CN104098643A - Diethylamine derivative of Cleistanine and preparation method and application thereof - Google Patents
Diethylamine derivative of Cleistanine and preparation method and application thereof Download PDFInfo
- Publication number
- CN104098643A CN104098643A CN201410305193.1A CN201410305193A CN104098643A CN 104098643 A CN104098643 A CN 104098643A CN 201410305193 A CN201410305193 A CN 201410305193A CN 104098643 A CN104098643 A CN 104098643A
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- CN
- China
- Prior art keywords
- flowers
- derivative
- ketone cleistanone
- trees ketone
- trees
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 title 1
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- 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 description 21
- 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 claims description 21
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
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- 238000002054 transplantation Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 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
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000036269 ulceration Effects 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
-
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a derivative of Cleistanine, a preparation method and application of Cleistanine in preparing anti-bacterial medicines. According to the invention, a novel Cleistanine derivative is synthesized, and the invention discloses the preparation method thereof; the pharmacological experiments show that the derivative of Cleistanine has antibacterial effect and value for developing anti-bacterial medicines.
Description
Technical field
The present invention relates to organic synthesis and pharmaceutical chemistry field, be specifically related to close flowers and trees ketone Cleistanone derivative, preparation method and its usage.
Background technology
The mankind's health and lives in the enhancing serious threat of the diffusion of pathogenic bacterium and resistance thereof, antibacterials are widely used in acquired immune deficiency syndrome (AIDS) as routine administration, organ transplantation and chronic wasting disease are (as cancer, diabetes, uremia etc.) treatment, although the antimicrobial agent of using clinically is at present (as KETOKONAZOL, amikacin, gentamicin, voriconazole, itraconazole, Terbinafine, amphotericin, fluconazole 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 tube stimulates, dizzy, irritated etc., so find the novel antibacterial medicine of mechanism of action uniqueness, become one of focus of current medicament research and development.
Helicobacter pylori (Helicobacter pylori, Hp) is a kind of Gram-negative spiral bacteria.Studies show that, helicobacter pylori is the main pathogenesis of acute and chronic gastritis and Stomach duodenum ulcer, and may be relevant with the morbidity of stomach mucous membrane dependency lymphoid tissue (MALT) malignant lymphoma with cancer of the stomach.Recently, the World Health Organization is classified as I class carcinogens by Hp, and it plays a leading role in cancer of the stomach development.Current popular treatment H
pthe scheme infecting is to take the triple therapy that proton pump inhibitor (PPI) adds two kinds of microbiotic (clarithromycin, amoxycilline Trihydrate bp, tsiklomitsin, metronidazole etc. select two kinds) simultaneously.The main factor that affects triple therapy is considered to the resistance of Hp to antiseptic-germicide; Another serious problems are that proton pump inhibitor can bring out maldigestion, and a large amount of antiseptic-germicides cause the serious destruction of flora in digestive tube.Therefore, find the active kind new medicine thing of efficient, safe anti-Hp and become an important and urgent task.
Global morbidity lungy is in recent years increases trend, according to the World Health Organization (WHO), estimate, the whole world is subject to mycobacterium tuberculosis (Mycobacterium tuberculosis at present, MTB) population infecting accounts for 1/3rd of world population, and wherein the infected of 5～10% becomes tuberculosis patient.There are every year active tuberculosis patient 1,300,000 examples in China, infectivity pulmonary tuberculosis approximately 600,000 examples wherein, and wherein infectivity pulmonary tuberculosis approximately 600,000 examples, are one of the high burden of global tuberculosis countries.
From antitubercular agent, come out one after another, make treatment lungy play epoch-making variation.Yet due to the treatment management of tuberculosis patient standard very not still, irregular chemotherapy, abuse antitubercular agent, makes drug resistance of tuberculosis situation day by day serious, and the variation of resistance more trends towards multi-medicament resistance simultaneously, and this causes very big difficulty to preventing and controlling lungy.Therefore find new antitubercular agent, the antitubercular agent 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 derivative, thereby the potential drug that obtains high-efficiency low-toxicity there is important value most.
The compound the present invention relates to closes flowers and trees ketone Cleistanone and is one and within 2011, delivers (Van Trinh ThiThanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.
volume2011, Issue22,pages4108 – 4111, August2011) compound, we close flowers and trees ketone Cleistanone to compound and have carried out structural modification, have obtained a new flowers and trees ketone Cleistanone derivative that closes, and its anti-microbial activity is evaluated, it has anti-microbial activity.
Summary of the invention
The invention discloses one and close flowers and trees ketone Cleistanone derivative, its structure is:
The present invention closes flowers and trees ketone Cleistanone derivative (III) and can prepare by method below:
(1) close flowers and trees ketone Cleistanone (I) and react the O-bromotrifluoromethane derivative (II) that obtains closing flowers and trees ketone Cleistanone with glycol dibromide;
(2) the O-bromotrifluoromethane derivative (II) that closes flowers and trees ketone Cleistanone makes and closes flowers and trees ketone Cleistanone derivative (III) with diethylamine generation substitution reaction.
The preparation method who further closes flowers and trees ketone Cleistanone derivative (III) is:
(1) 440mg compound is closed to flowers and trees ketone Cleistanone (I) and be dissolved in 10mL benzene, to the Tetrabutyl amonium bromide that adds 0.04g in solution, 50% sodium hydroxide solution of the glycol dibromide of 3.760g and 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, reaction solution is poured in frozen water, used immediately dichloromethane extraction twice, merge organic phase solution; Then to organic phase solution successively water and saturated common salt water washing 3 times, 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, moving phase is: sherwood oil/acetone=100:1, v/v, collects the yellow yellow solid of concentrating elution band to obtain closing the O-bromotrifluoromethane derivative (II) of flowers and trees ketone Cleistanone.
(2) the O-bromotrifluoromethane derivative that closes flowers and trees ketone Cleistanone of 273mg is dissolved in the middle of 20mL acetonitrile, adds wherein the Anhydrous potassium carbonate of 345mg, the potassiumiodide of 84mg and the diethylamine of 1460mg, mixture reflux 8h; After reaction finishes, reaction solution is poured in frozen water, used equivalent dichloromethane extraction three times, merge organic phase; Water and saturated common salt water washing merge organic phase afterwards successively, then use anhydrous sodium sulfate drying, and concentrating under reduced pressure is removed solvent and obtained product crude product; Product crude product purification by silica gel column chromatography, moving phase is: sherwood oil/acetone=100:1, v/v, collects the faint yellow gluey solid that faint yellow concentrated elution band obtains closing flowers and trees ketone Cleistanone derivative (III).
Compound disclosed by the invention can be made pharmacy acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the flowers and trees ketone Cleistanone derivative (III) that closes of the present invention has good anti-microbial effect.Pharmacy acceptable salt of the present invention and its compound have same drug effect.
Further, the experiment in vitro of compound III shows, chemicals III has very strong anti-human body fungi activity, and therefore chemicals III of the present invention is expected to be used to prepare novel anti-human body fungi-medicine.
Further, the experiment in vitro of compound III shows, compound III has very strong anti Helicobacter pylori activity, explanation for the diseases such as the closely-related acute and chronic gastritis of Hp, duodenal ulcer, compound III 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 compound III shows, compound III has the effect of very strong inhibition intestinal bacteria, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus, cryptococcus neoformans, so compound III can be used as the compound with antibacterial actions, and be expected to be applied in preparing anti-bacterial drug.
Further, according to the result of tentative experiment, the minimal inhibitory concentration of this compound to bacille Calmette-Guerin vaccine, the H37Rv strain of mycobacterium tuberculosis type strain and three kinds of tubercule bacilluss of substance of medicines-resistant branched tubercle bacillus (MDR MTB) that the present invention has used solid medium By Dilution, experimental result confirms that compound III has very strong anti-tubercle bacillus and anti-drug resistance tubercule bacillus is active, can be used as the lead compound for the treatment of tubercle bacillus affection disease, also can be used for preparation treatment tuberculosis medicine.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subject to any restriction of specific embodiment, but be limited by claim.
Embodiment
The preparation that embodiment 1 compound closes flowers and trees ketone Cleistanone
Compound closes document (the Van Trinh Thi Thanh et al. that the preparation method of flowers and trees ketone Cleistanone (I) delivers with reference to people such as Van Trinh Thi Thanh, 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton.Volume2011, Issue22, pages4108 – 4111, method August2011).
Embodiment 2 closes O-bromotrifluoromethane derivative (II) synthetic of flowers and trees ketone Cleistanone
Compound I (440mg, 1.00mmol) is dissolved in to 10mL benzene, in solution, adds Tetrabutyl amonium bromide (TBAB) (0.04g), 50% sodium hydroxide solution of glycol dibromide (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, reaction solution is poured in frozen water, used immediately dichloromethane extraction twice, merge organic phase solution.Then to organic phase solution successively water and saturated common salt water washing 3 times, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.(moving phase is product purification by silica gel column chromatography for crude product: sherwood oil/acetone=100:1, v/v), collect the yellow yellow solid (344mg, 63%) of concentrating elution band to obtain Compound I I.
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；found547.3159.
Embodiment 3 closes O-(diethylin) ethyl derivative (III) synthetic of flowers and trees ketone Cleistanone
Compound I I (273mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds wherein Anhydrous potassium carbonate (345mg, 2.5mmol), potassiumiodide (84mg, 0.5mmol) and diethylamine (1460mg, 20mmol), mixture reflux 8h.After reaction finishes, reaction solution is poured in frozen water, used equivalent dichloromethane extraction three times, merge organic phase.Water and saturated common salt water washing merge organic phase afterwards successively, then use anhydrous sodium sulfate drying, and concentrating under reduced pressure is removed solvent and obtained product crude product.Product for crude product purification by silica gel column chromatography (moving phase is: sherwood oil/acetone=100:1, v/v), collect the faint yellow gluey solid (169.8mg, 63%) that faint yellow concentrated elution band obtains compound III.
1H?NMR(500MHz,DMSO-d6)δ5.04(s,1H),4.85(s,1H),4.37(s,1H),3.54(s,2H),2.91(s,4H),2.64(s,2H),2.41(d,J＝17.2Hz,2H),2.30(s,1H),2.21(d,J＝22.5Hz,2H),1.82(s,1H),1.65(s,2H),1.58(d,J＝9.0Hz,2H),1.49(d,J＝5.7Hz,2H),1.39(d,J＝13.4Hz,3H),1.36–1.28(m,3H),1.28–1.26(m,1H),1.26–1.14(m,8H),1.06(s,6H),0.92(d,J＝19.4Hz,13H),0.82(s,3H),0.71(s,1H).
13C?NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.65(s),66.82(s),59.77(s),52.54(d,J＝3.0Hz),51.21(s),47.92(s),47.73(s),44.13(s),42.30(s),41.77(s),40.65(s),40.17(s),38.86(s),38.68(s),37.26(s),36.27(s),33.35(s),32.97(s),29.89(s),27.21(s),26.08(s),24.27(s),23.97(s),20.78(s),18.46(s),18.01(s),16.98(s),12.33(s).
HRMS(ESI):m/z[M+H]
+calcd?for?C
36H
62NO
2:540.4781；found:540.4787。
Embodiment 4 compound III anti-helicobactor pylori activities
1) strains tested
Helicobacter pylori (Helicobacter pylori, Hp) reference culture ATCC43504 is purchased from U.S.'s bacterial classification and preserves center (American Type Culture Collection, ATCC).12 strain Hp clinical strains are picked up from Nanjing drum tower hospital Dndoscope Laboratory and are accepted gastroscopic patient; Patient to peptide ulceration, duodenal bulbar inflammation or gastritis verrucosa in continuous gastroscopy, first through RUT experiment, be defined as Hp positive, get again antral gastric mucosa 1-2 piece, after chopping, be inoculated in containing 8% horse serum, trimethoprim (trimethropin, TMP) in the Columbia selectivity nutrient agar of 1.25g/L, polymyxin (polymyxin) B2500U/L, vancomycin (vancomycin) 10mg/L, in 37 ℃ of (5%O under micro-oxygen environment
2, 10%CO
2and 85%N
2) cultivate 72 hours.Collect bacterium, through smear gramstaining, oxydase, catalase and urease are accredited as after the positive, the pure culture of going down to posterity, and 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 can produce the needed micro-aerobic environment of Hp by chemical reaction.
3) biological activity determination
Adopt paper disk method (Microbiological paper method) to measure the restraining effect of compound to helicobacter pylori, with agar dilution, measure the minimum inhibitory concentration (minimal inhibitory concentration, MIC) of test sample.
I. paper disk method experiment
(A) prepare substratum by the Columbia substratum preparing after high pressure steam sterilization, be cooled to 50-60 ℃, add 8% horse serum or Sheep Blood, mix in the culture dish that is poured into sterilizing, every ware 7-10ml, substratum thickness is 1.5mm (aseptic technique).
(B) switching experimental bacteria (be coated with bacterium) with microscale sampler get diluted 10
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 ℃ of drying bakers and take out after 15min, object makes agar surface dry, standby.
(C) pasting the sample scraps of paper gets 6 μ l testing samples (mass concentration 2mg/ml) with microscale sampler and injects 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 aseptic technique respectively the scraps of paper be close to containing bacterio-agar surface, paste at a certain distance a piece of paper sheet.Every kind of bacterium is cooked 3 wares, and acquired results is asked its mean value.
(D) cultivate each plate is placed in to micro-aerobic bag, sealing, opens producer gas generator, then is placed in 37 ℃ of incubators and cultivates 72h.
(E) survey antibacterial circle diameter and take out after flat board, measure respectively each scraps of paper size of antibacterial circle diameter around.With reference to the result of control group, can draw the result of testing sample sensitive experiment.In triplicate.
II. agar dilution is measured MIC
(A) first the preparation of medicine flat board becomes dimethyl sulfoxide (DMSO) for compound (DMSO) solution preparation of test the mother liquor of 0.5mg/ml, 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, the concentration of DMSO in medium is less than 1%.The test compounds solution that 1ml is prepared be incubated the 8ml Colombia substratum in 50 ℃, separately add 1ml and be incubated in the horse serum of 50 ℃ and fully mix, cast that cooling in culture dish (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 bacteriostatic action, MIC value is these in worthwhile).
(B) switching experimental bacteria (be coated with bacterium) with microscale sampler draw diluted 1 * 10
8the bacteria suspension 0.1ml of CFU/ml Hp spreads upon culture dish surface equably, is inverted in 37 ℃ of drying bakers and takes out after 15min, and object makes agar surface dry, standby.
(C) determine that MIC (contains culture dish to be measured: 85%N at micro-aerobic bag
2, 10%CO
2and 5%O
2) in, be incubated 37 ℃ and cultivate 72 hours, observe Hp growing state, with blank group contrast, take and there is no the sample of bacteria growing minimum concentration completely as minimum inhibitory concentration (minimal inhibitory concentration, MIC) value.Positive control is Ampicillin Trihydrate (Ampicillin).
Experimental result
Experiment in vitro shows, chemicals III has very strong anti Helicobacter pylori activity, and paper disk method shows that its antibacterial circle diameter is 21mm (ATCC43504).With agar dilution, show that it can suppress the growth of 5 random clinical strains and 1 reference culture (ATCC43504) completely, minimal inhibitory concentration (MIC) is 1.5 μ g/ml.With Ampicillin Trihydrate, make positive control, its Cmin (MIC) that 6 strain test bacterium are suppressed is completely 1.0 μ g/ml.
Conclusion: it is active that chemicals III has stronger inhibition Hp, illustrate for the disease such as the closely-related acute and chronic gastritis of Hp, duodenal ulcer, chemicals III 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.
Embodiment 5 chemicals III antibacterial activities
Antibacterial activity test is the method that adopts concentration dilution, each mensuration in triplicate, and test pathogenic bacteria has intestinal bacteria, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus, cryptococcus neoformans, and bacterial concentration is 10
5individual/mL.Compound III initial concentration is 50.00 μ g/mL (5% dimethyl sulfoxide (DMSO) DMSO), gradient dilution to 0.10 μ g/mL, (ultimate density of formation has: 25.00,12.50,6.25,3.13,1.56,0.78,0.39,0.20,0.10 and 0.05 μ g/mL) in 96 orifice plates for the bacterium liquid of equivalent volumes and test sample mixed culture, microbial culture temperature is respectively 37 ℃, after incubation time 24h, observe, if find, there is no that minimum concentration in processing hole that bacterium colony forms is sample lowest concentration of antimicrobial, i.e. MIC value.Compound III the anti-bacterial result is in Table 1.
Table 1 compound III antibacterium MIC value (μ g/mL)
Conclusion: compound III has very strong antibacterial activity, therefore compound III of the present invention is expected to be used to prepare novel anti-bacterial drug.
Embodiment 6 compound III anti-tubercle bacillus are active
(1) the anti-bacille Calmette-Guerin vaccine of solid medium By Dilution compound III (BCG) absolute concentration
Scraping bacille Calmette-Guerin vaccine culture from inclined-plane, joins in 3ml Middlebrook7H9 broth culture,
Add a small amount of granulated glass sphere, screw test tube cap, on vortex oscillation device, high vibration grinds, and than turbid, is made into bacille Calmette-Guerin vaccine (BCG) bacteria suspension of 1mg/ml with standard Maxwell opacity tube (MacFarland No.1).
Compound III is made into the stoste of high density with DMSO, with the aseptic ultrapure water of the tween-80 containing 5%, dilute stoste to desired concn, the compound III of having diluted is joined to 4mlMiddlebrook7H11 nutrient agar (this substratum 121 ℃ of high pressure steam sterilizations 15 minutes, be cooled to 50～55 ℃) by required dosage, mix, make containing compound III, 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.
The bacille Calmette-Guerin vaccine that is 1mg/ml by concentration (BCG) bacteria suspension dips ring of numbers with transfering loop, be inoculated in respectively on the substratum and blank medium slant containing compound III series concentration, be placed in 37 ℃ and cultivate 4～8 weeks, observation experiment result, result is as shown in table 2.
Conventional substratum when Middlebrook7H9 broth culture used and Middlebrook7H11 nutrient agar carry out tubercule bacillus cultivation for those skilled in the art in the present embodiment, its formula adopts conventional formulation.(2) solid medium By Dilution compound III Killing Mycobacterium Tuberculosis type strain H37Rv strain absolute concentration
Scraping mycobacterium tuberculosis type strain H37Rv strain culture from inclined-plane, join in 3mlMiddlebrook7H9 broth culture, add a small amount of granulated glass sphere, screw test tube cap, on vortex oscillation device, high vibration grinds, than turbid, be made into the H37Rv strain bacteria suspension of 1mg/ml with standard Maxwell opacity tube (MacFarland No.1).
Compound III is made into respectively to the stoste of high density with DMSO, with the aseptic ultrapure water of the tween-80 containing 5%, dilute stoste to desired concn, the compound III of having diluted is joined to 4ml Middlebrook7H11 nutrient agar (this substratum 121 ℃ of high pressure steam sterilizations 15 minutes, be cooled to 50～55 ℃) by required dosage, mix, make containing compound III, 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.
The H37Rv strain bacteria suspension that is 1mg/ml by concentration dips ring of numbers with transfering loop, is inoculated in respectively on the substratum and blank medium slant containing compound III series concentration, and be placed in 37 ℃ and cultivate 4～8 weeks, observation experiment result, result is as shown in table 2.
(3) the clinical separation of the solid medium By Dilution compound III tuberculosis mycobacterium MTB of resistance to ISRE strain absolute concentration
The clinical separation of the scraping mycobacterium tuberculosis MTB of resistance to ISRE strain (resistance to vazadrine, Streptomycin sulphate, Rifampin, the clinical separator column of Tibutol mycobacterium tuberculosis) culture from inclined-plane, join in 3ml Middlebrook7H9 broth culture, add a small amount of granulated glass sphere, screw test tube cap, on vortex oscillation device, high vibration grinds, than turbid, be made into the bacteria suspension of 1mg/ml with standard Maxwell opacity tube (MacFarland No.1).
Compound III is made into respectively to the stoste of high density with DMSO, with the aseptic ultrapure water of the tween-80 containing 5%, dilute stoste to desired concn, the compound III of having diluted is joined to 4ml Middlebrook7H11 nutrient agar (this substratum 121 ℃ of high pressure steam sterilizations 15 minutes, be cooled to 50～55 ℃) by required dosage, mix, make containing compound III, 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.
The clinical separation of the mycobacterium tuberculosis MTB of the resistance to ISRE strain bacteria suspension that is 1mg/ml by concentration dips ring of numbers with transfering loop, be inoculated in respectively on the substratum and blank medium slant containing compound III series concentration, be placed in 37 ℃ and cultivate 4～8 weeks, observation experiment result, result is as shown in table 2.
Table 2 solid medium By Dilution compound III anti-tubercle bacillus absolute concentration result
Conclusion: compound III has very strong anti-tubercle bacillus and anti-drug resistance tubercule bacillus is active, can be used as the lead compound for the treatment of tubercle bacillus affection disease, also can be used for preparation treatment tuberculosis medicine.
The anti-human body fungi activity of embodiment 7 compound III
Anti-human body fungi activity experiment is the method that adopts concentration dilution, each mensuration in triplicate, and the pathogenic bacteria of test has trichophyton, microsporum lanosum and trichophyton tonsurans, and bacterial concentration is 10
5individual/mL.Compound III initial concentration is 50.00 μ g/mL (5% dimethyl sulfoxide (DMSO) DMSO), gradient dilution to 0.10 μ g/mL, (ultimate density of formation has: 25.00,12.50,6.25,3.13,1.56,0.78,0.39,0.20,0.10 and 0.05 μ g/mL) in 96 orifice plates for the bacterium liquid of equivalent volumes and test sample mixed culture, Human Fungi culture temperature is respectively 28 ℃, after incubation time 24h, observe, if find, there is no that minimum concentration in processing hole that bacterium colony forms is sample lowest concentration of antimicrobial, i.e. MIC value.This experiment positive control is KETOKONAZOL, and the anti-Human Fungi of chemicals III the results are shown in Table 3.
The anti-Human Fungi MIC of table 3 chemicals III value (μ g/mL)
Conclusion: chemicals III has very strong anti-human body fungi activity, therefore chemicals III of the present invention is expected to be used to prepare novel anti-human body fungi-medicine.
The preparation of embodiment 8 compound III tablet involved in the present invention
Get a kind of in the middle of 20 grams of compound III or its pharmacy acceptable salt, add 180 grams of conventional auxiliary materials preparing tablet, mix, conventional tabletting machine is made 1000.
The preparation of embodiment 9 compound III capsule involved in the present invention
Get a kind of in the middle of 20 grams of compound III or its pharmacy acceptable salt, add the conventional auxiliary material of preparing capsule as 180 grams of starch, mix, encapsulatedly make 1000.
Claims (11)
- One kind there is structure shown in formula III close flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof:
- 2. the preparation method who closes flowers and trees ketone Cleistanone derivative as claimed in claim 1, is characterized by:(1) close flowers and trees ketone Cleistanone (I) and react the O-bromotrifluoromethane derivative (II) that obtains closing flowers and trees ketone Cleistanone with glycol dibromide;(2) the O-bromotrifluoromethane derivative (II) that closes flowers and trees ketone Cleistanone makes and closes flowers and trees ketone Cleistanone derivative (III) with diethylamine generation substitution reaction.
- 3. the preparation method who closes flowers and trees ketone Cleistanone derivative as claimed in claim 2, is characterized by:(1) 440mg compound is closed to flowers and trees ketone Cleistanone (I) and be dissolved in 10mL benzene, to the Tetrabutyl amonium bromide that adds 0.04g in solution, 50% sodium hydroxide solution of the glycol dibromide of 3.760g and 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, reaction solution is poured in frozen water, used immediately dichloromethane extraction twice, merge organic phase solution; Then to organic phase solution successively water and saturated common salt water washing 3 times, 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, moving phase is: sherwood oil/acetone=100:1, v/v, collects the yellow yellow solid of concentrating elution band to obtain closing the O-bromotrifluoromethane derivative (II) of flowers and trees ketone Cleistanone.(2) the O-bromotrifluoromethane derivative that closes flowers and trees ketone Cleistanone of 273mg is dissolved in the middle of 20mL acetonitrile, adds wherein the Anhydrous potassium carbonate of 345mg, the potassiumiodide of 84mg and the diethylamine of 1460mg, mixture reflux 8h; After reaction finishes, reaction solution is poured in frozen water, used equivalent dichloromethane extraction three times, merge organic phase; Water and saturated common salt water washing merge organic phase afterwards successively, then use anhydrous sodium sulfate drying, and concentrating under reduced pressure is removed solvent and obtained product crude product; Product crude product purification by silica gel column chromatography, moving phase is: sherwood oil/acetone=100:1, v/v, collects the faint yellow gluey solid that faint yellow concentrated elution band obtains closing flowers and trees ketone Cleistanone derivative (III).
- 4. as claimed in claim 1ly close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof.
- As claimed in claim 4 a kind of there is structure shown in formula III close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof, it is characterized by: described bacterium is bacterium.
- As claimed in claim 4 a kind of there is structure shown in formula III close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof, it is characterized by: described bacterium is fungi.
- As claimed in claim 4 a kind of there is structure shown in formula III close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof, it is characterized by: described bacterium is helicobacter pylori.
- As claimed in claim 4 a kind of there is structure shown in formula III close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof, it is characterized by: described bacterium is tubercule bacillus.
- As claimed in claim 6 a kind of there is structure shown in formula III close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof, it is characterized by: described fungi is trichophyton, microsporum lanosum or trichophyton tonsurans.
- As claimed in claim 5 a kind of there is structure shown in formula III close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof, it is characterized by: described bacterium is intestinal bacteria, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus or cryptococcus neoformans.
- 11. as claimed in claim 8 a kind of there is structure shown in formula III close the application in preparation antibacterials of flowers and trees ketone Cleistanone derivative and pharmacy acceptable salt thereof, it is characterized by: described tubercule bacillus is bacille Calmette-Guerin vaccine, the H37Rv strain of mycobacterium tuberculosis type strain and substance of medicines-resistant branched tubercle bacillus.
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Cited By (4)
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| CN104402964A (en) * | 2014-12-10 | 2015-03-11 | 南京大学 | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof |
| CN104447938A (en) * | 2014-11-05 | 2015-03-25 | 南京大学 | O-(piperazinyl) ethyl derivative of cleistanone, preparation method of O-(piperazinyl) ethyl derivative of cleistanone and use of O-(piperazinyl) ethyl derivative of cleistanone |
| CN104758296A (en) * | 2015-03-10 | 2015-07-08 | 江苏卓见医疗用品有限公司 | Chitosan composite material containing novel active molecule, preparation method and application thereof |
| CN104840470A (en) * | 2015-04-15 | 2015-08-19 | 南京广康协生物医药技术有限公司 | Application of cleistanone O-(1H-tetrazole)ethyl derivative in preparation of antibacterial drugs |
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| CN103232513A (en) * | 2013-05-09 | 2013-08-07 | 南京中医药大学 | Method for preparing tirucallol |
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| CN103232513A (en) * | 2013-05-09 | 2013-08-07 | 南京中医药大学 | Method for preparing tirucallol |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447938A (en) * | 2014-11-05 | 2015-03-25 | 南京大学 | O-(piperazinyl) ethyl derivative of cleistanone, preparation method of O-(piperazinyl) ethyl derivative of cleistanone and use of O-(piperazinyl) ethyl derivative of cleistanone |
| CN104447938B (en) * | 2014-11-05 | 2016-11-30 | 南京大学 | O-(piperazinyl) ethyl derivative of Cleistanone, preparation method and its usage |
| CN104402964A (en) * | 2014-12-10 | 2015-03-11 | 南京大学 | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof |
| CN104402964B (en) * | 2014-12-10 | 2016-06-15 | 南京大学 | O-(imidazole radicals) ethyl derivative of Cleistanone, preparation method and its usage |
| CN104758296A (en) * | 2015-03-10 | 2015-07-08 | 江苏卓见医疗用品有限公司 | Chitosan composite material containing novel active molecule, preparation method and application thereof |
| CN104840470A (en) * | 2015-04-15 | 2015-08-19 | 南京广康协生物医药技术有限公司 | Application of cleistanone O-(1H-tetrazole)ethyl derivative in preparation of antibacterial drugs |
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