CN104523706A - Application of O-(imidazolyl) ethyl derivative of cleistanone in preparation of antibacterial drug - Google Patents
Application of O-(imidazolyl) ethyl derivative of cleistanone in preparation of antibacterial drug Download PDFInfo
- Publication number
- CN104523706A CN104523706A CN201410757885.XA CN201410757885A CN104523706A CN 104523706 A CN104523706 A CN 104523706A CN 201410757885 A CN201410757885 A CN 201410757885A CN 104523706 A CN104523706 A CN 104523706A
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- Prior art keywords
- muell
- miq
- arg
- ethyl derivative
- imidazole radicals
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- XURLTFUKDPZAPN-QFIPXVFZSA-N Cleistanone Natural products O(C)[C@H]1OC(=O)c2c(-c3cc4OCOc4cc3)c3c(c(O)c12)cc(OC)c(OC)c3 XURLTFUKDPZAPN-QFIPXVFZSA-N 0.000 title claims abstract description 83
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 229940124350 antibacterial drug Drugs 0.000 title abstract description 5
- GEIFQLXIDUDMNZ-PCJVTFPHSA-N (4aR,4bR,6aR,8S,10aR,10bR,12R,12aR)-12-hydroxy-1,1,1',1',4a,10a,10b-heptamethyl-3'-methylidenespiro[3,4,4b,5,6,6a,7,9,10,11,12,12a-dodecahydrochrysene-8,2'-cyclopentane]-2-one Chemical compound CC1(C)CCC(=C)[C@@]11C[C@@H](CC[C@H]2[C@]3(C[C@@H](O)[C@H]4C(C)(C)C(=O)CC[C@@]42C)C)[C@@]3(C)CC1 GEIFQLXIDUDMNZ-PCJVTFPHSA-N 0.000 claims abstract description 80
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 33
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 130
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- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, and particularly relates to an O-(imidazolyl) ethyl derivative of cleistanone, as well as a preparation method and application thereof in preparation of an antibacterial drug. The invention synthesizes a novel O-(imidazolyl) ethyl derivative of the cleistanone and discloses the preparation method thereof. Pharmacological experiments show that the O-(imidazolyl) ethyl derivative of the cleistanone has an antibacterial effect and has a value for developing antibacterial drugs.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O-(imidazole radicals) ethyl derivative, the preparation method and its usage of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Background technology
Helicobacter pylori (Helicobacter pylori, Hp) is a kind of Gram-negative spiral bacteria.Research display, helicobacter pylori is the primary pathogenic event of acute and chronic gastritis and taste-blindness rate, and may fall ill relevant with gastric cancer stomach function regulating mucosa-associated lymphoid tissue (MALT) malignant lymphoma.Recently, Hp is classified as I class carcinogen by World Health Organization (WHO), and it plays a leading role in stomach cancer development.Simultaneously the scheme that popular at present treatment Hp infects takes the triple therapy that proton pump inhibitor (PPI) adds two kinds of antibiotic (clarithromycin, amoxicillin, tetracycline, metronidazole etc. select two kinds).The main factor affecting triple therapy is considered to the drug resistance of Hp to antibacterial; Another serious problems are that proton pump inhibitor can bring out dyspepsia, and a large amount of antibacterial then causes the serious destruction of flora in digestive tract.Therefore, find the active kind new medicine thing of efficient, safe anti-Hp and become an important and urgent task.
The health and lives of the mankind in the diffusion of pathogenic bacterium and the enhancing serious threat of drug resistance thereof, antibacterials are widely used in acquired immune deficiency syndrome (AIDS) as routine administration, organ transplantation and Chronic consumptions are (as cancer, diabetes, uremia etc.) treatment, although the antimicrobial agent used clinically is at present (as ketoconazole, amikacin, gentamycin, voriconazole, itraconazole, terbinafine, amphotericin, fluconazol etc.) better to the curative effect of skin and superficial place infection, but the cumulative toxicity of these antibacterials is stronger, usually cause lesions of liver and kidney, digestive tract stimulates, dizzy, irritated etc., so the novel antibacterial medicine finding mechanism of action uniqueness becomes one of focus of current medicament research and development.
Global morbidity lungy is in increasing trend in recent years, estimate according to World Health Organization (WHO) (WHO), the current whole world is by mycobacterium tuberculosis (Mycobacterium tuberculosis, MTB) population infected accounts for 1/3rd of world population, and wherein the infected of 5 ~ 10% becomes tuberculosis patient.There is active tuberculosis patient 1,300,000 example in China, wherein infectiousness pulmonary tuberculosis about 600,000 example every year, wherein infectiousness pulmonary tuberculosis about 600,000 example, is one of global tuberculosis high burden country.
Come out one after another from antituberculotics, make treatment lungy play epoch-making change.But due to the Case management still not very specification of tuberculosis patient, irregular chemotherapy, abuse antituberculotics, makes drug resistance of tuberculosis situation day by day serious, and the change of drug resistance more trends towards multi-medicament drug resistance simultaneously, this causes extreme difficulties to preventing and controlling lungy.Therefore find new antituberculotics, the antituberculotics of especially anti-multidrug resistance is to protection people's health, significant.
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus the potential drug obtaining high-efficiency low-toxicity has important value.
At present for antibacterial treatment, there is no specific medicament clinically, major part medicine has inevitable toxic and side effects while the antibacterial symptom of alleviation, from natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus the potential drug obtaining high-efficiency low-toxicity has important value.
The compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh ThiThanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.
volume 2011, Issue 22,pages 4108 – 4111, August 2011) compound, we have carried out structural modification to compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, obtain O-(imidazole radicals) ethyl derivative of a new Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, and its antibacterial activity is evaluated, it has antibacterial activity.
Summary of the invention
The invention discloses O-(imidazole radicals) ethyl derivative of a Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, its structure is:
O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention is by method preparation below:
(1) Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone;
(2) O-bromoethyl derivant (II) and the imidazoles generation substitution reaction of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone obtain O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
The preparation method of O-(imidazole radicals) ethyl derivative (III) of further Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is:
(1) 440mg compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution; Then use water and saturated common salt water washing 3 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
(2) the O-bromoethyl derivant (II) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr of 273mg wood ketone Cleistanone is dissolved in the middle of 35mL acetonitrile, adds the Anhydrous potassium carbonate of 690mg wherein, the potassium iodide of 252mg and the imidazoles of 870mg, mixture reflux 3h; After reaction terminates, reactant liquor is poured in 45mL frozen water, with equivalent dichloromethane extraction three times, merge organic facies; Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:0.2, v/v, collects brown and concentrates elution band namely to obtain the brown solid of O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention has good antibacterial action.Pharmaceutically acceptable salt of the present invention has same drug effect with its compound.
Further, the experiment in vitro of O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone shows, chemicals III has very strong human body fungi activity, and therefore O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention is expected to be used to prepare novel anti-human fungi medicine.
Further, the experiment in vitro of O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone shows, O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has very strong anti Helicobacter pylori activity, illustrate for the disease such as the closely-related acute and chronic gastritis of helicobacter pylori, duodenal ulcer, O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is the compound of a great exploitation potential for its.It can be directly used in the treatment of corresponding disease and the preparation of related drugs.
Further, the experiment in vitro of O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone shows, O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has the effect of very strong suppression escherichia coli, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus, neogenesis cryptococcus, so O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone can be used as the compound with antibacterial actions, and be expected to be applied preparing in anti-bacterial drug.
Further, according to the result of preliminary test, the present invention with solid medium By Dilution this compound to the minimal inhibitory concentration of bacillus calmette-guerin vaccine, the H37Rv strain of mycobacterium tuberculosis type strain and substance of medicines-resistant branched tubercle bacillus (MDR MTB) three kinds of tulases, experimental result confirms that O-(imidazole radicals) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has very strong anti-tubercle bacillus and anti-drug resistance tulase is active, can be used as the lead compound for the treatment of tubercle bacillus affection disease, also can be used for preparation treatment tubercular drugs.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Document (the Van Trinh Thi Thanh et al. that the people such as the preparation method reference Van Trinh Thi Thanh of compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) deliver, 2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound I (440mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.04g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 3 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1, v/v), collects the yellow yellow solid (344mg, 63%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
32H
52BrO
2:547.3151；found 547.3159.
The synthesis of O-(imidazole radicals) ethyl derivative (III) of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compound II per (273mg, 0.5mmol) is dissolved in the middle of 35mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (252mg, 1.5mmol) and imidazoles (870mg, 10mmol), mixture reflux 3h.After reaction terminates, reactant liquor is poured in 45mL frozen water, with equivalent dichloromethane extraction three times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:0.2, v/v), collecting brown concentrates elution band namely to obtain the brown solid (157.6mg, 59%) of O-(imidazole radicals) ethyl derivative of Cleistanone.
1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.15(s,1H),6.74(s,1H),4.61(s,1H),4.52(t,J＝33.6Hz,4H),3.86(s,2H),2.63(s,1H),2.34(s,1H),2.22(d,J＝12.3Hz,2H),2.18(s,1H),1.86(s,2H),1.77(s,1H),1.62(d,J＝4.2Hz,3H),1.53(s,1H),1.46(d,J＝5.8Hz,2H),1.41(s,1H),1.35(d,J＝5.7Hz,2H),1.27(s,1H),1.22(t,J＝6.9Hz,3H),1.01(s,6H),0.93(d,J＝12.0Hz,13H),0.84(s,3H),0.76(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.55(s),154.43(s),139.74(s),128.08(s),119.24(s),105.13(s),74.61(s),67.62(s),59.67(s),52.51(s),51.14(s),47.82(s),44.10(d,J＝5.7Hz),42.22(s),41.69(s),40.60(s),40.09(s),38.78(s),38.63(s),37.18(s),36.19(s),33.30(s),32.89(s),29.81(s),27.16(s),26.00(s),24.19(s),23.92(s),20.70(s),18.38(s),17.92(s),16.92(s).
HRMS(ESI):m/z[M+H]
+calcd for C
35H
55N
2O
2 +:535.4264；found:535.4259。
O-(imidazole radicals) the ethyl derivative antibacterial activity of embodiment 4 Cleistanone
O-(imidazole radicals) ethyl derivative (III) the human body fungi activity of experimental example 1 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
The experiment of human body fungi activity is the method adopting concentration dilution, and in triplicate, the pathogen of test has trichophyton, microsporum canis and trichophyton tonsurans to each mensuration, and bacterial concentration is 10
5individual/mL.O-(dimethylamino) ethyl derivative (III) initial concentration of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is 50.00 μ g/mL (5% dimethyl sulfoxide DMSO), gradient dilution to 0.10 μ g/mL, (ultimate density of formation has: 25.00 in 96 orifice plates for the bacterium liquid of equivalent volumes and test sample Mixed culture, 12.50, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10 and 0.05 μ g/mL), Human Fungi cultivation temperature is respectively 28 DEG C, observe after incubation time 24h, if find, in the disposal hole not having bacterium colony to be formed, that minimum concentration is sample lowest concentration of antimicrobial, i.e. MIC value.This experiment positive control is ketoconazole, and chemicals III human body fungus the results are shown in Table 1.
O-(imidazole radicals) ethyl derivative (III) human body fungus MIC value (μ g/mL) of table 1 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Conclusion: O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has very strong human body fungi activity, therefore O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention is expected to be used to prepare novel anti-human fungi medicine.
O-(imidazole radicals) ethyl derivative (III) anti-helicobactor pylori activity of experimental example 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
1) strains tested
Helicobacter pylori (Helicobacter pylori, Hp) reference culture ATCC 43504 is purchased from U.S.'s Culture Collection (American Type Culture Collection, ATCC).13 strain Hp clinical strains are picked up from Nanjing drum tower hospital Dndoscope Laboratory and are accepted gastroscopic patient; To the patient of peptic ulcer, duodenal bulbar inflammation or gastritis verrucosa in continuous gastroscopy, first be defined as Hp positive through RUT experiment, get antral gastric mucosa 1-2 block again, be inoculated in containing 8% horse serum, trimethoprim (trimethropin after chopping, in the Columbia selectivity agar culture medium of TMP) 1.25g/L, polymyxin (polymyxin) B2500U/L, vancomycin (vancomycin) 10mg/L, in 37 DEG C of (5%O under micro-oxygen environment
2, 10%CO
2and 85%N
2) cultivate 72 hours.Collect antibacterial, through smear Gram’s staining, after oxidase, catalase and urease are accredited as the positive, pure culture of going down to posterity, obtained strains is as experimental strain.
2) strain culturing
We adopt micro-aerobic bag (purchased from Shanghai Medical Univ) to carry out the strain culturing of HP, and it produces the micro-aerobic environment required for Hp by chemical reaction.
3) biological activity determination
Paper disk method (Microbiological paper method) is adopted to measure the inhibitory action of compound to helicobacter pylori, the minimum inhibitory concentration (minimal inhibitoryconcentration, MIC) of test sample is measured with agar dilution.
I. paper disk method experiment
(A) culture medium is prepared by the Columbia culture medium for preparing after high pressure steam sterilization, be cooled to 50-60 DEG C, add 8% horse serum or Sheep Blood, mixing is poured in the culture dish of sterilizing, every ware 7-10ml, culture medium thickness is 1.5mm (sterile working).
(B) experimental bacteria of transferring (being coated with bacterium) gets diluted 10 with microscale sampler
8cFU/ml (1OD
660=10
8cFU/ml) the bacteria suspension 0.1ml of Hp spreads upon suitable culture dish surface equably.Be inverted in 37 DEG C of drying bakers and take out after 15min, object makes agar surface dry, for subsequent use.
(C) paste sample scraps of paper microscale sampler to get 6 μ l testing samples (mass concentration 2mg/ml) and inject on the round filter paper of sterilizing.With aseptic nipper tweezer containing the scraps of paper of sample and the blank scraps of paper of contrast, by sterile working respectively the scraps of paper be close to containing bacterio-agar surface, paste a piece of paper sheet at a certain distance.Often kind of bacterium is cooked 3 wares, and acquired results asks its meansigma methods.
(D) cultivate each plate is placed in micro-aerobic bag, sealing, opens gas generator, then is placed in 37 DEG C of incubators and cultivates 72h.
(E), after surveying antibacterial circle diameter taking-up flat board, the size of antibacterial circle diameter around each scraps of paper is measured respectively.With reference to the result of matched group, the result of testing sample sensitive experiment can be drawn.In triplicate.
II. agar dilution measures MIC
(A) first compound dimethyl sulfoxide (DMSO) solution preparation of test is become the mother solution of 0.5mg/ml by the preparation of Drug plates, then with sterilized water dilution, is finally made into 100.0,80.0,60.0,45.0,40.0,35.0,30.0,25.0,20.0,15.0,10.0, the concentration series of 5.0 and 2.5 μ g/ml, DMSO concentration is in media as well less than 1%.The test compounds solution that 1ml is prepared be incubated 8ml Columbia medium in 50 DEG C, separately add the horse serum that 1ml is incubated in 50 DEG C and fully mix, cast in culture dish cool (in culture dish, the final concentration of chemicals is 10.0,8.0,6.0,4.5,4.0,3.5,3.0,2.5,2.0,1.5,1.0,0.5 and 0.25 μ g/ml, if there is bacteriostasis, then MIC value namely these worthwhile in one).
(B) experimental bacteria of transferring (being coated with bacterium) draws diluted 1 × 10 with microscale sampler
8the bacteria suspension 0.1ml of CFU/ml Hp spreads upon culture dish surface equably, is inverted in 37 DEG C of drying bakers and takes out after 15min, and object makes agar surface dry, for subsequent use.
(C) determine that test dish (contains: 85%N at micro-aerobic bag by MIC
2, 10%CO
2and 5%O
2) in, be incubated 37 DEG C and cultivate 72 hours, observe Hp growing state, contrast with blank group, there is no the sample least concentration of bacteria growing completely for minimum inhibitory concentration (minimal inhibitory concentration, MIC) value.Positive control is ampicillin (Ampicillin).
Experimental result
Experiment in vitro shows, O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has very strong anti Helicobacter pylori activity, and it is 27mm (ATCC43504) that paper disk method shows its antibacterial circle diameter.With agar dilution display, it can suppress the growth of 5 random clinical strains and 1 reference culture (ATCC43504) completely, and minimal inhibitory concentration (MIC) is 3.5 μ g/ml.Make positive control with ampicillin, its Cmin (MIC) suppressed completely 6 strain test bacterium is 2.0 μ g/ml.
Conclusion: O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has stronger suppression helicobacter pylori activity, illustrate for the disease such as the closely-related acute and chronic gastritis of helicobacter pylori, duodenal ulcer, O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is the compound of a great exploitation potential for its.It can be directly used in the treatment of corresponding disease and the preparation of related drugs.
O-(imidazole radicals) ethyl derivative (III) antibacterial activity of experimental example 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Antibacterial activity test is the method adopting concentration dilution, and in triplicate, test pathogen has escherichia coli, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus, neogenesis cryptococcus to each mensuration, and bacterial concentration is 10
5individual/mL.O-(imidazole radicals) ethyl derivative (III) initial concentration of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is 50.00 μ g/mL (5% dimethyl sulfoxide DMSO), gradient dilution to 0.10 μ g/mL, (ultimate density of formation has: 25.00 in 96 orifice plates for the bacterium liquid of equivalent volumes and test sample Mixed culture, 12.50, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10 and 0.05 μ g/mL), antibacterial culturing temperature is respectively 37 DEG C, observe after incubation time 24h, if find, in the disposal hole not having bacterium colony to be formed, that minimum concentration is sample lowest concentration of antimicrobial, i.e. MIC value.O-(imidazole radicals) ethyl derivative (III) the anti-bacterial result of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is in table 2.
O-(imidazole radicals) ethyl derivative (III) antibacterium MIC value (μ g/mL) of table 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Conclusion: O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has very strong antibacterial activity, therefore O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention is expected to be used to prepare novel anti-bacterial drug.
O-(imidazole radicals) ethyl derivative (III) anti-tubercle bacillus of experimental example 4 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is active
(1) O-(imidazole radicals) ethyl derivative (III) anti-bacillus calmette-guerin vaccine (BCG) absolute concentration of solid medium By Dilution Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Scraping BCG cultures from inclined-plane, join in 3ml Middlebrook7H9 broth bouillon, add a small amount of bead, screw test tube cap, high vibration grinding in vortex oscillator, with standard Maxwell opacity tube (MacFarland No.1) than turbid, be namely made into bacillus calmette-guerin vaccine (BCG) bacteria suspension of 1mg/ml.
O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is made into the stock solution of high concentration with DMSO, by the tween 80 aseptic ultra-pure water dilution stock solution containing 5% to desired concn, O-(imidazole radicals) ethyl derivative (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr diluted wood ketone Cleistanone is joined 4mlMiddlebrook7H11 agar culture medium (this culture medium 121 DEG C of high pressure steam sterilizations 15 minutes by required dosage, be cooled to 50 ~ 55 DEG C), mixing, make O-(imidazole radicals) ethyl derivative (III) containing Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, concentration is respectively 6.0ug/ml, 4.0ug/ml, 3.0ug/ml, 2.0ug/ml, 1.5ug/ml, 1.0ug/ml, 0.75ug/ml, the isocyatic slant medium of 0.5ug/ml.
Be that bacillus calmette-guerin vaccine (BCG) the bacteria suspension inoculating loop of 1mg/ml dips ring of numbers by concentration, be inoculated in containing in the culture medium of O-(imidazole radicals) ethyl derivative (III) series concentration of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and blank medium slant respectively, be placed in 37 DEG C to cultivate 4 ~ 8 weeks, observation experiment result, result is as shown in table 3.
In the present embodiment, Middlebrook7H9 broth bouillon used and Middlebrook7H11 agar culture medium are the conventional culture medium that those skilled in the art carry out when tulase is cultivated, and its formula adopts conventional formulation.
(2) O-(imidazole radicals) ethyl derivative (III) the Killing Mycobacterium Tuberculosis type strain H37Rv strain absolute concentration of solid medium By Dilution Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Scraping mycobacterium tuberculosis type strain H37Rv strain culture from inclined-plane, join in 3mlMiddlebrook7H9 broth bouillon, add a small amount of bead, screw test tube cap, high vibration grinding in vortex oscillator, with standard Maxwell opacity tube (MacFarland No.1) than turbid, be namely made into the H37Rv strain bacteria suspension of 1mg/ml.
O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is made into respectively the stock solution of high concentration with DMSO, by the tween 80 aseptic ultra-pure water dilution stock solution containing 5% to desired concn, O-(imidazole radicals) ethyl derivative (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr diluted wood ketone Cleistanone is joined 4mlMiddlebrook7H11 agar culture medium (this culture medium 121 DEG C of high pressure steam sterilizations 15 minutes by required dosage, be cooled to 50 ~ 55 DEG C), mixing, make O-(imidazole radicals) ethyl derivative (III) containing Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, concentration is respectively 6.0ug/ml, 4.0ug/ml, 3.0ug/ml, 2.0ug/ml, 1.5ug/ml, 1.0ug/ml, 0.75ug/ml, the isocyatic slant medium of 0.5ug/ml.
Be that the H37Rv strain bacteria suspension inoculating loop of 1mg/ml dips ring of numbers by concentration, be inoculated in containing in the culture medium of O-(imidazole radicals) ethyl derivative (III) series concentration of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and blank medium slant respectively, be placed in 37 DEG C to cultivate 4 ~ 8 weeks, observation experiment result, result is as shown in table 3.
(3) the clinical separation of O-(imidazole radicals) ethyl derivative (III) the Ad tuberculosis MTB of the resistance to ISRE strain absolute concentration of solid medium By Dilution Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
The clinical separation of the scraping mycobacterium tuberculosis MTB of resistance to ISRE strain (resistance to isoniazid, streptomycin, rifampicin, the clinical detached dowel of ethambutol mycobacterium tuberculosis) culture from inclined-plane, join in 3ml Middlebrook7H9 broth bouillon, add a small amount of bead, screw test tube cap, high vibration grinding in vortex oscillator, with standard Maxwell opacity tube (MacFarland No.1) than turbid, be namely made into the bacteria suspension of 1mg/ml.
O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is made into respectively the stock solution of high concentration with DMSO, by the tween 80 aseptic ultra-pure water dilution stock solution containing 5% to desired concn, O-(imidazole radicals) ethyl derivative (III) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr diluted wood ketone Cleistanone is joined 4mlMiddlebrook7H11 agar culture medium (this culture medium 121 DEG C of high pressure steam sterilizations 15 minutes by required dosage, be cooled to 50 ~ 55 DEG C), mixing, make O-(imidazole radicals) ethyl derivative (III) containing Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, concentration is respectively 6.0ug/ml, 4.0ug/ml, 3.0ug/ml, 2.0ug/ml, 1.5ug/ml, 1.0ug/ml, 0.75ug/ml, the isocyatic slant medium of 0.5ug/ml.
Be that the clinical separation of the mycobacterium tuberculosis MTB of the resistance to ISRE strain bacteria suspension inoculating loop of 1mg/ml dips ring of numbers by concentration, be inoculated in containing in the culture medium of O-(imidazole radicals) ethyl derivative (III) series concentration of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and blank medium slant respectively, be placed in 37 DEG C to cultivate 4 ~ 8 weeks, observation experiment result, result is as shown in table 3.
O-(imidazole radicals) ethyl derivative (III) the anti-tubercle bacillus absolute concentration result of table 3 solid medium By Dilution Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Conclusion: O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has very strong anti-tubercle bacillus and anti-drug resistance tulase is active, can be used as the lead compound for the treatment of tubercle bacillus affection disease, also can be used for preparation treatment tubercular drugs.
The preparation of O-(imidazole radicals) the ethyl derivative tablet of embodiment 5 Cleistanone involved in the present invention
Get the one in the middle of O-(imidazole radicals) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of O-(imidazole radicals) the derivatized composite capsule of embodiment 6 Cleistanone involved in the present invention
Get the one in the middle of O-(imidazole radicals) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (8)
1. one kind has O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in antibacterials thereof of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III:
2. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in preparation antibacterials thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 1, is characterized by: described bacterium is antibacterial.
3. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in antibacterials thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 1, is characterized by: described bacterium is fungus.
4. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in antibacterials thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 1, is characterized by: described bacterium is helicobacter pylori.
5. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in antibacterials thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 1, is characterized by: described bacterium is tulase.
6. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in antibacterials thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 3, is characterized by: described fungus is trichophyton, microsporum canis or trichophyton tonsurans.
7. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in antibacterials thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 2, is characterized by: described antibacterial is escherichia coli, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus or neogenesis cryptococcus.
8. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in antibacterials thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 5, is characterized by: described tulase is bacillus calmette-guerin vaccine, the H37Rv strain of mycobacterium tuberculosis type strain and substance of medicines-resistant branched tubercle bacillus.
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| CHIMMANI RAMES: "Arylnaphthalide Lignans from Cleistanthus collinus1)", 《CHEM. PHARM. BULL.》 * |
| PAULO M.: "Chemical constituents of the plants of the genus", 《PHYTOCHEM REV》 * |
| VAN TRINH THI THANH: "Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New", 《EUR. J. ORG. CHEM.》 * |
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