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Dihydroarteannuin derivatives and application thereof

A technology of dihydroartemisinin and derivatives, applied in the directions of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, antibacterial drugs, etc., to achieve the effect of enhancing antibacterial efficacy

Inactive Publication Date: 2012-09-19
ARMY MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, whether dihydroartemisinin has an antibacterial effect, whether it can improve bacterial resistance to antibiotics, enhance the antibacterial efficacy of antibiotics, and whether it is effective against bacterial infections has not been reported.

Method used

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  • Dihydroarteannuin derivatives and application thereof
  • Dihydroarteannuin derivatives and application thereof
  • Dihydroarteannuin derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In this example, taking preferred compounds as examples, dihydroartemisinin ethoxyimidazole derivatives IED (4k), 4MIED (4l), and 2MIED (4m) were chemically synthesized. Now in conjunction with the following synthetic route for specific description.

[0024]

[0025] Preparation of 12β-(2-bromoethoxy)dihydroartemisinin (3):

[0026] In a 250mL round bottom flask, add 2-bromoethanol (2) 3.103g (24mmol) and Et 2 O 100mL, add BF under ice-bath cooling 3 .Et 2 O 4.0mL, continue to stir and react for 1.5h, add dihydroartemisinin (1) 5.690g (20mmol), continue ice bath cooling and stirring reaction, TLC monitors the reaction process. After the reaction is completed, add saturated NaHCO 3 Terminate the reaction. Separate the layers, extract the aqueous layer with EtOAc (30mL x2), combine the organic phases, wash with saturated brine 40mL, anhydrous MgSO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure. The crude product was recrystalli...

Embodiment 2

[0034] synthetic compound 1 HNMR, 13 The structure was identified by CNMR and HRMS, and further characterized by optical rotation.

[0035] After identification, the structures of the synthesized dihydroartemisinin ethoxyimidazole derivatives 4k, 4l, 4m are as follows:

[0036]

[0037] The data characterization of the above dihydroartemisinin ethoxyimidazole derivatives in the present invention is as follows:

[0038] 4k(IED): 12β-(2-(1H-imidazol-1-yl)ethoxy)dihydroartemisinin

[0039] Yield: 89.1%;Yellow oily; (c 1.1mg / mL, CHCl 3 ). 1 H NMR (300MHz, CDCl 3 )δppm: 0.85(3H,d,J=7.2Hz,H-14),0.94(3H,d,J=6.1Hz,H-13),1.44(3H,s,H-15),1.22-2.07( 10H,m,H-2,H-3,H-7,H-8,H-9,and H-10),2.32-2.38(1H,m,H-1),2.61-2.63(1H,m ,H-11),3.62-3.68(1H,m,H-16),4.15-4.21(3H,m,H-16and H-17),4.76(1H,s,H-12),5.11(1H, s,H-5).7.00(1H,s,H-19),7.09(1H,s,H-18),7.62(1H,s,H-20); 13 C NMR (75MHz, CDCl3 )δppm: 128.7(C-20), 123.1(C-19), 118.9(C-18), 104.1(C-4), 102.0(C-12), 87.8(C-5), 80.8(C-6 ),67.0...

Embodiment 3

[0045] This experimental example is to study the effect of dihydroartemisinin derivatives and β-lactam antibiotics on the minimum inhibitory concentration (MIC) of Escherichia coli when used alone.

[0046] Using the microwell dilution method, adjust the bacterial concentration to 10 5 CFU / mL, inoculated in a 96-well sterile culture plate, dihydroartemisinin derivatives and β-lactam antibiotics ampicillin and cefuroxime were diluted with normal saline respectively. Add various drugs into the culture wells containing bacteria, and serially dilute, the final concentrations of the drugs in the 1st to 10th wells are 2048, 1024, 512, 256, 128, 64, 32, 16, 8, 4, 2μg / mL . Incubate in a 37°C incubator for 24 hours, read the positive and negative control wells, the negative control wells are clear, and the positive control wells are turbid. The MIC of a drug on bacteria is the lowest drug concentration that inhibits the growth of bacteria visible to the naked eye after 24 hours. The...

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PUM

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Abstract

The invention relates to synergistic dihydroarteannuin oxyethylimidazole derivatives and application thereof. The dihydroarteannuin oxyethylimidazole derivatives have the structure disclosed as one of Formulae I-III, and can be used for preparing an antimicrobial synergist for antibiotics. The dihydroarteannuin derivatives can inhibit growth of multidrug-resistant Escherichia coli when being used independently or combined with beta-lactam antibiotics, reverse the drug resistance of the antibacterial drug to bacteria, and enhance the antimicrobial efficacy of antibiotics.

Description

technical field [0001] The invention relates to the field of pharmaceutical applications, in particular to dihydroartemisinin derivatives and their application as antibacterial synergists of β-lactam antibiotics. Background technique [0002] Infectious disease is a disease caused by pathogenic microorganisms invading the body and multiplying in large quantities in the body. It is one of the important reasons for the death of clinical patients. Bacterial infection used to be the number one cause of death for humans. The invention of antibiotics has brought hope to humans, but the widespread use of antibiotics has led to more and more bacteria developing drug resistance. If the problem of overuse of antibiotics is not solved, the next darkness awaits mankind. [0003] Artemisia annua extracts have been used to treat malaria-related fever for more than a thousand years. In addition to the traditional antimalarial effects, artemisia annua substances also have anti-asthma, anti...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/546A61K31/43A61K31/4178A61P31/04
CPCY02A50/30
Inventor 周红杨大成吴翀刘建
Owner ARMY MEDICAL UNIV
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