CN113336720B - Guanidyl thiazole compound and preparation method and application thereof - Google Patents
Guanidyl thiazole compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a guanidino thiazole compound, a preparation method and application thereof. The structural formula of the guanidino thiazole compound is shown as a formula (IV). The invention designs and synthesizes a series of thiazole compounds with brand new structures by introducing lipophilic side chains at the C2 site and hydrophilic guanidyl at the C5 site of a thiazole ring, and the preparation method comprises the following steps: taking an aldehyde compound (I) and thiosemicarbazide as raw materials, carrying out condensation reaction to obtain a first-step product (II), reacting the first-step product (II) with 3-chloroacetylacetone to obtain a second-step product (III), and reacting the second-step product (III) with aminoguanidine hydrochloride to obtain a final product (IV). The guanidino thiazole compounds have antibacterial activity, especially have good antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, and can be used as antibacterial candidate compounds.
Description
The technical field is as follows:
the invention belongs to the technical field of antibiosis, relates to an antibacterial drug or an industrial bactericide, and particularly relates to a guanidino thiazole compound with a new structure, and a preparation method and application thereof.
Background art:
bacterial infection is a common disease and also a common source of material or product deterioration in industry. Seriously threatens the health of human beings and industrial production. Although several classes of bactericidal drugs or agents are currently available in medicine and industry, the self-survival ability of microorganisms has prompted some resistance to these agents with a long history of use. The discovery of new targets and bactericides of entirely new structures has become an important topic of research in this field. The 2-methyl-4-isothiazoline-3-ketone (MIT) is a broad-spectrum and high-efficiency bactericide widely used in industry, and has the structural characteristics that five elements simultaneously contain nitrogen and sulfur heteroatoms and have ketone groups on rings, and a guanidine thiazole compound with a brand-new structure is constructed through isomerization treatment and derivation, so that the bactericide with the brand-new structure can be generated.
Disclosure of Invention
The first purpose of the invention is to provide a guanidinothiazole compound or a salt thereof with novel structure and remarkable antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa.
The structural formula of the guanidino thiazole compound is shown as the formula (IV):
wherein R is selected from
Preferably, R is selected from
The second purpose of the invention is to provide a preparation method of the guanidinothiazole compound with the structural formula shown in the formula (IV), the preparation method takes an aldehyde compound (I) and thiosemicarbazide as raw materials, a first step product (II) is obtained through condensation reaction, the first step product (II) reacts with 3-chloroacetylacetone to obtain a second step product (III), the second step product (III) reacts with aminoguanidine hydrochloride to obtain a final product (IV), and the synthesis reaction formula of the guanidinothiazole compound is as follows:
wherein R is selected from
Preferably, R is selected from
Further preferably, the method comprises the following steps: the first step is as follows: taking an aldehyde compound (I) and thiosemicarbazide as raw materials, and carrying out condensation reaction to obtain a first-step product (II); the second step is that: adding the product (II) in the first step, 3-chloroacetoacetone and ethanol into a reactor, and stirring for reaction to obtain a product (III) in the second step; the third step: and (3) adding the product (III) obtained in the second step, aminoguanidine hydrochloride, lithium chloride and ethanol into a reactor, and stirring for reaction to obtain the guanidinothiazole compound with the structural formula shown in the formula (IV).
The total yield of the preparation method can be 32-50%.
Preferably, the mass ratio of the aldehyde compound to the thiosemicarbazide in the first step is 1: 1; the mass ratio of the first step product (II) to the 3-chloroacetoacetone in the second step is 1: 1.2; the mass ratio of the second-step product (III), aminoguanidine hydrochloride and lithium chloride is 1:1.3: 0.4; the stirring reaction in the second step and the third step is a stirring reaction at 70 ℃.
Preferably, the aldehyde compound is selected from 4- (p-methoxyphenyl) benzaldehyde, 4- (p-trifluoromethylphenyl) benzaldehyde, 4- (p-fluorophenyl) benzaldehyde, 4- (pyrrolidin-1-yl) benzaldehyde, 2-fluorobenzaldehyde and 2-hydroxybenzaldehyde.
The third purpose of the invention is to provide the application of the guanidino thiazole compound with the structural formula shown as the formula (IV) or the salt thereof in preparing antibacterial agents.
Preferably, the antibacterial agent is an anti-staphylococcus aureus, anti-escherichia coli and/or anti-pseudomonas aeruginosa agent.
The fourth object of the present invention is to provide an antibacterial agent containing the above-mentioned guanidinothiazole compound of the formula (IV) or a salt thereof as an active ingredient.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, 2-methyl-4-isothiazoline-3-ketone (MIT) is modified according to the modern medicine design theory and organic synthesis experimental technology, a series of guanidino thiazole compounds with brand new structures are designed and synthesized, and antibacterial activity research is carried out. The research result shows that: the guanidinothiazole compound with the novel structure has obvious antibacterial activity on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa and has great application value in treating diseases caused by bacterial infection or industrial microorganism hazards. Some target objects have obvious antibacterial effects on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa, are superior to a control medicament 2-methyl-4-isothiazoline-3-ketone (MIT), and can be used as antibacterial candidate compounds for research.
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1
Preparation of 2- (2- (4- (p-methoxyphenyl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVa):
adding 5mmol of 4- (p-methoxyphenyl) benzaldehyde, 5mmol of thiosemicarbazide and 30mL of ethanol into a 100mL flask, stirring and reacting at 70 ℃ for 6 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a first-step product IIa, namely 1- ((thioureidoimino) methyl) -4- (p-methoxyphenyl) benzene, wherein the yield is 90%.
2mmol of the first-step product IIa, 2.4mmol of 3-chloroacetoacetone and 20mL of ethanol are added into a 100mL flask, the mixture is stirred and reacted for 3 hours at 70 ℃, the reaction is finished, the mixture is filtered, filter residues are collected and air-dried to obtain a second-step product IIIa, namely 2- (2- (4- (p-methoxyphenyl) benzylidene) hydrazino) -4-methyl-5-carbonyl) -thiazole, and the yield is 60%.
Adding 1mmol of the second step product IIIa, 1.3mmol of aminoguanidine hydrochloride, 0.4mmol of lithium chloride and 50mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 24 hours, after the reaction is finished, performing reduced pressure spin drying, and purifying by silica gel column chromatography (300 meshes 400, the volume ratio of the eluent methanol to dichloromethane is 1: 5) to finally obtain the target product (IVa), wherein the yield is 60 percent and the total yield is 32 percent.1H NMR(400MHz,DMSO)δ12.33 and 11.81(1H,-NH-,exchanged by D2O),10.68(s,1H,-NH-),8.10(s,1H,-CH＝),7.74–7.66(m,6H,phenyl),7.43(s,3H,-NH2and＝NH),7.05(d,J＝8.6Hz,2H,phenyl),3.82(s,3H,-CH3),2.43(s,3H,-CH3),2.33(s,3H,-CH3)。ESI-MS m/z:422.1[M+H]+。
Example 2
Preparation of 2- (2- (4- (p-trifluoromethylphenyl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVb):
adding 5mmol of 4- (p-trifluoromethylphenyl) benzaldehyde, 5mmol of thiosemicarbazide and 30mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 6 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a first-step product IIb, namely 1- ((thioureidoimino) methyl) -4- (p-trifluoromethylphenyl) benzene, wherein the yield is 90%.
Adding 2mmol of the first step product IIb, 2.4mmol of 3-chloroacetylacetone and 20mL of ethanol into a 100mL flask, stirring and reacting for 3 hours at 70 ℃, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a second step product IIIb, namely 2- (2- (4- (p-trifluoromethylphenyl) benzylidene) hydrazino) -4-methyl-5-carbonyl) -thiazole with the yield of 70%.
Adding 1mmol of the second step product IIIb, 1.3mmol of aminoguanidine hydrochloride, 0.4mmol of lithium chloride and 50mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 24 hours, after the reaction is finished, performing reduced pressure spin drying, and purifying by silica gel column chromatography (300 meshes 400, the volume ratio of the eluent methanol to dichloromethane is 1: 5) to finally obtain the target product (IVb), wherein the yield is 50% and the total yield is 32%.1H NMR(400MHz,DMSO)δ12.33 and 11.81(1H,-NH-),10.89(s,1H,-NH-),8.14(s,1H,-CH＝),7.96(d,J＝8.2Hz,2H,phenyl),7.86–7.83(m,6H,phenyl),7.49(s,3H,-NH2and＝NH),2.43(s,3H,-CH3),2.35(s,3H,-CH3)。ESI-MS m/z:460.1[M+H]+。
Example 3
Preparation of 2- (2- (4- (p-fluorophenyl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVc) procedure:
adding 5mmol of 4- (p-fluorophenyl) benzaldehyde, 5mmol of thiosemicarbazide and 30mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 6 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a first-step product IIc, namely 1- ((thioureidoimino) methyl) -4- (p-fluorophenyl) benzene, with the yield of 90%.
Adding 2mmol of the first-step product IIc, 2.4mmol of 3-chloroacetoacetone and 20mL of ethanol into a 100mL flask, stirring at 70 ℃ for reacting for 3 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a second-step product IIIc, namely 2- (2- (4- (p-fluorophenyl) benzylidene) hydrazino) -4-methyl-5-carbonyl) -thiazole with the yield of 80%.
Adding 1mmol of the second step product IIIc, 1.3mmol of aminoguanidine hydrochloride, 0.4mmol of lithium chloride and 50mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 24 hours, after the reaction is finished, performing reduced pressure spin drying, and purifying by silica gel column chromatography (300 meshes 400, the volume ratio of the eluent methanol to dichloromethane is 1: 5) to finally obtain the target product (IVc), wherein the yield is 50% and the total yield is 36%.1H NMR(400MHz,DMSO)δ12.33 and 11.81(1H,-NH-,exchanged by D2O),10.88(s,1H,-NH-),8.13(s,1H,-CH＝),7.79–7.73(m,6H,phenyl),7.49(s,3H,-NH2and＝NH),7.33(t,J＝8.8Hz,2H,phenyl),2.43(s,3H,-CH3),2.35(s,3H,-CH3)。ESI-MS m/z:410.1[M+H]+。
Example 4
Preparation of 2- (2- (4- (pyrrolidin-1-yl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVd):
adding 5mmol of 4- (pyrrolidine-1-yl) benzaldehyde, 5mmol of thiosemicarbazide and 30mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 6 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a first-step product IId, namely 1- ((thioureidoimino) methyl) -4- (pyrrolidine-1-yl) benzene, with the yield of 90%.
Adding 2mmol of the first step product IId, 2.4mmol of 3-chloroacetylacetone and 20mL of ethanol into a 100mL flask, stirring and reacting for 3 hours at 70 ℃, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a second step product IIId, namely 2- (2- (4- (pyrrolidine-1-yl) benzylidene) hydrazino) -4-methyl-5-carbonyl) -thiazole, with the yield of 60%.
Adding 1mmol of the second step product IIId, 1.3mmol of aminoguanidine hydrochloride, 0.4mmol of lithium chloride and 50mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 24 hours, after the reaction is finished, performing reduced pressure spin drying, and purifying by silica gel column chromatography (300 meshes 400, the volume ratio of the eluent methanol to dichloromethane is 1: 5) to finally obtain the target product (IVd), wherein the yield is 60 percent and the total yield is 32 percent.1H NMR(400MHz,DMSO)δ11.32((s,1H,-NH-),10.81(s,1H,-NH-),7.96(s,1H,-CH＝),7.50–7.40(m,5H,phenyl,-NH2and＝NH),6.58(d,J＝8.6Hz,2H,phenyl),3.29(s,4H,pyrrolidine),2.41(s,3H,-CH3),2.33(s,3H,-CH3),1.98(s,4H,pyrrolidine)。ESI-MS m/z:385.1[M+H]+。
Example 5
Preparation of 2- (2- (2-fluorobenzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVe):
adding 5mmol of 2-fluorobenzaldehyde, 5mmol of thiosemicarbazide and 30mL of ethanol into a 100mL flask, stirring at 70 ℃ for reacting for 6 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a first-step product IIe, namely 1- ((thioureidoimino) methyl) -2-fluorobenzene, wherein the yield is 90%.
Adding 2mmol of the first step product IIe, 2.4mmol of 3-chloroacetylacetone and 20mL of ethanol into a 100mL flask, stirring at 70 ℃ for reacting for 3 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a second step product IIIe, namely 2- (2- (2-fluoro benzylidene) hydrazino) -4-methyl-5-carbonyl) -thiazole, with the yield of 80%.
Adding 1mmol of the second step product IIIe, 1.3mmol of aminoguanidine hydrochloride, 0.4mmol of lithium chloride and 50mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 24 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to finally obtain the target product (IVe), wherein the yield is 70% and the total yield is 50%.1H NMR(400MHz,DMSO)δ11.05((s,1H,-NH-),10.81(1H,-NH-,exchanged by D2O),8.28(s,1H,-CH＝),7.89(t,J＝7.6Hz,1H,phenyl),7.55–7.44(m,4H,phenyl,-NH2and＝NH),7.29(t,J＝8.0Hz,2H,phenyl),2.43(s,3H,-CH3),2.35(s,3H,-CH3)。ESI-MS m/z:334.1[M+H]+。
Example 6
Preparation of 2- (2- (2-hydroxybenzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVf):
adding 5mmol of 2-hydroxybenzaldehyde, 5mmol of thiosemicarbazide and 30mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 6 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a first-step product IIf, namely 5- ((thioureidoimino) methyl) -2-hydroxybenzene, wherein the yield is 90%.
Adding 2mmol of the first step product IIf, 2.4mmol of 3-chloroacetylacetone and 20mL of ethanol into a 100mL flask, stirring at 70 ℃ for reacting for 3 hours, filtering after the reaction is finished, collecting filter residues, and air-drying to obtain a second step product IIIf, namely 2- (2- (2-hydroxybenzylidene) hydrazino) -4-methyl-5-carbonyl) -thiazole, wherein the yield is 90%.
Adding 1mmol of the second step product IIIf, 1.3mmol of aminoguanidine hydrochloride, 0.4mmol of lithium chloride and 50mL of ethanol into a 100mL flask, stirring at 70 ℃ for reaction for 24 hours, after the reaction is finished, performing reduced pressure spin drying, and purifying by silica gel column chromatography (300 meshes 400, the volume ratio of eluent methanol to dichloromethane is 1: 5) to finally obtain the target product (IVf), wherein the yield is 60 percent and the total yield is 49 percent.1H NMR(400MHz,DMSO)δ11.40((s,1H,-NH-),10.81(1H,-NH-,exchanged by D2O),10.45(s,1H,-OH),8.40(s,1H,-CH＝),7.70–7.61(m,4H,phenyl,-NH2and＝NH),7.23(t,J＝7.5Hz,1H,phenyl),6.95(d,J＝8.1Hz,1H,phenyl),6.88(t,J＝7.3Hz,1H,phenyl),2.40(s,3H,-CH3),2.36(s,3H,-CH3)。ESI-MS m/z:332.1[M+H]+。
Example 7
Antibacterial activity test of target compound:
MIC of the target compound (guanidinothiazole compound prepared in examples 1-6) was determined by microdilution using 2-methyl-4-isothiazolin-3-one (MIT) as a control agent, and antibacterial activity of the target compound against Staphylococcus aureus (Staphylococcus aureus ATCC 6538P), Escherichia coli (Escherichia coli ATCC 8739), and Pseudomonas aeruginosa (Pseudomonas aeruginosa ATCC 9027) was determined.
The microdilution method comprises the following experimental steps:
to column 1 of a 96-well plate, 200. mu.L of a test sample (2-methyl-4-isothiazolin-3-one and a guanidinothiazole compound prepared in examples 1 to 6) at a concentration of 256. mu.g/mL was added, and to columns 2 to 12, 100. mu.L of MH broth was added, and then 100. mu.L was taken from column 1 and added to column 2, 100. mu.L was taken from column 2 and added to column 3, and so on, and finally 100. mu.L was taken from column 10 and added to column 11, and then 100. mu.L of the excess liquid was taken and discarded. Taking 100 μ L of 106Adding cfu/mL bacterial solution into each hole of the 1 st to 11 th rows, and taking 100 mu L bacterial solution with the concentration of 106Adding cfu/mL bacterial liquid into the first four holes of the 12 th row, adding 100 mu L MH broth into the second four holes of the 12 th row, wherein the volume of each hole is 200 mu L, the concentration of samples to be detected in the 1 st row to the 11 th row is 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125 mu g/mL in sequence, the first four holes of the 12 th row are added with bacteria and not added with medicine (positive growth control), and the second four holes of the 12 th row are added with no bacteria and not added with medicine (sterile control). Three replicates were made for each sample tested. After culturing the 96-well plate in an oven at 37 ℃ for 24 hours, OD was measured with a microplate reader600Value, OD600The concentration of wells with values close to the sterile control is the minimum inhibitory concentration MIC.
The results show that:
(1) MICs of 2-methyl-4-isothiazolin-3-one (MIT) to staphylococcus aureus, escherichia coli and pseudomonas aeruginosa were 16. mu.g/mL, 16. mu.g/mL and 16. mu.g/mL, respectively.
(2) The MICs of the 2- (2- (4- (p-methoxyphenyl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVa) to staphylococcus aureus, escherichia coli and pseudomonas aeruginosa are respectively 8 mug/mL, 16 mug/mL and 32 mug/mL, the bacteriostasis to the escherichia coli is equivalent to that of a control medicament 2-methyl-4-isothiazolin-3-ketone (MIT), and the bacteriostasis to the staphylococcus aureus is superior to that of the control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(3) The MICs of 2- (2- (4- (p-trifluoromethylphenyl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVb) on staphylococcus aureus, escherichia coli and pseudomonas aeruginosa are 16 mug/mL, 32 mug/mL and 64 mug/mL respectively, and the bacteriostatic action on the staphylococcus aureus is equivalent to that of a control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(4) The MICs of the 2- (2- (4- (p-fluorophenyl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVc) to staphylococcus aureus, escherichia coli and pseudomonas aeruginosa are respectively 8 mug/mL, 16 mug/mL and 64 mug/mL, the bacteriostasis to escherichia coli is equivalent to that of a control medicament 2-methyl-4-isothiazolin-3-ketone (MIT), and the bacteriostasis to staphylococcus aureus is superior to that of the control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(5) The MICs of the 2- (2- (4- (pyrrolidine-1-yl) benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVd) to staphylococcus aureus, escherichia coli and pseudomonas aeruginosa are respectively 8 mug/mL, 8 mug/mL and 8 mug/mL, and the bacteriostatic action to the staphylococcus aureus, the escherichia coli and the pseudomonas aeruginosa is superior to that of a control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(6) The MICs of 2- (2- (2-fluoro benzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVe) to staphylococcus aureus, escherichia coli and pseudomonas aeruginosa are 16 mug/mL, 32 mug/mL and 64 mug/mL respectively, and the bacteriostatic action to the staphylococcus aureus is equivalent to that of a control medicament 2-methyl-4-isothiazolin-3-ketone (MIT).
(7) The MICs of the 2- (2- (2-hydroxybenzylidene) hydrazino) -4-methyl-5- (1- (guanidinoimino) ethyl) -thiazole (IVf) to staphylococcus aureus, escherichia coli and pseudomonas aeruginosa are respectively 2 mug/mL, 8 mug/mL and 16 mug/mL, the bacteriostasis to the pseudomonas aeruginosa is equivalent to that of a control medicament 2-methyl-4-isothiazolin-3-one (MIT), and the bacteriostasis to the staphylococcus aureus and the escherichia coli is superior to that of the control medicament 2-methyl-4-isothiazolin-3-one (MIT).
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the 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 these modifications and adaptations should be considered within the scope of the invention.
Claims (8)
1. A guanidinothiazole compound or a salt thereof, the guanidinothiazole compound having a structural formula as shown in formula (IV):
r is selected from
2. A process for preparing a guanidinothiazole compound according to claim 1, wherein the aldehyde compound (I) and thiosemicarbazide are used as raw materials, and condensation reaction is carried out to obtain a first step product (II), the first step product (II) is reacted with 3-chloroacetoacetone to obtain a second step product (III), and the second step product (III) is reacted with aminoguanidine hydrochloride to obtain a final product, the guanidinothiazole compound having the following synthesis reaction formula:
wherein R is selected from
3. The method of claim 2, comprising the steps of: the first step is as follows: taking an aldehyde compound (I) and thiosemicarbazide as raw materials, and carrying out condensation reaction to obtain a first-step product (II); the second step is that: adding the product (II) in the first step, 3-chloroacetoacetone and ethanol into a reactor, and stirring for reaction to obtain a product (III) in the second step; the third step: and (3) adding the product (III) in the second step, aminoguanidine hydrochloride, lithium chloride and ethanol into a reactor, and stirring for reaction to obtain the guanidinothiazole compound.
4. The process according to claim 3, characterized in that the mass ratio of the aldehyde compound and the thiosemicarbazide in the first step is 1: 1; the mass ratio of the first step product (II) to the 3-chloroacetoacetone in the second step is 1: 1.2; the mass ratio of the second-step product (III), aminoguanidine hydrochloride and lithium chloride is 1:1.3: 0.4; the stirring reaction in the second step and the third step is a stirring reaction at 70 ℃.
5. Use of the guanidinothiazole compound of claim 1 or a salt thereof for the preparation of an antibacterial agent.
6. The use according to claim 5, wherein the antibacterial agent is an anti-Staphylococcus aureus, Escherichia coli and/or Pseudomonas aeruginosa agent.
7. An antibacterial agent characterized by containing the guanidinothiazole compound of claim 1 or a salt thereof as an active ingredient.
8. The antibacterial agent according to claim 7, wherein the antibacterial agent is an antibacterial agent against Staphylococcus aureus, Escherichia coli and/or Pseudomonas aeruginosa.
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| 《Novel molecular discovery of promising amidine-based thiazole analogues as potent dual Matrix Metalloproteinase-2 and 9 inhibitors: Anticancer activity data with prominent cell cycle arrest and DNA fragmentation analysis effects》;Abdelsattar M. Omar等;《Bioorganic Chemistry》;20200602;第101卷;摘要，表4化合物4a-e * |
| 《The rational design, synthesis, and antimicrobial investigation of 2-Amino-4-Methylthiazole analogues inhibitors of GlcN-6-P synthase》;Abdelsattar M. Omar等;《Bioorganic Chemistry》;20200321;第99卷;Scheme 1中化合物4a-e；表1-3；摘要 * |
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