CN114605352B - Gallic acid derivative containing 1,3, 4-thiadiazole amide and preparation method and application thereof - Google Patents
Gallic acid derivative containing 1,3, 4-thiadiazole amide and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a gallic acid derivative containing 1,3, 4-thiadiazole amide. The invention also relates to a synthesis method of the derivative, which comprises the following steps: the gallic acid is firstly prepared into 3,4, 5-trihydroxybenzoyl isothiocyanate, then the 3,4, 5-trihydroxybenzoyl isothiocyanate reacts with substituted aromatic hydrazide to prepare 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide, and then the N- (5-substituted-1, 3, 4-thiadiazole-2-yl) -3,4, 5-trihydroxybenzoamide compound is obtained by cyclization under the acidic condition. The invention has the advantages of easily obtained raw materials, mild reaction conditions, simple and safe synthesis method operation, little environmental pollution and convenient post-treatment. The compound synthesized by the invention has inhibition effect on vibrio parahaemolyticus and vibrio harveyi.
Description
Technical Field
The invention relates to the field of preparation of medicinal compounds, in particular to gallic acid derivatives containing 1,3, 4-thiadiazole amide, a preparation method thereof and application of the gallic acid derivatives in inhibiting vibrio parahaemolyticus and vibrio harveyi.
Background
Vibrio parahaemolyticus (Vibrio parahaemolyticus) and Vibrio harveyi (Vibrio harveyi) are gram-negative bacilli which are widely distributed in aquatic environments, body surfaces of marine animals and marine sediments, and are common pathogenic bacteria causing death of fishes, shrimps, shellfish and the like in the aquaculture process. Vibrio parahaemolyticus is also a highly pathogenic food-borne pathogen, and can cause food poisoning of human beings by polluting aquatic products, and the main clinical symptoms of human beings after infection are nausea, diarrhea, vomiting and low fever, so that serious patients even suffer from dehydration and shock coma. Vibrio harveyi is the main pathogen of photophobia and is capable of infecting a variety of marine vertebrates and invertebrates, and the symptoms and pathology of the onset vary from species to species, but its typical symptoms are corneal opacity and bulbar herniation. At present, chemical synthetic drugs such as antibiotics are still used for preventing and treating bacterial diseases, however, the long-term use of antibiotics can lead to continuous appearance of drug-resistant strains. Therefore, the demand for novel antibacterial agents for mariculture production is increasing, and searching for novel lead compounds or compound frameworks and developing novel aquatic antibacterial agents has become a hotspot of current aquatic disease prevention and control research.
The Chinese gall is one of traditional Chinese medicinal materials in China, has the functions of bacteriostasis, antidiarrheal, hemostasis and the like, and has good and stable bacteriostasis activity on aquatic pathogenic bacteria. Gallic acid is the main active ingredient of gallnut, is a natural polyphenol compound with the simplest chemical structure, has rich biological activity, such as antibiosis, antioxidation, anti-tumor, antivirus, anti-inflammatory and the like, has wide inhibition effect on gram negative bacteria and positive bacteria, and is expected to become a new generation of antibacterial medicament.
The 1,3, 4-thiadiazole compounds are important five-membered heterocyclic compounds, the structural framework of the 'N-C-S' can form a complex with metal ions in organisms, the complex shows good biological activity, and particularly in the aspect of antibiosis, a plurality of bactericides have been successfully developed at present. Amide structures are also found in many antibacterial agents, such as mandipropamid, fluopicolide, ethaboxam, and the like. A plurality of compounds containing 1,3, 4-thiadiazole amide structures are synthesized, and related researches show that the compounds have good biological activity, including antibiosis, weeding, disinsection, antivirus and the like, and the medicines containing 1,3, 4-thiadiazole amide structures clinically at present mainly comprise bactericides such as methiadipamide, antibiotics such as cefazolin and the like. It is of great importance to develop new compounds containing 1,3, 4-thiadiazolamide structures.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel gallic acid derivative containing 1,3, 4-thiadiazole amide aiming at the defects of the prior art.
The invention aims to provide a method for rapidly and efficiently synthesizing gallic acid derivatives containing 1,3, 4-thiadiazole amide.
It is another object of the present invention to provide the use of the above gallic acid derivatives containing 1,3, 4-thiadiazolamide for inhibiting Vibrio harveyi and Vibrio parahaemolyticus.
In order to solve the technical problems, the invention provides a gallic acid derivative containing 1,3, 4-thiadiazole amide, which has the structural formula shown as follows:
r is selected from 4-ClC 6 H 4 -，4-FC 6 H 4 -，3-OCH 3 C 6 H 4 -，4-BrC 6 H 4 -，C 4 H 3 S-，2-FC 6 H 4 -，C 6 H 5 -，4-OHC 6 H 4 -, or 4-CH 3 C 6 H 4 -。
The technical problems to be solved by the invention can be further realized by the following technical scheme. The invention also discloses a synthesis method of the gallic acid derivative containing 1,3, 4-thiadiazole amide, which comprises the following steps:
(1) Firstly, gallic acid, trichloroisocyanuric acid, triphenylphosphine and potassium thiocyanate react to generate 3,4, 5-trihydroxybenzoyl isothiocyanate;
(2) Reacting 3,4, 5-trihydroxybenzoyl isothiocyanate with substituted aromatic hydrazide to obtain 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide; the substituents of the substituted aromatic hydrazide are selected from 4-ClC 6 H 4 -，4-FC 6 H 4 -，3-OCH 3 C 6 H 4 -，4-BrC 6 H 4 -，C 4 H 3 S-，2-FC 6 H 4 -，C 6 H 5 -，4-OHC 6 H 4 -，4-CH 3 C 6 H 4 -
(3) The 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide reacts under the acidic condition to obtain N- (5-substituted-1, 3, 4-thiadiazole-2-yl) -3,4, 5-trihydroxybenzamide.
The synthesis method is further preferably as follows:
1. in step (1): acetonitrile is used as a solvent for reaction, trichloroisocyanuric acid and triphenylphosphine are added at low temperature, gallic acid is added, and finally potassium thiocyanate is added, wherein the mole ratio of the gallic acid to the trichloroisocyanuric acid to the triphenylphosphine to the potassium thiocyanate is 1: (1-1.5): (0.2-0.8): (1.2-1.8), the reaction temperature is 0-30 ℃ and the reaction time is 12-14h.
2. In step (2): the reaction solvent is dioxane, and the molar ratio of 3,4, 5-trihydroxybenzoyl isothiocyanate to substituted aromatic hydrazide is 1: (0.5-1), the reaction temperature is 50-70 ℃ and the reaction time is 6-8h.
3. In step (3): absolute ethyl alcohol is used as solvent for reaction, H 2 SO 4 Catalyzing, pH is 1-5, reaction temperature is 70-90 deg.c, reaction time4-6h.
4. In step (1): after the reaction is completed, the reaction solution is filtered by suction and concentrated to obtain a crude product of the 3,4, 5-trihydroxybenzoyl isothiocyanate.
5. In the step (2): after the reaction, concentrating to remove part of dioxane, adding dichloromethane while stirring to separate out solid, suction filtering, and using petroleum ether for the solid: ethyl acetate= (1-25): 1 pulping for 1-3h, and filtering to obtain 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide.
6. In the step (3): after the reaction, dripping the reaction liquid into water, stirring, precipitating a large amount of solid, filtering, washing the solid for 1-3 times by using water, and recrystallizing by using absolute ethyl alcohol to obtain the N- (5-substituted-1, 3, 4-thiadiazole-2-yl) -3,4, 5-trihydroxybenzamide.
The invention also discloses the application of the gallic acid derivative containing 1,3, 4-thiadiazole amide or the gallic acid derivative containing 1,3, 4-thiadiazole amide synthesized by any one of the technical schemes of the synthesis method, wherein the application is the application of the gallic acid derivative containing 1,3, 4-thiadiazole amide in preparing antibacterial drugs, and the inhibited bacteria are vibrio harveyi and vibrio parahaemolyticus in marine vibrio.
The synthetic route of the synthetic method of the invention is as follows:
compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a gallic acid derivative containing 1,3, 4-thiadiazole amide of a compound with a marine vibrio antibacterial activity. The biological activity is higher, and the inhibition effect on the marine vibrio is better.
2. The synthesis method disclosed by the invention is simple and convenient to operate, safe and mild in reaction condition; the raw materials are easy to obtain, the traditional temperature control is adopted in the reaction, the experimental steps are simple, the post-treatment is more convenient, and the application range is widened.
Detailed Description
The following further describes specific embodiments of the present invention in order to provide a better understanding of the present invention, and does not constitute a limitation on the claims thereof.
Example 1 a method for synthesizing gallic acid derivatives containing 1,3, 4-thiadiazolamide comprising the steps of:
(1) Preparation of 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide: firstly, gallic acid, trichloroisocyanuric acid, triphenylphosphine and potassium thiocyanate react to generate 3,4, 5-trihydroxybenzoyl isothiocyanate; acetonitrile is used as a solvent for reaction, trichloroisocyanuric acid and triphenylphosphine are added at low temperature, gallic acid is added, and finally potassium thiocyanate is added, wherein the mole ratio of the gallic acid to the trichloroisocyanuric acid to the triphenylphosphine to the potassium thiocyanate is 1:1.1:0.3:1.3, the reaction temperature is 15 ℃, and the reaction time is 14h.
Reacting 3,4, 5-trihydroxybenzoyl isothiocyanate with substituted aromatic hydrazide to obtain 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide; the reaction solvent is dioxane, and the molar ratio of 3,4, 5-trihydroxybenzoyl isothiocyanate to substituted aromatic hydrazide is 1:0.5, the reaction temperature is 55 ℃, and the reaction time is 8h. The substituents of the substituted aromatic hydrazide are selected from 4-ClC 6 H 4 -，4-FC 6 H 4 -，3-OCH 3 C 6 H 4 -，4-BrC 6 H 4 -，C 4 H 3 S-，2-FC 6 H 4 -，C 6 H 5 -，4-OHC 6 H 4 -，4-CH 3 C 6 H 4 -。
(2) Preparation of N- (5-substituted-1, 3, 4-thiadiazol-2-yl) -3,4, 5-trihydroxybenzamides: reacting 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide under an acidic condition to obtain N- (5-substituted-1, 3, 4-thiadiazole-2-yl) -3,4, 5-trihydroxybenzamide; absolute ethyl alcohol is used as solvent for reaction, H 2 SO 4 Catalytic, pH is 3, reaction temperature is 70 ℃, and reaction time is 6h.
Example 2 a method for synthesizing gallic acid derivatives containing 1,3, 4-thiadiazolamide comprising the steps of:
(1) Preparation of 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide: firstly, gallic acid, trichloroisocyanuric acid, triphenylphosphine and potassium thiocyanate react to generate 3,4, 5-trihydroxybenzoyl isothiocyanate; acetonitrile is used as a solvent for reaction, trichloroisocyanuric acid and triphenylphosphine are added at low temperature, gallic acid is added, and finally potassium thiocyanate is added, wherein the mole ratio of the gallic acid to the trichloroisocyanuric acid to the triphenylphosphine to the potassium thiocyanate is 1:1.25:0.4:1.5, the reaction temperature is 20 ℃ and the reaction time is 13h.
Reacting 3,4, 5-trihydroxybenzoyl isothiocyanate with substituted aromatic hydrazide to obtain 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide; the reaction solvent is dioxane, and the molar ratio of 3,4, 5-trihydroxybenzoyl isothiocyanate to substituted aromatic hydrazide is 1:0.6, the reaction temperature is 60 ℃, and the reaction time is 8 hours. The substituents of the substituted aromatic hydrazide are selected from 4-ClC 6 H 4 -，4-FC 6 H 4 -，3-OCH 3 C 6 H 4 -，4-BrC 6 H 4 -，C 4 H 3 S-，2-FC 6 H 4 -，C 6 H 5 -，4-OHC 6 H 4 -，4-CH 3 C 6 H 4 -。
(2) Preparation of N- (5-substituted-1, 3, 4-thiadiazol-2-yl) -3,4, 5-trihydroxybenzamides: reacting 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide under an acidic condition to obtain N- (5-substituted-1, 3, 4-thiadiazole-2-yl) -3,4, 5-trihydroxybenzamide; absolute ethyl alcohol is used as solvent for reaction, H 2 SO 4 Catalytic pH is 2, reaction temperature is 85 ℃, and reaction time is 4h.
Example 3 a method for synthesizing gallic acid derivatives containing 1,3, 4-thiadiazolamide comprising the steps of:
(1) Preparation of 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide: firstly, gallic acid, trichloroisocyanuric acid, triphenylphosphine and potassium thiocyanate react to generate 3,4, 5-trihydroxybenzoyl isothiocyanate; acetonitrile is used as a solvent for reaction, trichloroisocyanuric acid and triphenylphosphine are added at low temperature, gallic acid is added, and finally potassium thiocyanate is added, wherein the mole ratio of the gallic acid to the trichloroisocyanuric acid to the triphenylphosphine to the potassium thiocyanate is 1:1.35:0.5:1.7, the reaction temperature is 25 ℃, and the reaction time is 12h.
Reacting 3,4, 5-trihydroxybenzoyl isothiocyanate with substituted aromatic hydrazide to obtain 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide; the reaction solvent is dioxane, and the molar ratio of 3,4, 5-trihydroxybenzoyl isothiocyanate to substituted aromatic hydrazide is 1:0.7, the reaction temperature is 65 ℃ and the reaction time is 8h. The substituents of the substituted aromatic hydrazide are selected from 4-ClC 6 H 4 -，4-FC 6 H 4 -，3-OCH 3 C 6 H 4 -，4-BrC 6 H 4 -，C 4 H 3 S-，2-FC 6 H 4 -，C 6 H 5 -，4-OHC 6 H 4 -，4-CH 3 C 6 H 4 -。
(2) Preparation of N- (5-substituted-1, 3, 4-thiadiazol-2-yl) -3,4, 5-trihydroxybenzamides: reacting 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide under an acidic condition to obtain N- (5-substituted-1, 3, 4-thiadiazole-2-yl) -3,4, 5-trihydroxybenzamide; absolute ethyl alcohol is used as solvent for reaction, H 2 SO 4 Catalytic, pH 4, reaction temperature 76 ℃, reaction time 6h.
Example 4 synthesis test one of gallic acid derivatives containing 1,3, 4-thiadiazolamide:
in a 50mL round bottom flask, 4mL of absolute ethanol, 0.15g of compound IV (the code of the compound is the same as the reaction route, and the following is the same), namely 1- (benzoyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide is added in sequence, and then H is dripped 2 SO 4 The reaction temperature was 85℃and the reaction time was 4h, to pH 2. After the reaction, the reaction solution is dropped into 15mL of water, stirred for 30 mm, solid is separated out, suction filtration is carried out, the solid is washed with water for 3 times, and then absolute ethyl alcohol is used for recrystallization, thus obtaining the compound V, namely N- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -3,4, 5-trihydroxybenzamide, which is white solid with the yield of 70 percent. P. is greater than 310 ℃; IR (KBr), v/cm -1 :3625,3601,3407,3288,2979,1676,1604,1542,1033,752；1H NMR(500MHz,DMSO-d6),δ＝12.72(s,1H,NH),9.30(s,2H,OH),9.11(s,1H,OH),7.96(d,J＝5.5Hz,2H,Ar-H),7.54(s,1H,Ar-H),7.52(d,J＝1.3Hz,2H,Ar-H),7.14(s,2H,Ar-H)；HRMS(ESI):m/z[M﹣H] - calcd for:C 15 H 10 N 3 O 4 S ﹣ :328.0392；Found:328.0399。
Example 5 Synthesis test II of gallic acid derivatives containing 1,3, 4-thiadiazolamide:
adding 4mL of absolute ethyl alcohol and 0.2g of compound IV (1- (2-F-benzoyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide) into a 50mL round-bottom flask in sequence, and then dripping H 2 SO 4 The reaction temperature was 80℃and the reaction time was 5h, to pH 3. After the reaction, the reaction solution is dropped into 15mL of water, stirred for 30 mm, solid is separated out, suction filtration is carried out, the solid is washed with water for 3 times, and then absolute ethyl alcohol is used for recrystallization, thus obtaining the compound V, namely N- (5- (2-F-phenyl) -1,3, 4-thiadiazol-2-yl) -3,4, 5-trihydroxybenzamide, which is a pale yellow solid with the yield of 71 percent. P. is greater than 310 ℃; IR (KBr), v/cm -1 :3625,3602,3401,3288,2982,1682,1607,1542,1027,780；1H NMR(500MHz,DMSO-d6),δ＝12.79(s,1H,NH),9.31(s,2H,OH),9.12(s,1H,OH),8.26(t,J＝7.0Hz,1H,Ar-H),7.60(td,J＝7.3,1.7Hz,1H,Ar-H),7.47(dd,J＝11.2,8.4Hz,1H,Ar-H),7.40(t,J＝7.6Hz,1H,Ar-H),7.15(s,2H,Ar-H)；HRMS(ESI):m/z[M﹣H] - calcd for:C 15 H 9 FN 3 O 4 S ﹣ :346.0298；Found:346.0294。
Example 6 method for synthesizing gallic acid derivatives containing 1,3, 4-thiadiazolamide experiment three: synthetic methods referring to examples 4 and 5, the substituent structures, reaction times, and product yields of the prepared compounds are shown in the following table:
example 7 antimicrobial activity test experiment of gallic acid derivatives containing 1,3, 4-thiadiazolamide:
the antibacterial activity test substance is a gallic acid derivative containing 1,3, 4-thiadiazole amide of a synthesized target compound; the antibacterial activity test adopts strains of vibrio harveyi and vibrio parahaemolyticus.
The oxford cup method is used for identifying the antibacterial activity of a test object, and is a medicament diffusion method, a double-layer flat plate added with the oxford cup is placed in an incubator, on one hand, pathogenic bacteria start to grow and reproduce, and on the other hand, antibacterial compounds are spherically diffused to form a decreasing concentration gradient. Pathogenic bacteria around the medicine are killed or inhibited, a transparent inhibition zone is formed, and the size of the inhibition zone reflects the inhibition degree of the inhibition substances on the indicator bacteria. For the more active compounds, the Minimum Inhibitory Concentration (MIC) was further determined.
Antibacterial activity assay of test substance: under aseptic conditions, about 20mL of sterilized beef extract peptone agar medium was poured into the plate, after solidification, 200. Mu.L of bacterial suspension was added, the coating rod was spread uniformly, and the plate was left stand for 10min. The oxford cup is vertically and uniformly placed on a culture medium, 200 mu L of samples to be tested are added into the cup, each sample is subjected to 3 times of parallel experiments, and after the samples are transferred to a constant temperature incubator at 37 ℃ for culturing for 18 hours, the diameter of a bacteriostasis zone is measured by an electronic digital display calliper. The results were averaged over three measurements.
The diameter of the inhibition zone of the compound on vibrio harveyi and vibrio parahaemolyticus at the concentration of 1mg/mL of the test solution is expressed as mean value ± standard deviation, n=3.
The series of compounds were each prepared as a 1mg/mL solution in DMSO, and the MIC was further determined for compounds with a zone of inhibition diameter greater than 13mm, with the specific test results shown in Table 1 below:
TABLE 1 results of in vitro inhibition of Vibrio harveyi Activity test of target Compounds
Note that: the oxford cup had a diameter of 7.80mm.
The result shows that the synthesized gallic acid derivatives of the target compound 1,3, 4-thiadiazole amide have different degrees of inhibition effects on vibrio harveyi, and the activity is generally higher than other substitutions when the substituent on the benzene ring is 4-F; when the substituent is a thiophene ring, the activity is equivalent to the substitution of a benzene ring. When the compound substituent is 4-FC 6 H 4 When the inhibition rate was the best in the case of the compound (2), the MIC was further measured to be 0.0313mg/mL.
The series of compounds were each prepared as a 1mg/mL solution in DMSO, and the MIC was further determined for compounds with a zone of inhibition diameter greater than 12mm, with the specific test results shown in Table 2 below:
TABLE 2 results of in vitro inhibition of Vibrio parahaemolyticus Activity test of target Compounds
Note that: the oxford cup had a diameter of 7.80mm.
As a result, the synthesized gallic acid derivative of the target compound 1,3, 4-thiadiazole amide has different degrees of inhibition effects on vibrio parahaemolyticus, and the activity of the substituent on the benzene ring is generally higher than that of the substituent at other positions when the substituent is at para position. When the compound substituent is 4-ClC 6 H 4 The inhibition rate was optimal when (Compound 1) was used, and MIC was further determined to be 0.0625mg/mL.
As is clear from tables 1 and 2, the gallic acid derivatives containing 1,3, 4-thiadiazolamide, which are the target compounds synthesized, have various degrees of inhibition on Vibrio harveyi and Vibrio parahaemolyticus, when the substituent is 4-FC 6 H 4 - (Compound 2) has the best inhibitory effect on Vibrio harveyi, MIC of 0.0313mg/mL; when taking outThe substituent is 4-ClC 6 H 4 - (Compound 1) has an optimal inhibitory effect on Vibrio parahaemolyticus, and has a MIC of 0.0625mg/mL.
In conclusion, the method disclosed by the invention is simple and safe to operate, high in economy, wide in application range and simple and convenient to post-treat, and is a rapid and effective synthesis method; the raw materials are easy to obtain and the price is low. Meanwhile, the synthesized gallic acid derivative containing 1,3, 4-thiadiazole amide has different degrees of inhibition effects on vibrio harveyi and vibrio parahaemolyticus, and is superior to the raw material gallic acid, so that the structural compound has larger implementation value and potential social and economic values.
The above embodiments of the present invention are only examples, and therefore, the scope of the present invention is not limited thereto, but all changes, modifications, substitutions and variations made by the present invention are included in the scope of the present invention.
Claims (9)
1. A gallic acid derivative containing 1,3, 4-thiadiazole amide, which is characterized by the following structural formula:
wherein: r is selected from 4-ClC 6 H 4 -，4-FC 6 H 4 -，3-OCH 3 C 6 H 4 -，4-BrC 6 H 4 -，C 4 H 3 S-，2-FC 6 H 4 -，C 6 H 5 -。
2. A method for synthesizing a gallic acid derivative comprising 1,3, 4-thiadiazolamide according to claim 1, which comprises the steps of:
(1) Firstly, gallic acid, trichloroisocyanuric acid, triphenylphosphine and potassium thiocyanate react to generate 3,4, 5-trihydroxybenzoyl isothiocyanate;
(2) Reacting 3,4, 5-trihydroxybenzoyl isothiocyanate with substituted aromatic hydrazide to obtain 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide; the substituents of the substituted aromatic hydrazide are selected from 4-ClC 6 H 4 -，4-FC 6 H 4 -，3-OCH 3 C 6 H 4 -，4-BrC 6 H 4 -，C 4 H 3 S-，2-FC 6 H 4 -，C 6 H 5 -；
(3) 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide reacts under acidic condition to obtainN- (5-substituted-1, 3, 4-thiadiazol-2-yl) -3,4, 5-trihydroxybenzamide.
3. The synthesis method according to claim 2, characterized in that: in step (1): acetonitrile is used as a solvent for reaction, trichloroisocyanuric acid and triphenylphosphine are added, gallic acid is added, potassium thiocyanate is finally added, and the mole ratio of gallic acid, trichloroisocyanuric acid, triphenylphosphine and potassium thiocyanate is 1: (1-1.5): (0.2-0.8): (1.2-1.8), the reaction temperature is 0-30 ℃ and the reaction time is 12-14h.
4. The synthesis method according to claim 2, characterized in that: in step (2): the reaction solvent is dioxane, and the molar ratio of 3,4, 5-trihydroxybenzoyl isothiocyanate to substituted aromatic hydrazide is 1: (0.5-1), the reaction temperature is 50-70 ℃ and the reaction time is 6-8h.
5. The synthesis method according to claim 2, characterized in that: in step (3): absolute ethyl alcohol is used as solvent for reaction, H 2 SO 4 Catalyzing, pH is 1-5, reaction temperature is 70-90 deg.c, and reaction time is 4-6 hr.
6. The synthesis method according to claim 2, characterized in that: in step (1): after the reaction is completed, the reaction solution is filtered by suction and concentrated to obtain a crude product of the 3,4, 5-trihydroxybenzoyl isothiocyanate.
7. The synthesis method according to claim 2, wherein: in the step (2): after the reaction, concentrating to remove part of dioxane, adding dichloromethane while stirring to separate out solid, suction filtering, and using petroleum ether for the solid: ethyl acetate= (1-25): 1 pulping for 1-3h, and filtering to obtain 1- (substituted aromatic acyl) -4- (3, 4, 5-trihydroxybenzoyl) thiosemicarbazide.
8. The synthesis method according to claim 2, wherein: in the step (3): after the reaction, dripping the reaction liquid into water, stirring, precipitating a large amount of solids, filtering, washing the solids with water for 1-3 times, and recrystallizing with absolute ethanol to obtainN- (5-substituted-1, 3, 4-thiadiazol-2-yl) -3,4, 5-trihydroxybenzamide.
9. Use of a gallic acid derivative comprising 1,3, 4-thiadiazolamide according to claim 1 or a gallic acid derivative comprising 1,3, 4-thiadiazolamide synthesized by the method according to any one of claims 2-8, characterized in that: the application is the application of gallic acid derivatives containing 1,3, 4-thiadiazole amide in preparing antibacterial drugs, and the inhibited bacteria are vibrio parahaemolyticus and vibrio harveyi.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2147025A1 (en) * | 1971-09-21 | 1973-03-29 | Basf Ag | NEW MESOIONIC 1,3,4-THIADIAZOLIMINE (5) DERIVATIVES AND A METHOD FOR THEIR PRODUCTION |
| CN102675302A (en) * | 2011-03-17 | 2012-09-19 | 南京大学 | Thiadiazole derivative containing 1,4-benzdioxanand preparation method and antibacterial activity thereof |
| CN112480031A (en) * | 2020-11-26 | 2021-03-12 | 江苏海洋大学 | Emodin amide derivatives containing 1,3, 4-thiadiazole, and synthesis method and application thereof |
| CN113788772A (en) * | 2021-10-15 | 2021-12-14 | 江苏海洋大学 | Gallic acid derivative containing thiosemicarbazide, and synthesis method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2147025A1 (en) * | 1971-09-21 | 1973-03-29 | Basf Ag | NEW MESOIONIC 1,3,4-THIADIAZOLIMINE (5) DERIVATIVES AND A METHOD FOR THEIR PRODUCTION |
| CN102675302A (en) * | 2011-03-17 | 2012-09-19 | 南京大学 | Thiadiazole derivative containing 1,4-benzdioxanand preparation method and antibacterial activity thereof |
| CN112480031A (en) * | 2020-11-26 | 2021-03-12 | 江苏海洋大学 | Emodin amide derivatives containing 1,3, 4-thiadiazole, and synthesis method and application thereof |
| CN113788772A (en) * | 2021-10-15 | 2021-12-14 | 江苏海洋大学 | Gallic acid derivative containing thiosemicarbazide, and synthesis method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Yingjun Li et al..Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors.《Bioorganic & Medicinal Chemistry Letters》.2014,第4125-4128页. * |
| 齐志文等.三甲氧基没食子酸1，2，4-噻二唑-3，5-二酮衍生物的 合成及其对HL60 细胞增殖的抑制作用.《林产化学与工业》.2020,第40卷(第3期),第123-129页. * |
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