CN107935950B - Triazole Schiff base compound and preparation method and application thereof - Google Patents
Triazole Schiff base compound and preparation method and application thereof Download PDFInfo
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- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
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Abstract
The invention provides a triazole Schiff base compound and a preparation method and application thereof, wherein the compound is a 1,3, 4-oxadiazole modified 1,2, 4-triazole Schiff base compound, two or more heterocyclic active centers are simultaneously introduced into drug molecules, so that the biological activity of the drug molecules can be obviously improved, according to the principle of biological activity superposition, the 'o-hydroxyphenyl' molecular fragment is reasonably assembled with '1, 2, 4-triazole' and '1, 3, 4-oxadiazole', a class of 1,3, 4-oxadiazole modified 1,2, 4-triazole Schiff base compounds are designed and synthesized, and biological activity tests show that, the compound has good inhibitory activity on gram negative, gram positive, fungi and the like, shows broad-spectrum antibacterial activity, has great development potential and has good application prospect; the preparation method has simple process and easy implementation, the yield can reach 40-60 percent, and the preparation method is suitable for the requirement of large-scale industrial production.
Description
Technical Field
The invention relates to the field of chemical medicines, in particular to a triazole Schiff base compound and a preparation method and application thereof
Background
It has been found that 1,2, 4-triazoles have various activities such as antibacterial, anticancer, antiviral, anti-inflammatory, anticonvulsant, and are highly favored (1, El S H.El A, El S H El T, Mohy E D A El F, et al Eur. J.Med. chem.2013,66,106-,
E,Karaali N,Y1lmaz F,et al.Arch.Pharm.Chem.Life Sci.2013,346,556-561), and meanwhile, the 1,3, 4-oxadiazole compound has excellent biological activities such as antibiosis, anticancer and the like (1, Kumar, B P N, Mohana K N, Malesha L, et al. int.J.Med.Chem.2013,2013, 1-6; 2. muhammad N A, Khawaja A Y, Shahid H, et al.J.mol.Structure.2017, 1129, 50-59).
However, as bacterial resistance rapidly increases due to abuse of antibiotic drugs, the infection rate and the morbidity rate of bacteria rapidly increase. Therefore, the development of new efficient broad-spectrum bactericides has become an urgent important issue in the field of biological medicine.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a triazole Schiff base compound.
Another technical problem to be solved by the present invention is to provide a method for preparing the above triazole schiff base compound.
Another technical problem to be solved by the present invention is to provide the use of the above triazole schiff base compounds.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a triazole Schiff base compound is a 1,3, 4-oxadiazole modified 1,2, 4-triazole Schiff base compound and has the structural formula shown in the formula (I):
wherein R is1Is methyl; r2Is hydrogen, fluoro, chloro, bromo, methyl or methoxy.
Preferably, the above triazole Schiff base compound is selected from the group consisting of2When hydrogen, it is: 5- (4- (2-hydroxy-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol.
Preferably, the above triazole Schiff base compound is selected from the group consisting of2When the fluorine radical is used, the formula is as follows: 5- (4- (2-hydroxy-5-fluoro-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol.
Preferably, the above triazole Schiff base compound is selected from the group consisting of2When the chlorine radical is adopted, the formula is as follows: 5- (4- (2-hydroxy-5-chloro-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol.
Preferably, the above triazole Schiff base compound is selected from the group consisting of2When the bromine radical is bromine radical, the compound is: 5- (4- (2-hydroxy-5-bromo-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol.
Preferably, the above triazole Schiff base compound is selected from the group consisting of2When methyl, is: 5- (4- (2-hydroxy-5-methyl-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol.
Preferably, the above triazole Schiff base compound is selected from the group consisting of2When methoxy, it is: 5- (4- (2-hydroxy-5-methoxy-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol.
The preparation method of the triazole Schiff base compound comprises the following specific steps:
(1) dissolving 3-methyl-4-amino-5-ethoxycarbonylmethylthio-1, 2, 4-triazole in methanol, adding hydrazine hydrate, reacting at 0-70 ℃, tracking the reaction by Thin Layer Chromatography (TLC), using a developing agent which is a mixture of dichloromethane and methanol with a volume ratio of 6:1, removing partial solvent when the raw material point disappears, and crystallizing to obtain an intermediate 3-methyl-4-amino-5-acetic acid hydrazide;
(2) dissolving alkali in ethanol, adding 3-methyl-4-amino-5-acetic acid hydrazide, dissolving completely, adding CS2Stirring the mixture at 40-80 ℃, tracking the reaction by Thin Layer Chromatography (TLC), using a developing solvent which is a mixture of dichloromethane and methanol with the volume ratio of 3:1, filtering when the raw material point disappears, and recrystallizing the mixture by using ethanol to obtain an intermediate 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol;
(3) mixing 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol with ethanol, stirring, adding substituted salicylaldehyde, adjusting pH to 5-6 with dilute hydrochloric acid, stirring at 40-80 deg.C for reaction, tracking the reaction by Thin Layer Chromatography (TLC), using a mixture of dichloromethane and methanol with a volume ratio of 10:1 as a developing agent, concentrating the reaction solution when the raw material point disappears, and separating by silica gel column chromatography to obtain the target compound, wherein the substituted salicylaldehyde is salicylaldehyde, 5-bromosalicylaldehyde, 5-chlorosalicylaldehyde, 5-fluorosalicylaldehyde, 5-methylsalicylaldehyde or 5-methoxysalicylaldehyde.
Preferably, in the preparation method of the triazole schiff base compound, in the step (1), the molar ratio of the 3-methyl-4-amino-5-ethoxycarbonylmethylthio-1, 2, 4-triazole to the hydrazine hydrate is 1: 2-4; the dosage ratio of the 3-methyl-4-amino-5-ethoxycarbonylmethylthio-1, 2, 4-triazole to the methanol is 1mmol:4-8 mL.
Preferably, the preparation method of the triazole Schiff base compound comprises the step (2) of reacting 3-methyl-4-amino-5-acetic acid hydrazide with CS2The molar ratio of (A) to (B) is 1: 2-4; the dosage ratio of the 3-methyl-4-amino-5-acetic acid hydrazide to the ethanol is 1mmol:2-5 mL; the molar ratio of the 3-methyl-4-amino-5-acetic acid hydrazide to the base is 1: 2-4.
Preferably, in the preparation method of the triazole schiff base compound, the base in the step (2) is KOH.
Preferably, in the preparation method of the triazole schiff base compound, in the step (3), the molar ratio of the 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol to the salicylaldehyde is 1: 1-1.5; the dosage ratio of the 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol to the ethanol is 1mmol:1-3 mL.
An intermediate product of the preparation method is 3-methyl-4-amino-5-acetic acid hydrazide which has a structural formula shown in a formula (II):
an intermediate product of the above preparation method, which is 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol, has the structural formula shown in formula (iii):
the triazole Schiff base compound is applied to the preparation of antibacterial drugs.
Preferably, the application of the triazole Schiff base compound is that the antibacterial drug is an anti-gram-negative bacterium, anti-gram-positive bacterium or antifungal drug.
The invention has the beneficial effects that:
according to the triazole Schiff base compound, two or more heterocyclic active centers are simultaneously introduced into a drug molecule, the biological activity of the compound can be obviously improved, according to a biological activity superposition principle, an o-hydroxyphenyl molecular fragment and 1,2, 4-triazole and 1,3, 4-oxadiazole are reasonably assembled, a 1,3, 4-oxadiazole modified 1,2, 4-triazole Schiff base compound is designed and synthesized, and biological activity tests show that the compound has good inhibitory activity on gram negative, gram positive, fungi and the like, shows broad-spectrum antibacterial activity, has great development potential and has good application prospect; the preparation method has simple process and easy implementation, the yield can reach 40-60 percent, and the preparation method is suitable for the requirement of large-scale industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of compound a;
FIG. 2 is a carbon spectrum of compound a;
FIG. 3 is a hydrogen spectrum of compound b;
FIG. 4 is a carbon spectrum of compound b;
FIG. 5 is a hydrogen spectrum of compound c;
FIG. 6 is a carbon spectrum of compound c;
FIG. 7 is a hydrogen spectrum of compound d;
FIG. 8 is a carbon spectrum of compound d;
FIG. 9 is a hydrogen spectrum of compound e;
FIG. 10 is a carbon spectrum of compound e;
FIG. 11 is a hydrogen spectrum of compound f;
FIG. 12 is a carbon spectrum of compound f.
Detailed Description
To find out the good curative effect and the multiple finenessesAntibacterial drugs with inhibiting effect are combined with the knowledge of the antibacterial drugs, a class of 1,3, 4-oxadiazole modified 1,2, 4-triazole Schiff base compounds are designed and synthesized, and the in vitro antibacterial activity test is carried out on the obtained target compounds. The compounds are found to have strong antibacterial activity and have the prospect of being developed into new antibacterial drugs. The structure of the target compound has been subjected to High Resolution Mass Spectrometry (HRMS), nuclear magnetic resonance hydrogen spectroscopy (H: (M))1H-NMR) and nuclear magnetic resonance carbon Spectroscopy (C13C-NMR).
Example 1
Preparation of 5- (4- (2-hydroxy-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol as follows:
1) 20mL of methanol was added to a 50mL three-necked flask, 2.16g (10mmol) of 3-methyl-4-amino-5-ethoxycarbonylmethylthio-1, 2, 4-triazole was added with stirring to completely dissolve it, 1.2mL (30mmol) of hydrazine hydrate was slowly added dropwise, the reaction was followed by Thin Layer Chromatography (TLC) using a mixture of dichloromethane and methanol in a volume ratio of 6:1 as a developing solvent, and after completion of the reaction, a part of the solvent was removed by rotation and crystallization to obtain 1.6g of 3-methyl-4-amino-5-acetic acid hydrazide in a yield of 78.8%. m.p.146-148 ℃.1H NMR(400MHz,DMSO-d6),9.30(s,1H,NH),5.88(s,2H,NH2),4.31(s,2H,NH2),3.76(s,2H,CH2),2.28(s,3H,CH3).13C NMR(100MHz,DMSO-d6),167.20,153.80,151.01,33.87,10.24.ESI-MS,m/z:203.0720[M+H]+.
2) Adding 15mL of ethanol into a 100mL three-necked flask, adding 1.12g (20mmol) of KOH, stirring to dissolve, adding 2.03g (10mmol) of 3-methyl-4-amino-5-acetic acid hydrazide under stirring, heating to 40 deg.C, and slowly adding 2mL (30mmol) of CS2After 15mL of the ethanol solution was added, the mixture was heated to reflux. The reaction was followed by Thin Layer Chromatography (TLC) using a mixture of dichloromethane and methanol in a 3:1 volume ratio as the developing solvent, and after the starting material spot disappeared, filtration and recrystallization from ethanol gave 1.90g of 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol in 77.8% yield. m.p.192-194 ℃.1H NMR(400MHz,DMSO-d6),5.94(s,2H,NH2),4.45(s,2H,CH2),2.29(s,3H,CH3).13C NMR(100MHz,DMSO-d6),178.48,161.07,153.34,149.25,25.38,10.28.ESI-MS,m/z:245.0272[M+H]+。
3) 20mL of ethanol is added into a 50mL round-bottom flask, 2.44g (10mmol) of 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol is slowly added and stirred to be dissolved, 1.34g (1.1mmol) of salicylaldehyde is added, the pH is adjusted to 5-6 by dilute hydrochloric acid, the stirring reaction is carried out at 78 ℃, Thin Layer Chromatography (TLC) is used for tracking, a developing agent is a mixture of dichloromethane and methanol with the volume ratio of 10:1, when a raw material point disappears, a reaction solution is concentrated, silica gel column chromatography is carried out, and 1.49g of a target compound is obtained. The yield was 42.9%. Melting point: 191-193 ℃. The product thus obtained is designated by the reference numeral compound a.
As shown in FIG. 1-2, by NMR1H-NMR), nuclear magnetic resonance carbon spectrum (C13C-NMR), High Resolution Mass Spectrometry (HRMS) confirmed the structure of compound a:1H NMR(400MHz,DMSO-d6),14.47(1H,s,SH),10.55(1H,s,OH),8.96(1H,s,N＝CH),7.87(1H,dd,J＝7.2,1.2Hz,ArH),7.46(1H,m,ArH),7.00(1H,d,J＝8.4Hz,ArH),6.96(1H,t,J＝7.6Hz,ArH),4.42(2H,s,CH2),2.42(3H,s,CH3).13C NMR(100MHz,DMSO-d6),177.86,162.49,160.48,158.62,149.73,143.60,134.79,127.72,119.69,117.81,116.70,26.47,10.95.ESI-MS,m/z:349.0550[M+H]+。
example 2
The preparation of 5- (4- (2-hydroxy-5-bromo-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was as follows:
1) 3-methyl-4-amino-5-acetic acid hydrazide was prepared in the same manner as in example 1.
2)5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was prepared in the same manner as in example 1.
3) 20mL of ethanol is added into a 50mL round-bottom flask, 2.44g (10mmol) of 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol is slowly added and stirred to be dissolved, 2.21g (1.1mmol) of 5-bromosalicylaldehyde is added, the PH value is adjusted to 5-6 by dilute hydrochloric acid, the reaction is stirred at 78 ℃, Thin Layer Chromatography (TLC) is used for tracking, a developing agent is a mixture of dichloromethane and methanol with the volume ratio of 10:1, when a raw material point disappears, a reaction solution is concentrated, silica gel column chromatography is carried out, and 2.15g of a target compound is obtained. The yield was 50.7%. Melting point: 201 ℃ and 203 ℃. The product thus obtained is designated compound b.
As shown in FIGS. 3 to 4, by NMR1H-NMR), nuclear magnetic resonance carbon spectrum (C13C-NMR), High Resolution Mass Spectrometry (HRMS) confirmed the structure of compound b:1H NMR(400MHz,DMSO-d6),14.45(1H,s,SH),10.90(1H,s,OH),8.91(1H,s,N＝CH),7.97(1H,d,J＝2.8Hz,ArH),7.60(1H,dd,J＝8.8,2.4Hz,ArH),6.97(1H,d,J＝8.8Hz,ArH),4.42(2H,s,CH2),2.43(3H,s,CH3).13C NMR(100MHz,DMSO-d6),177.85,160.20,160.07,157.76,149.86,143.71,136.87,129.16,119.97,118.96,110.86,26.56,11.03.ESI-MS,m/z:426.9652[M+H]+。
example 3
The preparation of 5- (4- (2-hydroxy-5-chloro-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was as follows:
1) 3-methyl-4-amino-5-acetic acid hydrazide was prepared in the same manner as in example 1.
2)5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was prepared in the same manner as in example 1.
3) 20mL of ethanol is added into a 50mL round-bottom flask, 2.44g (10mmol) of 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol is slowly added and stirred to be dissolved, 1.71g (1.1mmol) of 5-chlorosalicylaldehyde is added, the pH value is adjusted to 5-6 by dilute hydrochloric acid, the reaction is stirred at 78 ℃, Thin Layer Chromatography (TLC) is used for tracking, a developing agent is a mixture of dichloromethane and methanol with the volume ratio of 10:1, when a raw material point disappears, a reaction solution is concentrated, and silica gel column chromatography is carried out to obtain 1.69g of a target compound. The yield was 44.2%. Melting point: 199 ℃ and 201 ℃. The product thus obtained is designated by the reference numeral compound c.
As shown in FIGS. 5 to 6, by NMR1H-NMR), nuclear magnetic resonance carbon spectrum (C13C-NMR), High Resolution Mass Spectrometry (HRMS) confirmed the structure of compound C:1H NMR(400MHz,DMSO-d6),14.46(1H,s,SH),10.88(1H,s,OH),8.92(1H,s,N＝CH),7.84(1H,d,J＝2.8Hz,ArH),7.49(1H,dd,J＝8.8,2.4Hz,ArH),7.02(1H,d,J＝9.2Hz,ArH),4.42(2H,s,CH2),2.43(3H,s,CH3).13C NMR(100MHz,DMSO-d6),177.85,160.20,160.17,157.38,149.88,143.72,134.10,126.18,123.44,119.39,118.65,26.58,11.02.ESI-MS,m/z:383.0162[M+H]+。
example 4
The preparation of 5- (4- (2-hydroxy-5-fluoro-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was as follows:
1) 3-methyl-4-amino-5-acetic acid hydrazide was prepared in the same manner as in example 1.
2)5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was prepared in the same manner as in example 1.
3) 20mL of ethanol is added into a 50mL round-bottom flask, 2.44g (10mmol) of 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol is slowly added and stirred to be dissolved, 1.54g (1.1mmol) of 5-fluorosalicylaldehyde is added, the PH value is adjusted to 5-6 by dilute hydrochloric acid, the reaction is stirred at 78 ℃, Thin Layer Chromatography (TLC) is used for tracking, a developing agent is a mixture of dichloromethane and methanol with the volume ratio of 10:1, when a raw material point disappears, a reaction solution is concentrated, silica gel column chromatography is carried out, and 1.79g of a target compound is obtained. The yield was 48.9%. Melting point: 198-200 ℃. The product thus obtained is designated by the number compound d.
As shown in FIGS. 7 to 8, by NMR1H-NMR), nuclear magnetic resonance carbon spectrum (C13C-NMR), High Resolution Mass Spectrometry (HRMS) confirmed the structure of compound d:1H NMR(400MHz,DMSO-d6),14.46(1H,s,SH),10.59(1H,s,OH),8.93(1H,s,N＝CH),7.60(1H,dd,J＝9.2,3.2Hz,ArH),7.34(1H,td,J＝8.4,3.2Hz,ArH),7.01(1H,dd,J＝9.2,4.4Hz,ArH),4.42(2H,s,CH2),2.43(3H,s,CH3).13C NMR(100MHz,DMSO-d6),177.84,160.37,156.49,155.08,154.15,149.90,143.62,121.69,118.52,118.23,112.18,26.61,10.99.ESI-MS,m/z:367.0455[M+H]+
example 5
The preparation of 5- (4- (2-hydroxy-5-methyl-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was as follows:
1) 3-methyl-4-amino-5-acetic acid hydrazide was prepared in the same manner as in example 1.
2)5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was prepared in the same manner as in example 1.
3) 20mL of ethanol is added into a 50mL round-bottom flask, 2.44g (10mmol) of 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol is slowly added and stirred to be dissolved, 1.49g (1.1mmol) of 5-methyl salicylaldehyde is added, the pH value is adjusted to 5-6 by dilute hydrochloric acid, the reaction is stirred at 78 ℃, Thin Layer Chromatography (TLC) is used for tracking, a developing agent is a mixture of dichloromethane and methanol with the volume ratio of 10:1, when a raw material point disappears, a reaction solution is concentrated, silica gel column chromatography is carried out, and 1.56g of a target compound is obtained. The yield was 43.2%. Melting point: 192 ℃ and 194 ℃. The product obtained is designated by the number compound e.
As shown in FIGS. 9 to 10, by NMR1H-NMR), nuclear magnetic resonance carbon spectrum (C13C-NMR), High Resolution Mass Spectrometry (HRMS) confirmed the structure of compound e:1H NMR(400MHz,DMSO-d6),14.46(1H,s,SH),10.32(1H,s,OH),8.91(1H,s,N＝CH),7.66(1H,s,ArH),7.28(1H,dd,J＝8.4,2.0Hz,ArH),6.90(1H,d,J＝8.4Hz,ArH),4.41(2H,s,CH2),2.41(3H,s,CH3),2.27(3H,s,CH3).13C NMR(100MHz,DMSO-d6),177.86,162.80,160.25,156.63,149.67,143.53,135.68,128.61,127.29,117.37,116.63,26.55,19.93,10.77.ESI-MS,m/z:363.0698[M+H]+。
example 6
The preparation of 5- (4- (2-hydroxy-5-methoxy-benzyl) amino-5-methyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was as follows:
1) 3-methyl-4-amino-5-acetic acid hydrazide was prepared in the same manner as in example 1.
2)5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol was prepared in the same manner as in example 1.
3) 20mL of ethanol is added into a 50mL round-bottom flask, 2.44g (10mmol) of 5- (4-amino-5-phenyl-4H-1, 2, 4-triazole-3-sulfanyl) -1,3, 4-oxadiazole-2-thiol is slowly added and stirred to be dissolved, 1.67g (1.1mmol) of 5-methoxysalicylaldehyde is added, the PH value is adjusted to 5-6 by dilute hydrochloric acid, the reaction is stirred at 78 ℃, Thin Layer Chromatography (TLC) is used for tracking, a developing agent is a mixture of dichloromethane and methanol with the volume ratio of 10:1, when a raw material point disappears, a reaction solution is concentrated, silica gel column chromatography is carried out, and 1.53g of a target compound is obtained. The yield was 40.5%. Melting point: 193-. The product thus obtained is designated by the number compound f.
As shown in FIGS. 11 to 12, by NMR1H-NMR), nuclear magnetic resonance carbon spectrum (C13C-NMR), High Resolution Mass Spectrometry (HRMS) confirmed the structure of compound f:1H NMR(400MHz,DMSO-d6),14.46(1H,s,SH),10.14(1H,s,OH),8.92(1H,s,N＝CH),7.34 1H,d,J＝3.2Hz,ArH),7.10(1H,dd,J＝9.2,3.2Hz,ArH),6.94(1H,d,J＝8.8Hz,ArH),4.43(2H,s,CH2),3.75(3H,s,OCH3),2.42(3H,s,CH3).13C NMR(100MHz,DMSO-d6),177.83,161.96,160.20,153.06,152.24,149.74,143.51,122.49,117.93,117.66,109.59,55.52,26.44,10.88.ESI-MS,m/z:379.0647[M+H]+。
examples of the bacteriostatic test
Biological activity test of 1,3, 4-oxadiazole modified 1,2, 4-triazole Schiff base compounds
The specific operation is as follows:
1) preparation of antibacterial drug stock solution
The preparation concentration is 256 mu g.mL-1The antibacterial agent stock solution of (1) is 10mL, 3.4mg of the compound is weighed by an analytical balance, the used agent is powder, and the effective force of the agent is 750 mug. multidot.mL-1. The diluent dosage is calculated as: 3.4mg × 750. mu.g/mL-1)/256μg·mL-1Dissolve the drug in 2mL DMF and 8mL distilled water 10.0 mL. Storing the antibacterial agent stock solution below 0 ℃.
2) Culture medium
Preparing a corresponding culture medium: nutrient broth medium for culturing bacteria, and liquid glucose medium for culturing fungi.
3) Preparation of diluted antibacterial agent
10 sterile test tubes (13X 100mm) were lined up, except for tube 1, 1.0mL of medium was added to each tube, and an antimicrobial stock solution (e.g., 256. mu.g. mL) was added to tube 1-1)2mL of the mixture was added to the 2 nd tube after being mixed, 1mL of the mixture was added to the 3 rd tube after being mixed, the mixture was continued to the 9 th tube, 1mL of the mixture was extracted from the 9 th tube and discarded, and the 10 th tube was a negative control containing no drug. The drug concentrations of the 1 st to 9 th tubes were 256, 128, 64, 32, 16, 8, 4, 2, 1. mu.g.mL, respectively-1。
4) Inoculum preparation
Selecting bacterial colony to prepare bacterial suspension with 0.5 McLeod's ratio, diluting with liquid culture medium at ratio of 1: 1000 (about 1-2 × 10)8CFU·mL-1) Adding 100 mu L of the culture medium into each tube, sealing the tube, placing the tube in a 37 ℃ constant temperature incubator, culturing bacteria for 16-20h, and culturing fungi for 72h to obtain a judgment result.
5) Result judgment
After the bacteria are cultured for 16-20h and the fungi are cultured for 72h, checking the result and recording the data. The negative control strains were first checked for good performance and were guaranteed to be free of contamination. And then visually observing, wherein the lowest concentration tube is the growth of the sterile strain, namely the Minimum Inhibitory Concentration (MIC) of the tested strain.
The compounds of examples 1-6 were tested for bacteriostatic biological activity according to the methods described in the experimental bacteriostatic examples above, and the results are shown in table 1 below.
In vitro minimal inhibitory concentrations (μ g-mL) of the Compounds of Table 1-1)
Table 1 the test results show that: the compound shows good inhibitory activity to escherichia coli, staphylococcus aureus and candida albicans, has development value and application prospect of broad-spectrum antibacterial agents, and can provide a lead compound, a basic theory and a technical support for development of safe and efficient new antimicrobial drugs.
The above detailed description of the composition satisfying the requirement for growth and repair of body tissues and the preparation method thereof with reference to the examples is illustrative and not restrictive, and several examples can be cited within the scope defined, and thus, variations and modifications thereof without departing from the general inventive concept should fall within the scope of the present invention.
Claims (9)
1. A triazole schiff base compound, which is characterized in that: is a 1,3, 4-oxadiazole modified 1,2, 4-triazole Schiff base compound and has the structural formula of a compound shown in the formula (I):
wherein R is1Is methyl; r2Is hydrogen, fluorine, chlorine, bromine, methyl or methoxy.
2. A method for producing the triazole schiff base compound according to claim 1, characterized in that: the method comprises the following specific steps:
(1) dissolving 3-methyl-4-amino-5-ethoxycarbonylmethylthio-1, 2, 4-triazole in methanol, adding hydrazine hydrate, reacting at 0-70 ℃, tracking the reaction by Thin Layer Chromatography (TLC), using a developing agent which is a mixture of dichloromethane and methanol with the volume ratio of 6:1, removing part of solvent by spinning when the raw material point disappears, and crystallizing to obtain a compound of formula (II);
(2) dissolving alkali in ethanol, adding the compound of formula (II) for complete dissolution, and adding the compound containing CS2Stirring the mixture at 40-80 ℃ for reaction, tracking the reaction by Thin Layer Chromatography (TLC), using a mixture of dichloromethane and methanol with the volume ratio of 3:1 as a developing agent, filtering the mixture when the raw material point disappears, and recrystallizing the mixture by using ethanol to obtain a compound of a formula (III);
a compound of formula (III)
(3) Mixing the compound shown in the formula (III) and ethanol, uniformly stirring, adding substituted salicylaldehyde, adjusting the pH value to 5-6 by using dilute hydrochloric acid, stirring for reaction at 40-80 ℃, tracking the reaction by using thin-layer chromatography (TLC), wherein a developing agent is a mixture of dichloromethane and methanol with the volume ratio of 10:1, concentrating a reaction solution when the raw material point disappears, and carrying out silica gel column chromatography separation to obtain a target compound, wherein the substituted salicylaldehyde is salicylaldehyde, 5-bromosalicylaldehyde, 5-chlorosalicylaldehyde, 5-fluorosalicylaldehyde, 5-methyl salicylaldehyde or 5-methoxysalicylaldehyde.
3. The method for producing a triazole schiff base compound according to claim 2, characterized in that: in the step (1), the molar ratio of the 3-methyl-4-amino-5-ethoxycarbonylmethylthio-1, 2, 4-triazole to the hydrazine hydrate is 1: 2-4; the dosage ratio of the 3-methyl-4-amino-5-ethoxycarbonylmethylthio-1, 2, 4-triazole to the methanol is 1mmol:4-8 mL.
4. The method for producing a triazole schiff base compound according to claim 2, characterized in that: the compound of formula (II) in the step (2) and CS2The molar ratio of (A) to (B) is 1: 2-4;
the dosage ratio of the compound of the formula (II) to the ethanol is 1mmol:2-5 mL;
the molar ratio of the compound of formula (II) to the base is 1: 2-4.
5. The method for producing a triazole schiff base compound according to claim 2, characterized in that: the alkali in the step (2) is KOH.
6. The method for producing a triazole schiff base compound according to claim 2, characterized in that: the molar ratio of the compound in the formula (III) in the step (3) to the salicylaldehyde is 1: 1-1.5;
the dosage ratio of the compound shown in the formula (III) to the ethanol is 1mmol:1-3 mL.
7. An intermediate product of the production method according to claim 2, characterized in that: having the formula (III):
8. use of the triazole schiff base compounds of claim 1 for the preparation of antibacterial agents.
9. Use of triazole schiff base compounds according to claim 8, characterized in that: the antibacterial agent is an antibacterial agent against gram-negative bacteria, gram-positive bacteria or fungi.
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| (E)-N-benzylidene-3-(benzylthio)-5-p-tolyl-4H-1,2,4-triazol-4-amine, C23H20N4S;Qichun Ding et al.,;《Zeitschrift fuer Kristallographie - New Crystal Structures》;20170916;第232卷(第6期);第1009-1010页 * |
| 3-三氟甲基-4-氨基-5-巯基-1 , 2 , 4-三唑衍生物的合成及其抗真菌活性研究;俞世冲等;《药物化学》;20070430;第24卷(第2期);第122-125页 * |
| 含1,2,4-三唑和1,3,4-噁二唑硫醚类化合物的合成及结构表征;王海卫等;《有机化学》;20121231;第32卷;第1888-1893页 * |
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