CN109575007B - Aminothiazole isatin compound and preparation method and application thereof - Google Patents
Aminothiazole isatin compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an aminothiazole isatin compound and a preparation method and application thereof, belonging to the technical field of chemical synthesis, wherein the aminothiazole isatin compound and a medicinal salt thereof are shown in a structural general formula I, the compound has certain inhibitory activity on gram-positive bacteria, gram-negative bacteria and fungi, and can be used for preparing antibacterial and/or antifungal medicaments, so that more efficient and safe candidate medicaments are provided for clinical antimicrobial treatment, and the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly-appeared harmful microorganisms and the like are solved. In addition, the aminothiazole isatin compound can also be used for preparing a DNA intercalator. The preparation raw materials are simple, cheap and easy to obtain, and the synthetic route is short.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an aminothiazole isatin compound, and a preparation method and application thereof.
Background
Isatin, also known as indolidione, is an endogenous active substance present in mammalian tissues and fluids. Research shows that the isatin and the derivatives thereof have various physiological and pharmacological activities, the multifunctionality of the isatin and the derivatives thereof draws attention of people, the synthesis and the structural modification of the isatin and the derivatives thereof become hot spots for the research and development of new drugs at present, and the isatin derivatives with various structural diversity are generated at the same time. The isatin can be subjected to comprehensive structural modification, including N1, C2, C3, C5 and C6, particularly the C3-carbonyl carbon is most abundantly modified, and the C3-substituted isatin derivatives have various physiological and pharmacological activities such as antibiosis, anticancer, antivirus and anticonvulsant, and particularly have great attention in the antibacterial field. Therefore, C3 substituted isatin structure molecule becomes one of the compounds which are much sought after in modern drug discovery, and the wider structural modification of the compounds is a research direction with great development potential, shows attractive medicinal prospect and is worth attention and intensive research. The 2-aminothiazole is an important five-membered aromatic heterocycle, widely exists in many clinical antibacterial drugs such as cephalosporin, sulfathiazole, abafungin and the like, and is widely used for modification and research and development of drugs by researchers based on unique chemical structures of the 2-aminothiazole. Therefore, the 2-aminothiazole fragment is hybridized to three positions of the active molecule isatin and bridged by Schiff base, which is a promising research subject and is expected to develop a series of novel broad-spectrum antibacterial agents with high activity.
Disclosure of Invention
In view of the above, an object of the present invention is to provide aminothiazole isatin compounds and pharmaceutically acceptable salts thereof; the second purpose is to provide a preparation method of the aminothiazole isatin compound and the medicinal salt thereof; the third purpose is to provide the application of the aminothiazole isatin compound and the medicinal salt thereof in the preparation of antibacterial and/or antifungal medicaments; the fourth purpose is to provide the application of the aminothiazole isatin compound and the medicinal salt thereof in the preparation of a DNA intercalator.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the aminothiazole isatin compound and the medicinal salt thereof is shown as the general formula I:
in the formula (I), the compound is shown in the specification,
R1is hydrogen, alkyl or benzyl;
R2，R3is hydrogen, F, Cl, Br, I, CN, CF3、OCH3Or NO2。
Preferably, the first and second liquid crystal materials are,
R1is hydrogen, ethyl, butyl, hexyl, octyl, decyl, dodecyl, p-fluorobenzyl, p-chlorobenzyl, o-fluorobenzylA phenyl, o-chlorobenzyl or 2, 4-dichlorobenzyl group;
R2is hydrogen.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
2. The preparation method of the aminothiazole isatin compound and the pharmaceutically acceptable salts thereof comprises the following steps:
a. preparation of intermediate II: taking one of isatin, 5-substituted isatin or 5, 6-disubstituted isatin as an initial raw material to react with different halogenated alkanes or benzyl halide to obtain an intermediate II;
b. preparation of intermediate III: carrying out condensation reaction on the intermediate II serving as a raw material and semicarbazide hydrochloride to obtain an intermediate III with different substitutions;
c. preparation of aminothiazole isatin compounds shown in general formula I and pharmaceutically acceptable salts thereof: dissolving the intermediate III with different substitutions in ethanol, and performing a condensation and ring-closing reaction with chloroacetaldehyde.
Preferably, the first and second liquid crystal materials are,
in the step a, reacting for 8 hours at 80 ℃ by using acetonitrile as a solvent and potassium carbonate as a base;
in the step b, the solvent used in the condensation reaction is ethanol, and the reflux reaction is carried out for 12 hours at the temperature of 80 ℃;
in the step c, the solvent used in the condensation ring-closing reaction is ethanol, and the reflux reaction is carried out for 24-36h at the temperature of 80 ℃.
3. The application of the aminothiazole isatin compound and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments.
Preferably, the bacteria is at least one of staphylococcus aureus, methicillin-resistant staphylococcus aureus, klebsiella pneumoniae, escherichia coli, enterococcus faecalis, acinetobacter baumannii or pseudomonas aeruginosa; the fungus is at least one of Candida tropicalis, Aspergillus fumigatus, Candida albicans or Candida parapsilosis.
4. The application of the aminothiazole isatin compound and the pharmaceutically acceptable salt thereof in the preparation of a DNA intercalator.
Preferably, the DNA is MRSA strain DNA.
The invention has the beneficial effects that: the invention utilizes the principle of drug design and amalgamation, introduces an important structural fragment 2-aminothiazole at the C3 position of isatin through Schiff base bridging, effectively modifies the N1 position of the isatin, designs and synthesizes a series of aminothiazole isatin compounds with novel structures, and the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923 and staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922 and acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023 and candida parapsilosis ATCC20019) through in-vitro antimicrobial activity detection, can be used for preparing antibacterial and/or antifungal drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial treatment and being beneficial to solving the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly appeared harmful microorganisms and the like. In addition, the aminothiazole isatin compound can also be used for preparing a DNA intercalator. The preparation raw materials are simple, cheap and easy to obtain, and the synthetic route is short.
Drawings
In order to make the object, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:
FIG. 1 is a graph showing the competition effect between compound I-3 and neutral red and DNA.
Detailed Description
The preferred embodiments of the present invention will be described in detail below.
Example 1
Preparation of intermediates II and III
Reference "Ngo, h.x.; green, k.d.; gajadera, c.s.; willby, m.j.; holbrook, s.y.l.; hou, c.garzan, a.mayhoub, a.s.; posey, j.e.; tsodikov, o.v.; Garneau-Tsodikova, s.potent1,2,4-Triazino [5,6b ] indele-3-thioether Inhibitors of the kanamyin Resistance Enzyme from Mycobacterium tuberculosis. acs infection. dis.2018,4, 1030-; wang, w.m.; lia, z.s.; wang, y.; intermediates II and III were prepared by the method disclosed in Wang J.G.first identification of isotope-b-microorganisms as novel inhibitors of New Delhi metals-b-lactamase-1: Chemical Synthesis, biological evaluation and molecular characterization, Chinese chem.Lett.2018,29, 899-902 ".
Example 2
Preparation of Compound I-1
A50 mL round bottom flask was charged with the corresponding intermediate III (110.13mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-1(82.20 mg). Yield: 67.3 percent; a yellow powder; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ13.27(s,1H),11.22(s,1H),7.53(d,J＝7.5Hz,1H),7.43(d,J＝3.3Hz,1H),7.34(t,J＝7.7Hz,1H),7.21(d,J＝3.1Hz,1H),7.09(t,J＝7.5Hz,1H),6.96(d,J＝7.8Hz,1H)ppm。
example 3
Preparation of Compound I-2
A50 mL round bottom flask was charged with the corresponding intermediate III (124.15mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-2(90.55 mg). Yield: 66.5 percent; a yellow powder; melting point: 222.4-224.1 ℃;1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),7.57(d,J＝7.4Hz,1H),7.44(d,J＝2.6Hz,1H),7.41(t,J＝7.7Hz,1H),7.22(d,J＝7.0Hz,2H),7.14(t,J＝7.5Hz,1H),3.82(q,J＝7.0Hz,2H),1.22(t,J＝7.0Hz,3H)ppm。
example 4
Preparation of Compound I-3
A50 mL round bottom flask was charged with the corresponding intermediate III (138.18mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-3(102.43 mg). Yield: 68.2 percent; a yellow powder; melting point: 100.3-102.5 ℃;1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),7.55(d,J＝7.2Hz,1H),7.44(d,J＝3.5Hz,1H),7.40(t,J＝7.7Hz,1H),7.22(d,J＝3.5Hz,1H),7.19(d,J＝8.0Hz,1H),7.14(t,J＝7.8Hz,1H),3.77(t,J＝7.1Hz,2H),1.63(dt,J＝14.9,7.3Hz,2H),1.33(dd,J＝15.0,7.5Hz,2H),0.91(t,J＝7.4Hz,3H)ppm。
example 5
Preparation of Compound I-4
A50 mL round bottom flask was charged with the corresponding intermediate III (152.21mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-4(101.32 mg). Yield: 61.7 percent; a yellow powder; melting point: 98.5-100.7 ℃;1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),7.55(d,J＝7.2Hz,1H),7.44(d,J＝3.5Hz,1H),7.40(t,J＝7.7Hz,1H),7.22(d,J＝3.5Hz,1H),7.19(d,J＝7.9Hz,1H),7.14(t,J＝7.5Hz,1H),3.76(t,J＝7.2Hz,2H),1.66–1.60(m,2H),1.33–1.24(m,6H),0.84(t,J＝7.0Hz,3H)ppm。
example 6
Preparation of Compound I-5
A50 mL round bottom flask was charged with the corresponding intermediate III (166.24mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-5(123.52 mg). Yield: 69.3 percent; a yellow powder; melting point: 98.3-100.4 ℃;1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),7.54(d,J＝7.5Hz,1H),7.44(d,J＝3.5Hz,1H),7.39(t,J＝7.7Hz,1H),7.21(d,J＝3.5Hz,1H),7.16(d,J＝8.0Hz,1H),7.12(t,J＝7.5Hz,1H),3.75(t,J＝7.1Hz,2H),1.66–1.59(m,2H),1.29–1.20(m,10H),0.82(t,J＝7.0Hz,3H)ppm。
example 7
Preparation of Compound I-6
A50 mL round bottom flask was charged with the corresponding intermediate III (180.26mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-6(125.74 mg). Yield: 65.4 percent; a yellow powder; melting point: 98.5-100.7 ℃;1H NMR(600MHz,DMSO-d6)δ13.21(s,1H),7.56(d,J＝7.2Hz,1H),7.44(d,J＝3.5Hz,1H),7.40(t,J＝7.2Hz,1H),7.22(d,J＝3.5Hz,1H),7.19(d,J＝7.9Hz,1H),7.14(t,J＝7.4Hz,1H),3.77(t,J＝7.1Hz,2H),1.63(dd,J＝13.9,7.0Hz,2H),1.21(s,14H),0.82(d,J＝7.1Hz,3H)ppm。
example 8
Preparation of Compound I-7
A50 mL round bottom flask was charged with the corresponding intermediate III (194.29mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-7(131.00 mg). Yield: 63.5 percent; a yellow powder; melting point: 98.4-100.6 ℃;1H NMR(600MHz,DMSO-d6)δ13.20(s,1H),7.55(d,J＝7.4Hz,1H),7.43(d,J＝3.5Hz,1H),7.39(t,J＝7.7Hz,1H),7.21(d,J＝3.4Hz,1H),7.17(d,J＝7.9Hz,1H),7.13(t,J＝7.5Hz,1H),3.76(t,J＝7.1Hz,2H),1.65–1.59(m,2H),1.27(s,4H),1.19(s,18H),0.83(t,J＝7.0Hz,3H)ppm。
example 9
Preparation of Compound I-8
A50 mL round bottom flask was charged with the corresponding intermediate III (130.16mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5 m)mol) and ethanol (30mL) at 80 ℃ for 24h, and the reaction is followed by thin layer chromatography until the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-8(89.28 mg). Yield: 62.8 percent; a yellow powder; melting point: 126.8-128.9 ℃;1H NMR(600MHz,DMSO-d6)δ7.58(d,J＝7.4Hz,1H),7.45(d,J＝3.5Hz,1H),7.39(t,J＝7.7Hz,1H),7.23(d,J＝3.5Hz,1H),7.15(t,J＝7.5Hz,1H),7.10(d,J＝7.9Hz,1H),5.90(ddd,J＝22.3,10.3,5.1Hz,1H),5.25–5.19(m,2H),4.43(d,J＝5.1Hz,2H)ppm。
example 10
Preparation of Compound I-9
A50 mL round bottom flask was charged with the corresponding intermediate III (129.16mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-9(94.16 mg). Yield: 66.7 percent; a yellow powder; melting point: 218.4-220.1 ℃;1H NMR(600MHz,DMSO-d6)δ13.05(s,1H),7.61(d,J＝7.4Hz,1H),7.48–7.45(m,2H),7.26(d,J＝7.9Hz,1H),7.24(d,J＝2.6Hz,1H),7.20(t,J＝7.5Hz,1H),4.68(d,J＝2.4Hz,2H),3.35(s,1H)ppm。
example 11
Preparation of Compound I-10
A50 mL round bottom flask was charged with the corresponding intermediate III (164.19mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-10(121.40 mg). Yield: 68.9 percent; a yellow powder; melting point: 167.8-169.6 ℃;1H NMR(600MHz,DMSO-d6)δ13.17(s,1H),7.58(d,J＝7.4Hz,1H),7.45(d,J＝3.6Hz,2H),7.44(d,J＝5.5Hz,1H),7.34(t,J＝7.8Hz,1H),7.23(d,J＝3.5Hz,1H),7.18(d,J＝8.9Hz,2H),7.13(d,J＝7.7Hz,1H),7.08(d,J＝7.9Hz,1H),5.01(s,2H)ppm。
example 12
Preparation of Compound I-11
A50 mL round bottom flask was charged with the corresponding intermediate III (172.41mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-11(121.35 mg). Yield: 65.8 percent; a yellow powder; melting point: 172.5-174.8 ℃;1H NMR(600MHz,DMSO-d6)δ1H NMR(600MHz,DMSO)δ13.16(s,1H),7.58(s,1H),7.46(d,J＝3.5Hz,1H),7.41(d,J＝2.6Hz,4H),7.34(t,J＝7.2Hz,1H),7.24(d,J＝3.4Hz,1H),7.14(t,J＝7.6Hz,1H),7.06(d,J＝7.9Hz,1H),5.03(s,2H)ppm。
example 13
Preparation of Compound I-12
A50 mL round bottom flask was charged with the corresponding intermediate III (164.19mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-12(118.93 mg). Yield: 67.5 percent; a yellow powder; melting point: 183.2-185.3 deg.c;1H NMR(600MHz,DMSO-d6)δ1H NMR(600MHz,DMSO)δ13.14(s,1H),7.59(d,J＝7.3Hz,1H),7.46(d,J＝3.5Hz,1H),7.35(dd,J＝9.1,6.4Hz,3H),7.24(d,J＝3.6Hz,2H),7.18–7.13(m,2H),7.04(d,J＝7.9Hz,1H),5.07(s,2H)ppm。
example 14
Preparation of Compound I-13
A50 mL round bottom flask was charged with the corresponding intermediate III (172.41mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-13(115.82 mg). Yield: 62.8 percent; a yellow powder; melting point: 147.2-149.5 ℃;1H NMR(600MHz,DMSO-d6)δ13.13(s,1H),7.62(t,J＝7.2Hz,2H),7.58(t,J＝7.8Hz,1H),7.53(s,1H),7.51(s,1H),7.45(d,J＝5.5Hz,1H),7.34(t,J＝6.7Hz,2H),7.28(t,J＝7.6Hz,2H),7.15(s,1H),6.93(t,J＝7.3Hz,1H),6.87(d,J＝7.9Hz,1H),4.95(s,2H)ppm。
example 15
Preparation of Compound I-14
A50 mL round bottom flask was charged with the corresponding intermediate III (189.63mg,0.50mmol), chloroacetaldehyde (117.75mg,1.5mmol), and ethanol (30mL), reacted at 80 ℃ under reflux for 24h, followed by thin layer chromatography to the end of the reaction. And then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain the compound I-14(133.89 mg). Yield: 66.4 percent; a yellow powder; melting point: 182.8-184.1 ℃;1H NMR(600MHz,DMSO-d6)δ13.09(s,1H),7.70(d,J＝2.1Hz,1H),7.62(d,J＝7.5Hz,1H),7.45(d,J＝3.5Hz,1H),7.38–7.34(m,2H),7.26(d,J＝8.5Hz,1H),7.24(d,J＝3.6Hz,1H),7.16(t,J＝7.5Hz,1H),6.95(d,J＝7.9Hz,1H),5.06(s,2H)ppm。
example 16
In vitro antimicrobial activity of aminothiazole isatin compounds
The Minimal Inhibitory Concentrations (MIC) of the aminothiazole isatin compounds prepared in examples 2 to 15 against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC20019) were tested by a 96-well microdilution method in accordance with the Clinical Laboratory Standards Institute (CLSI) set by the national Committee of America, the compounds to be tested were dissolved in a small amount of dimethyl sulfoxide, diluted with water to a solution having a concentration of 1.28mg/mL, and then diluted to 512. mu.g/mL with the culture medium, after incubation at 35 ℃ for 24h and shaking the plates well on a shaker, MIC was determined at 490nm and the results are shown in tables 1-3.
TABLE 1 in vitro gram-positive activity data (MIC, μ g/mL) for aminothiazole isatins I-1-I-14
As can be seen from Table 1, most of the aminothiazole isatin compounds of the present invention showed good inhibitory activity against the gram-positive strains tested, and among them, especially aminothiazole isatin compound I-3 showed not only a broad antibacterial spectrum in the test strains but also effective inhibition of the growth of MRSA and enterococcus faecalis strains with MIC values of 4. mu.g/mL and 2. mu.g/mL, respectively. In addition, when the alkyl chain of the aminothiazole isatin compound I-3 is substituted by a shorter or longer alkyl chain, the antibacterial activity of the aminothiazole isatin compound I-3 cannot be effectively improved, and the antibacterial ability of the aminothiazole isatin compound I-3 is reduced along with the growth of the alkyl chain. In addition, when the alkyl chain was substituted with benzyl group, its effect on biological activity was significant, and in particular, aminothiazole isatin compound I-10 showed a relatively broad antibacterial spectrum with MIC values centered between 2 and 128 μ g/mL, showing the best inhibitory activity against enterococcus faecalis, with MIC values of 2 μ g/mL, 1/4 for chloramphenicol (MIC 8 μ g/mL), and 1/2 for norfloxacin (MIC 4 μ g/mL).
TABLE 2 in vitro gram-negative activity data (MIC, μ g/mL) for aminothiazole isatins I-1-I-14
As can be seen from Table 2, the aminothiazole isatin compounds I-3 also showed relatively good biological activity against the tested gram-negative bacteria, and the MIC value ranged from 2 to 4. mu.g/mL. Furthermore, we found that the biological activity of compound I-3 was significantly reduced when the length of the alkyl chain at position N1 was increased, especially compounds I-6 and I-7, which are decyl and dodecyl substituted, were essentially inactive in individual strains, indicating that carbon chain lengths of moderate length are more beneficial for biological activity.
TABLE 3 in vitro antifungal Activity data (MIC, μ g/mL) for aminothiazole isatins I-1-I-14
As shown in Table 3, the aminothiazole isatin compounds I-1-I-14 prepared in examples 2-15 of the invention also have certain inhibitory effect on the tested fungi, and particularly, the aminothiazole isatin compound I-3 has the optimal antifungal activity, can completely inhibit the growth of Candida albicans ATCC90023 and Candida tropicalis, and has MIC values of 2 mug/mL, and other individual compounds also show better antibacterial activity which is comparable to or even stronger than that of the reference drug fluconazole.
Example 17
Aminothiazole isatin compound as DNA intercalator
The aminothiazole isatin compound II-3 can be effectively inserted into DNA as an artificial intercalator. The ultraviolet absorption spectrum and Neutral red (Neutral red) of the DNA probe are used for detecting the intercalation effect as shown in figure 1, and as can be seen from figure 1, the ultraviolet absorption intensity of the compound II-3 is continuously increased at about 440nm along with the continuous increase of the concentration of the compound II-3, which is mainly caused by the fact that the compound II-3 is intercalated into DNA and forms a supramolecular complex with the DNA.
Example 18
Pharmaceutical application of aminothiazole isatin compounds
According to the antimicrobial activity detection result, the aminothiazole isatin compound has better antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicaments for clinical use. The medicines can be single-ingredient preparations, for example, the medicines are prepared from aminothiazole isatin compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound is prepared by the aminothiazole isatin compound with one structure, the existing antibacterial and antifungal active ingredients (such as sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or the compound is prepared by a plurality of aminothiazole isatin compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-3 tablets
Prescription: the tablet is prepared from compound I-310 g, lactose 187g, corn starch 50g, magnesium stearate 3.0g, and ethanol solution with volume percentage concentration of 70% in a proper amount, and is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-3 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound I-3 capsules
Prescription: compound I-325 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound I-3 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each tablet weighs 50mg, and the content of active ingredient is 25 mg.
3. Preparation of Compound I-3 granules
Prescription: compound I-326 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound I-3, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-3 injection
Prescription: 1000mL of the compound I-310 g, 500mL of propylene glycol and 500mL of water for injection were prepared in total.
The preparation method comprises the following steps: weighing the compound I-3, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the compound I-3.
5. Preparation of compound I-3 powder injection
The preparation method comprises the following steps: and subpackaging the compound I-3 sterile powder under the sterile condition to obtain the compound I-3.
6. Preparation of Compound I-3 eye drops
Prescription: 33.78 g of compound I, 0.9g of sodium chloride, 3g of phenethyl alcohol, a proper amount of boric acid buffer solution and distilled water are added to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-3 and sodium chloride, adding into 500mL of distilled water, dissolving completely, adjusting pH to 6.5 with boric acid buffer solution, adding distilled water to 1000mL, stirring well, filtering with microporous membrane, filling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr.
7. Preparation of Compound I-4 Liniment
Prescription: compound I-44 g, potassium soap 7.5g, camphor 5g, distilled water to 100 mL.
The preparation method comprises the following steps: dissolving camphor with 95 percent ethanol solution by volume percentage for later use; heating potassium soap to liquefy, weighing compound I-4, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full volume.
8. Preparation of suppository of compound I-4
Prescription: compound I-44 g, gelatin 14g, glycerin 70g, distilled water to 100mL, metric 100.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound I-4, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-5 ointment
Prescription: 50.5-2 g of compound I, 6-8 g of hexadecanol, 8-10 g of white vaseline, 8-19 g of liquid paraffin, 2-5 g of monoglyceride, 2-5 g of polyoxyethylene (40) stearate, 5-10 g of glycerol, 0.1g of ethylparaben and distilled water added to 100 g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely dissolve, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound I-5, stirring, and cooling.
10. Preparation of compound I-11 and fluconazole compound powder injection
Prescription: compound I-1150 g, fluconazole 50g and sodium benzoate 1g, and 100 bottles are prepared.
The preparation method comprises the following steps: taking the compound I-11, the fluconazole and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the compound I-11.
11. Preparation of Compound I-10 Aerosol
Prescription: 102.5 g of compound I, 203 g of Span, 4g of talcum powder (100 meshes) and trichlorofluoromethane added to a proper amount.
The preparation method comprises the following steps: respectively placing the compound I-10, the Span20 and the talcum powder in a vacuum drying oven for drying for a plurality of hours, placing in a dryer for cooling to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the trichloromonofluoromethane.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (9)
1. The aminothiazole isatin compound and the pharmaceutically acceptable salt thereof are characterized by being any one of the following compounds:
2. the aminothiazole isatins and pharmaceutically acceptable salts thereof of claim 1 wherein the pharmaceutically acceptable salt is a hydrochloride, nitrate or acetate salt.
3. A process for the preparation of aminothiazole isatins and pharmaceutically acceptable salts thereof as claimed in any one of claims 1 or 2, which comprises the steps of:
a. preparation of intermediate II: taking isatin as an initial raw material to react with different halogenated alkanes or benzyl halide to obtain an intermediate II;
b. preparation of intermediate III: carrying out condensation reaction on the intermediate II serving as a raw material and semicarbazide hydrochloride to obtain an intermediate III with different substitutions;
c. preparation of aminothiazole isatin compounds shown in general formula I and pharmaceutically acceptable salts thereof: dissolving the intermediate III with different substitutions in ethanol, and performing condensation and ring closure reaction with chloroacetaldehyde; the general formula I is any one of the following:
4. the method of claim 3,
in the step a, reacting for 8 hours at 80 ℃ by using acetonitrile as a solvent and potassium carbonate as a base;
in the step b, the solvent used in the condensation reaction is ethanol, and the reflux reaction is carried out for 12 hours at the temperature of 80 ℃;
in the step c, the solvent used in the condensation ring-closing reaction is ethanol, and the reflux reaction is carried out for 24-36h at the temperature of 80 ℃.
5. Use of the aminothiazole isatin compounds and pharmaceutically acceptable salts thereof as claimed in any one of claims 1 or 2 for the preparation of antibacterial and/or antifungal medicaments.
6. The use of claim 5, wherein the bacteria is at least one of Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, enterococcus faecalis, Acinetobacter baumannii, or Pseudomonas aeruginosa; the fungus is at least one of Candida tropicalis, Aspergillus fumigatus, Candida albicans or Candida parapsilosis.
7. The use of claim 6, wherein the Staphylococcus aureus is methicillin-resistant Staphylococcus aureus.
8. Use of the aminothiazole isatin compounds and pharmaceutically acceptable salts thereof as claimed in any one of claims 1 or 2 for the preparation of DNA intercalators.
9. Use according to claim 8, wherein the DNA is MRSA strain DNA.
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