Norvancomycin-type dimer derivative, preparation method and medicinal application thereof

A technology of norvancomycin, dimer, applied in the field of medicine, to achieve the effect of high antibacterial activity

Active Publication Date: 2017-01-11
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the formation of dimers with antibacterial activity by norvancomy

Method used

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  • Norvancomycin-type dimer derivative, preparation method and medicinal application thereof
  • Norvancomycin-type dimer derivative, preparation method and medicinal application thereof
  • Norvancomycin-type dimer derivative, preparation method and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of norvancomycin dimer derivative 1a

[0026]

[0027] Lead compound 2a (100mg, 0.062mmol) was added to a 25mL three-neck flask, dissolved in 5mL DMF, and after the temperature was lowered to 0°C, DIEA (16.03mg, 0.124mmol) and 0.1% equivalent of CuSO were added 4 .5H 2 O as a catalyst, under nitrogen protection, TfN was added dropwise at 0 °C 3 The DCM solution was added to the reaction system, and reacted at 0°C for 8h. TLC monitors that the basic reaction of the raw materials is complete. Slowly add DCM dropwise to the system, gradually insoluble matter is produced, continue to drop DCM until no insoluble matter is produced, centrifuge, discard the supernatant, and obtain lavender powdery solid 3a (92 mg , yield 90.7%);

[0028] Add compound 3a (100mg, 0.061mmol) into a 10mL three-neck flask, dissolve it with 5mL DMF, add DIEA (31.6mg, 0.244mmol), after compound 3a is completely dissolved, N 2 Add bridge chain I (8mg, 0.0305mmol) and 0.1% CuI under pr...

Embodiment 2

[0039] The test of embodiment 2 in vitro antibacterial activity

[0040] Adopt the final product (1) a-c of embodiment 1 to carry out the test of in vitro bacteriostatic activity; Concrete method carries out antimicrobial drug minimum inhibitory concentration determination (Minimal Inhibitory concentration MIC) to carry out;

[0041] Take 1ml of antibacterial drugs of different types and different concentrations and pour them into 9cm sterile empty plates, then immediately pour 19ml of sterile M-H agar cooled to about 55°C on the plates, and mix well with the liquid to make the culture medium antibacterial drugs The final concentrations were 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06 μg / ml; at the same time, M-H plates without antibacterial drugs were prepared as controls; bacterial inoculations were incubated for 18 hours The bacteria were added to sterile normal saline with an inoculation needle to prepare a bacterial solution with a concentration of 0.5 McFarland ...

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Abstract

The invention belongs to the technical field of medicines and relates to novel glycopeptides antibiotics, and particularly relates to a norvancomycin-type dimer derivative represented as the formula (1), a pharmaceutically acceptable salt thereof and a preparation method thereof, and an application of the compound in preparation of medicines for treating or preventing bacterial infectious diseases. In the invention, an in-vitro antibacterial experiment is carried out and proves that the compound has significant stronger antibacterial activities on various Gram-positive bacteria than vancomycin and norvancomycin. The compound further can be used for preparing medicines, especially anti-bacterial infection medicines. The formula (1) is described as follows, wherein a bridge chain X may be the following six structures; R refers to hydrogen or substituted or non-substituted C1-C12 alkyl groups, naphthenic groups, hetero-naphthenic groups, aryl groups, hetero-aromatic substituted groups, and C1-C12 alkylacyl groups, aroyl groups, and alkylsulfonyl groups.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to novel glycopeptide antibiotics, in particular to norvancomycin dimer derivatives, pharmaceutically acceptable salts thereof, and preparation methods thereof, and the use of the compounds in the preparation of Use in medicines for treating or preventing bacterial infectious diseases. Background technique [0002] Studies have revealed that glycopeptide antibiotics are a class of antibiotics with very complex structures that are effective against Gram-positive drug-resistant bacteria. Currently, these antibiotics that are widely used in clinical practice include vancomycin, norvancomycin and teicoplanin Ning et al.; they have a similar heptapeptide oxygen-linked cup-shaped rigid framework system and special amino sugar substituents in structure. Among them, vancomycin, as a representative and most widely used natural glycopeptide antibiotic, was as early as in It was isolated from ...

Claims

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Application Information

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IPC IPC(8): C07K9/00A61K38/14A61P31/04
Inventor 孙逊徐亮江永伟蒋喆
Owner FUDAN UNIV
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