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Isatin derivative and application thereof in preparation of medicines for resisting super-drug-resistance bacteria

A technology of indolindione and antibacterial drugs, which is applied in the field of indolindione derivatives and the preparation of anti-drug-resistant bacteria drugs, can solve the problems of not indicating the inhibitory effect of drug-resistant bacteria, and achieve a strong inhibitory effect Effect

Inactive Publication Date: 2012-05-23
NANKAI UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Hall M.D. et al. (J.Med.Chem., 2009, 52(10), 3191-3204) reported compounds of structural formula (F), which have a strong inhibitory effect on multiple drug-resistant cancer cells and are being Conduct preclinical studies, but the literature does not indicate that this type of compound has an inhibitory effect on drug-resistant bacteria

Method used

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  • Isatin derivative and application thereof in preparation of medicines for resisting super-drug-resistance bacteria
  • Isatin derivative and application thereof in preparation of medicines for resisting super-drug-resistance bacteria
  • Isatin derivative and application thereof in preparation of medicines for resisting super-drug-resistance bacteria

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the synthesis of compound WJG-1

[0030]

[0031] Add 3.0g (20mmol) indolindione into 40mL glacial acetic acid, add 9.8g Br dropwise at room temperature 2 (61mmol) is dissolved in the solution of 10mL acetic acid, stirs 0.5h, then heats up and refluxes 1.5h, separates out red crystal, suction filtration, oven dry, obtain product 5,7-dibromoindolindione 5.8g, productive rate is about 94%.

[0032]Add 2.0g (6.6mmol) of 5,7-dibromoindolindione and 0.9g (6.6mmol) of anhydrous potassium carbonate into a 100mL three-necked flask filled with 45mL of DMF, heat to 65°C, and add 1.9g after 1h (13.2mmol) m-fluorine substituted benzyl chloride, after 2 hours of reaction, 2 times the volume of water was added, filtered and washed with water to obtain a red solid, and dried to obtain N-m-fluorobenzyl-5,7-dibromoindolindione 2.4 g, yield 89%.

[0033] Add 6.17g (37mmol) of 30% hydrazine hydrate into the reaction flask, acidify with 35% hydrochloric acid under cooli...

Embodiment 2

[0036] Embodiment 2: the synthesis of compound WJG-4

[0037]

[0038] Add 4.0mL (40mmol) of chloral hydrate and 45.9g (324mmol) of anhydrous sodium sulfate to 120mL of water. After the internal temperature rises to 40°C, stir until it becomes clear. Add 7.9g (36.0mmol) of o-iodine dropwise within 10 to 15 minutes. A solution composed of aniline and 50mL 5% hydrochloric acid, continue to react at this temperature for 0.5h, a large amount of white precipitates precipitate, quickly add 7.5g (108mmol) of hydroxylamine hydrochloride and raise the internal temperature to 75°C, a flocculent solid is formed, continue to react for 4h After that, the reaction was stopped, cooled to room temperature, filtered and dried to obtain 8.9 g of 2-iodo-1-isonitroso-acetanilide brown powder with a yield of 85%.

[0039] Preheat 25mL of concentrated sulfuric acid to 75°C, control the reaction temperature at 75-80°C, add 7.3g (25mmol) 2-iodo-1-isonitroso-acetanilide in batches within 0.5h under...

Embodiment 3

[0044] Example 3: Determination of anti-MRSA activity of indolindione derivatives.

[0045] 1. Test material

[0046] Mueller-Hinton Broth (Beijing Oboxing Biotechnology Co., Ltd.), tryptone (UK OXOID company), yeast extract powder (UK OXOID company), sodium chloride (Sinopharm Chemical Reagent Co., Ltd.), 96-well cell culture plate ( flat bottom) (Corning, U.S.), positive control drug vancomycin (Amresco, U.S.), dimethyl sulfoxide DMSO (Sinopharm Chemical Reagent Co., Ltd.), MHB medium (use an electronic balance to weigh 24 grams of Mueller-HintonBroth The dry powder was dissolved in 1000 ml of distilled water, adjusted to pH 7.2, and sterilized at 121° C. for 20 minutes using an autoclave). Methicillin-resistant Staphylococcus aureus MRSA (clinically isolated drug-resistant strain from Beijing Chaoyang Hospital Affiliated to Capital Medical University, stored in a freezer at -80°C in glycerol tubes), Staphylococcus aureus (Staphylococcusaureus ATCC6538), Bacillus subtilis (...

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Abstract

The invention relates to an isatin derivative and application thereof in preparation of medicines for resisting super-drug-resistance bacteria. The isatin derivative has very strong inhibitory action on MRSA (Methicillin-resistant Staphylococcus Aureus) and can be used for preparing novel effective anti-microbial medicines. The medicines can be made into injections, tablets, pills, capsules, suspending agents or emulsions. The administration routes of the medicines can be of oral administration and percutaneous, venous or intramuscular injection. The isatin derivative is as shown in the chemical structural formula (I), wherein in the formula, R1 is H, phenyl or p-fluorophenyl; R2 is F, C1, Br, I or H; R3 is F, C1, Br, I or H; R4 is H, CH3 and o-fluorobenzyl, m-fluorobenzyl and p-fluorobenzyl.

Description

technical field [0001] The invention relates to indoline diketone (isatin) derivatives and their application in the preparation of drugs against drug-resistant bacteria, especially for superbugs such as methicillin-resistant Staphylococcus aureus (methicillin-resistant Staphylococcus aureus, MRSA) Has a strong inhibitory effect. Background technique [0002] Since British scientist Jevons first discovered methicillin-resistant Staphylococcus aureus (MRSA) in 1961, MRSA infection has spread around the world at an alarming rate. The high rate of infection has become a major problem in clinical treatment, and the frequency of nosocomial infection is getting higher and higher due to hospital and community infections, becoming a veritable "super bacteria". Rice once reported (J.Infect.Dis., 2008, 197, 1079-1081) that "ESKAPE" is a very important fatal drug-resistant bacteria at present. Infectious diseases, data show that MRSA causes more deaths in the United States than HIV an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/40A61K31/404A61P31/04
Inventor 王建国张立新李正名代焕琴王伟民宋福行谭海忠郭徽
Owner NANKAI UNIV
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