CN110590766B - Coumarin-thiazole ester derivatives, and preparation method and application thereof - Google Patents

Coumarin-thiazole ester derivatives, and preparation method and application thereof Download PDF

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CN110590766B
CN110590766B CN201910941256.5A CN201910941256A CN110590766B CN 110590766 B CN110590766 B CN 110590766B CN 201910941256 A CN201910941256 A CN 201910941256A CN 110590766 B CN110590766 B CN 110590766B
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coumarin
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吕献海
刘浩
夏东国
程祥
巩杰秀
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Abstract

The invention discloses a coumarin-thiazole ester derivative and a preparation method and application thereof, belonging to the technical field of biochemistry, wherein the coumarin-thiazole ester derivative takes an intermediate 4 and an intermediate 7 as raw materials, a catalytic amount of DCC and DMAP is added, and a target product can be synthesized through one-step reaction after reacting for 10-15 hours at 0 ℃. The application provides a foundation for developing a novel antibacterial agent taking coumarin-thiazole ester derivatives as active ingredients.

Description

Coumarin-thiazole ester derivatives, and preparation method and application thereof
Technical Field
The invention relates to the technical field of biochemistry, and particularly relates to a coumarin-thiazole ester derivative and a preparation method and application thereof.
Background
The spread of drug-resistant bacteria poses a significant threat to human health and increases morbidity and mortality. Microbial infections such as bacteria and fungi cause about one fifth of the total deaths in the world. With respect to antibiotic resistant bacteria, over the last two decades, the U.S. food and drug administration and the european drug administration have disclosed that only two new classes of antibiotics (lipopeptides and oxazolidinones) have been developed and approved.
As a basic ribozyme of cells, DNA topoisomerase (DNA Topo) is involved in life processes such as cell replication, transcription and mitosis. Bacterial topoisomerase II (DNA helicase) and topoisomerase IV (Topo IV) are effective targets for the development of novel antibacterial agents. Topo II inhibitors have two main structural classes, namely quinolones and coumarins. However, mutation of the carbostyril binding site of Topo II results in resistance to the carbostyril. To address this problem, an effective approach is to retain the existing antibiotic core scaffold and continually change the new compounds without reducing their antibacterial activity.
The neomycin is one of representative drugs of coumarin antibiotics, and has a good inhibition effect on DNA topoisomerase. Coumarin is widely present in secondary plant metabolites. There have been and are described to date a number of 1800 different natural coumarins, many of which have high levels of biological activity, such as insecticidal, antioxidant, anticancer, anti-HIV, antifungal, antibacterial and antibiotic activity. Therefore, modification of the coumarin backbone to discover novel topoisomerase II inhibitors is feasible and of great significance to address existing bacterial resistance issues.
Disclosure of Invention
It is an object of the present invention to address at least the above problems and to provide at least the advantages described hereinafter.
The invention also aims to provide a coumarin-thiazole ester derivative, and the invention provides 24 coumarin-thiazole ester derivatives, provides chemical structures thereof and verifies antibacterial activity thereof.
The invention also aims to provide a preparation method of the coumarin-thiazole ester derivatives, a series of coumarin-thiazole ester derivatives are prepared by taking thiazole and coumarin as raw materials and substituting different substituents, and the method and the used equipment are simple and easy to implement.
The invention also provides an application of the coumarin-thiazole ester derivatives, and the identification result shows that the coumarin-thiazole ester derivatives have obvious inhibition effects on staphylococcus aureus, listeria, escherichia coli and salmonella by applying a series of prepared coumarin-thiazole ester derivatives to different bacterial diseases.
To achieve these objects and other advantages in accordance with the present invention, there is provided a coumarin-thiazole ester derivative, represented by the following formula i:
Figure BDA0002222951990000021
wherein R is 1 Is hydrogen or halogen; r is 2 Is a diethylamino group; r is 3 Is phenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, p-tolyl, isobutyl or naphthyl; when R is 1 When the position has a substituent, R 2 The position is hydrogen; when R is 2 When the position has a substituent, R 1 The site is hydrogen.
The invention also provides a preparation method of the coumarin-thiazole ester derivative, which comprises the following steps:
and dissolving the intermediate 4 and the intermediate 7, adding DCC and DMAP, reacting at 0 ℃ for 10-15 hours, and purifying to obtain the coumarin-thiazole ester derivative.
Figure BDA0002222951990000031
Wherein R is 1 Is hydrogen or halogen; r 2 Is diethylamino; r 3 Is phenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, p-tolyl, isobutyl or naphthyl; wherein when R is 1 When the position has a substituent, R 2 The position is hydrogen; when R is 2 When a position has a substituent, R 1 The site is hydrogen.
Preferably, the preparation method of the intermediate 4 comprises the following steps:
dissolving salicylaldehyde 1 and Meldrum's acid 2, adding pyridine and acetic acid, refluxing, waiting for crude product crystallization, and washing with alcohol after suction filtration to obtain intermediate 4, wherein the preparation process of the intermediate 4 is as follows, and in the process of preparing the intermediate 4 from salicylaldehyde 1 and Meldrum's acid 2, the intermediate 3 is a transition product:
Figure BDA0002222951990000032
wherein R is 1 Is hydrogen or halogen; r 2 Is a diethylamino group; when R is 1 When the position has a substituent, R 2 The position is hydrogen; when R is 2 When a position has a substituent, R 1 The position is hydrogen, a is piperidine, acetic acid and ethanol, and b is reflux for 2h.
Preferably, the preparation method of the intermediate 7 comprises the following steps:
adding the compound 5 and ultra-dry tetrahydrofuran into a container filled with nitrogen, cooling to 78 ℃ below zero, then adding n-butyl lithium, reacting for a period of time, adding the compound 6 into the container, continuing to react for a period of time, heating the reaction to room temperature, continuing to react for a period of time, quenching the reaction with water after the reaction is finished, and purifying to obtain an intermediate 7, wherein the preparation process of the intermediate 7 is as follows:
Figure BDA0002222951990000041
wherein R is 3 Is phenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, p-tolyl, isobutyl or naphthyl.
Preferably, the molar ratio of intermediate 4 to intermediate 7 is 1.1.
Preferably, the molar ratio of the added amounts of DCC and DMAP is 1.5.
Preferably, the molar ratio of salicylaldehyde 1 to mucic acid 2 is 1.
Preferably, the molar ratio of the added pyridine to the added acetic acid is 4.
Preferably, the molar ratio of compound 5 to compound 6 is 1.
Preferably, n-butyllithium is added and the reaction is carried out for 0.75h, the compound 6 is added and the reaction is carried out for 1h, and the reaction is carried out for 2h after the temperature is raised to room temperature.
The invention also provides application of the coumarin-thiazole ester derivative in serving as an antibacterial agent.
The invention has at least the following beneficial effects:
the coumarin-thiazole ester derivatives disclosed by the invention take an intermediate 4 and an intermediate 7 as raw materials, catalytic amount of DCC and DMAP is added, the reaction is carried out for 10-15 hours at 0 ℃, and a target product can be synthesized through one-step reaction, and the post-treatment of the synthesis methodThe process is simple. The method of the invention prepares 24 different derivatives, provides the chemical structures of the derivatives and verifies the antibacterial activity of the derivatives, and the result shows that most compounds have general inhibition effect; the compound 8p shows excellent antibacterial activity and IC on 4 bacteria 50 The values were 21.386,17.142,28.401 and 15.971. Mu.M, respectively. Of these compounds, 8i and 8v exhibited the best antibacterial activity against staphylococcus aureus, and 8x exhibited the best antibacterial activity against listeria. The application provides a foundation for developing a novel antibacterial agent taking coumarin-thiazole ester derivatives as active ingredients.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without inventive exercise.
FIG. 1 is a synthetic route diagram of the present invention.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
Example 1
A method for preparing compound 1:
(1) 2-hydroxybenzaldehyde 1 (0.02 mol) and Meldrum's acid 2 (0.02 mol) were dissolved in ethanol, followed by addition of piperidine and acetic acid as catalysts, and refluxing in ethanol. Then crystallizing the crude product in a solvent, filtering and washing with ethanol to obtain an intermediate 4;
(2) 4, 5-dimethylthiazole (5) (1mL, 9.45mmol) and THF were added to a round-bottom flask charged with nitrogen, and the mixture was cooled to-78 ℃. N-butyllithium (1.9M, 6mL, 11.3mmol) was then added dropwise to the flask. The mixture was stirred at-78 ℃ for 45 minutes. Benzaldehyde 6 (28.4 mmol) was then added and the reaction mixture was stirred at-78 ℃ for 1 h. Thereafter, the reaction system was warmed to room temperature and reacted for 2 hours. Finally, water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate and water. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue obtained is purified by recrystallization (ethyl acetate/petroleum ether) to give intermediate 7;
(3) Intermediate 4 and intermediate 7 were dissolved in dichloromethane in a glass flask, and then DCC and DMAP were added as condensing agents to react at 0 ℃ for 10 to 15 hours. After monitoring the reaction for completion by Thin Layer Chromatography (TLC), the mixture was filtered under vacuum and concentrated. Finally, the above crude product was isolated and purified by column chromatography (petroleum ether/ethyl acetate = 4).
Compound 1: (4, 5-Dimethylthiazol-2-yl) (phenyl) methyl 2-oxo-2H-chromene-3-carboxylate (8 a), having the formula:
Figure BDA0002222951990000061
1 H NMR(600MHz,CDCl 3 )δ8.48(s,1H),7.62–7.54(m,3H),7.42(d,J＝7.4Hz,2H),7.28(dd,J＝11.3,5.7Hz,4H),7.23(t,J＝7.3Hz,1H),2.22(dd,J＝30.7,16.9Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ170,162.96,156.71,155.03,148.62,134.35,129.54,128.71,128.42,127.98,127.20,126.45,124.86,118.09,117.79,116.67,116.64,61.92,14.20,11.24.MS(ESI):392.09(C 22 H 17 NO 4 S,[M+H] + ).Anal.Calcd for C 22 H 17 NO 4 S:C,67.50；H,4.38；N,3.58；O,16.35；S,8.19；Found:C,67.48；H,4.39；N,3.57；O,16.33；S,8.20。
example 2
The preparation method of the compound 2 is different from that of the example 1 only in that p-chlorobenzaldehyde is used instead of benzaldehyde in the step (2) of the example 1, and other steps are the same as those of the example 1. Compound 2 is (4-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 2-oxo-2H-chromene-3-carboxylate, having the following structural formula:
Figure BDA0002222951990000071
1 H NMR(600MHz,CDCl 3 )δ8.58(s,1H),7.66–7.58(m,2H),7.53(d,J＝8.4Hz,2H),7.40–7.26(m,4H),7.15(s,1H),2.27(dd,J＝19.4,11.3Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ162.95,161.71,155.40,153.17,149.54,136.31,134.67,129.66,128.92,128.67,127.90,127.74,124.84,117.78,117.56,116.85,116.05,75.32,14.66,11.22.MS(ESI):426.05(C 22 H 16 ClNO 4 S,[M+H] + ).Anal.Calcd for C 22 H 16 ClNO 4 S:C,62.05；H,3.79；Cl,8.32；N,3.29；O,15.03；S,7.53；Found:C,62.04；H,3.80；Cl,8.31；N,3.28；O,15.01；S,7.51。
example 3
The preparation method of compound 3 is different from that of example 1 only in that benzaldehyde in step (2) of example 1 is replaced with isobutyraldehyde, and the other steps are the same as those of example 1. Compound 3 is 1- (4, 5-dimethylthiazol-2-yl) -2-methylpropyl 2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000081
1 H NMR(600MHz,CDCl 3 )δ8.53(s,1H),7.61(dd,J＝15.8,7.6Hz,2H),7.34–7.28(m,2H),5.95(d,J＝6.6Hz,1H),2.28(d,J＝2.8Hz,6H),2.25(s,1H),0.98(d,J＝6.8Hz,3H),0.93(dd,J＝20.5,6.8Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ169.26,163.24,162.06,156.22,155.25,148.80,134.43,129.59,126.48,125.82,124.77,117.80,116.73,79.04,33.33,18.64,14.63,11.16.MS(ESI):358.10(C 19 H 19 NO 4 S,[M+H] + ).Anal.Calcd for C 19 H 19 NO 4 S:C,63.85；H,5.36；N,3.92；O,17.90；S,8.97；Found:C,63.83；H,5.37；N,3.91；O,17.91；S,8.99。
example 4
The preparation method of compound 4 is different from that of example 1 only in that 1-naphthaldehyde is used instead of benzaldehyde in step (2) of example 1, and the other steps are the same as those of example 1. Compound 4 is (4, 5-dimethylthiazol-2-yl) (naphthalen-1-yl) methyl 2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000091
1 H NMR(600MHz,CDCl 3 )δ8.62(s,1H),8.26(d,J＝8.4Hz,1H),7.98–7.90(m,2H),7.87(d,J＝8.1Hz,2H),7.67–7.61(m,1H),7.60(d,J＝7.7Hz,1H),7.56–7.46(m,3H),7.38–7.29(m,2H),2.29(d,J＝16.4Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ163.37,161.73,156.27,155.37,149.48,148.50,134.53,133.83,133.57,130.48,129.64,129.58,128.77,128.15,126.67,125.89,125.39,125.37,124.76,123.72,117.83,116.79,73.43,14.70,11.25.MS(ESI):442.10(C 26 H 19 NO 4 S,[M+H] + ).Anal.Calcd for C 26 H 19 NO 4 S:C,70.73；H,4.34；N,3.17；O,14.50；S,7.26；Found:C,70.72；H,4.32；N,3.18；O,14.51；S,7.25。
example 5
The preparation method of compound 5 is different from that of example 1 only in that m-chlorobenzaldehyde is used instead of benzaldehyde in step (2) of example 1, and the other steps are the same as those of example 1. Compound 5 is (3-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000101
1 H NMR(600MHz,CDCl 3 )δ8.61(s,1H),7.81(d,J＝7.7Hz,1H),7.67–7.59(m,2H),7.57(s,1H),7.40(d,J＝8.5Hz,1H),7.38–7.28(m,4H),2.31(d,J＝4.2Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ161.63,161.52,156.23,155.35,149.46,148.94,133.18,129.94,129.71,129.66,128.78,127.27,124.81,117.80,117.59,116.81,72.29,14.75,11.26.MS(ESI):426.05(C 22 H 16 ClNO 4 S,[M+H] + ).Anal.Calcd for C 22 H 16 ClNO 4 S:C,62.05；H,3.79；Cl,8.32；N,3.29；O,15.03；S,7.53；Found:C,62.03；H,3.77；Cl,8.31；N,3.30；O,15.05；S,7.51。
example 6
The preparation method of compound 6 is different from that of example 1 only in that o-chlorobenzaldehyde is used instead of benzaldehyde in step (2) of example 1, and the other steps are the same as those of example 1. Compound 6 is (2-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000102
1 H NMR(600MHz,CDCl 3 )δ8.60(s,1H),7.80(d,J＝6.8Hz,1H),7.66–7.59(m,2H),7.56(s,1H),7.38(d,J＝7.7Hz,1H),7.31(dt,J＝23.3,7.8Hz,4H),2.30(d,J＝4.5Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ161.62,161.50,156.23,155.33,149.47,135.59,133.16,129.94,129.68,128.77,128.13,127.27,118.02,117.78,117.54,116.78,72.27,14.74,11.25.MS(ESI):426.05(C 22 H 16 ClNO 4 S,[M+H] + ).Anal.Calcd for C 22 H 16 ClNO 4 S:C,62.05；H,3.79；Cl,8.32；N,3.29；O,15.03；S,7.53；Found:C,62.03；H,3.78；Cl,8.30；N,3.28；O,15.04；S,7.55。
example 7
Process for the preparation of compound 7 and intermediatesExample 1 differs in that R 1 Methyl and m-chlorobenzaldehyde were used instead of benzaldehyde in step (2) of example 1, and the other steps were the same as those of example 1. Compound 7 is (3-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl-6-methyl-2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000111
1 H NMR(600MHz,CDCl 3 )δ8.55(s,1H),7.79(dd,J＝7.7,1.4Hz,1H),7.55(s,1H),7.43(dd,J＝8.5,1.3Hz,1H),7.38(d,J＝7.7Hz,2H),7.30(ddt,J＝9.0,7.5,4.0Hz,2H),7.22(d,J＝8.5Hz,1H),2.39(s,3H),2.30(d,J＝5.0Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ161.69,161.59,156.52,153.49,149.54,148.91,135.83,134.71,129.93,129.69,129.29,128.77,127.28,117.53,117.24,116.48,72.21,20.63,14.75,11.27.MS(ESI):440.06(C 23 H 18 ClNO 4 S,[M+H] + ).Anal.Calcd for C 23 H 18 ClNO 4 S:C,62.80；H,4.12；Cl,8.06；N,3.18；O,14.55；S,7.29；Found:C,62.81；H,4.13；Cl,8.04；N,3.17；O,14.53；S,7.28。
example 8
Compound 8 was prepared by a method different from that of example 1 in that R 1 The procedure of example 1 was repeated except that p-tolualdehyde was used in place of benzaldehyde in step (2) of example 1 for bromine. Compound 8 is (4, 5-dimethylthiazol-2-yl) (p-tolyl) methyl 6-bromo-2-oxo-2H-chromene-3-carboxylic acid methyl ester, of the formula:
Figure BDA0002222951990000121
1 H NMR(600MHz,CDCl 3 )δ8.49(s,1H),7.75(d,J＝2.2Hz,1H),7.72(dd,J＝8.8,2.3Hz,1H),7.47(d,J＝8.1Hz,2H),7.25(d,J＝8.9Hz,1H),7.21–7.15(m,3H),2.34(s,3H),2.30(d,J＝10.5Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ163.53,161.18,155.50,154.12,148.57,147.69,138.80,137.14,134.73,131.65,129.43,127.26,126.49,119.26,118.54,117.33,76.12,21.19,14.68,11.22.MS(ESI):484.01(C 23 H 18 BrNO 4 S,[M+H] + ).Anal.Calcd for C 23 H 18 BrNO 4 S:C,57.03；H,3.75；Br,16.50；N,2.89；O,13.21；S,6.62；Found:C,57.01；H,3.76；Br,16.51；N,2.88；O,13.20；S,6.63。
example 9
The preparation of compound 9 differs from example 1 only in that R 1 The other steps are the same as those of example 1 for bromine. Compound 9 is (4, 5-dimethylthiazol-2-yl) (phenyl) methyl 6-bromo-2-oxo-2H-chromene-3-carboxylic acid methyl ester, formula shown below:
Figure BDA0002222951990000131
1 H NMR(600MHz,CDCl 3 )δ8.50(s,1H),7.79–7.67(m,2H),7.58(d,J＝7.3Hz,2H),7.35(dt,J＝28.0,7.0Hz,3H),7.24–7.17(m,2H),2.29(d,J＝8.7Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ163.28,161.27,155.50,154.09,148.57,147.85,137.62,137.19,131.68,128.82,128.73,127.22,119.23,118.75,118.52,117.34,76.14,14.68,11.23.MS(ESI):470.00(C 22 H 16 BrNO 4 S,[M+H] + ).Anal.Calcd for C 22 H 16 BrNO 4 S:C,56.18；H,3.43；Br,16.99；N,2.98；O,13.61；S,6.82；Found:C,56.17；H,3.42；Br,16.97；N,2.96；O,13.60；S,6.83。
example 10
Compound 10 was prepared by a method different from that of example 1 in that R 1 The procedure of example 1 was repeated except that p-chlorobenzaldehyde was used in place of benzaldehyde in step (2) of example 1. Compound 10 is (4-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 6-bromo-2-oxo-2H-chromene-3-carboxylic acid methyl ester, having the following structural formula:
Figure BDA0002222951990000141
1 H NMR(600MHz,CDCl 3 )δ8.49(s,1H),7.77–7.71(m,2H),7.54(d,J＝8.4Hz,2H),7.36(d,J＝8.5Hz,2H),7.27(s,1H),7.25(s,1H),7.16(s,1H),2.31(d,J＝13.6Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ162.69,161.27,155.49,154.14,148.75,148.04,137.32,136.12,134.82,131.69,128.97,128.67,119.18,118.64,118.56,117.42,75.50,14.68,11.24.MS(ESI):503.96(C 22 H 15 BrClNO 4 S,[M+H] + ).Anal.Calcd for C 22 H 15 BrClNO 4 S:C,52.35；H,3.00；Br,15.83；Cl,7.02；N,2.77；O,12.68；S,6.35；Found:C,52.36；H,3.02；Br,15.84；Cl,7.03；N,2.78；O,12.67；S,6.33。
example 11
Compound 11 was prepared by a method different from that of example 1 in that R 1 The procedure of example 1 was repeated except that the benzaldehyde in step (2) of example 1 was replaced with isobutyraldehyde and bromine was used. Compound 11 is 1- (4, 5-dimethylthiazol-2-yl) -2-methylpropyl-6-bromo-2-oxo-2H-chromene-3-carboxylate, having the following structural formula:
Figure BDA0002222951990000142
1 H NMR(600MHz,CDCl 3 )δ8.45(s,1H),7.76(d,J＝2.1Hz,1H),7.72(dd,J＝8.8,2.2Hz,1H),7.24(s,1H),5.96(d,J＝6.6Hz,1H),2.44(dq,J＝13.5,6.7Hz,1H),2.31(d,J＝4.1Hz,6H),1.09(d,J＝6.7Hz,3H),1.00(d,J＝6.8Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ162.97,161.68,155.56,154.04,148.14,147.29,137.07,131.61,126.57,119.26,118.53,117.32,79.33,33.35,18.66,14.70,11.23.MS(ESI):436.01(C 19 H 18 BrNO 4 S,[M+H] + ).Anal.Calcd for C 19 H 18 BrNO 4 S:C,52.30；H,4.16；Br,18.31；N,3.21；O,14.67；S,7.35；Found:C,52.31；H,4.15；Br,18.30；N,3.22；O,14.65；S,7.34。
example 12
Compound 12 was prepared by a method different from that of example 1 in that R 1 The procedure of example 1 was repeated except that 1-naphthaldehyde was used in place of benzaldehyde in step (2) of example 1 as bromine. Compound 12 is (4, 5-dimethylthiazol-2-yl) (naphthalen-1-yl) methyl 6-bromo-2-oxo-2H-chromene-3-carboxylic acid methyl ester, having the formula:
Figure BDA0002222951990000151
1 H NMR(600MHz,CDCl 3 )δ8.52(s,1H),8.23(d,J＝8.5Hz,1H),7.94(s,1H),7.89(dd,J＝17.6,7.6Hz,3H),7.73(dd,J＝4.8,2.0Hz,1H),7.71(d,J＝4.2Hz,1H),7.69–7.65(m,1H),7.57–7.47(m,3H),2.29(d,J＝17.3Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ163.13,161.30,155.58,154.11,148.59,147.95,137.17,133.82,133.38,131.66,130.90,130.43,129.68,128.81,128.25,126.73,125.94,125.36,123.64,119.25,118.83,118.52,117.34,73.64,14.72,11.27.MS(ESI):520.01(C 26 H 18 BrNO 4 S,[M+H] + ).Anal.Calcd for C 26 H 18 BrNO 4 S:C,60.01；H,3.49；Br,15.35；N,2.69；O,12.30；S,6.16；Found:C,60.02；H,3.47；Br,15.36；N,2.68；O,12.31；S,6.15。
example 13
Compound 13 was prepared by a method different from that of example 1 in that R 1 The procedure of example 1 was repeated except that the benzaldehyde used in step (2) of example 1 was replaced with bromine and m-benzaldehyde. Compound 13 is (3-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 6-bromo-2-oxo-2H-chromene-3-carboxylic acid methyl ester, formula shown below:
Figure BDA0002222951990000161
1 H NMR(600MHz,CDCl 3 )δ8.51(s,1H),7.79–7.69(m,3H),7.55(s,1H),7.40(dd,J＝7.6,1.0Hz,1H),7.36–7.28(m,2H),7.24(d,J＝8.8Hz,1H),2.31(d,J＝5.3Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ161.39,161.09,155.54,154.09,149.01,147.94,137.21,131.68,130.03,129.74,128.74,127.29,119.22,118.68,118.53,117.37,72.47,14.76,11.28.MS(ESI):503.96(C 22 H 15 BrClNO 4 S,[M+H] + ).Anal.Calcd for C 22 H 15 BrClNO 4 S:C,52.35；H,3.00；Br,15.83；Cl,7.02；N,2.77；O,12.68；S,6.35；Found:C,52.36；H,3.02；Br,15.82；Cl,7.01；N,2.75；O,12.67；S,6.37。
example 14
Compound 14 was prepared by a method different from that of example 1 in that R 1 The procedure of example 1 was repeated except that the benzaldehyde in step (2) of example 1 was replaced by a nitro group and m-chlorobenzaldehyde. Compound 14 is (3-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl-6-nitro-2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000171
1 H NMR(600MHz,CDCl 3 )δ10.56(s,1H),8.71(d,J＝2.7Hz,1H),8.34(dd,J＝9.2,2.8Hz,1H),7.63–7.60(m,1H),7.47(dd,J＝5.2,3.9Hz,1H),7.37–7.34(m,2H),7.22(d,J＝9.2Hz,1H),7.07(s,1H),2.34(s,6H). 13 C NMR(150MHz,CDCl 3 )δ187.26,163.13,161.17,149.21,142.25,133.10,130.63,130.47,130.13,127.90,127.77,124.67,114.98,77.15,14.75,11.38.MS(ESI):471.03(C 22 H 15 ClN 2 O 6 S,[M+H] + ).Anal.Calcd for C 22 H 15 ClN 2 O 6 S:C,56.12；H,3.21；Cl,7.53；N,5.95；O,20.39；S,6.81；Found:C,56.10；H,3.20；Cl,7.52；N,5.93；O,20.38；S,6.82。
example 15
Compound 15 was prepared by the method different from example 1 except that R was used 1 The other steps were the same as in example 1, except for chlorine. Compound 15 is (4, 5-dimethylthiazol-2-yl) (phenyl) methyl6-chloro-2-oxo-2H-chromene-3-carboxylic acid methyl ester, of the formula:
Figure BDA0002222951990000181
1 H NMR(600MHz,CDCl 3 )δ8.51(s,1H),7.59(dd,J＝9.7,4.3Hz,4H),7.38(t,J＝7.4Hz,2H),7.36–7.28(m,2H),7.20(s,1H),2.30(d,J＝8.8Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ163.29,161.21,155.64,153.63,148.58,148.03,137.59,134.45,130.19,128.86,128.77,128.61,127.23,118.69,118.30,76.15,14.72,11.28.MS(ESI):426.05(C 22 H 16 ClNO 4 S,[M+H] + ).Anal.Calcd for C 22 H 16 ClNO 4 S:C,62.05；H,3.79；Cl,8.32；N,3.29；O,15.03；S,7.53；Found:C,62.04；H,3.78；Cl,8.31；N,3.28；O,15.04；S,7.55。
example 16
Compound 16 was prepared by a method different from that of example 1 in that R 1 The procedure of example 1 was repeated except that p-chlorobenzaldehyde was used instead of benzaldehyde in step (2) of example 1. Compound 16 is (4-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl-6-chloro-2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000191
1 H NMR(600MHz,CDCl 3 )δ8.51(s,1H),7.62–7.58(m,2H),7.53(d,J＝8.4Hz,2H),7.34(dd,J＝20.7,8.5Hz,3H),7.16(s,1H),2.31(d,J＝14.0Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ162.71,161.30,155.53,153.68,148.72,148.11,136.13,134.81,134.50,130.24,128.96,128.67,124.33,123.42,118.71,118.68,118.29,75.49,14.66,11.23.MS(ESI):460.01(C 22 H 15 Cl 2 NO 4 S,[M+H] + ).Anal.Calcd for C 22 H 15 Cl 2 NO 4 S:C,57.40；H,3.28；Cl,15.40；N,3.04；O,13.90；S,6.96；Found:C,57.41；H,3.29；Cl,15.41；N,3.03；O,13.91；S,6.97。
example 17
Compound 17 was prepared by a method different from example 1 in that R 1 The procedure of example 1 was repeated except that 1-naphthaldehyde was used in place of benzaldehyde in step (2) of example 1 as chlorine. Compound 17 is (4, 5-dimethylthiazol-2-yl) (naphthalen-1-yl) methyl 6-chloro-2-oxo-2H-chromene-3-carboxylic acid methyl ester, having the formula:
Figure BDA0002222951990000192
1 H NMR(600MHz,CDCl 3 )δ8.52(s,1H),8.24(d,J＝8.5Hz,1H),8.12(s,1H),7.94(s,1H),7.91(d,J＝7.0Hz,1H),7.88(d,J＝7.9Hz,3H),7.72(d,J＝8.8Hz,2H),7.31(d,J＝8.9Hz,2H),2.30(s,3H),2.28(s,3H). 13 C NMR(150MHz,CDCl 3 )δ163.06,162.66,158.44,153.48,153.09,152.11,146.95,139.44,134.06,132.71,130.45,128.38,127.85,119.08,118.24,118.18,108.68,62.17,14.15,14.05.MS(ESI):476.06(C 26 H 18 ClNO 4 S,[M+H] + ).Anal.Calcd for C 26 H 18 ClNO 4 S:C,65.61；H,3.81；Cl,7.45；N,2.94；O,13.45；S,6.74；Found:C,65.60；H,3.80；Cl,7.46；N,2.96；O,13.43；S,6.75。
example 18
Compound 18 was prepared by a method different from example 1 in that R 1 The procedure of example 1 was repeated except that the benzaldehyde in step (2) of example 1 was replaced by chlorine and m-chlorobenzaldehyde. Compound 18 is (3-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 6-chloro-2-oxo-2H-chromene-3-carboxylate, having the following structural formula:
Figure BDA0002222951990000201
1 H NMR(600MHz,CDCl 3 )δ8.43(s,1H),7.72(s,1H),7.58(d,J＝7.9Hz,2H),7.55–7.50(m,2H),7.32(s,1H),7.30(s,1H),1.94(d,J＝11.5Hz,3H),1.83(d,J＝12.7Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ163.30,162.65,158.45,156.12,154.48,153.09,152.10,146.98,139.45,134.07,132.72,130.45,128.38,127.85,119.07,118.24,118.19,62.18,14.15,14.06.MS(ESI):460.01(C 22 H 15 Cl 2 NO 4 S,[M+H] + ).Anal.Calcd for C 22 H 15 Cl 2 NO 4 S:C,57.40；H,3.28；Cl,15.40；N,3.04；O,13.90；S,6.96；Found:C,57.41；H,3.27；Cl,15.41；N,3.03；O,13.92；S,6.95。
example 19
Compound 19 was prepared by a method different from example 1 in that R 2 The procedure of example 1 was repeated except for using diethylamino and p-tolualdehyde instead of benzaldehyde in step (2) of example 1. Compound 19 is (4, 5-dimethylthiazol-2-yl) (p-tolyl) methyl 7- (diethylamino) -2-oxo-2H-chromene-3-carboxylic acid methyl ester, of the formula:
Figure BDA0002222951990000211
1 H NMR(600MHz,CDCl 3 )δ8.42(s,1H),7.66(s,1H),7.35(d,J＝8.9Hz,1H),7.28(s,1H),6.59(d,J＝8.8Hz,2H),6.47(d,J＝5.6Hz,2H),6.42(s,1H),3.51(s,4H),2.41(s,3H),2.31-2.30(d,J＝6Hz,6H),1.25-1.22(t,J＝6Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ165.13,164.23,160.17,158.45,158.19,156.89,153.62,152.83,151.62,149.09,142.03,130.94,129.88,117.96,109.45,109.14,107.69,107.33,97.05,96.76,61.10,14.33,12.40,12.38.MS(ESI):477.18(C 27 H 28 N 2 O 4 S,[M+H] + ).Anal.Calcd for C 27 H 28 N 2 O 4 S:C,68.05；H,5.92；N,5.88；O,13.43；S,6.73；Found:C,68.04；H,5.91；N,5.87；O,13.41；S,6.74。
example 20
Compound 20 was prepared by a method different from that of example 1 in that R 2 The other steps were the same as in example 1, except for diethylamino. Compound 20 is (4, 5-dimethylthiazol-2-yl) (phenyl) methyl 7- (diethylamino) -2-oxo-2H-chromene-3-carboxylate, having the formula:
Figure BDA0002222951990000221
1 H NMR(600MHz,CDCl 3 )δ8.42(s,1H),7.67(s,1H),7.35(d,J＝12.1Hz,1H),7.29–7.27(m,1H),7.25(s,1H),6.60(s,2H),6.47(s,2H),6.43(s,1H),3.48-3.44(m,4H),2.41-2.39(t,J＝6Hz,6H),1.25-1.22(m,6H). 13 C NMR(150MHz,CDCl 3 )δ165.03,162.10,156.15,153.32,150.75,147.43,141.68,128.59,128.28,126.52,124.60,123.79,119.07,115.79,108.04,105.46,92.07,73.65,49.16,14.53,14.06,11.26.MS(ESI):463.16(C 26 H 26 N 2 O 4 S,[M+H] + ).Anal.Calcd for C 26 H 26 N 2 O 4 S:C,67.51；H,5.67；N,6.06；O,13.84；S,6.93；Found:C,67.50；H,5.66；N,6.05；O,13.85；S,6.94。
example 21
Compound 21 was prepared by a method different from example 1 in that R 2 The procedure of example 1 was repeated except for using diethylamino and 1-naphthaldehyde instead of benzaldehyde in step (2) of example 1. Compound 21 is (4, 5-dimethylthiazol-2-yl) (naphthalen-1-yl) methyl 7- (diethylamino) -2-oxo-2H-chromene-3-carboxylic acid methyl ester, formula:
Figure BDA0002222951990000231
1 H NMR(600MHz,CDCl 3 )δ8.48(d,J＝7.8Hz,1H),8.29(t,J＝8.1Hz,1H),7.93(d,J＝7.8Hz,1H),7.90(t,J＝7.3Hz,1H),7.86–7.82(m,2H),7.53–7.45(m,3H),7.32(t,J＝8.4Hz,1H),6.57(d,J＝14.6Hz,1H),6.43(d,J＝7.7Hz,1H),3.46–3.39(m,4H),2.27(t,J＝8.0Hz,6H),1.25-1.19(m,6H). 13 C NMR(150MHz,CDCl 3 )δ164.20,162.28,158.67,157.82,153.09,149.73,148.33,133.81,131.22,130.62,128.64,126.52,125.75,125.45,125.37,123.95,109.50,108.14,107.73,96.73,72.59,45.06,14.69,12.40,11.23.MS(ESI):513.18(C 30 H 28 N 2 O 4 S,[M+H] + ).Anal.Calcd for C 30 H 28 N 2 O 4 S:C,70.29；H,5.51；N,5.46；O,12.48；S,6.25；Found:C,70.28；H,5.50；N,5.48；O,12.46；S,6.24。
example 22
Compound 22 is prepared by a process different from that of example 1 in that R 2 The procedure of example 1 was repeated except for substituting diethylamino and m-chlorobenzaldehyde for benzaldehyde in step (2) of example 1. Compound 22 is (3-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 7- (diethylamino) -2-oxo-2H-chromene-3-carboxylic acid methyl ester, having the following structural formula:
Figure BDA0002222951990000241
1 H NMR(600MHz,CDCl 3 )δ8.48(s,1H),7.58(s,1H),7.50(d,J＝7.0Hz,1H),7.36(d,J＝8.9Hz,1H),7.31–7.28(m,2H),7.15(s,1H),6.60(d,J＝8.9Hz,1H),6.45(s,1H),3.45(q,J＝7.1Hz,4H),2.31(s,3H),2.29(s,3H). 13 C NMR(150MHz,CDCl 3 )δ163.59,162.54,158.74,157.75,153.22,149.77,148.53,140.34,134.46,131.30,129.88,128.61,128.37,127.41,127.33,125.51,124.69,109.59,107.72,96.75,74.41,45.10,14.67,12.41,11.21.MS(ESI):497.12(C 26 H 25 ClN 2 O 4 S,[M+H] + ).Anal.Calcd for C 26 H 25 ClN 2 O 4 S:C,62.83；H,5.07；Cl,7.13；N,5.64；O,12.88；S,6.45；Found:C,62.81；H,5.06；Cl,7.11；N,5.65；O,12.89；S,6.44。
example 23
Compound 23 was prepared by a method different from that of example 1 in that R 2 Is diethylamino and o-chlorobenzaldehyde instead of benzaldehyde in step (2) of example 1, and the other steps are the same asProcedure of example 1. Compound 23 is (2-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 7- (diethylamino) -2-oxo-2H-chromene-3-carboxylic acid methyl ester, of the formula:
Figure BDA0002222951990000251
1 H NMR(600MHz,CDCl 3 )δ8.48(s,1H),7.81(d,J＝7.7Hz,1H),7.54(s,1H),7.38(d,J＝7.9Hz,1H),7.34(d,J＝9.0Hz,1H),7.32(d,J＝7.6Hz,1H),7.28(d,J＝7.7Hz,1H),6.59(dd,J＝8.9,2.1Hz,1H),6.44(s,1H),3.44(q,J＝7.1Hz,4H),2.30(d,J＝6.2Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ162.51,162.47,158.68,157.80,153.12,149.74,148.72,136.20,133.17,131.23,129.62,129.60,128.88,128.18,127.73,127.16,109.53,107.73,96.74,71.56,45.07,14.73,12.41,11.23.MS(ESI):497.12(C 26 H 25 ClN 2 O 4 S,[M+H] + ).Anal.Calcd for C 26 H 25 ClN 2 O 4 S:C,62.83；H,5.07；Cl,7.13；N,5.64；O,12.88；S,6.45；Found:C,62.84；H,5.09；Cl,7.11；N,5.65；O,12.90；S,6.44。
example 24
Compound 24 was prepared by a method different from that of example 1 in that R 2 The procedure of example 1 was repeated except for using diethylamino and p-chlorobenzaldehyde instead of benzaldehyde in step (2) of example 1. Compound 24 is (4-chlorophenyl) (4, 5-dimethylthiazol-2-yl) methyl 7- (diethylamino) -2-oxo-2H-chromene-3-carboxylate, having the following structural formula:
Figure BDA0002222951990000261
1 H NMR(600MHz,CDCl 3 )δ8.46(s,1H),7.54(d,J＝8.4Hz,2H),7.33(dd,J＝14.3,8.7Hz,3H),7.14(s,1H),6.59(dd,J＝8.9,2.2Hz,1H),6.43(d,J＝1.8Hz,1H),3.44–3.40(m,4H),2.30-2.27(m,6H),1.22(t,J＝6Hz,6H). 13 C NMR(150MHz,CDCl 3 )δ163.87,162.66,158.71,156.87,153.20,149.79,148.48,136.94,134.34,131.31,129.91,128.79,128.69,127.33,109.62,107.67,96.67,74.49,45.11,14.70,12.41,10.93.MS(ESI):497.12(C 26 H 25 ClN 2 O 4 S,[M+H] + ).Anal.Calcd for C 26 H 25 ClN 2 O 4 S:C,62.83；H,5.07；Cl,7.13；N,5.64；O,12.88；S,6.45；Found:C,62.85；H,5.06；Cl,7.12；N,5.65；O,12.89；S,6.46.
example 25 study of antibacterial Activity of coumarin-thiazole ester derivatives subjects: coumarin-thiazole ester derivatives, i.e., compounds 1-24, prepared in examples 1-24, respectively.
Preparing bacterial liquid to be detected: picking up a small amount of lawn from the slant of fresh strain, inoculating in liquid culture medium suitable for bacterial growth, and culturing in an incubator at 37 deg.C for 18-24h. After culturing, 2-3mL of sterile physiological saline is added, the thalli are washed sufficiently by a sterile inoculating needle, suspension is sucked out of the inclined plane by a sterile suction tube with a cotton pipe opening to a sterile test tube, and then counting is carried out. The bacteria were then diluted 50-fold with MH medium to a final concentration of 10 3 -10 5 cfu/mL。
Control drugs: novobiocin, ciprofloxacin, gatifloxacin, levofloxacin.
Preparing a drug sensitive plate: the compound is prepared into 1mg/mL mother solution, diluted into solutions of 50, 25, 12.5, 6.25 and 3.125 mu g/mL by a two-fold dilution method, and four concentrations of 50, 12.5, 6.25 and 3.125 mu g/mL are selected for carrying out experiments. The first 96-well plate was used as a blank control and 100ul of medium was added, and the second was used as a positive control and 100ul of bacterial suspension was added. The remaining wells were filled with 90. Mu.l of the bacterial suspension and 10. Mu.L of the drug solution. Each drug solution concentration was replicated 3 times.
Culturing: the bacteria were incubated in an incubator at 37 ℃ for 24 hours, then 50. Mu.L of 2mg/mL MTT solution was added thereto and allowed to act for 4-5 hours, 50. Mu.L of 2mg/mL MTT solution prepared with PBS was added to each well and allowed to act for 12 hours, and then OD values of the wells were measured at 600nm using an enzyme-labeled analyzer.
The results are shown in Table 1:
TABLE 1 antibacterial Activity of coumarin-thiazole ester derivatives
Figure BDA0002222951990000271
Figure BDA0002222951990000281
The results show that: the coumarin-thiazole ester derivative disclosed by the invention has relatively strong inhibitory activity on four bacteria including staphylococcus aureus, listeria, escherichia coli and salmonella, wherein the compound 8p has excellent antibacterial activity on 4 bacteria, and IC 50 The values were 21.386,17.142,28.401 and 15.971. Mu.M, respectively. Of these compounds, 8i and 8v exhibited the best antibacterial activity against staphylococcus aureus, and 8x exhibited the best antibacterial activity against listeria.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solutions of the present invention can be made by those skilled in the art without departing from the spirit of the present invention, and the technical solutions of the present invention are within the scope of the present invention defined by the claims.

Claims (10)

1. The coumarin-thiazole ester derivative is characterized by having the following structural formula:
Figure FDA0003967652480000011
2. a method for preparing coumarin-thiazole ester derivatives according to claim 1, which comprises the following steps:
dissolving the intermediate 4 and the intermediate 7, adding DCC and DMAP, reacting at 0 ℃ for 10-15 hours, and purifying to obtain coumarin-thiazole ester derivatives;
Figure FDA0003967652480000012
wherein R is 1 、R 2 、R 3 The same as the corresponding substituents in the product.
3. The method for preparing coumarin-thiazole ester derivatives according to claim 2, wherein the intermediate 4 is prepared as follows:
dissolving salicylaldehyde 1 and Meldrum's acid 2, adding piperidine and acetic acid, refluxing, waiting for crude product crystallization, and performing suction filtration and alcohol washing to obtain an intermediate 4, wherein the preparation process of the intermediate 4 is as follows:
Figure FDA0003967652480000021
4. the method for preparing coumarin-thiazole ester derivatives according to claim 2, wherein the intermediate 7 is prepared as follows:
adding a compound 5 and ultra-dry tetrahydrofuran into a container filled with nitrogen, cooling to 78 ℃ below zero, then adding n-butyllithium, reacting for a period of time, adding a compound 6 into the container, continuing to react for a period of time, heating a reaction system to room temperature, continuing to react for a period of time, quenching the reaction with water after the reaction is finished, and purifying to obtain an intermediate 7, wherein the preparation process of the intermediate 7 is as follows:
Figure FDA0003967652480000022
5. the method of preparing coumarin-thiazole ester derivatives according to claim 2, wherein the molar ratio of intermediate 4 to intermediate 7 is 1.1.
6. The method for preparing coumarin-thiazole ester derivatives according to claim 2, wherein the molar ratio of the amounts of DCC and DMAP added is 1.5.
7. The method for preparing coumarin-thiazole ester derivatives according to claim 3, wherein the molar ratio of salicylaldehyde 1 to mucic acid 2 is 1.
8. The method according to claim 3, wherein the molar ratio of piperidine to acetic acid is 4.
9. The method for preparing coumarin-thiazole ester derivatives according to claim 4, wherein the molar ratio of the compound 5 to the compound 6 is 1.
10. The use of coumarin-thiazole ester derivatives according to claim 1 for the preparation of antibacterial agents.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107382998A (en) * 2017-09-05 2017-11-24 河南农业大学 A kind of fluorine-containing cumarin thiazole compound and its synthetic method
CN110283166A (en) * 2019-07-31 2019-09-27 西南大学 Thiazole coumarin kind compound of ethyoxyl bridging and its preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107382998A (en) * 2017-09-05 2017-11-24 河南农业大学 A kind of fluorine-containing cumarin thiazole compound and its synthetic method
CN110283166A (en) * 2019-07-31 2019-09-27 西南大学 Thiazole coumarin kind compound of ethyoxyl bridging and its preparation method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Discovery of Novel Triazole-Containing Pyrazole Ester Derivatives as Potential Antibacterial Agents;Ming-Jie Chu等;《Molecules 》;20190403;摘要 *
Novel coumarin-thiazolyl ester derivatives as potential DNA gyrase Inhibitors: Design, synthesis, and antibacterial activity;Hao Liu等;《Bioorganic Chemistry》;20200504;摘要 *

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