CN116425698A - Methylthiazole compound and preparation method and application thereof - Google Patents
Methylthiazole compound and preparation method and application thereof Download PDFInfo
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- CN116425698A CN116425698A CN202310705970.0A CN202310705970A CN116425698A CN 116425698 A CN116425698 A CN 116425698A CN 202310705970 A CN202310705970 A CN 202310705970A CN 116425698 A CN116425698 A CN 116425698A
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- -1 Methylthiazole compound Chemical class 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 25
- 241000588724 Escherichia coli Species 0.000 claims abstract description 15
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 14
- VVIUKYOXYSWCOF-UHFFFAOYSA-N (4-acetylphenyl)thiourea Chemical compound CC(=O)C1=CC=C(NC(N)=S)C=C1 VVIUKYOXYSWCOF-UHFFFAOYSA-N 0.000 claims abstract description 11
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 claims abstract description 11
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006846 Hantzsch Thiazole synthesis reaction Methods 0.000 claims abstract description 3
- 239000012467 final product Substances 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 239000003242 anti bacterial agent Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 230000000941 anti-staphylcoccal effect Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000002262 Schiff base Substances 0.000 claims 1
- 150000004753 Schiff bases Chemical class 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 19
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 14
- VZWOXDYRBDIHMA-UHFFFAOYSA-N 2-methyl-1,3-thiazole Chemical class CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000013461 design Methods 0.000 abstract description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 abstract 1
- 229940100555 2-methyl-4-isothiazolin-3-one Drugs 0.000 description 16
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 16
- BEGLCMHJXHIJLR-UHFFFAOYSA-N methylisothiazolinone Chemical compound CN1SC=CC1=O BEGLCMHJXHIJLR-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 8
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000003899 bactericide agent Substances 0.000 description 5
- ZSSUKQHPALINBY-UHFFFAOYSA-N Secamine Natural products CCC1=CCCN(CCc2c3C(CCC(C(=O)OC)(c4[nH]c5ccccc5c4CCN6CCC=C(CC)C6)n3c7ccccc27)C(=O)OC)C1 ZSSUKQHPALINBY-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- AGQLOTJUTCKLOE-UHFFFAOYSA-N 2-chloro-1-(4-fluorophenyl)propan-1-one Chemical compound CC(Cl)C(=O)C1=CC=C(F)C=C1 AGQLOTJUTCKLOE-UHFFFAOYSA-N 0.000 description 3
- GIHSMBINQBEFLD-UHFFFAOYSA-N 2-chloro-1-[4-(2-methylpropyl)phenyl]propan-1-one Chemical compound CC(C)CC1=CC=C(C(=O)C(C)Cl)C=C1 GIHSMBINQBEFLD-UHFFFAOYSA-N 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- AVMPEHALQVCQQQ-UHFFFAOYSA-N 2-chloro-1-(4-methylphenyl)propan-1-one Chemical compound CC(Cl)C(=O)C1=CC=C(C)C=C1 AVMPEHALQVCQQQ-UHFFFAOYSA-N 0.000 description 2
- AXCPQHPNAZONTH-UHFFFAOYSA-N 2-chloro-1-phenylpropan-1-one Chemical compound CC(Cl)C(=O)C1=CC=CC=C1 AXCPQHPNAZONTH-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a methylthiazole compound and a preparation method and application thereof. The structural formula of the methylthiazole compound is shown as a formula (III). The invention designs and synthesizes a series of methylthiazole compounds with brand new structures by introducing hydrophilic aminoguanidine at the C2 position and lipophilic side chains at the C4 position of a thiazole ring, and the preparation method comprises the following steps: taking 1- (4-acetylphenyl) thiourea and 2-chloro-1-substituent propan-1-one (I) as raw materials, and carrying out Hantzsch thiazole synthesis reaction to obtain a first-step product (II), wherein the first-step product (II) reacts with aminoguanidine hydrochloride to obtain a final product (III). The methylthiazole compound has antibacterial activity, especially has good antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, and can be used as an antibacterial candidate compound.
Description
Technical Field
The invention belongs to the technical field of antibiosis, relates to an antibacterial drug or an industrial bactericide, and in particular relates to a methylthiazole compound with a novel structure, and a preparation method and application thereof.
Background
Bacterial infection is a common disease and is also a common source of deterioration of materials or products in industry. Severely threatens human health and industrial production. Although several classes of bactericides or agents are currently available both pharmaceutically and industrially, the self-survival ability of microorganisms has prompted some resistance to these agents with a long history of their use. The discovery of new targets and bactericides of new structures has become an important topic of research in this area. The 2-methyl-4-isothiazolin-3-ketone (MIT) is a broad-spectrum and high-efficiency bactericide widely used in industry, and is structurally characterized in that five-membered contains nitrogen and sulfur heteroatoms and has ketone groups on the ring, and a methylthiazole compound with a brand new structure is constructed through isomerism treatment and derivative, so that the bactericide with the brand new structure is likely to be generated.
Disclosure of Invention
The first object of the invention is to provide a methylthiazole compound or a salt thereof which has a novel structure and obvious antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa.
The structural formula of the methylthiazole compound is shown as a formula (III):
Preferably, R is selected from
Or->
。
The second purpose of the invention is to provide a preparation method of the methylthiazole compound shown in the structural formula (III), wherein 1- (4-acetylphenyl) thiourea and 2-chloro-1-substituent propan-1-one (I) are used as raw materials, a first-step product (I) is obtained through a Hantzsch thiazole synthesis reaction, the first-step product (I) reacts with aminoguanidine hydrochloride to prepare a final product (III), and the synthesis reaction formula of the methylthiazole compound is as follows:
wherein R is selected from
、/>
、/>
Or->
。
Preferably, R is selected from
Or->
。
Further preferably, the method comprises the following steps: the first step: adding 1- (4-acetylphenyl) thiourea, 2-chloro-1-substituent propan-1-one (I) and ethanol into a reactor, heating and stirring for reaction to obtain a first-step product (II); and a second step of: adding the product (I), aminoguanidine hydrochloride, lithium chloride and ethanol in the first step into a reactor, and heating and stirring to react to obtain the methylthiazole compound shown in the structural formula (III).
The total yield of the preparation method disclosed by the invention can be 49% -72%.
Preferably, the ratio of the amounts of the substances of the 1- (4-acetylphenyl) thiourea and the 2-chloro-1-substituent propan-1-one (I) described in the first step is 1:1.2; the ratio of the amounts of the product (II) of the first step, aminoguanidine hydrochloride and lithium chloride in the second step is 1:1.3:0.4; the heating and stirring reaction is carried out at 70 ℃.
Preferably, the 2-chloro-1-substituent propan-1-one (I) is selected from 2-chloro-1- (4-fluorophenyl) propan-1-one or 2-chloro-1- (4-isobutylphenyl) propan-1-one.
The third object of the present invention is to provide an application of the methylthiazole compound having the structural formula shown in formula (III) or a salt thereof in the preparation of an antibacterial agent.
Preferably, the antibacterial agent is an anti-staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa agent.
A fourth object of the present invention is to provide an antibacterial agent comprising the methylthiazole compound having the structural formula shown in formula (III) or a salt thereof as an active ingredient.
Compared with the prior art, the invention has the following beneficial effects:
according to modern medicine design theory and organic synthesis experimental technology, 2-methyl-4-isothiazolin-3-ketone (MIT) is modified, a series of methylthiazole compounds with brand new structures are designed and synthesized, and antibacterial activity research is carried out. The research results show that: the methylthiazole compound with novel structure has remarkable antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, and has great application value in treating bacterial infection diseases or industrial microorganism harm. Some target substances have remarkable antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, are superior to a control medicament 2-methyl-4-isothiazolin-3-one (MIT), and can be used as antibacterial candidate compounds for research.
Detailed Description
The following examples are further illustrative of the invention and are not intended to be limiting thereof.
Example 1
Preparation procedure of 2- ((4- (1- (guanidinoimino) ethyl) phenyl) amino) -4-phenyl-5-methyl-thiazole (IIIa):
2 mmol of the first-step product IIa, 2.6 mmol of aminoguanidine hydrochloride, 0.8 mmol of lithium chloride and 50 mL ethanol are added into a 100 mL flask, stirred and reacted for 24 hours at 70 ℃, after the reaction is finished, the mixture is dried by spin-drying under reduced pressure, and silica gel column chromatography (300-400 meshes, the eluent is methanol and dichloromethane in a volume ratio of 1:5) is purified, so that the target product (IIIa) is finally obtained, the yield is 80%, and the total yield is 64%. 1 H NMR (400 MHz, DMSO-d 6 , δ): 10.97 (s, 1H, guanidine), 10.22 (s, 1H, sec amine), 7.84 (m, 5H, guanidine and 1-benzene), 7.75 (d, J = 7.5 Hz, 2H, 1-benzene), 7.53 (m, 3H,1-benzene), 7.26 (d, J = 7.5 Hz, 2H, 1-benzene), 2.39 (s, 3H, methyl), 2.32 (s, 3H, methyl)。HRMS (ESI) m/z: [M+H] + calcd for C 19 H 21 N 6 S, 365.1548; found 365.1560。
Example 2
Preparation procedure of 2- ((4- (1- (guanidinoimino) ethyl) phenyl) amino) -4- (4-methylphenyl) -5-methyl-thiazole (IIIb):
Adding 2 mmol of the first-step product IIb, 2.6 mmol of aminoguanidine hydrochloride, 0.8 mmol of lithium chloride and 50 mL ethanol into a 100 mL flask, stirring and reacting for 24 hours at 70 ℃, performing vacuum spin-drying after the reaction is finished, purifying by silica gel column chromatography (300-400 meshes, eluting agent is methanol: dichloromethane with volume ratio of 1:5), finally obtaining the target product (IIIb), the yield is 80%,the total yield was 72%. 1 H NMR (400 MHz, DMSO-d 6 , δ): 10.97 (s, 1H, guanidine), 10.22 (s, 1H, sec amine), 7.84 (s, 3H, guanidine), 7.75 (d, J = 7.5 Hz, 2H, 1-benzene), 7.59 (d, J = 7.5 Hz, 2H, 1-benzene), 7.26 (d, J = 7.5 Hz, 2H, 1-benzene), 7.15 (d, J = 7.5 Hz, 2H, 1-benzene), 2.39 (s, 3H, methyl), 2.34 (s, 3H, methyl), 2.32 (s, 3H, methyl)。HRMS (ESI) m/z: [M+H] + calcd for C 20 H 23 N 6 S, 379.1704; found 379.1724。
Example 3
Preparation procedure of 2- ((4- (1- (guanidinoimino) ethyl) phenyl) amino) -4- (4-fluorophenyl) -5-methyl-thiazole (IIIc):
2 mmol of the first-step product IIc, 2.6 mmol of aminoguanidine hydrochloride, 0.8 mmol of lithium chloride and 50 mL ethanol are added into a 100 mL flask, the mixture is stirred and reacted for 24 hours at 70 ℃, after the reaction is finished, the mixture is dried by spin-drying under reduced pressure, and silica gel column chromatography (300-400 meshes, the eluent is methanol and dichloromethane in a volume ratio of 1:5) is performed, so that the target product (IIIc) is finally obtained, the yield is 80%, and the total yield is 56%. 1 H NMR (400 MHz, DMSO-d 6 , δ): 10.97 (s, 1H, guanidine), 10.22 (s, 1H, sec amine), 7.84 (m, 5H, guanidine and 1-benzene), 7.75 (d, J = 7.5 Hz, 2H, 1-benzene), 7.31 (m, 4H, 1-benzene), 2.39 (s, 3H, methyl), 2.32 (s, 3H, methyl)。HRMS (ESI) m/z: [M+H] + calcd for C 19 H 20 FN 6 S, 383.1454; found 383.1466。
Example 4
Preparation procedure of 2- ((4- (1- (guanidinoimino) ethyl) phenyl) amino) -4- (4-isobutylphenyl) -5-methyl-thiazole (IIId):
2 mmol of the first-step product IId, 2.6 mmol of aminoguanidine hydrochloride, 0.8 mmol of lithium chloride and 50 mL ethanol are added into a 100 mL flask, the mixture is stirred and reacted for 24 hours at 70 ℃, after the reaction is finished, the mixture is dried by spin-drying under reduced pressure, and silica gel column chromatography (300-400 meshes, the eluent is methanol and dichloromethane in a volume ratio of 1:5) is performed, so that the target product (IIId) is finally obtained, and the yield is 70% and the total yield is 49%. 1 H NMR (400 MHz, DMSO-d 6 , δ): 10.97 (s, 1H, guanidine), 10.22 (s, 1H, sec amine), 7.84 (s, 3H, guanidine), 7.75 (d, J = 7.5 Hz, 2H, 1-benzene), 7.64 (d, J = 7.5 Hz, 2H, 1-benzene), 7.32 (d, J = 7.5 Hz, 2H, 1-benzene), 7.26 (d, J = 7.5 Hz, 2H, 1-benzene), 2.43 (s, 2H, methylene), 2.39 (s, 3H, methyl), 2.32 (s, 3H, methyl), 1.82 (m, 1H, methine), 0.87 (s, 6H,methyl)。HRMS (ESI) m/z: [M+H] + calcd for C 23 H 29 N 6 S, 421.2174; found 421.2185。
Example 5
Antibacterial Activity test of the target Compound:
2-methyl-4-isothiazolin-3-one (MIT) is used as a control reagent, MIC of the target substance is measured by a micro dilution method, and the concentration of the target compound (methylthiazoles prepared in examples 1-4) on staphylococcus aureus is measuredStaphylococcus aureus ATCC 6538P and Escherichia coliEscherichia coli ATCC 8739), pseudomonas aeruginosaPseudomonas aeruginosaATCC 9027).
The experimental procedure of the microdilution method is as follows:
200. Mu.L of concentrate was added to column 1 of a 96-well plateThe sample to be tested (2-methyl-4-isothiazolin-3-one and methylthiazoles prepared in examples 1-4) was prepared at a degree of 256. Mu.g/mL, 100. Mu.L of MH broth was added to each of columns 2-12, 100. Mu.L was added to mix from column 1, 100. Mu.L was added to mix from column 2, 3 rd, and so forth, and finally 100. Mu.L was added to mix from column 10, and 100. Mu.L of excess liquid was removed for disposal. 100 mu L of the mixture is taken to have the concentration of 10 6 Adding cfu/mL bacterial liquid into each well of columns 1-11, taking 100 mu L of bacterial liquid with concentration of 10 6 cfu/mL of bacterial liquid is added into four holes before the 12 th column, 100 mu L of MH broth is added into four holes after the 12 th column, the final volume of each hole is 200 mu L, the concentrations of samples to be detected in the 1 st to 11 th columns are 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.12 mu g/mL in sequence, the four holes before the 12 th column are no-dosing (positive growth control), and the four holes after the 12 th column are no-dosing (sterile control). Three replicates were made for each sample tested. After culturing the 96-well plate in a 37 ℃ oven for 24 hours, measuring OD by using an enzyme-labeled instrument 600 Value, OD 600 The concentration of wells with values close to the sterile control was the minimum inhibitory concentration MIC.
The results show that:
(1) MIC of 2-methyl-4-isothiazolin-3-one (MIT) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa was 16 mug/mL, 16 mug/mL and 16 mug/mL respectively.
(2) 2- ((4- (1- (guanidyl imino) ethyl) phenyl) amino) -4-phenyl-5-methyl-thiazole (IIIa) has the MIC of 8 mug/mL, 32 mug/mL and 64 mug/mL on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa respectively, and the antibacterial effect on staphylococcus aureus is superior to that of a control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(3) 2- ((4- (1- (guanidyl imino) ethyl) phenyl) amino) -4- (4-methylphenyl) -5-methyl-thiazole (IIIb) has the MIC of 8 mug/mL, 16 mug/mL and 64 mug/mL on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa respectively, the antibacterial effect on staphylococcus aureus is superior to that of a control medicament 2-methyl-4-isothiazolin-3-one (MIT), and the antibacterial effect on escherichia coli is equivalent to that of the control medicament 2-methyl-4-isothiazolin-3-one (MIT).
(4) The MIC of 2- ((4- (1- (guanidyl imino) ethyl) phenyl) amino) -4- (4-fluorophenyl) -5-methyl-thiazole (IIIc) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is 0.5 mug/mL, 0.5 mug/mL and the antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is better than that of the control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(5) The MIC of 2- ((4- (1- (guanidyl imino) ethyl) phenyl) amino) -4- (4-isobutylphenyl) -5-methyl-thiazole (IIId) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is 0.5 mug/mL, 0.5 mug/mL and 1 mug/mL respectively, and the antibacterial effect on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa is better than that of the control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that the above-mentioned preferred embodiment should not be construed as limiting the invention, and the scope of the invention should be defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and such modifications and adaptations are intended to be comprehended within the scope of the invention.
Claims (10)
1. The structural formula of the methylthiazole compound is shown as formula (III):
2. The methylthiazole compound or a salt thereof according to claim 1, wherein R is selected from the group consisting of
Or->
。
3. The method for preparing the methylthiazole compound or the salt thereof according to claim 1, which is characterized in that 1- (4-acetylphenyl) thiourea and 2-chloro-1-substituent propan-1-one (I) are taken as raw materials, a first step of product (II) is obtained through Hantzsch thiazole synthesis reaction, the first step of product (II) reacts with aminoguanidine hydrochloride through Schiff base to prepare a final product methylthiazole compound (III), and the synthesis reaction formula of the methylthiazole compound is as follows:
4. The process of claim 3 wherein R is selected from the group consisting of
Or (b)
。
5. A method of preparation according to claim 3, comprising the steps of: the first step: adding 1- (4-acetylphenyl) thiourea, 2-chloro-1-substituent propan-1-one (I) and ethanol into a reactor, heating and stirring for reaction to obtain a first-step product (II); and a second step of: adding the product (II), aminoguanidine hydrochloride, lithium chloride and ethanol in the first step into a reactor, and heating and stirring to react to obtain the methylthiazole compound.
6. The process according to claim 5, wherein the ratio of the amounts of the substances of 1- (4-acetylphenyl) thiourea and 2-chloro-1-substituted propan-1-one (I) in the first step is 1:1.2; the ratio of the amounts of the product (II) of the first step, aminoguanidine hydrochloride and lithium chloride in the second step is 1:1.3:0.4; the heating and stirring reaction is carried out at 70 ℃.
7. Use of a methylthiazole compound or a salt thereof as claimed in claim 1 in the preparation of an antibacterial agent.
8. The use according to claim 7, wherein the antibacterial agent is an anti-staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa agent.
9. An antibacterial agent comprising the methylthiazole compound of claim 1 or a salt thereof as an active ingredient.
10. The antibacterial agent of claim 9, wherein the antibacterial agent is an anti-staphylococcus aureus, escherichia coli and/or pseudomonas aeruginosa agent.
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