CN105616423A - Composition and application of composition to antibacterial medicine - Google Patents
Composition and application of composition to antibacterial medicine Download PDFInfo
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- CN105616423A CN105616423A CN201511017425.4A CN201511017425A CN105616423A CN 105616423 A CN105616423 A CN 105616423A CN 201511017425 A CN201511017425 A CN 201511017425A CN 105616423 A CN105616423 A CN 105616423A
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- compound
- antibacterials
- medicine
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The invention relates to the field of organic synthesis and medicine chemistry, in particular to a composition, a preparation method and application of the composition to preparation of antibacterial medicine. The invention discloses the composition and the preparation method of the composition. Pharmacological experiments show that the composition has the antibacterial effect, and has antibacterial medicine development values.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, it is specifically related to composition, preparation method and its usage.
Background technology
The health and lives of the mankind in the diffusion of pathogenic bacterium and the enhancing serious threat of resistance thereof, antibacterials as routine administration extensively for acquired immune deficiency syndrome (AIDS), organ transplantation and chronic wasting disease are (such as cancer, diabetes, uremia etc.) treatment, although the antimicrobial agent of current clinical upper use is (such as KETOKONAZOL, amikacin, gentamicin, voriconazole, itraconazole, Terbinafine, amphotericin, fluconazole etc.) curative effect of skin and superficial place infection is better, but the cumulative toxicity of these antibacterials is stronger, usually cause lesions of liver and kidney, digestive tube stimulates, dizzy, irritated etc., so finding one of novel antibacterial medicine focus becoming current medicament research and development of mechanism of action uniqueness.
Helicobacter pylori (Helicobacterpylori, Hp) is a kind of Gram-negative spirrillum bacterium. Research display, helicobacter pylori is the primary pathogenic event of acute and chronic gastritis and taste-blindness rate, and may be relevant with the morbidity of stomach mucous membrane associated lymphoid sample tissue (MALT) malignant lymphoma with cancer of the stomach. Recently, Hp is classified as I class carcinogens by the World Health Organization, and it plays leading role in stomach cancer development. Simultaneously the scheme that popular at present treatment Hp infects takes the triple therapy of proton pump inhibitor (PPI) kind of the microbiotic (clarithromycin, amoxycilline Trihydrate bp, tsiklomitsin, metronidazole etc. select two kinds) that adds two. The main factor affecting triple therapy is considered as Hp to the resistance of antiseptic-germicide; Another serious problems are that proton pump inhibitor can bring out maldigestion, and a large amount of antiseptic-germicide then causes the serious destruction of bacterium group in digestive tube. Therefore, find the active kind new medicine thing of efficient, safe anti-Hp and become an important and urgent task.
The morbidity of whole world tuberculosis is in increasing trend in recent years, estimate according to the World Health Organization (WHO), the whole world is by mycobacterium tuberculosis (Mycobacteriumtuberculosis at present, MTB) population infected accounts for 1/3rd of world population, and wherein the infected of 5��10% becomes tuberculosis patient. China occurs active tuberculosis patient 1,300,000 example every year, wherein infectivity pulmonary tuberculosis about 600,000 example, wherein infectivity pulmonary tuberculosis about 600,000 example, is one of whole world tuberculosis high burden country.
Come out one after another from antitubercular agent, make the treatment of tuberculosis play epoch-making change. But the Case management still not very specification due to tuberculosis patient, irregular chemotherapy, abuse antitubercular agent, makes tuberculosis resistance situation day by day serious, and the change of resistance more trends towards multiple medicine resistance simultaneously, this causes very big difficulty to the preventing and controlling of tuberculosis. Therefore finding 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, thus the potential drug obtaining high-efficiency low-toxicity has important value most.
The Compound I that the present invention relates to is one and delivers (Fan-YuMengetal. in 2011, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1,502 1505) compound, Compound I has been carried out structural modification by us, obtain two new derivatives and compound III and compound IV, and prepared composition by compound III and compound IV and said composition anti-microbial activity has been evaluated, it has anti-microbial activity.
Summary of the invention
The present invention discloses a new composition, and said composition is made up of compound III and compound IV, and in said composition, the mass percent of compound III and compound IV is respectively 70% and 30%.
Composition disclosed by the invention can make pharmacy acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the composition of the present invention has good anti-microbial effect. The pharmacy acceptable salt of the present invention has same drug effect.
Further, the experiment in vitro of composition shows, composition has very strong human body fungi activity, and therefore the composition of the present invention is expected to be used to prepare novel anti-human fungi medicine.
Further, the experiment in vitro of composition shows, composition has very strong anti Helicobacter pylori activity, illustrates that composition is the compound of a great exploitation potential for its for diseases such as the acute and chronic gastritis closely related with Hp, duodenal ulcers. It can be directly used in the treatment of corresponding disease and the preparation of related drugs.
Further, the experiment in vitro of composition shows, composition has the effect of very strong suppression intestinal bacteria, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus, cryptococcus neoformans, so composition can be used as the compound with antibacterial actions, and it is expected to be applied preparing in anti-bacterial drug.
Further, result according to tentative experiment, the present invention's solid medium dilution method determines composition to the minimal inhibitory concentration of bacille Calmette-Guerin vaccine, mycobacterium tuberculosis standard strain H37Rv strain and substance of medicines-resistant branched tubercle bacillus (MDRMTB) three kinds of tubercule bacilluss, experimental result confirms that composition has very strong anti-tubercle bacillus and anti-drug resistance tubercule bacillus activity, can be used as the lead compound for the treatment of tubercle bacillus affection disease, it is possible to for the preparation for the treatment of tuberculosis medicine.
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 is limited by claim.
Embodiment
The preparation of embodiment 1 compound S chiglautoneA
Document (the Fan-YuMengetal. that the preparation method of compound S chiglautoneA (I) delivers with reference to people such as Fan-YuMeng, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1,502 1505) method.
The synthesis of O-bromotrifluoromethane derivative (II) of embodiment 2SchiglautoneA
By Compound I (502mg, 1.00mmol) it is dissolved in 15mL benzene, adds in solution Tetrabutyl amonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-ethylene dibromide (7.520g, 40.00mmol) and 6mL. Mixture stirs 8h at 35 degrees Celsius. After 8h, reaction solution is poured in frozen water, immediately with dichloromethane extraction twice, merge organic phase solution. Then to organic phase solution successively with water and saturated common salt water washing 3 times, then with 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=100:1.0, v/v), collects brown concentrated wash-out band and flings to the brown ceramic powder (508mg, 71%) that namely solvent obtains Compound I I.
1HNMR(500MHz,DMSO-d6) �� 13.40 (s, 1H), 6.10 (s, 1H), 5.63 (s, 1H), 5.53 (s, 1H), 3.85 (d, J=11.2Hz, 4H), 3.52 (d, J=10.8Hz, 4H), 2.96 (s, 1H), 2.20 (s, 1H), 2.16 (s, 2H), 2.00 (s, 1H), 1.84 (d, J=13.9Hz, 4H), 1.69 (s, 1H), 1.58 (dd, J=22.2, 8.5Hz, 4H), 1.51 (s, 1H), 1.47 (s, 1H), 1.26 (dd, J=9.1, 4.4Hz, 4H), 1.21 (s, 1H), 1.08 0.98 (m, 4H), 0.96-0.94 (m, 9H), 0.94-0.85 (m, 6H).
13CNMR(125MHz,DMSO-d6)��211.46(s),209.14(s),170.06(s),161.12(s),143.51(s),132.01(s),127.77(s),85.96(s),82.40(s),70.19(s),69.10(s),57.14(s),52.73(s),51.90(s),45.77(s),40.67(s),38.57(s),38.32(s),35.04(s),33.55(s),33.27(s),29.85(s),28.98(s),26.71(s),25.50(s),24.05(s),22.31(s),21.06(s),20.56(s),20.00(s),18.69(s),18.11(s),15.07(s).
HRMS(ESI)m/z[M-H]-calcdforC34H51Br2O6: 715.2032; Found715.2027.
The synthesis of O-(morpholinyl) ethyl derivative (III) of embodiment 3SchiglautoneA
Compound I I (358mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassiumiodide (168mg, 1.0mmol) and morpholine (3484mg, 40mmol), mixture reflux 4h. Reaction solution is poured in 20mL frozen water after terminating by reaction, with equivalent dichloromethane extraction 2 times, merges organic phase. Organic phase after merging with water and saturated common salt water washing successively, then with 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 (moving phase is: sherwood oil/acetone=100:0.5, v/v), collects yellow and concentrates wash-out band and fling to the brown ceramic powder (247.5mg, 68%) that namely solvent obtains compound III.
1HNMR (500MHz, DMSO-d6) �� 15.28 (s, 1H), 6.10 (s, 1H), 5.55 (s, 1H), 5.30 (s, 1H), 3.53 (s, 8H), 3.46 (d, J=4.5Hz, 4H), 2.98 (s, 1H), 2.52 (d, J=1.8Hz, 4H), 2.45 (s, 8H), 2.28 (s, 2H), 2.16 (s, 1H), 1.87 1.77 (m, 5H), 1.78 (s, 1H), 1.67 (s, 1H), 1.59 (s, 1H), 1.57 1.50 (m, 3H), 1.46 (s, 1H), 1.31 (s, 1H), 1.26 (dd, J=19.5, 10.5Hz, 4H), 1.04 0.92 (m, 10H), 0.89 (s, 3H), 0.87 (d, J=20.0Hz, 3H), 0.82 (s, 3H).
13CNMR(125MHz,DMSO-d6)��211.29(s),208.87(s),169.90(s),160.93(s),143.32(s),131.85(s),127.58(s),85.77(s),82.24(s),66.79(s),66.55(s),65.94(s),56.97(s),54.25(s),52.72(s),52.54(s),51.71(s),45.61(s),40.48(s),38.38(s),38.16(s),34.85(s),33.36(s),29.67(s),28.80(s),26.53(s),25.32(s),23.87(s),22.13(s),20.88(s),20.38(s),19.82(s),18.51(s),17.93(s),14.89(s).
HRMS(ESI):m/z[M+H]+calcdforC42H69N2O8: 729.5054; Found:729.5051.
The synthesis of O-(two hydroxyethylamines) ethyl derivative of embodiment 4SchiglautoneA
Compound I I (358mg, 0.5mmol) is dissolved in 15mL acetonitrile, adds Anhydrous potassium carbonate (0.345g, 2.5mmol), potassiumiodide (0.084g, 0.5mmol) and diethanolamine (1.0514g, 10mmol), mixture reflux 9h. Reaction solution is poured in cold water after terminating by reaction, with dichloromethane extraction three times, merges organic phase, and successively with water and saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure removes solvent. Product, with purification by silica gel column chromatography (sherwood oil/acetone 100:1, v/v), obtains the faint yellow solid (0.199g, 52%) of O-(two hydroxyethylamines) ethyl derivative of SchiglautoneA.
1HNMR (500MHz, DMSO-d6) �� 17.77 (s, 1H), 6.00 (s, 1H), 5.40 (s, 1H), 5.20 (s, 1H), 3.37 (d, J=17.8Hz, 4H), 3.28 (s, 8H), 2.87 (s, 1H), 2.51 (d, J=6.5Hz, 4H), 2.43 (s, 8H), 2.24 (s, 2H), 2.06 (d, J=12.7Hz, 2H), 1.76 1.68 (m, 5H), 1.57 (s, 1H), 1.53 1.39 (m, 8H), 1.36 (s, 1H), 1.24 (s, 1H), 1.20 1.14 (m, 3H), 1.11 (s, 1H), 0.94 0.82 (m, 10H), 0.80 (s, 3H), 0.76 (s, 3H), 0.72 (d, J=20.0Hz, 3H).
13CNMR(125MHz,DMSO-d6)��211.39(s),208.98(s),169.80(s),160.73(s),143.02(s),131.42(s),127.05(s),85.91(s),82.25(s),66.70(s),65.63(s),58.62(s),56.55(s),56.61(s),53.30(s),52.45(s),51.52(s),45.29(s),40.06(s),38.52(s),38.17(s),34.73(s),33.17(s),29.35(s),28.38(s),26.34(s),25.00(s),23.45(s),22.05(s),20.67(s),20.07(s),19.31(s),18.41(s),17.73(s),14.59(s).
HRMS(ESI):m/z[M+H]+calcdforC42H73N2O10: 765.5265; Found:765.5261.
The synthesis of O-(the two chlorine ethylamino-s) ethyl derivative (IV) of embodiment 5SchiglautoneA
O-(two hydroxyethylamines) ethyl derivative (382mg, 0.5mmol) of SchiglautoneA embodiment 4 obtained is dissolved in 8mL chloroform, dropwise adds sulfur oxychloride (0.238g, 2mmol), reactant reflux 2h. Reactant being cooled to room temperature, drips and add the excessive sulfur oxychloride of methanolysis, concentrating under reduced pressure is except desolventizing. Product, through purification by silica gel column chromatography (sherwood oil/acetone 100:1, v/v), obtains the faint yellow colloidal solid (0.297g, 71%) of compound IV.
1HNMR (500MHz, DMSO-d6) �� 13.87 (s, 1H), 6.01 (s, 1H), 5.50 (d, J=8.4Hz, 2H), 3.61 (s, 4H), 3.55 (s, 4H), 3.45 (s, 2H), 3.40 (s, 2H), 2.98 (s, 1H), 2.73 (d, J=17.4Hz, 4H), 2.67 2.57 (m, 6H), 2.54 (s, 2H), 2.40 (s, 1H), 2.10 (s, 1H), 1.99 (s, 2H), 1.78 (s, 1H), 1.73 (d, J=16.9Hz, 4H), 1.58 (d, J=3.0Hz, 2H), 1.46 (d, J=3.0Hz, 2H), 1.43 (s, 1H), 1.37 (s, 1H), 1.22 (s, 1H), 1.17 (dd, J=18.9, 11.1Hz, 4H), 0.95 0.83 (m, 10H), 0.80 (d, J=20.0Hz, 3H), 0.78 (d, J=20.0Hz, 3H), 0.73 (d, J=20.0Hz, 3H).
13CNMR(125MHz,DMSO-d6)��211.19(s),208.87(s),169.79(s),160.85(s),143.24(s),131.74(s),127.50(s),85.69(s),82.13(s),66.71(s),65.84(s),56.87(s),55.80(s),53.19(s),52.44(s),51.64(s),45.51(s),40.38(s),39.22(s),38.30(s),38.05(s),34.77(s),33.28(s),29.56(s),28.72(s),26.45(s),25.21(s),23.79(s),22.05(s),20.77(s),20.30(s),19.76(s),18.41(s),17.85(s),14.81(s).
HRMS(ESI):m/z[M+H]+calcdforC42H69Cl4N2O6: 839.3880; Found:839.3881.
Embodiment 6 composition human body fungi activity
The preparation of composition: the powder of 30mg compound IV crossing 200 order nets after crossing the powder of the 70mg compound III of 200 order nets and grinding after grinding is loaded in tubule with cover and namely obtains 100mg composition with the mixing of turbine stirring instrument, it may also be useful to time obtain the solution of composition with the composition of this 100mg of water dissolution.
The experiment of human body fungi activity is the method adopting concentration dilution, measures every time and repeats three times, and the pathogenic bacteria of test has trichophyton, microsporum lanosum and disconnected Trichophyton, and bacterial concentration is 105Individual/mL. The initial concentration of medicine is 50.00 �� g/mL (5% dimethyl sulfoxide (DMSO) DMSO), gradient dilution to 0.10 �� g/mL, the bacterium liquid of equivalent volumes and test sample mixed culture (the final concentration of formation has: 25.00,12.50,6.25,3.13,1.56,0.78,0.39,0.20,0.10 and 0.05 �� g/mL) in 96 orifice plates, human body fungus culture temperature is respectively 28 DEG C, observe after incubation time 24h, if finding, 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 KETOKONAZOL, and composition human body fungi the results are shown in Table 1.
Table 1 composition human body fungi MIC value (�� g/mL)
Conclusion: composition has very strong human body fungi activity, therefore the composition of the present invention is expected to be used to prepare novel anti-human fungi medicine. Compound III and compound IV, therefore can not for the preparation of novel anti-human fungi medicine without human body fungi activity.
Embodiment 7 composition anti-helicobactor pylori activity
1) strains tested
Helicobacter pylori (Helicobacterpylori, Hp) reference culture ATCC43504 is purchased from U.S.'s fungi preservation center (AmericanTypeCultureCollection, ATCC). 13 strain Hp clinical strains pick up from the patient that Nanjing drum tower hospital Dndoscope Laboratory accepts gastroscopy; To the patient of peptide ulceration, duodenal bulbar inflammation or gastritis verrucosa in continuous gastroscopy, first it is defined as Hp positive person through RUT experiment, get antral gastric mucosa 1-2 block again, it is inoculated in containing 8% horse serum, trimethoprim (trimethropin after chopping, TMP) in the Columbia selectivity nutrient agar of 1.25g/L, polymyxin (polymyxin) B2500U/L, vancomycin (vancomycin) 10mg/L, in 37 DEG C of (5%O under micro-oxygen environment2, 10%CO2And 85%N2) cultivate 72 hours. Collecting bacterium, through smear gramstaining, after oxydase, 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 (Microbiologicalpapermethod) is adopted to measure medicine to the restraining effect of helicobacter pylori, the minimum inhibitory concentration (minimalinhibitoryconcentration, MIC) of test sample is measured with agar dilution.
I. paper disk method experiment
(A) substratum is prepared by the Columbia substratum for preparing after high pressure steam sterilization, it is cooled to 50-60 DEG C, add 8% horse serum or sheep blood, in the mixed even culture dish being poured into sterilizing, every ware 7-10ml, substratum thickness is 1.5mm (aseptic technique).
(B) experimental bacteria of transferring (being coated with bacterium) gets diluted 10 with microscale sampler8CFU/ml(1OD660=108CFU/ml) the bacteria suspension 0.1ml of Hp evenly spreads upon suitable culture dish surface. Being inverted in 37 DEG C of drying bakers after 15min and take out, object makes agar surface dry, for subsequent use.
(C) paste sample scraps of paper microscale sampler to get 6 �� l testing sample (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 comparison, by aseptic technique respectively the scraps of paper be close to containing bacterium agar surface, paste a piece of paper sheet at a certain distance. Often kind of bacterium is cooked 3 wares, and gained result seeks its mean value.
(D) cultivating each plate is placed in micro-aerobic bag, sealing, opens producer 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 control group, the result of testing sample sensitive experiment can be drawn. Repeat three times.
II. agar dilution measures MIC
(A) first medicine dimethyl sulfoxide (DMSO) (DMSO) solution of test is mixed with the mother liquor 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 �� g/ml, DMSO concentration in media as well is less than 1%. The testing drug solution prepared by 1ml, with being incubated the 8ml Colombia substratum in 50 DEG C, separately adds 1ml and is incubated the horse serum in 50 DEG C and fully mixes even, cast in culture dish cooling (final concentration of culture dish Chinese traditional medicine 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 �� g/ml, if there being bacteriostatic action, then MIC value namely these worthwhile in one).
(B) experimental bacteria of transferring (being coated with bacterium) draws diluted 1 �� 10 with microscale sampler8The bacteria suspension 0.1ml of CFU/mlHp evenly spreads upon culture dish surface, is inverted in 37 DEG C of drying bakers after 15min and takes out, and object makes agar surface dry, for subsequent use.
(C) determine that culture dish to be measured (is contained: 85%N by MIC at micro-aerobic bag2, 10%CO2And 5%O2) in, it is incubated 37 DEG C and cultivates 72 hours, observe Hp growing state, contrast with blank group, there is no the sample minimum concentration of bacteria growing completely as minimum inhibitory concentration (minimalinhibitoryconcentration, MIC) value. Positive control is Ampicillin Trihydrate (Ampicillin).
Experimental result
Experiment in vitro shows, composition has very strong anti Helicobacter pylori activity, and it is 21mm (ATCC43504) that paper disk method shows its antibacterial circle diameter. Showing it with agar dilution and can suppress 5 random clinical strains and the growth of 1 reference culture (ATCC43504) completely, minimal inhibitory concentration (MIC) is 2.0 �� g/ml. Making positive control with Ampicillin Trihydrate, its minimum concentration (MIC) suppressed completely by 6 strain test bacterium is 1.5 �� g/ml. Compound III and compound IV are without anti Helicobacter pylori activity.
Conclusion: it is active that composition has stronger suppression Hp, illustrates that composition is the medicine of a great exploitation potential for its for diseases such as the acute and chronic gastritis closely related with Hp, duodenal ulcers. It can be directly used in the treatment of corresponding disease and the preparation of related drugs. Compound III and compound IV, without anti Helicobacter pylori activity, cannot be used for the treatment of corresponding disease and the preparation of related drugs.
Embodiment 8 composition antibacterial activity
Antibacterial activity test is the method adopting concentration dilution, measures every time and repeats three times, and test pathogenic bacteria has intestinal bacteria, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus, cryptococcus neoformans, and bacterial concentration is 105Individual/mL. Medicine initial concentration is 50.00 �� g/mL (5% dimethyl sulfoxide (DMSO) DMSO), gradient dilution to 0.10 �� g/mL, the bacterium liquid of equivalent volumes and test sample mixed culture (the final concentration of formation has: 25.00,12.50,6.25,3.13,1.56,0.78,0.39,0.20,0.10 and 0.05 �� g/mL) in 96 orifice plates, microbial culture temperature is respectively 37 DEG C, observe after incubation time 24h, if finding, in the disposal hole not having bacterium colony to be formed, that minimum concentration is sample lowest concentration of antimicrobial, i.e. MIC value. Composition the anti-bacterial result is in table 2.
Table 2 composition antibacterium MIC value (�� g/mL)
Conclusion: composition has very strong antibacterial activity, therefore the composition of the present invention is expected to be used to prepare novel anti-bacterial drug. Compound III and compound IV, without antibacterial activity, can not be used to prepare novel anti-bacterial drug.
Embodiment 8 composition anti-tubercle bacillus is active
(1) solid medium dilution method measures composition anti-bacille Calmette-Guerin vaccine (BCG) absolute concentration
Bacille Calmette-Guerin vaccine culture is scraped from inclined-plane, join in 3mlMiddlebrook7H9 broth culture, add a small amount of granulated glass sphere, screw test tube lid, high vibration grinding in vortex oscillator, with standard Maxwell than turbid pipe (MacFarlandNo.1) than turbid, namely it is made into bacille Calmette-Guerin vaccine (BCG) bacteria suspension of 1mg/ml.
Medicine DMSO is made into the stoste of high density, by the aseptic ultrapure water dilution stoste of tween-80 containing 5% to desired concn, the medicine diluted is joined 4mlMiddlebrook7H11 nutrient agar (this substratum 121 DEG C of high pressure steam sterilizations 15 minutes, be cooled to 50��55 DEG C) by required dosage, mixed even, make drug containing, concentration is respectively 6.0ug/ml, 4.0ug/ml, 3.0ug/ml, 2.0ug/ml, 1.5ug/ml, 1.0ug/ml, the slant medium of 0.75ug/ml, 0.5ug/ml isoconcentration.
Bacille Calmette-Guerin vaccine (BCG) the bacteria suspension transfering loop that concentration is 1mg/ml is dipped several ring, it is inoculated in the substratum containing each medicine series concentration and blank medium slant respectively, being 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 culture used and Middlebrook7H11 nutrient agar are that those skilled in the art carry out conventional substratum when tubercule bacillus is cultivated, and its formula adopts conventional formulation.
(2) solid medium dilution method measures composition Killing Mycobacterium Tuberculosis standard strain H37Rv strain absolute concentration
Mycobacterium tuberculosis standard strain H37Rv strain culture is scraped from inclined-plane, join in 3mlMiddlebrook7H9 broth culture, add a small amount of granulated glass sphere, screw test tube lid, high vibration grinding in vortex oscillator, with standard Maxwell than turbid pipe (MacFarlandNo.1) than turbid, namely it is made into the H37Rv strain bacteria suspension of 1mg/ml.
Medicine is made into DMSO respectively the stoste of high density, by the aseptic ultrapure water dilution stoste of tween-80 containing 5% to desired concn, the medicine diluted is joined 4mlMiddlebrook7H11 nutrient agar (this substratum 121 DEG C of high pressure steam sterilizations 15 minutes, be cooled to 50��55 DEG C) by required dosage, mixed even, make drug containing, concentration is respectively 6.0ug/ml, 4.0ug/ml, 3.0ug/ml, 2.0ug/ml, 1.5ug/ml, 1.0ug/ml, the slant medium of 0.75ug/ml, 0.5ug/ml isoconcentration.
The H37Rv strain bacteria suspension transfering loop that concentration is 1mg/ml being dipped several ring, in the substratum being inoculated in drug containing series concentration respectively and blank medium slant, is placed in 37 DEG C and cultivates 4��8 weeks, observation experiment result, result is as shown in table 3.
(3) solid medium dilution method measures the resistance to ISREMTB strain absolute concentration of the medicine clinical separation of tuberculosis mycobacterium
The clinical separation of mycobacterium tuberculosis resistance to ISREMTB strain (resistance to vazadrine, Streptomycin sulphate, Rifampin, the clinical separator column of Tibutol mycobacterium tuberculosis) culture is scraped from inclined-plane, join in 3mlMiddlebrook7H9 broth culture, add a small amount of granulated glass sphere, screw test tube lid, high vibration grinding in vortex oscillator, with standard Maxwell than turbid pipe (MacFarlandNo.1) than turbid, namely it is made into the bacteria suspension of 1mg/ml.
Medicine is made into DMSO respectively the stoste of high density, by the aseptic ultrapure water dilution stoste of tween-80 containing 5% to desired concn, the medicine diluted is joined 4mlMiddlebrook7H11 nutrient agar (this substratum 121 DEG C of high pressure steam sterilizations 15 minutes, be cooled to 50��55 DEG C) by required dosage, mixed even, make drug containing, concentration is respectively 6.0ug/ml, 4.0ug/ml, 3.0ug/ml, 2.0ug/ml, 1.5ug/ml, 1.0ug/ml, the slant medium of 0.75ug/ml, 0.5ug/ml isoconcentration.
The clinical separation of the mycobacterium tuberculosis resistance to ISREMTB strain bacteria suspension transfering loop that concentration is 1mg/ml is dipped several ring, it is inoculated in the substratum containing each medicine series concentration and blank medium slant respectively, being placed in 37 DEG C to cultivate 4��8 weeks, observation experiment result, result is as shown in table 3.
Table 3 solid medium dilution method measures composition anti-tubercle bacillus absolute concentration result
Table 4 solid medium dilution method measures compound III anti-tubercle bacillus absolute concentration result
Table 3 solid medium dilution method measures compound IV anti-tubercle bacillus absolute concentration result
Conclusion: composition has very strong anti-tubercle bacillus and anti-drug resistance tubercule bacillus activity, can be used as the lead compound for the treatment of tubercle bacillus affection disease, it is possible to for the preparation for the treatment of tuberculosis medicine. Compound III and compound IV are active without anti-tubercle bacillus and anti-drug resistance tubercule bacillus, can not as the lead compound for the treatment of tubercle bacillus affection disease, can not for the preparation for the treatment of tuberculosis medicine.
The preparation of embodiment 9 composition tablet involved in the present invention
Getting 2 grams of compositions, add the conventional auxiliary material 18 grams preparing tablet, mixed even, conventional tabletting machine makes 100.
The preparation of embodiment 10 composition capsule involved in the present invention
Get 2 grams of compositions, add the conventional auxiliary material preparing capsule such as starch 18 grams, mixed even, encapsulated make 100.
Claims (10)
1. a composition, is characterized by said composition and is made up of compound III and compound IV, and in said composition, the mass percent of compound III and compound IV is respectively 70% and 30%,
2. the preparation method of composition as claimed in claim 1, is characterized by: according to mass percent, the powder of the powder of compound III and compound IV is respectively 70% and 30% and fully mixes.
3. application in antibacterials of a composition as claimed in claim 1.
4. the application of composition as claimed in claim 3 in antibacterials, is characterized by: described bacterium is bacterium.
5. the application of composition as claimed in claim 3 in antibacterials, is characterized by: described bacterium is fungi.
6. the application of composition as claimed in claim 3 in antibacterials, is characterized by: described bacterium is helicobacter pylori.
7. the application of composition as claimed in claim 3 in antibacterials, is characterized by: described bacterium is tubercule bacillus.
8. the application of composition as claimed in claim 5 in antibacterials, is characterized by: described fungi is trichophyton, microsporum lanosum or disconnected Trichophyton.
9. the application of composition as claimed in claim 4 in antibacterials, is characterized by: described bacterium is intestinal bacteria, fluorescent pseudomonas, Staphylococcus aureus, Bacillus proteus or cryptococcus neoformans.
10. the application of composition as claimed in claim 7 in antibacterials, is characterized by: described tubercule bacillus is bacille Calmette-Guerin vaccine, mycobacterium tuberculosis standard strain H37Rv strain and substance of medicines-resistant branched tubercle bacillus.
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| CN104083377A (en) * | 2014-06-25 | 2014-10-08 | 南京广康协生物医药技术有限公司 | Application of Cleistanone dimethylamine derivative in preparation of antibacterial drugs |
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| CN104083377A (en) * | 2014-06-25 | 2014-10-08 | 南京广康协生物医药技术有限公司 | Application of Cleistanone dimethylamine derivative in preparation of antibacterial drugs |
| CN104887668A (en) * | 2015-05-12 | 2015-09-09 | 南京广康协生物医药技术有限公司 | Application of Daphmalenine A derivate in antibacterial agent preparation |
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