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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- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical class OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 title claims abstract description 67
- -1 1,3, 4-thiadiazole amide Chemical class 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- WDFYIPJFPCZXMS-UHFFFAOYSA-N OC(C=C(C=C1O)C(N=C=S)=O)=C1O Chemical compound OC(C=C(C=C1O)C(N=C=S)=O)=C1O WDFYIPJFPCZXMS-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229940074391 gallic acid Drugs 0.000 claims abstract description 18
- 235000004515 gallic acid Nutrition 0.000 claims abstract description 18
- 125000003118 aryl group Chemical group 0.000 claims abstract description 16
- 241000607618 Vibrio harveyi Species 0.000 claims abstract description 15
- 241000607272 Vibrio parahaemolyticus Species 0.000 claims abstract description 15
- 238000001308 synthesis method Methods 0.000 claims abstract description 13
- 230000002378 acidificating effect Effects 0.000 claims abstract description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 30
- 230000035484 reaction time Effects 0.000 claims description 17
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims description 15
- 229940116357 potassium thiocyanate Drugs 0.000 claims description 15
- 229950009390 symclosene Drugs 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- GVCAFUYKBNBKAQ-UHFFFAOYSA-N 1,3,4-thiadiazole-2-carboxamide Chemical compound NC(=O)C1=NN=CS1 GVCAFUYKBNBKAQ-UHFFFAOYSA-N 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 125000000532 dioxanyl group Chemical group 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 229940124350 antibacterial drug Drugs 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 24
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- 238000003912 environmental pollution Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 244000052616 bacterial pathogen Species 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 241000607598 Vibrio Species 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 150000004869 1,3,4-thiadiazoles Chemical class 0.000 description 1
- KWLVWJPJKJMCSH-UHFFFAOYSA-N 2-(4-chlorophenyl)-N-{2-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]ethyl}-2-(prop-2-yn-1-yloxy)acetamide Chemical compound C1=C(OCC#C)C(OC)=CC(CCNC(=O)C(OCC#C)C=2C=CC(Cl)=CC=2)=C1 KWLVWJPJKJMCSH-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000143060 Americamysis bahia Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000005782 Fluopicolide Substances 0.000 description 1
- 206010016952 Food poisoning Diseases 0.000 description 1
- 208000019331 Foodborne disease Diseases 0.000 description 1
- 239000005804 Mandipropamid Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NQRFDNJEBWAUBL-UHFFFAOYSA-N N-[cyano(2-thienyl)methyl]-4-ethyl-2-(ethylamino)-1,3-thiazole-5-carboxamide Chemical compound S1C(NCC)=NC(CC)=C1C(=O)NC(C#N)C1=CC=CS1 NQRFDNJEBWAUBL-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 235000014220 Rhus chinensis Nutrition 0.000 description 1
- 240000003152 Rhus chinensis Species 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011482 antibacterial activity assay Methods 0.000 description 1
- 238000009360 aquaculture Methods 0.000 description 1
- 244000144974 aquaculture Species 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 231100000269 corneal opacity Toxicity 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000010227 cup method (microbiological evaluation) Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- GBOYJIHYACSLGN-UHFFFAOYSA-N fluopicolide Chemical compound ClC1=CC(C(F)(F)F)=CN=C1CNC(=O)C1=C(Cl)C=CC=C1Cl GBOYJIHYACSLGN-UHFFFAOYSA-N 0.000 description 1
- 244000078673 foodborn pathogen Species 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000009364 mariculture Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Dentistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plant Pathology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pest Control & Pesticides (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Agronomy & Crop Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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