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Isoniazid caffeic acid amidated derivative and application thereof in anti-mycobacterium tuberculosis drug

A technology of caffeic acid amide and isoniazid, which is applied in the field of medicine, can solve the problems of liver damage and inability to effectively inhibit drug-resistant Mycobacterium tuberculosis, and achieve high activity and the effect of inhibiting drug-resistant Mycobacterium tuberculosis

Inactive Publication Date: 2015-09-23
LANZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The invention discloses an amidated derivative of isoniazid caffeic acid, which is: (E)-N'-(3-(3,4-dihydroxyphenyl)acryloyl)isoniazid, which solves the problem of existing derivatives The drug cannot effectively inhibit drug-resistant Mycobacterium tuberculosis, and is likely to cause liver damage. This derivative is higher than isoniazid in inhibiting the activity of drug-resistant Mycobacterium tuberculosis, and is less likely to cause liver damage. Compared with the first-line anti-tuberculosis drug isoniazid It has dual effects and can be used for the treatment of drug-resistant tuberculosis, providing a new option for the preparation of anti-tuberculosis drugs

Method used

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  • Isoniazid caffeic acid amidated derivative and application thereof in anti-mycobacterium tuberculosis drug
  • Isoniazid caffeic acid amidated derivative and application thereof in anti-mycobacterium tuberculosis drug
  • Isoniazid caffeic acid amidated derivative and application thereof in anti-mycobacterium tuberculosis drug

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Example 1 Preparation of Isoniazid Caffeic Acid Amidated Derivatives

[0023] 1. Preparation of Caffeic Acid

[0024] Stir and reflux 0.02mol of 3,4-dihydroxybenzaldehyde, 0.03mol of malonic acid and an appropriate amount of catalyst at 118°C for 1 to 2 hours. TLC detects that the benzaldehyde disappears completely and the reaction is complete. After reflux finishes, carry out steam distillation, remove unreacted benzaldehyde. If the color is darker, add 2-3g of activated carbon, boil for a few minutes to decolorize, filter while it is hot, and add hydrochloric acid to the hot filtrate under stirring until it is obviously acidic (pH: 4-5). After cooling, after all the crystals are precipitated, filter with suction, wash with water, and dry to obtain the crude product. After separation and purification by column chromatography, the product was dried to obtain the target product caffeic acid (3,4-dihydroxycinnamic acid), which was weighed to calculate the yield.

[002...

Embodiment 2

[0031] Example two isoniazid caffeic acid amidated derivatives in vitro inhibition of drug-resistant Mycobacterium tuberculosis test

[0032] Experimental material: drug-resistant Mycobacterium tuberculosis (H 37 R v ), donated by Lanzhou Pulmonary Hospital, Gansu Province.

[0033] Middlebrook7H9 was provided by Becton, Dickinson and Company (BD), and other reagents in the medium were of domestic analytical grade.

[0034] Modified 7H9 medium formula: 10% azodicarbonamide (ADC), 0.05% Tween-80 and 0.5% glycerol, Middlebrook7H9 medium (distilled water 897.5ml, Middlebrook7H9 powder 4.7g, 100% glycerol 2ml , 100% Tween 800.5ml).

[0035] The present embodiment adopts the 2-fold dilution method to detect that the compound of the present invention is effective against drug-resistant Mycobacterium tuberculosis H 37 R v inhibitory effect.

[0036] First, the isoniazid caffeic acid amidated derivatives obtained in Example 1 were formulated into different concentrations of test...

Embodiment 3

[0041] The hydrolysis kinetic characteristic of embodiment three isoniazid caffeic acid amidated derivatives in blood plasma

[0042] Adopt HPLC method to detect the hydrolysis kinetics characteristic of isoniazid caffeic acid amidated derivative of the present invention in blood plasma, method is: after compound is hydrolyzed in the blood plasma of 80%PBS (PH7.4) 12h, adopt C 18 The column is used for HPLC detection, detection conditions: the mobile phase is methanol-water (45:55), pH=3.5, the detection wavelength is 290nm, the column temperature is 25°C; the injection volume is 10μL, and the flow rate is 1.0mL·min -1 , while using caffeic acid as a reference substance for hydrolysis kinetics detection, the results are shown in Figure 5 . Wherein A is the HPLC figure measured after the PBS buffer solution of the amidated derivative of isoniazid caffeic acid is hydrolyzed in plasma, B is the HPLC figure measured by the PBS buffer solution of the reference substance isoniazid...

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Abstract

The present invention belongs to the technical field of medicines, discloses an isoniazid caffeic acid amidated derivative as follows: (E)-N '-(3-(3,4-dihydroxyphenyl) acryloyl) isoniazid, and also discloses a method for preparing the derivative. Isoniazid is a commonly-used first-line anti-tuberculosis drug, but the isoniazid has the shortcomings of being fast in metabolic rate, low in producing tendency of drug resistance, and low in tendency to cause liver injury, and the like. The present invention discloses the isoniazid caffeic acid amidated derivative (E)-N '-(3-(3,4-dihydroxyphenyl) acryloyl) isoniazid, and solves the problems that the isoniazid derivative in the prior art cannot effectively suppress drug-resistant mycobacterium tuberculosis, and has low tendency to cause liver injury, and the like, the drug-resistant mycobacterium tuberculosis inhibiting activity of the isoniazid derivative is higher than that of isoniazid, the isoniazid derivative has low tendency to cause liver injury, compared with the first-line anti-tuberculosis drug isoniazid, the isoniazid derivative has a dual effect, can be used for the treatment of drug-resistant tuberculosis, and provides a new choice for the preparation of anti-tuberculosis drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to an amidated derivative of isoniazid caffeic acid, which is: (E)-N'-(3-(3,4-dihydroxyphenyl)acryloyl)isoniazid, specifically It relates to the preparation method of the derivative and its application in the preparation of anti-tuberculosis drugs. technical background [0002] Drug-induced liver disease (DIH) refers to the liver damage caused by the drug itself or its metabolites after the use of one or several drugs, and oxidative stress plays an important role in drug-induced liver injury. [0003] Isoniazid (INH) is the first-line anti-tuberculosis drug commonly used at present, but liver toxicity is the main adverse reaction of isoniazid, and it is a typical anti-tuberculosis drug that causes drug-induced liver disease. Oxidative stress plays an important role in isoniazid-induced liver injury. At present, it is believed that INH is mainly caused by its metabolites hydrazine an...

Claims

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Application Information

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IPC IPC(8): C07D213/86A61P31/06
CPCC07D213/86
Inventor 李红玉吴争荣郑丽芳
Owner LANZHOU UNIVERSITY
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