CN102675337A - Dihydroarteannuin derivatives and application thereof - Google Patents
Dihydroarteannuin derivatives and application thereof Download PDFInfo
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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
The present invention relates to the medicinal application field, relate in particular to dihydroqinghaosu and as the application of the Trimethoprim of β-Nei Xiananleikangshengsu.
Background technology
Infection is owing in the pathogenic micro-organism intrusive body, breed caused disease in vivo in large quantities, is one of dead major reason of clinical patient.Infectation of bacteria once was human first cause of the death, and antibiotic invention has brought human light of hope, but antibiotic generally the use causes increasing bacterium to produce resistance.If do not solve the problem of microbiotic abuse, what wait for the mankind will be dark next time.
Artemisinin is used for treating the relevant heating of malaria has had the history in more than 1,000 year, except that traditional antimalarial effect, sweet wormwood class material also have relieving asthma, anticancer, schistosomicide and to the effect of others such as immune adjusting.The research of relevant Artemisinin and verivate thereof both at home and abroad is a lot, but research range mainly concentrates on antimalarial, anticancer, antischistosomal effect and the mechanism thereof.
Dihydroartemisinin (dihydroartemisinin), molecular formula are C15H24O5, and molecular weight 284.35 is the verivates with antimalarial drug Artemisinin of sesquiterpene structure.Report the anti-inflammatory action of Artemisinin and verivate thereof is existing: Artemisinin can suppress the activation of the synthetic and NF-κ B of LPS/TNF-α inducibility NO synthase; Artesunate to LPS and merge that Interferon, rabbit stimulates Turnover of Mouse Peritoneal Macrophages NO synthetic the obvious suppression effect arranged; Artesunate also has similar provide protection to the mouse macrophage RAW264.7 that LPS stimulates; Tan Yuqing etc. find that also Artemisinin, Artemisinin can reduce endotoxin shock mouse LPO, ACP, intracellular toxin, TNF-α, P450 concentration; Increased SOD is active; Reduce mouse death rate, prolong the mean survival time of mouse, Mouse Liver, lung tissue form are also had the certain protection effect; Discovery Artemisinins such as Wang Jun can suppress CpG ODN, LPS, heat-inactivated EC inducing cell release inflammatory factor, and the Sepsis model mice is had remarkable provide protection.But whether Dihydroartemisinin has anti-microbial effect, whether can improve the resistance of bacterial antibiotic, strengthen antibiotic antibacterial efficacy and infection that bacterium is caused whether effective, do not appear in the newspapers.
China is the main grown place of Artemisinin and its verivate; Because this curative effect of medication is high, toxicity is low; WHO has classified Artemisinin as the main medicine of world's treatment malaria, and China is enlarging sweet wormwood plantation and Artemisinin production, the indication of therefore finding or widening artemisinin derivatives; Be applied to the control of bacterial infective diseases, undoubtedly to the utilization that improves artemisinin derivatives, increase its economic worth and improve the resistance phenomenon that the microbiotic abuse caused significant.
Summary of the invention
The object of the present invention is to provide a kind of Dihydroartemisinin oxyethyl group imidazole derivative, it has the structure of one of the following formula I of being selected from-III,
Formula I-III is called after 12 β-(2-(1H-imidazoles-1-yl) oxyethyl group) dihydroarteannuin, 12 β-(2-(4-methyl isophthalic acid H-imidazoles-1-yl) oxyethyl group) dihydroarteannuin and 12 β-(2-(2-methyl isophthalic acid H-imidazoles-1-yl) oxyethyl group) dihydroarteannuin respectively; Hereinafter replaces with compound I ED (4k), 4MIED (4l) and 2MIED (4m) respectively.
The present invention also provides the application of above-mentioned Dihydroartemisinin oxyethyl group imidazole derivative in the antibiotic Trimethoprim of preparation.
The effective constituent of said synergistic agent is Dihydroartemisinin oxyethyl group imidazole derivative; Perhaps the effective constituent of said synergistic agent be Dihydroartemisinin oxyethyl group imidazole derivative and microbiotic as effective constituent, the mass ratio of the two is 1:1 ~ 4096:1.
Above-mentioned two kinds of compositions can produce Synergistic antimicrobial and render a service, and can reduce the minimum inhibitory concentration (MIC) of antibacterials.
In a preferred embodiment, said microbiotic is a β-Nei Xiananleikangshengsu, more preferably Ampicillin Trihydrate or cephalofruxin.
Above-mentioned bacterium mainly is meant the escherichia coli in the gram-negative bacteria.
Dihydroartemisinin oxyethyl group imidazole derivative uses the effect of the growth of unrestraint escherichia coli separately, with the antibacterial efficacy that can obviously strengthen β-Nei Xiananleikangshengsu after the β-Nei Xiananleikangshengsu combined utilization.
At first, the inventor has designed and synthesized oxyethyl group imidazoles dihydroqinghaosu, and it has been carried out the structure evaluation; Secondly; Vitro antibacterial activity to the synthetic dihydroqinghaosu has carried out the pharmacology analysis; Find that Dihydroartemisinin oxyethyl group imidazole derivative uses the effect of unrestraint escherichia coli growth separately; Yet with find after the microbiotic combined utilization, can obviously strengthen antibiotic antibacterial efficacy after itself and the microbiotic combined utilization, reduce antibiotic using dosage.
Gained dihydroqinghaosu and β-Nei Xiananleikangshengsu combined utilization can suppress the growth of resistance escherichia coli, reverse antibacterials to drug-resistance of bacteria, strengthen antibiotic antibacterial efficacy.This institute gets the pharmaceutical potential that dihydroqinghaosu and β-Nei Xiananleikangshengsu have the bacterial infection disease that combination therapy resistance escherichia coli causes, and is expected to become the new tool of clinical drug-resistant bacterium associated diseases pharmacological agent.
Therefore, the present invention has widened the purposes of dihydroqinghaosu, has improved the antibacterial efficacy of β-Nei Xiananleikangshengsu, the resistance phenomenon that has alleviated the β-Nei Xiananleikangshengsu abuse and caused.
For let above and other objects of the present invention, feature and advantage can be more obviously understandable, hereinafter is special lifts preferred embodiment, and conjunction with figs., elaborates as follows.
Description of drawings
Fig. 1 representes that Dihydroartemisinin oxyethyl group imidazole derivative IED, 4MIED, the collaborative Ampicillin Trihydrate (AMP) of 2MIED are to the antibacterial curve of the associating of escherichia coli AG100A/pET28a-AcrB.
Fig. 2 representes that Dihydroartemisinin oxyethyl group imidazole derivative IED, 4MIED, the collaborative cephalofruxin (CFX) of 2MIED are to the antibacterial curve of the associating of escherichia coli AG100A/pET28a-AcrB.
Embodiment
Below in conjunction with embodiment the present invention is further described, but said embodiment only is used to explain the present invention rather than restriction the present invention.
Embodiment 1
Present embodiment is example with the preferred compound, chemosynthesis Dihydroartemisinin oxyethyl group imidazole derivative IED (4k), 4MIED (4l), 2MIED (4m).To combine following synthetic route to carry out bright specifically at present.
The preparation of 12 β-(2-bromine oxethyl) dihydroarteannuin (3):
In the 250mL round-bottomed flask, add ethylene bromohyrin (2) 3.103g (24mmol) and Et
2O 100mL, the ice bath cooling adds BF down
3.Et
2O 4.0mL behind the continuation stirring reaction 1.5h, adds Dihydroartemisinin (1) 5.690g (20mmol), continues the reaction of ice bath cooling and stirring, TLC monitoring reaction process. after the reaction completion, add saturated NaHCO
3Termination reaction. separatory, water layer merges organic phase with EtOAc (30mL x2) extraction, saturated aqueous common salt 40mL washing, anhydrous MgSO
4Drying, vacuum rotary steam are removed and to be desolvated, and thick product is with sherwood oil and EtOAc mixed solvent recrystallization, suction filtration, vacuum-drying, white crystal 6.552g, yield 83.44%.
The preparation of Dihydroartemisinin oxyethyl group imidazole derivative 4k, 4l, 4m:
In the 100mL round-bottomed flask, add 3 successively, CH
3CN, K
2CO
3And YH, temperature control stirring reaction, TLC monitoring reaction process.Behind the stopped reaction, add CH
2Cl
215mL and saturated NaCl aqueous solution 20mL, separatory, water layer is used CH
2Cl
2(10mL x 2) extraction merges organic phase, saturated aqueous common salt 20mL washing, no Na
2SO
4Drying, vacuum rotary steam is removed CH
2Cl
2, column chromatography gets pure article, and experimental result is seen table 1.
The compound experiment result of table 1 Dihydroartemisinin oxyethyl group imidazole derivative (target molecule 4x)
The present embodiment compound method has easy, the characteristics that yield is high.
Embodiment 2
The synthetic compound warp
1HNMR,
13CNMR, HRMS identify structure, and further characterize with optically-active.
Through identifying that the structure of the synthetic Dihydroartemisinin oxyethyl group imidazole derivative 4k of institute, 4l, 4m is following:
The present invention is following to the data characterization of above Dihydroartemisinin oxyethyl group imidazole derivative:
4k (IED): 12 β-(2-(1H-imidazoles-1-yl) oxyethyl group) dihydroarteannuin
Yield:89.1%;Yellow?oily;
(c?1.1mg/mL,CHCl
3).
1H?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);
13C?NMR(75MHz,CDCl
3)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(C-16),52.3(C-1),47.2(C-17),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),26.1(C-8),24.6(C-15),24.3(C-2),20.3(C-14),13.0(C-13);HRMS?calcd?for?C
20H
30N
2O
5(M+H)
+379.2228,found?379.2221.
4l (4MIED): 12 β-(2-(4-methyl isophthalic acid H-imidazoles-1-yl) oxyethyl group) dihydroarteannuin
Yield:76.4%;Yellow?oily;
(c?1.1mg/mL,CHCl
3).
1H?NMR(300MHz,CDCl
3)δppm:0.91(3H,d,J=6.9Hz,H-14),0.95(3H,d,J=6.3Hz,H-13),1.45(3H,s,H-15),1.19-2.06(10H,m,H-2,H-3,H-7,H-8,H-9and?H-10),2.12(3H,s,H-21),2.32-2.43(1H,m,H-1),2.59-2.66(1H,m,H-11),3.40-3.52(4H,m,H-16andH-17),4.69(1H,d,J=2.7Hz,H-12),5.39(1H,s,H-5);
13C?NMR(75MHz,CDCl
3)δppm:127.8(C-18),127.2(C-20),118.8(C-19),104.2(C-4),102.0(C-12),87.8(C-5),80.9(C-6),66.9(C-16),52.4(C-1),47.8(C-17),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),26.1(C-8),24.6(C-15),24.2(C-2),20.3(C-14),13.0(C-13),12.7(C-21);HRMS?calcd?for?C
21H
32N
2O
5(M+H)
+393.2384,found?393.2382.
4m (2MIED): 12 β-(2-(2-methyl isophthalic acid H-imidazoles-1-yl) oxyethyl group) dihydroarteannuin
Yield:76.4%;Yellow?oily;
(c?1.1mg/mL,CHCl
3).
1H?NMR(300MHz,CDCl
3)δppm:0.85(3H,d,J=7.2Hz,H-14),0.94(3H,d,J=4.8Hz,H-13),1.43(3H,s,H-15),1.22-2.07(10H,m,H-2,H-3,H-7,H-8,H-9,and?H-10),2.29-2.34(1H,m,H-1),2.41(3H,s,H-21),2.61-2.63(1H,m,H-11),3.58-3.63(1H,m,H-16),3.99-4.16(3H,m,H-16and?H-17),4.76(1H,d,J=3.3Hz,H-12),5.08(1H,s,H-5).6.88(1H,s,H-19),6.92(1H,s,H-18);
13C?NMR(75MHz,CDCl
3)δppm:126.7(C-20and?C-19),118.9(C-18),104.2(C-4),102.0(C-12),87.8(C-5),80.9(C-6),66.8(C-16),52.4(C-1),45.8(C-17),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),26.1(C-8),24.6(C-15),24.2(C-2),20.3(C-14),13.0(C-13),12.9(C-21);HRMS?calcd?for?C
21H
32N
2O
5(M+H)
+393.2384,found?393.2386.
Embodiment 3
This experimental example is to study dihydroqinghaosu and β-Nei Xiananleikangshengsu when using separately, to the influence of the minimum inhibitory concentration (MIC) of escherichia coli.
Adopt the micropore dilution method, the adjustment bacterial concentration is 10
5CFU/mL is inoculated in the 96 hole sterile culture plates, and dihydroqinghaosu and β-Nei Xiananleikangshengsu Ampicillin Trihydrate, cephalofruxin dilute with saline water respectively.Add various medicines to containing in the microbial culture hole, doubling dilution successively, the ultimate density of the 1st～10 hole medicine is followed successively by 2048,1024,512,256,128,64,32,16,8,4,2 μ g/mL.Put 37 ℃ of incubators and hatch 24h, read the positive and negative control hole, negative control hole is limpid, and the positive control hole is muddy.Medicine is the lowest drug concentration that suppresses bacterium naked eyes visible growth behind the 24h to the MIC of bacterium.This time experimental result shows the independent use of dihydroqinghaosu bacteria growing inhibiting fully, and has observed β-Nei Xiananleikangshengsu Ampicillin Trihydrate, the cephalofruxin inhibitory effect to this escherichia coli, and the result is shown in table 2.
When table 2 β-Nei Xiananleikangshengsu and dihydroqinghaosu use separately to escherichia coli
The MIC of AG100A/pET28a-AcrB
Embodiment 4
This experimental example is to study after dihydroqinghaosu and the β-Nei Xiananleikangshengsu combined utilization influence to escherichia coli MIC.
Adopt checkerboard type micropore dilution method, the adjustment bacterial concentration is 10
5CFU/mL; Be inoculated in the 96 hole sterile culture plates; To use dosage and the different concns dihydroqinghaosu difference compatibility that is lower than MIC to the β-Nei Xiananleikangshengsu of the medium sensitivity of escherichia coli, the medicine behind the observation compatibility is to the influence of escherichia coli MIC.Though this time experimental result shows that dihydroqinghaosu uses bacteria growing inhibiting fully separately; But with the MIC that can obviously reduce β-Nei Xiananleikangshengsu after the β-Nei Xiananleikangshengsu combined utilization; Explain that there is collaborative inhibitory effect the collaborative back of dihydroqinghaosu and β-Nei Xiananleikangshengsu to bacterium, the result sees table 3.
Table 3 β-Nei Xiananleikangshengsu Ampicillin Trihydrate (AMP), cephalofruxin (CFX) and dihydroqinghaosu IED, 4MIED, 2MIED unite when using the MIC to escherichia coli AG100A/pET28a-AcrB
MIC result to escherichia coli AG100A/pET28a-AcrB compares with each medicine in the table 2, and visible AMP, CFX unite use back MIC with IED, 4MIED, 2MIED respectively all has reduction in various degree, sees table 4
Table 4
Present embodiment further adopts dihydroqinghaosu (IED, 4MIED, 2MIED) and β-Nei Xiananleikangshengsu Ampicillin Trihydrate (AMP), cephalofruxin (CFX) according to the proportioning in table 5, the table 6; Confirm that dihydroqinghaosu can produce Synergistic antimicrobial and render a service, reduce the minimum inhibitory concentration (MIC) of β-Nei Xiananleikangshengsu AMP, CFX.
Table 5 different concns IED, 4MIED, 2MIED and β-Nei Xiananleikangshengsu AMP, CFX associating
Microbiotic is to the MIC (μ g/mL) of escherichia coli AG100A/pET28a-AcrB during use
It is right that table 6IED, 4MIED, 2MIED and β-Nei Xiananleikangshengsu AMP, CFX unite when using
Escherichia coli AG100A/pET28a-AcrB can produce the minimum mass ratio of anti-microbial effect
Embodiment 5
This experimental example is to study dihydroqinghaosu and the inhibition strength of the collaborative back of the different β-Nei Xiananleikangshengsus that are lower than 1/2MIC concentration to the escherichia coli growth.
The adjustment bacterial concentration is 10
6CFU/mL, measuring bacterium liquid OD600 is 0.002 (1OD=5 * 10
8CFU/mL); With reference to experimental example 1 result; Adding final concentration respectively separately is 256 μ g/mL dihydroqinghaosus or the β-Nei Xiananleikangshengsu that is lower than 1/2MIC concentration, and after adding 256 μ g/mL dihydroqinghaosus simultaneously and being lower than the β-Nei Xiananleikangshengsu of 1/2MIC concentration, places 37 ℃ of constant temperature shaking table 150rpm jolting; Measure 1,3,5,7,9,12,18 respectively, the OD600 value of bacterium liquid during 24h, calculate the amount of bacteria of each time point.Measuring the result is shown in respectively among Fig. 1 and Fig. 2; Result of study shows that dihydroqinghaosu 256 μ g/mL can make the escherichia coli AG100A/pET28a-AcrB speed of growth slow down; Compare with independent use β-Nei Xiananleikangshengsu, united the obvious bacteria growing inhibiting of β-Nei Xiananleikangshengsu ability of dihydroqinghaosu, the inhibition degree is all stronger than using β-Nei Xiananleikangshengsu or dihydroqinghaosu separately; Along with the prolongation that suppresses the time, this difference is obvious further.
The present invention has improved antibiotic antibacterial efficacy with the combined utilization of dihydroqinghaosu and β-Nei Xiananleikangshengsu, and expection can also prevent dihydroqinghaosu and microbiotic combined utilization from, treat infectation of bacteria.
Though the embodiment of the invention is preferred dihydroqinghaosu IED, 4MIED, 2MIED; β-Nei Xiananleikangshengsu AMP, CFX have carried out experiment and illustration to escherichia coli; But can expecting, those skilled in the art the combined utilization of compound with the β-Nei Xiananleikangshengsu that removes AMP, CFX of similar above-mentioned dihydroqinghaosu can produce similar antibiotic reinforced effects to escherichia coli and other pathogenic bacterium.
Those skilled in the art can with Artemisinin and verivate and β-Nei Xiananleikangshengsu combined utilization, and can reach effect according to the invention equally according to content according to the invention.
The above is merely preferred embodiment of the present invention, is not to be used for limiting practical range of the present invention; If do not break away from the spirit and scope of the present invention, the present invention is made amendment or is equal to replacement, all should be encompassed in the middle of the protection domain of claim of the present invention.
Claims (7)
1. a Dihydroartemisinin oxyethyl group imidazole derivative is characterized in that having the structure of one of the following formula I of being selected from-III,
2. the application of the described Dihydroartemisinin oxyethyl group of claim 1 imidazole derivative in the antibiotic Trimethoprim of preparation.
3. application as claimed in claim 2 is characterized in that, the effective constituent of said synergistic agent is Dihydroartemisinin oxyethyl group imidazole derivative.
4. application as claimed in claim 2 is characterized in that, the effective constituent of said synergistic agent is Dihydroartemisinin oxyethyl group imidazole derivative and microbiotic, and the mass ratio of the two is 1:8 ~ 4096:1.
5. like each described application of claim 2-4, it is characterized in that said microbiotic is a β-Nei Xiananleikangshengsu.
6. application as claimed in claim 5 is characterized in that, said β-Nei Xiananleikangshengsu is Ampicillin Trihydrate or cephalofruxin.
7. like each described application of claim 2-4, it is characterized in that said bacterium is an escherichia coli.
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| CN110448551A (en) * | 2019-08-23 | 2019-11-15 | 西南大学 | Dihydroqinghaosu is preparing the application in anti-angiogenic medicaments |
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| CN104418864A (en) * | 2013-08-30 | 2015-03-18 | 西南大学 | Conjugates of dihydroartemisinin and quinolones compounds as well as preparation method and application thereof |
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| CN110590804A (en) * | 2019-08-28 | 2019-12-20 | 西南大学 | Dihydroartemisinin carboxyl-containing phenol/esterphenol/amido phenol conjugate, synthetic method and application |
| CN110590804B (en) * | 2019-08-28 | 2022-03-04 | 西南大学 | Dihydroartemisinin carboxyl-containing phenol/esterphenol/amido phenol conjugate, synthetic method and application |
| CN110960680A (en) * | 2019-12-25 | 2020-04-07 | 中国中医科学院中药研究所 | Microbial drug resistance related gene expression inhibitor and application thereof |
| CN112608329A (en) * | 2020-12-28 | 2021-04-06 | 桂林南药股份有限公司 | Artemisinin derivative and preparation method and application thereof |
| CN112608329B (en) * | 2020-12-28 | 2022-02-18 | 桂林南药股份有限公司 | Artemisinin derivative and preparation method and application thereof |
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