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Quinoxaline-N1,N4-dioxide derivative capable of inhibiting activity of DNA topoisomerase, preparation method and application of quinoxaline-N1,N4-dioxide derivative

A topoisomerase, dioxide technology, applied in the field of biochemistry

Pending Publication Date: 2019-12-10
HUAZHONG AGRI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, with the extensive use of FQs, bacteria have gradually developed resistance to FQs; therefore, in response to the increasingly serious problem of drug resistance, it is urgent to develop new and highly effective antibacterial drugs

Method used

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  • Quinoxaline-N1,N4-dioxide derivative capable of inhibiting activity of DNA topoisomerase, preparation method and application of quinoxaline-N1,N4-dioxide derivative
  • Quinoxaline-N1,N4-dioxide derivative capable of inhibiting activity of DNA topoisomerase, preparation method and application of quinoxaline-N1,N4-dioxide derivative
  • Quinoxaline-N1,N4-dioxide derivative capable of inhibiting activity of DNA topoisomerase, preparation method and application of quinoxaline-N1,N4-dioxide derivative

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Experimental program
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Effect test

Embodiment 1

[0034] With quinoxaline ring C 3 methyl substitution, C 7 Take fluorine atom substitution as an example to illustrate

[0035] In this embodiment, quinoxaline-N 1 ,N 4 -The synthetic reaction formula of the dioxide derivative is as follows:

[0036]

[0037] Concrete preparation steps:

[0038] 1. Add 25mL tetrahydrofuran to a 50mL round-bottom reaction flask, then add 3g 4,5-difluoro-2-nitroaniline, 80mL sodium hypochlorite, and 0.2g sodium hydroxide in sequence, and react at 0°C for 2 hours. Pour into a separatory funnel, extract twice with dichloromethane (25mL×2), combine the dichloromethane layers, evaporate the solvent under reduced pressure to obtain a light yellow solid, which is 5,6-difluoro-N-oxybenzene Furazan;

[0039] 2. Quinoxaline ring C 2 Position is ethyl formate, C 3 When the position is substituted with a methyl group:

[0040] Take 3.5g of 5,6-difluoro-N-oxybenzofurazan and place it in a 50mL round-bottomed reaction flask, add 25mL of acetone to...

Embodiment 2

[0051] 7-F-6-piperazine-3-CH 3 -Ethyl 2-quinoxalinecarboxylate-N 1 ,N 4 -The synthetic reaction formula of dioxide oxide is as follows:

[0052]

[0053] The preparation steps are as follows:

[0054] (1) Add 8.7g (0.05mol) 4,5-difluoro-2-nitroaniline to a 500mL three-necked flask, add 75mL tetrahydrofuran to fully dissolve it, then add 0.6g (0.015mol) sodium hydroxide as a catalyst, Add 240mL of sodium hypochlorite dropwise in an ice bath (0°C), and stir for 2 hours to react. After the reaction is complete, the reaction solution is extracted twice with dichloromethane (400mL × 2). The organic phase is collected and the solvent is distilled off under reduced pressure to obtain a light yellow solid. 7.0 g is 5,6-difluoro-N-oxybenzofurazan, and the yield is 81.4%.

[0055] (2) Add 3.44g (0.02mol) of 5,6-difluoro-N-oxybenzofurazan to a 50mL single-necked flask, add 25mL of acetone to dissolve, then add 3.9g (0.03mol) of ethyl acetoacetate, and 2.5 g potassium carbonate, s...

Embodiment 3

[0058] 7-F-6-piperazine-3-CH 3 -2-quinoxalinecarboxylic acid-N 1 ,N 4 -The synthetic reaction formula of dioxide oxide is as follows:

[0059]

[0060] The preparation steps are as follows:

[0061] Add the 7-F-6-piperazine-3-CH obtained in Example 2 to the 50mL one-necked flask 3 -Ethyl 2-quinoxalinecarboxylate-N 1 ,N 4 - Dioxide 3.5g (0.01mol), dissolved in tetrahydrofuran / water (v:v=2:1), add 1mol / L sodium hydroxide 24.5mL, carry out hydrolysis reaction at 50°C, after the reaction, add Dilute hydrochloric acid (1mol / L) to adjust the pH value of the reaction solution to 5-6, freeze and precipitate a solid at -20°C, filter and wash with ice ethanol to obtain 1.4 g of a khaki solid powder, which is 7-F-6-piperazine-3 -CH 3 -2-quinoxalinecarboxylic acid-N 1 ,N 4- Dioxide, 43.8% yield. Melting point 218.2-220.5℃; MS: [M+H] + 323.1077; 1 H NMR (600MHz,D 2 O)δ8.08(d,J=12.4Hz,1H),7.82(d,J=7.9Hz,1H), 3.61–3.50(m,4H),3.48–3.39(m,4H),2.53(s, 3H).

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Abstract

The invention belongs to the technical field of biochemistry, and particularly relates to a quinoxaline-N1,N4-dioxide derivative capable of inhibiting the activity of DNA topoisomerase, a preparationmethod and application of the quinoxaline-N1,N4-dioxide derivative. 4,5,-difluoro-2-nitroaniline is used as a raw material for synthesis of the quinoxaline-N1,N4-dioxide derivative, the quinoxaline-N1,N4-dioxide derivative reacts with sodium hypochlorite under catalysis of a basic catalyst, namely sodium hydroxide, and 5,6-difluoro-N-benzofuroxan is obtained; and then the quinoxaline-N1,N4-dioxidederivative reacts with different substrates in Beirut reaction and substitution reaction, and a series of the quinoxaline-N1,N4-dioxide derivative is obtained. According to the quinoxaline-N1,N4-dioxide derivative, the preparation method and application of the quinoxaline-N1,N4-dioxide derivative, quinoxoline-N1,N4-dioxide has good bacteriostatic activity to previously reported gram-negative bacteria, and also had good bacteriostatic activity to actinobacilluspleuropneumoniae and gram-positive bacteria such as staphylococcus aureus and streptococcus pneumoniae.

Description

technical field [0001] The invention belongs to the technical field of biochemistry, in particular to quinoxaline-N with the activity of inhibiting DNA topoisomerase 1 ,N 4 - Dioxide derivatives, preparation methods and applications. Background technique [0002] Quinoxaline-N 1 ,N 4 -Dioxide is a class of benzopiperazine heterocyclic compounds with broad-spectrum antibacterial activity and is widely used in the fields of medicine and agriculture. The earliest research on this type of drug is its antibacterial activity (Landquist et al., 1956; Silk, 1956), especially has a good inhibitory effect on Gram-negative bacteria (Wang Xu et al., 2009), such as Pasteurella avian , Escherichia coli, Salmonella gallinarum and Shigella have significant antibacterial effects (Kong Xingang, 2008). At the same time, these compounds can also improve the feed conversion rate and promote the growth and development of animals (Cihak et al., 1983; Cihaketal., 1983; Cihak et al., 1985). Qu...

Claims

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Application Information

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IPC IPC(8): C07D241/52C07D403/04A61P31/06A61P31/04
CPCC07D241/52C07D403/04A61P31/06A61P31/04
Inventor 袁宗辉张鹤营潘源虎张洁瞿玮谢书宇陶燕飞陈冬梅黄玲利刘振利谢长清
Owner HUAZHONG AGRI UNIV
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