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De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug

A technology for removing malonyl azamycin and malonyl azamycin, which is applied in the application field of preparing medicines for treating MRSA infection, and can solve the problems of loss of antimicrobial activity, poor solubility in water, and structural inadequacy. Stability and other issues, to achieve the effects of enhanced stability, significant inhibition and killing, and increased water solubility

Active Publication Date: 2015-01-28
JIANGXI AGRICULTURAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the activity needs to be further improved, and the structure is unstable, easy to degrade, and insoluble in water, which limits its wide application in clinical practice.
In 2011, we obtained the demalonyl azamycin F derivative (application number: 201110314705.7) through structural modification at the 17th position, and proved that its antibacterial activity has been enhanced, but it has not been proved that it has anti-resistant Activity of the fungus
According to the conventional method, before removing the malonyl group at the 23rd position, the hydroxyl group at the 17th position must be protected by alkylation, otherwise alkaline hydrolysis will cause hemicondensation in the structure while removing the malonyl group. Opening of the ketone ring, leading to loss of antibacterial activity

Method used

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  • De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug
  • De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug
  • De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Dissolve 100 mg of sodium hydride in 100 ml of methanol, and add 1.1 g (1 mmol) of azamycin F under stirring 5a , Stir bar reaction at 0°C for 12 h. The reaction mixture was neutralized with 5 M hydrochloric acid aqueous solution, concentrated under reduced pressure at 40°C, and the concentrate was separated by C-18 reverse-phase high-performance liquid chromatography, eluted with methanol-water solution with a volume ratio of 80:20, and the collected rich Malonyl azamycin F 5a The eluate was concentrated under reduced pressure at 37°C and freeze-dried to obtain 0.83 g demalonyl azamycin F 5a (1).

[0024] demalonyl azamycin F 5a (1): Molecular formula is C 54 h 95 N 3 o 14 , soluble in water, easily soluble in methanol and ethanol, m.p. 126.0~128.0℃, ESI-MS ( m / z ): 1010.7 [M+H] + . 13 C NMR (MeOH- d 4 , 100 MHz) δ ppm: 169.2(s), 157.4(s), 145.0(d), 139.3(s), 137.0(s), 135.3(d), 132.0(d), 129.4(d), 128.6(d), 127.4(d ), 127.0(d), 126.3(d), 99.7(s), 80.3(...

Embodiment 2

[0026] Dissolve 100 mg of sodium hydride in 100 ml of methanol, and add 1.1 g (1 mmol) of azamycin F under stirring 4a , Stir bar reaction at 5 °C for 8 h. The reaction mixture was neutralized with 5 M hydrochloric acid aqueous solution, concentrated under reduced pressure at 40°C, and the concentrate was separated by C-18 reverse-phase high-performance liquid chromatography, eluted with methanol-water solution with a volume ratio of 78:22, and the rich Malonyl azamycin F 4a The eluate was concentrated under reduced pressure at 37°C and freeze-dried to obtain 0.79 g demalonyl azamycin F 4a (2).

[0027] demalonyl azamycin F 4a (2): Molecular formula is C 53 h 93 N 3 o 14, soluble in water, easily soluble in methanol and ethanol, m.p. 126.5~127.7℃, ESI-MS ( m / z ): 996.7 [M+H] + . 13 C NMR (MeOH- d 4 , 100 MHz) δ ppm: 169.1(s), 158.3(s), 145.1(d), 139.3(s), 137.0(s), 135.2(d), 132.0(d), 129.4(d), 128.5(d), 127.4(d) ), 127.0(d), 126.3(d), 99.8(s), 80.3(d), 77.1(d)...

Embodiment 3

[0029] Dissolve 200 mg of sodium hydride in 250 ml of methanol, and add 2.1 g (2 mmol) of azamycin F under stirring 3a , Stir bar reaction at -5°C for 18 h. The reaction mixture was neutralized with 5 M hydrochloric acid aqueous solution, concentrated under reduced pressure at 40°C, and the concentrate was separated by C-18 reverse-phase high-performance liquid chromatography, eluted with methanol-water solution with a volume ratio of 78:22, and the rich Malonyl azamycin F 3a The eluate was concentrated under reduced pressure at 37°C and freeze-dried to obtain 1.5 g demalonyl azamycin F 3a (3).

[0030] demalonyl azamycin F 3a (3): Molecular formula is C 52 h 91 N 3 o 14 , soluble in water, easily soluble in methanol and ethanol, m.p. 126.3~127.5℃, ESI-MS ( m / z ): 982.6 [M+H] + . 13 C NMR (MeOH- d 4 , 100 MHz) δ ppm: 169.1(s), 158.7(s), 145.1(d), 139.3(s), 137.0(s), 135.2(d), 132.0(d), 129.4(d), 128.5(d), 127.4(d) ), 127.0(d), 126.3(d), 99.9(s), 80.3(d), 77.2(d...

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Abstract

The invention discloses a de-malonate monoacyl azalomycin F, a preparation method thereof and the application thereof to preparation of an MRSA (Methicillin-resistant Staphylococcus aureus) infection therapeutic drug. Azalomycin F reacts in an alkaline methanol solution to produce de-malonate azalomycin F, the de-malonate azalomycin F is separated to obtain the de-malonate monoacyl azalomycin F. The MRSA activity test shows that the MIC (Minimal Inhibitory Concentration) of the obtained de-malonate monoacyl azalomycin F to MRSA tester strain is 0.25-0.50 Mug / mL, which is 8-16 times of that of azalomycin F, and the de-malonate monoacyl azalomycin F has enhanced stability and water solubility. The de-malonate monoacyl azalomycin F has remarkable MRSA activity and a favorable development prospect and can be used for preparing an MRSA infection therapeutic drug.

Description

technical field [0001] The invention relates to demalonyl azamycin F, its preparation method and its application in the preparation of medicaments for treating MRSA infection. Background technique [0002] In recent years, methicillin-resistant Staphylococcus aureus (Methicillin-resistant Staphylococcus aureus , MRSA) infections spread all over the world, and the infection rate continues to rise, and resistance to various structural types of clinical antibiotics has emerged one after another. human life and health. The drug resistance of pathogenic bacteria is inherent in nature. During the use of antibiotics, people have enriched these drug-resistant bacteria and turned them into dominant pathogens for widespread transmission and infection. Long-term clinical and scientific research practices have shown that many antibacterial drugs can kill or inhibit sensitive pathogenic bacteria, but they cannot kill or inhibit drug-resistant bacteria, even if they have never been expo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/08A61K31/365A61P31/04
Inventor 袁干军苏秋玲
Owner JIANGXI AGRICULTURAL UNIVERSITY
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