyl, methoxy, and halogen;

[0014] For example, when R1 is hydrogen, the isatin derivative is isatin; when R1 is methyl and R2 is hydrogen, the isatin derivative is 7-methylisatin; when R1 is Br and R2 is hydrogen, the isatin derivative is 5-bromoisatin, 6-bromoisatin, or 7-bromoisatin; when R1 is hydrogen and R2 is benzyl, the isatin derivative is N-benzylisatin.

[0015] The acylhydrazine derivative has the structural formula shown in III:

[0016]

[0017] Wherein, R3 is one of p-toluenesulfonyl and benzenesulfonyl.

[0018] For example, when R3 is p-toluenesulfonyl, the acylhydrazine derivative is p-toluenesulfonylhydrazine; when R3 is benzenesulfonyl, the acylhydrazine derivative is benzenesulfonylhydrazine.

[0019] Furthermore, the solvent described in S1 is methanol; compared with other solvents such as ethanol, methanol is preferably used as the solvent to increase the yield of the product.

[0020] Furthermore, the reaction in S1 is carried out under ultrasonic conditions, the ultrasonic time is 2 hours, and the reaction temperature is 35-55°C; compared with reaction methods such as oil bath heating, ultrasonic conditions are beneficial to improving the product yield.

[0021] Furthermore, the molar ratio of the isatin derivative, proline, naphthoquinone, and acylhydrazine derivative is 1:1 to 2:1 to 2:1 to 1.5.

[0022] Furthermore, the feeding amount of the methanol is C 靛红 =0.2M.

[0023] And, the 3-spirocyclic indole one derivatives prepared according to the above preparation method.

[0024] The third object of the present application is to provide the use of the above-mentioned 3-spirocyclic indole one derivatives in resisting forest-borne pathogenic fungi.

[0025] Furthermore, the fungi are Rhizoctonia solani, Aspergillus niger, and Aspergillus pinocybe.

[0026] The beneficial effects of the present application are as follows: the present application prepares 3-spiroindolinone derivatives and applies them to resist forest pathogenic fungi. It is found that compared with the prior art, the derivatives synthesized by the present invention have moderate inhibitory effects on Rhizoctonia solani, Solanum solani, and Aspergillus niger, providing a new direction for the prevention and control of forest diseases and insect pests. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is compound 4a 1 H-NMR spectrum;

[0028] Figure 2 is compound 4a 13 C-NMR spectrum;

[0029] Figure 3 is compound 4b 1 H-NMR spectrum;

[0030] Figure 4 is compound 4b 13 C-NMR spectrum;

[0031] Figure 5 is compound 4c 1 H-NMR spectrum;

[0032] Figure 6 is compound 4c 13 C-NMR spectrum;

[0033] Figure 7 It is compound 4d 1 H-NMR spectrum;

[0034] Figure 8 It is compound 4d 13 C-NMR spectrum;

[0035] Figure 9 is compound 4e 1 H-NMR spectrum;

[0036] Figure 10 is compound 4e 13 C-NMR spectrum;

[0037] Figure 11 is compound 4f 1 H-NMR spectrum;

[0038] Figure 12 It is compound 4g 1 H-NMR spectrum;

[0039] Figure 13 It is compound 4h 1 H-NMR spectrum;

[0040] Figure 14 is compound 4i 1 H-NMR spectrum;

[0041] Figure 15 is compound 4j 1 H-NMR spectrum;

[0042] Figure 16 It is compound 4k 1 H-NMR spectrum;

[0043] Figure 17 is compound 4l 1 H-NMR spectrum;

[0044] Figure 18 It is compound 4m 1 H-NMR spectrum;

[0045] Figure 19 It is compound 4n 1 H-NMR spectrum;

[0046] Figure 20 It is compound 4o 1 H-NMR spectrum;

[0047] Figure 21 This is the chemical reaction process of Example 1.1. DETAILED DESCRIPTION

[0048] The present invention is further described in detail below with reference to specific examples. This embodiment is implemented based on the technology of the present invention, and a detailed implementation method and specific operation process are now given to illustrate that the present invention is creative, but the scope of protection of the present invention is not limited to the following examples.

[0049] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0050] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0051] Example 1 Preparation of 3-spiroindolone derivatives

[0052] Preparation: In a 25 mL sealed reaction tube equipped with a magnetic stirrer, an isatin derivative (1 mmol, 1.0 eq.), proline (1 mmol, 1.0 eq.), and naphthoquinone (1 mmol, 1.0 eq.) were added, and 5 mL of methanol was added. The mixture was ultrasonically cleaned for 2 h. An acylhydrazine derivative (1 mmol, 1.0 eq.) was added, and the mixture was heated to 70°C in an oil bath for 12 h. After the reaction was complete, the liquid was removed by filtration to obtain the product.

[0053] The specific added components of the isatin derivative and the acylhydrazine derivative, as well as the reaction products and yields are shown in Table 1; the nuclear magnetic resonance spectra, characterization data and standard nomenclature of the reaction products are shown in Table 2. Figure 21 Provided is a reaction process in which the isatin derivative is isatin and the acylhydrazine derivative is p-toluenesulfonylhydrazine.

[0054] Table 1 Raw materials and target product information

[0055]

[0056]

[0057]

[0058] Table 2

[0059]

[0060]

[0061]

[0062] Example 2 Antifungal Activity Test of 3-Spirocyclic Indole Derivatives

[0063] Test target: target compounds 4a-4o prepared in Example 1;

[0064] Test method: The mycelial growth rate method was used to determine the inhibitory activity of the target compound against three plant pathogens at 50 μg / mL. The test strains were Rhizoctonia solani, Valsasordida Nit, and Sphaeropsis-sapinea.

[0065] Experimental results: as shown in Table 3.

[0066] Table 3

[0067]

[0068]

[0069] (-) indicates no significant inhibition

[0070] Result analysis: At a concentration of 50 μg / ml, the 15 compounds we synthesized had inhibitory activity against Rhizoctonia solani and Aspergillus pinescens, and 7 compounds had inhibitory activity against Aspergillus niger. Among them, 4f had relatively high activity against the three tested bacteria.

[0071] Finally, it should be noted that the above implementation cases are only used to illustrate the technical solution of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred implementation cases, ordinary technicians in this field should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. 3-Spirocyclic indole derivatives having the general structural formula shown in I: (Ⅰ); in, R1 is any one of hydrogen, methyl, and halogen, R2 is any one of hydrogen, methyl, and benzyl, and R3 is any one of p-toluenesulfonyl and benzenesulfonyl.

2. A method for preparing the 3-spirocyclic indole derivatives according to claim 1, comprising the following steps: S1. dispersing an isatin derivative, proline, and naphthoquinone in a solvent to undergo a 1,3 dipolar cycloaddition reaction to obtain an intermediate; S2. Adding an acylhydrazine derivative to the intermediate to react to obtain a 3-spirocyclic indole derivative having the general structure as shown in claim 1; in, The indigo derivative has the structural formula shown in II: （Ⅱ）， Wherein, R1 is any one of hydrogen, methyl, and halogen; R2 is any one of hydrogen, methyl, and benzyl; The acylhydrazine derivative has the structural formula shown in III: （Ⅲ）， Wherein, R3 is one of p-toluenesulfonyl and benzenesulfonyl.

3. The preparation method according to claim 2, characterized in that: The solvent described in S1 is methanol.

4. The preparation method according to claim 2, characterized in that The reaction in S1 was carried out under ultrasonic conditions, the ultrasonic time was 2 h, and the reaction temperature was 35~55°C.

5. The preparation method according to claim 2, characterized in that: The reaction temperature in S2 is 70-90° C., and the reaction time is 24 h.

6. The preparation method according to claim 2, characterized in that: The molar ratio of the isatin derivative, proline, naphthoquinone and acylhydrazine derivative is 1:1-2:1-2:1-1.

5.

7. The preparation method according to claim 3, characterized in that: The feeding amount of the methanol is C 靛红 =0.2 M.

8. Use of the 3-spirocyclic indole derivatives according to claim 1 in combating forest pathogenic fungi, which is used for purposes other than treatment or diagnosis of diseases.

9. The application according to claim 8, characterized in that: The fungi are Rhizoctonia solani, Aspergillus niger, and Aspergillus pinocene.

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