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Novel small molecule compound, preparation method and application thereof in preparation of mycobacterium drugs for resisting drug-resistant mycobacterium tuberculosis and like

Technology of a small molecule compound, Mycobacterium tuberculosis, applied in the field of medicine

Active Publication Date: 2019-07-09
SICHUAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the emergence of rifampicin-resistant tuberculosis (RR-TB), multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), tuberculosis The treatment of TB has encountered unprecedented challenges. In 2015 alone, there were 480,000 new cases of MDR-TB

Method used

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  • Novel small molecule compound, preparation method and application thereof in preparation of mycobacterium drugs for resisting drug-resistant mycobacterium tuberculosis and like
  • Novel small molecule compound, preparation method and application thereof in preparation of mycobacterium drugs for resisting drug-resistant mycobacterium tuberculosis and like
  • Novel small molecule compound, preparation method and application thereof in preparation of mycobacterium drugs for resisting drug-resistant mycobacterium tuberculosis and like

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: ( Z / E )- N' Preparation of -(1-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)ethylidene)isonicotinic acid hydrazide (1-a)

[0044] .

[0045] Add 200mg (0.833mmol) 2-acetylfuro[2,3-b]-4,9-naphthoquinone, 171mg (1.250mmol) isoniazid, AcOH / EtOH=0.5:100 to a 10ml sealed reaction tube Solvent 3ml, stirred at 78°C for 15h. During the reaction, a yellow solid precipitated out. After the reaction, it was cooled to room temperature, filtered with suction, and washed with absolute ethanol several times to obtain 205 mg of a yellow solid with a yield of 68.5%. 1 H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 8.79 (s, 2H), 8.13 (s, 2H), 7.91 (s, 2H), 7.82 (s, 2H), 7.64 (s, 1H) , 2.45 (s, 3H). MS (m / z) 360.0911.

Embodiment 2

[0046] Example 2: N' Preparation of -(1-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)ethyl)isonicotinic acid hydrazide (1-b)

[0047] .

[0048]In a sealed 25ml reaction tube, add 800mg (3.333mmol) 2-acetylfuro[2,3-b]-4,9-naphthoquinone to 8ml methanol solution, add 380mg (9.999mmol) sodium borohydride, and seal Stir at room temperature for 3 hours, stir in air for 10 minutes, add distilled water drop by drop while stirring, precipitate a yellow solid, filter with suction, and dry to obtain 2-(1-hydroxyethyl)naphtho[2,3-b]furan- 771 mg of 4,9-diketone yellow solid, yield: 95.01%. In a 25ml pear-shaped flask, add 750mg (3.074mmol) of 2-(1-bromoethyl)naphtho[2,3-b]furan-4,9-dione into 8ml of dichloromethane solution, and stir for 5min. Add PBr dropwise 3 873.6ul (9.222mmol), stirred at room temperature for 2h, washed the reaction solution with distilled water several times, and spin-dried dichloromethane to obtain 2-(1-bromoethyl)naphtho[2,3-b]furan-4,9 - Diketone yello...

Embodiment 3

[0049] Example 3: N' Preparation of -(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-carbonyl)isonicotinic acid hydrazide (1-c)

[0050] .

[0051] In a sealed 10ml reaction tube, add 90mg (0.368mmol) of 4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-carboxylic acid and 209mg (0.550mmol) of HATU into 1.5ml of DMF solution, stirred at room temperature for 5min, added 56mg (0.55mmol) of triethylamine, and then added 75mg (0.55mmol) of isoniazid, and reacted at room temperature for 2h, while stirring, added H 2 O, a yellow solid was precipitated, filtered by suction, and spin-dried to obtain 40 mg of a yellow solid, the yield: 30.10%. 1 H NMR (400 MHz, DMSO) δ11.25 (s, 1H), 11.19 (s, 1H), 8.95 – 8.88 (m, 2H), 8.21 – 8.12 (m, 2H), 8.04 – 7.99 (m, 2H) , 7.97 – 7.90 (m, 2H), 7.84 (s, 1H). MS (m / z) 362.0701.

[0052] In order to evaluate the antibacterial activity of the compounds of the present invention, the compounds of the present invention were tested for their pharmacological act...

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Abstract

The invention discloses a novel small molecule compound and a preparation method and application thereof in preparation of mycobacterium drugs for resisting drug-resistant mycobacterium tuberculosis and like. The novel mycobacterium-resistant small molecule has a structural general formula (I), and the small molecule compound disclosed by the invention has a relatively good inhibition effect on mycobacteria. The antibacterial activity of mycobacterium smegmatis, mycobacterium tuberculosis H37Rv, H37Ra and drug-resistant mycobacterium tuberculosis are determined, and results show that the smallmolecule compound has good antibacterial activity on mycobacterium smegmatis, mycobacterium tuberculosis H37Rv, H37Ra and drug-resistant mycobacterium tuberculosis, and has an application prospect inpreparation of mycobacterium tuberculosis-resistant drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of novel small molecule compounds, a preparation method, and an application in antimycobacterial drugs. Background technique [0002] For a long time, infectious diseases caused by pathogenic microorganisms have been an important factor that endangers human health. The discovery and application of antibiotics is one of the greatest achievements of mankind in the field of medicine in the 20th century. Since then, the field of medicine has entered a golden age in which diseases caused by bacteria have been greatly reduced. However, with the overuse of antibiotics, a variety of antibiotic-resistant bacteria, such as rifampicin-resistant tuberculosis, have emerged. [0003] In addition, according to the statistics of the World Health Organization (WHO) in 2016, the number of new tuberculosis cases in the world is about 10.4 million, and it is estimated that 1.4 million peop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/443A61P31/06
CPCC07D405/12Y02A50/30
Inventor 罗有福张天宇
Owner SICHUAN UNIV
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