Rhodanine derivative as well as synthesis method and application thereof
By modifying the structure of rhodanine derivatives, novel rhodanine derivatives were synthesized, solving the problem of pathogen resistance and achieving efficient inhibition of various agricultural and forestry diseases, thus providing a green prevention and control solution.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NORTHEAST FORESTRY UNIV
- Filing Date
- 2025-12-19
- Publication Date
- 2026-05-12
AI Technical Summary
Existing chemical fungicides have led to pathogen resistance due to their long-term single mechanism of action, resulting in a significant decline in the control efficacy of traditional fungicides. This poses a severe challenge to the control of agricultural and forestry diseases, and the decay of agricultural products and contamination by fungal toxins threaten food safety.
By modifying the structure of rhodanine derivatives, a series of novel rhodanine derivatives were synthesized and applied to inhibit major agricultural and forestry pathogens such as Rhizoctonia solani, rice blast fungus, and Cynotrophomonas chrysogenum. This approach utilizes a highly efficient drug molecule design strategy to overcome resistance barriers.
Rhodanine derivatives exhibit significant inhibitory effects against *Cyclocarya paliurus* and broad-spectrum inhibitory activity against *Rhizoctonia solani*, *Oryza sativa*, and *Cyclocarya pinecone*, providing green control solutions, overcoming drug resistance, and improving control efficacy.
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Figure CN122010866A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis, specifically to rhodanine derivatives, their synthetic methods, and applications. Background Technology
[0002] Food and ecological security are crucial cornerstones of national security, impacting the national economy, people's livelihoods, and social stability. Diseases caused by plant pathogenic fungi not only severely threaten the stable and high yields of grain crops such as rice, but also pose a serious challenge to the control of major forest tree diseases such as poplar bark rot (caused by *Rhizoctonia solani*) and pine twig blight (caused by *Rhizoctonia solani*). For example, root rot and damping-off caused by *Rhizoctonia solani* can lead to crop yield reductions of 25% to 100%, severely restricting sustainable agricultural development. Although the use of chemical fungicides has controlled the spread of diseases to some extent, long-term reliance on agents with single mechanisms of action has forced pathogens to evolve complex drug resistance mechanisms, resulting in a significant decrease in the control efficacy of traditional fungicides. Furthermore, post-harvest rot caused by fungi and mycotoxin contamination of agricultural products also pose a potential threat to food safety. Therefore, developing novel plant fungal inhibitors that possess broad-spectrum antibacterial activity, are environmentally friendly, and can overcome existing drug resistance has become an urgent need to ensure safe agricultural and forestry production.
[0003] Rhodanine derivatives, due to their characteristic thiazole ring, aromatic methylene group, and thiogroup, have been proven to have significant pharmacological effects in antibacterial, antiviral, and antitumor fields. However, research on the development and application of rhodanine and its derivatives in agricultural chemistry, particularly as inhibitors of plant pathogenic fungi, is still in its early stages, and its potential agricultural application value has not yet been fully explored.
[0004] In view of this, based on the advantageous skeletal structure of rhodanine, this invention employs an efficient drug molecule design strategy to synthesize a series of novel rhodanine derivatives through structural modification. This invention aims to explore the potential of these compounds in controlling major agricultural and forestry pathogens such as Rhizoctonia solani, Rice blast fungus, and Cynotrophomonas aureus. Through structure-activity relationship studies, highly active candidate molecules are screened to overcome the resistance barriers of traditional fungicides, providing an efficient and low-toxicity innovative solution for the green control of fungal diseases in agricultural and forestry crops. Summary of the Invention
[0005] To achieve the above objectives, the first technical solution of this application discloses rhodanine derivatives having a structure as shown in general formula (I) or general formula (II):
[0006]
[0007] In general formula (Ⅰ):
[0008] R1 is selected from one of hydrogen, methyl, and n-butyl;
[0009] R2 is selected from one of phenyl, 4-(dimethylamino)phenyl, (E)-styryl, 2-hydroxynaphthyl-1-yl, 3,4-dimethoxyphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 4-chlorophenyl, 4-nitrophenyl, 2-methoxyphenyl, 1H-pyrrole-2-yl, naphthyl-2-yl, 3-bromo-5-chlorophenyl, (E)-2,6-dimethylhept-5-enyl, 6-bromo-2-hydroxynaphthyl-1-yl, 6-fluoro-3-nitronaphthyl-2-yl, 2,4-difluoro-3-nitronaphthyl-1-yl, 3-cyanophenyl, 4-(tert-butyl)phenyl, 4-(trifluoromethyl)phenyl, 5-bromothiophene-2-yl, benzo[d]thiazolyl, benzo[b]thiaphene-2-yl, and benzofuran-2-yl.
[0010] In general formula (II):
[0011] R1 is selected from hydrogen or methyl;
[0012] R2 is selected from one of phenyl, (E)-2-phenylvinyl, 5-bromothiophen-2-yl, benzo[b]thiophen-2-yl, 4-(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, and 2-methoxyphenyl.
[0013] The second technical solution of this application discloses a method for preparing the above-mentioned rhodanine derivatives, including the following steps:
[0014] (1) A nucleophilic addition reaction was carried out by mixing L-alanine or glycine, carbon disulfide and ammonia. The reaction product was purified by recrystallization to obtain intermediate 1.
[0015] (2) Intermediate 1 undergoes a nucleophilic substitution reaction with chloroacetic acid under alkaline conditions, followed by cyclization under acidic conditions, and crystallization to obtain intermediate 2;
[0016] (3) Intermediate 2 and aldehyde compounds are dissolved in an organic solvent and carried out an addition-elimination reaction in the presence of an alkaline catalyst. After the reaction is completed, the rhodanine derivative is obtained by post-treatment.
[0017] Furthermore, in step (1), the molar ratio of L-alanine or glycine, carbon disulfide and ammonia is 1:1:3-4; in step (2), the molar ratio of intermediate 1 to chloroacetic acid is 1:1-1.2; and in step (3), the molar ratio of intermediate 2 to aldehyde compounds is 1:1.
[0018] Furthermore, the solvent for the reaction in step (1) is water, the reaction is carried out under ice bath conditions, and the reaction time is 0.5-1 hour; the solvent used for recrystallization is ethanol.
[0019] Furthermore, in step (2), the alkaline conditions are the addition of sodium bicarbonate, the reaction temperature is 25 °C, and the reaction time is 1 hour; the acidic conditions are the addition of concentrated hydrochloric acid, and the reaction time is 12 hours; the crystallization process is carried out at 0 °C.
[0020] Furthermore, the aldehyde compound in step (3) is selected from aromatic aldehydes or alkyl aldehydes; the organic solvent is ethanol; the alkaline catalyst is ammonia; the reaction temperature is 60 °C and the reaction time is 1 hour.
[0021] Furthermore, the post-processing step (3) includes: filtering the reaction solution to remove the precipitate, adding water and dichloromethane to the filtrate, adjusting the pH value to 2-3, heating and rotary evaporating to precipitate the solid, and filtering to obtain the final product.
[0022] And rhodanine derivatives obtained according to the above preparation method.
[0023] The third technical solution of this application discloses the application of the above-mentioned rhodanine derivatives in the preparation of preparations for inhibiting or killing plant pathogenic fungi; wherein the plant pathogenic fungi include any one or more of the following: Rhizoctonia solani, Magnaphorthe oryzae, Cytospora chrysosperma, Sphaeropsis sapinea, or Fusarium oxysporum.
[0024] Beneficial effects: This application, through the preparation of rhodanine derivatives and their application in the treatment of fungi resistant to agricultural and forestry diseases, found that, compared with the prior art, the derivatives synthesized in this invention have a fairly good inhibitory effect on *Cyclocarya paliurus*, and also have a certain inhibitory effect on *Rhizoctonia solani*, *Oryza sativa*, *Pinococcus solani*, and *Fusarium oxysporum*, providing a new direction for the prevention and control of plant-derived diseases. Attached Figure Description
[0025] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments of the present invention will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0026] Figure 1 This is the synthesis roadmap for this application. Detailed Implementation
[0027] To make the technical problems solved, the technical solutions, and the beneficial effects of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
[0028] Example 1: Preparation of Rhodanine Derivatives
[0029] The specific synthesis route diagram is as follows: Figure 1 As shown, the specific preparation method is as follows:
[0030] Step 1: Add L-alanine (1 mol, 1 eq), carbon disulfide (1 mol, 1 eq), 2 mL of water and 25% ammonia (3 mol, 3 eq) to a three-necked flask, react in an ice bath for 0.5 h, add ethanol to crystallize, and obtain intermediate 1.
[0031] Step 2: Take intermediate 1 (1 mol, 1 eq) sodium bicarbonate (1.1 mol, 1.1 eq) and 12 mL of water, then add chloroacetic acid (1.1 mol, 1.1 eq) dropwise, incubate at 25℃ for 1 h, then add 15 mL of concentrated HCl, incubate at 0℃ for 12 h, and crystallize to obtain intermediate 2.
[0032] Step 3: Intermediate 2 (1 mol, 1 eq), then add 3 mL of ethanol and aldehyde compound (see attached) Figure 1 The solution was α-methylcinnamaldehyde (1 mol, 1 eq), followed by ammonia (1.5 mol, 1.5 eq). The reaction was carried out at 60 °C for 1 h. After the reaction was completed, the ammonium salt was obtained by filtration. 3 mL of water and 3 mL of DCM (dichloromethane) were added to the ammonium salt, followed by the addition of HCl to bring the pH to 2-3. The mixture was heated to 60 °C and rotary evaporated. A solid precipitated out, and the solid was filtered to obtain rhodanine derivatives.
[0033] It should be noted that the aldehyde compounds are aromatic aldehydes and alkyl aldehydes, and the types added, reaction products generated, and nuclear magnetic resonance characterization data are shown below.
[0034] Reaction product 1
[0035]
[0036] reaction product 2
[0037]
[0038] Reaction product 3
[0039]
[0040] Reaction product 4
[0041]
[0042] Reaction product 5
[0043]
[0044] Reaction product 6
[0045]
[0046] Reaction product 7
[0047]
[0048] Reaction product 8
[0049]
[0050] Reaction product 9
[0051]
[0052] Reaction product 10
[0053]
[0054] Reaction product 11
[0055]
[0056] Reaction product 12
[0057]
[0058] Reaction product 13
[0059]
[0060] Reaction product 14
[0061]
[0062] Reaction product 15
[0063]
[0064] Reaction product 16
[0065]
[0066] Reaction product 17
[0067]
[0068] Reaction product 18
[0069]
[0070] Reaction product 19
[0071]
[0072] Reaction product 20
[0073]
[0074] Reaction product 21
[0075]
[0076] Reaction product 22
[0077]
[0078] Reaction product 23
[0079]
[0080] Reaction product 24
[0081]
[0082] Reaction product 25
[0083]
[0084] Reaction product 26
[0085]
[0086] Example 2: Antifungal activity test of rhodanine derivatives
[0087] Test target: Target compounds 1-26 prepared in Example 1;
[0088] Test methods: The inhibitory activity of the target compound at 50 μg / mL against five plant pathogens was determined using the mycelial growth rate method. The tested species were Rhizoctonia solani, Magnaphaltheoryzae, Cytospora chrysosperma, Sphaeropsissapinea, and Fusarium oxysporum.
[0089] Experimental results: as shown in Table 1.
[0090] Table 1
[0091]
[0092] Example 3: EC50 of rhodanine derivatives against *Cyclocarya paliurus* 50 Measurement
[0093] Test target: Compounds 7, 912, and 15, the four highly active compounds screened in Example 2.
[0094] Test method: The EC50 of six compounds against *Cyclocarya paliurus* was determined using the mycelial growth rate method. 50 The test results are shown in Table 2.
[0095] Table 2
[0096]
[0097] Results Analysis: At a test concentration of 50 μg / mL, the two rhodanine derivatives synthesized in this invention exhibited varying degrees of inhibitory activity against a variety of plant pathogenic fungi, with the most significant inhibitory effect against *Cyclocarya paliurus*. Mycelial growth rate assays showed that compounds 7, 9, 12, and 15 all achieved 100% inhibition rates against *Cyclocarya paliurus* colony growth, demonstrating extremely strong fungicidal potential. Furthermore, all derivatives also exhibited broad-spectrum antifungal activity against *Rhizoctonia solani*, *Bacillus oryzae*, *Caesalpinia pinenifera*, and *Fusarium oxysporum*. For example, compound 16 showed inhibition rates of 72.28% and 64.65% against *Rhizoctonia solani* and *Caesalpinia pinenifera*, respectively.
[0098] Further toxicity assays (EC) 50 The results showed that the four highly active compounds screened above had an effect on the EC50 of *Cyclocarya paliurus*. 50 The values were all below 10 μg / mL, confirming its excellent antibacterial efficacy. Among them, compound 7 (R) 1 For hydrogen, R 2 The activity of 3,5-dimethoxyphenyl is the most prominent, and its EC50 is... 50 The value was as low as 2.259 μg / mL, indicating that specific benzene ring substituent modifications significantly enhanced the bioactivity of the target molecule.
[0099] In summary, through reasonable structural modification of the rhodanine skeleton, a series of novel derivatives with highly efficient and broad-spectrum antifungal activity were successfully obtained. In particular, the lead compounds screened against *Cyclocarya paliurus* (such as compound 8) exhibited excellent inhibitory activity, providing an important material basis and theoretical foundation for the development of novel agricultural and forestry fungicides.
[0100] The above-described embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be included within the protection scope of the present invention.
Claims
1. A rhodanine derivative used to inhibit or kill plant pathogenic fungi, characterized in that, It has a structure as shown in general formula (I) or general formula (II): ； In general formula (Ⅰ): R1 is selected from one of hydrogen, methyl, and n-butyl; R2 is selected from one of phenyl, 4-(dimethylamino)phenyl, (E)-styryl, 2-hydroxynaphthyl-1-yl, 3,4-dimethoxyphenyl, 4-methoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 4-chlorophenyl, 4-nitrophenyl, 2-methoxyphenyl, 1H-pyrrole-2-yl, naphthyl-2-yl, 3-bromo-5-chlorophenyl, (E)-2,6-dimethylhept-5-enyl, 6-bromo-2-hydroxynaphthyl-1-yl, 6-fluoro-3-nitronaphthyl-2-yl, 2,4-difluoro-3-nitronaphthyl-1-yl, 3-cyanophenyl, 4-(tert-butyl)phenyl, 4-(trifluoromethyl)phenyl, 5-bromothiophene-2-yl, benzo[d]thiazolyl, benzo[b]thiaphene-2-yl, and benzofuran-2-yl. In general formula (II): R1 is selected from hydrogen or methyl; R2 is selected from one of phenyl, (E)-2-phenylvinyl, 5-bromothiophen-2-yl, benzo[b]thiophen-2-yl, 4-(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, and 2-methoxyphenyl.
2. The method for preparing rhodanine derivatives for inhibiting or killing plant pathogenic fungi according to claim 1, characterized in that, Includes the following steps: (1) A nucleophilic addition reaction was carried out by mixing L-alanine or glycine, carbon disulfide and ammonia. The reaction product was purified by recrystallization to obtain intermediate 1. (2) Intermediate 1 undergoes a nucleophilic substitution reaction with chloroacetic acid under alkaline conditions, followed by cyclization under acidic conditions, and then crystallization to obtain intermediate 2; (3) Intermediate 2 and aldehyde compounds are dissolved in an organic solvent and carried out an addition-elimination reaction in the presence of an alkaline catalyst. After the reaction is completed, the rhodanine derivative is obtained by post-treatment.
3. The preparation method according to claim 2, characterized in that: The molar ratio of L-alanine or glycine, carbon disulfide and ammonia in step (1) is 1:1:3-4; the molar ratio of intermediate 1 and chloroacetic acid in step (2) is 1:1-1.2; the molar ratio of intermediate 2 and aldehyde compound in step (3) is 1:
1.
4. The preparation method according to claim 2, characterized in that: The solvent for the reaction in step (1) is water, the reaction is carried out under ice bath conditions, and the reaction time is 0.5-1 hour; the solvent used for recrystallization is ethanol.
5. The preparation method according to claim 2, characterized in that: The alkaline conditions in step (2) are the addition of sodium bicarbonate, a reaction temperature of 25 °C, and a reaction time of 1 hour; the acidic conditions are the addition of concentrated hydrochloric acid and a reaction time of 12 hours; the crystallization process is carried out at 0 °C.
6. The preparation method according to claim 2, characterized in that: The aldehyde compound in step (3) is selected from aromatic aldehydes or alkyl aldehydes; the organic solvent is ethanol; the alkaline catalyst is ammonia; the reaction temperature is 60 ℃ and the reaction time is 1 hour.
7. The preparation method according to claim 2, characterized in that: The post-processing steps in step (3) include: filtering the reaction solution to remove the precipitate, adding water and dichloromethane to the filtrate, adjusting the pH value to 2-3, heating and rotary evaporating to precipitate the solid, and filtering to obtain the final product.
8. A rhodanine derivative prepared according to any one of claims 2 to 7 for inhibiting or killing plant pathogenic fungi.
9. The use of a rhodanine derivative according to claim 1 or 8 for inhibiting or killing plant pathogenic fungi in the preparation of an agent for inhibiting or killing plant pathogenic fungi.
10. The application according to claim 9, characterized in that: The plant pathogenic fungi include any one or more of the following: Rhizoctonia solani, rice blast fungus, Chlorella vulgaris, Chlorella pulveratum, or Fusarium oxysporum.