CN101195627A - New application of benzo [C] phenanthridine and protopine in producing overriding resistant bacterium medicament - Google Patents
New application of benzo [C] phenanthridine and protopine in producing overriding resistant bacterium medicament Download PDFInfo
- Publication number
- CN101195627A CN101195627A CNA2007100664977A CN200710066497A CN101195627A CN 101195627 A CN101195627 A CN 101195627A CN A2007100664977 A CNA2007100664977 A CN A2007100664977A CN 200710066497 A CN200710066497 A CN 200710066497A CN 101195627 A CN101195627 A CN 101195627A
- Authority
- CN
- China
- Prior art keywords
- drug
- purposes according
- benzo
- general formula
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new application of benzo [C] phenanthridine as formula I and original tropine alkaloid for preparing anti-drug-resistant bacterial drug, wherein R1-R10, R12-R15 are hydrogen and hydroxyl groups, cycloalkyl or alkyl groups with 1-12 carbon atoms, alkox or acyloxy groups, benzyloxy, chlorine or other halide atoms, amido, methylol, aldehydo, aldehydo, acetonyl, carboxy group, mesyloxy, 4-methyl-benzene sulfonyl oxygen group, aryl sulfonyl oxygen group, biphenyl phosphine acyloxy and -OCONH2, R11 is hydrogen, methyl or oxygen atom, R5 and R6 (or R15 of the formula I), R14 and R15 are formed with double bonds, R12 or R13 and nearby N atoms are formed with double bonds, N atom can be tertiary or quaternary N type, the substituents of nearby carbons of R1-R10 can have dioxolane structure. The inventive alkaloid can effectively restrain and kill drug-resistant bacterials as MRSA and ESBLs.
Description
Technical field
The present invention relates to benzo [C] phenanthridines (Benzo[C] phenanthridine) and former tropine (Protopine) the Alkaloid purposes in the preparation drug-resistance bacteria medicine.
Background technology
The appearance of bacterial drug resistance and propagation have a strong impact on the development of human health cause.Along with antibiotic widespread use, increasing bacterium produces resistance to common antibiotics, and drug-resistant intensity increases the weight of day by day.Bacterial drug resistance often makes and fails to respond to any medical treatment, and infection increases the weight of, even dead.Simultaneously, futile treatment also makes medical expense increase, and comprising frequently being admitted to hospital and the prolongation of hospital stay of patient, thereby increases the weight of the burden of patient and society.Find the first strain methicillin-resistant staphylococcus aureus (methicillin-resistant staphylococcus aureus from Jevons in 1961 first in Britain, MRSA) since, domestic and international clinical separation MRSA positive rate is more and more higher, is up to 80%.With MSSA (methicillin-sensitive staphylococcusaureus, be MSSA) compare, MRSA is to multiple antibiotics resistance, virulence is strong and result of treatment is poor, be one of main germ that causes nosocomial infection, its first-selected antimicrobial drug is a vancomycin.Produce extended spectrum (extended-spectrum β-Lactamases, ESBLs) appearance of resistant organism, it is the product that third generation cephalosporin is used, nineteen eighty-three, behind the reported first ESBLs such as Knothe of Germany, its clinical recall rate and drug-resistant intensity are also increasing the weight of, and it produces bacterium (mainly is Klebsiella Pneumoniae and the escherichia coli in the enterobacter, especially based on the former) infection that causes becomes another treatment difficult point that medical circle is paid close attention to, and causes great attention both domestic and external.In recent years, the plant amedica monomer component also obtains paying close attention to the effect of resistant organism gradually, but so far seldom to the report of the effective plant constituent of resistant organism.
The application is at the domestic and international present situation of drug-fast bacteria infection clinically, be devoted to from herbal medicine, to screen effective to resistant organism, as to have new antimicrobial spectrum and mechanism of action antimicrobial drug, emphasis has carried out screening system and further investigation to the effect of wherein alkaloids, and the alkaloid of having found to contain isoquinoline 99.9 nuclear class from pilewort particularly benzo [C] phenanthridines and protopine shows than strong inhibitory activity aforementioned pathogenic agent.
Pilewort (Chelidonium major L.) is papaveracease (Papaveraceae) Chelidonium plant, all herbal medicine, bitter, cool in nature, poisonous.Its main effective constituent is the multiple morphinane alkaloid with remarkable physiologically active, comprises benzo phenanthridines type, protoberberine type, former tropine type and aporphine etc.Prior art mainly is anti-standard bacterium effect about the preparation and the anti-microbial effect research of the alkaloid that contains benzo [C] phenanthridines class and former tropine class and derivative thereof, suppresses gram positive organism, tubercule bacillus and fungi etc. as the pilewort total alkali external.Former tropine, sanguinarine(e) and white chelerythrine resist charcoal subcutaneous ulcer bacillus, staphylococcus is effective especially, in addition, Herba Chelidonii extract also has antivirus action, as adenovirus, herpes simplex virus, viral encephalitis, viral myocarditis etc. are all had effect, benzo phenanthridines quaternary amine alkali anti-inflammatory action is strong in the pilewort, toxicity is low, is applicable to treatment oral inflammation (Niu Changqun, He Liyi, Chinese Pharmaceutical Journal, 1994,29,138; ArnoldB.The Alkaloids Chemistry andPharmacology, Vol.26.New York:Academic Press Inc.1985:185).
The contriver retrieves following five patent documentations: patent documentation 1, and CN1061964A, the preparation side of benzo [C] phenanthridine derivatives states the compound of method preparation; Patent documentation 2, CN1238772A, novel phenanthridine derivatives; Patent documentation 3, CN1204321A (WO97/16483), phenanthridine derivatives and its preparation method and contain the medicine of phenanthridine derivatives; Patent documentation 4, WO97/41890 comprises the sterilant of benzo phenanthridine alkaloid; Patent documentation 5, CN200410042521.X, a kind of preparation and application of from plant, extracting protopine and pharmaceutical preparation thereof.
More than relate to the preparation of benzo [C] phenanthridines and former tropine analog derivative and the document of applied research, be limited to antitumor, platelet aggregation-against, anti-arrhythmia and insecticidal action; Though also mentioned antibacterium, fungi and antivirus action, do not have the effect of document prompting benzo [C] phenanthridines and protopine and derivative thereof to MRSA and product ESBLs resistant organism.
Make a general survey of report both domestic and external, also do not have a patent to refer in particular to the antimicrobial agent effect of benzo involved in the present invention [C] phenanthridine alkaloid and protopine.
200710066144.7) and contain the new medical use (application number: 200710065995.X of benzo [C] phenanthridine alkaloid and derivative thereof the inventor has applied for containing one of alkaloid of isoquinoline 99.9 nuclear class, i.e. the purposes of protoberberine (protoberberine) Alkaloid in the preparation drug-resistance bacteria medicine (application number:; Publication number: CN101084906A), wherein, the latter relates to the application of this Alkaloid aspect the preparation anti-hepatic-B virus medicine.The application draws as above further research work.
Summary of the invention
The objective of the invention is to propose a kind of benzo [C] phenanthridines and the new purposes of protopine in the preparation drug-resistance bacteria medicine, at the reality of the external and chronic drug-fast bacteria infection of China clinically, emphasis has carried out screening system and further investigation to the effect of the alkaloids in traditional herbal medicine, this two Alkaloid is to the gram-positive cocci and the negative bacillus class pathogenic agent of the antibiotic commonly used of isolating anti-various clinical in the clinical samples, particularly the MRSA demonstration suppresses more by force and kills activity, has wide spectrum antimicrobial agent activity.
The present invention proposes a kind of have general structure I contain benzo [C] phenanthridine alkaloid and derivative and II contain protopine and derivative thereof the new purposes aspect the preparation drug-resistance bacteria medicine,
Wherein, R
1To R
10, R
12To R
15For hydrogen, hydroxyl, chain or cycloalkyl, alkoxyl group or acyloxy, benzyloxy, chlorine and other halogen atoms, amino, methylol, aldehyde radical, carbonyl, acetonyl, carboxyl, sulfonyloxy, 4-methyl-phenylsulfonyloxy, aryl-sulfonyl oxygen, diphenylphosphine acyloxy with 1～12 carbon atom and-OCONH
2, R
11Be hydrogen or methyl or Sauerstoffatom.
Described R
5With R
6(or the R in general formula I
15), R
14With R
15Form two keys; R
12Or R
13Form two keys with adjacent N atom.The N atom can be uncle or season N form; R
1To R
10Substituting group can be the luxuriant structure of Er Evil on the adjacent carbons.
Above-mentioned compound that comprises and pharmaceutically acceptable salt or carrier are as the monomer of preparation drug-resistance bacteria medicine and the application in the composition thereof.
Described this pharmaceutically acceptable carrier is selected from following at least a: vehicle, tackiness agent, lubricant, disintegrating agent, Drug coating, emulsifying agent, suspension agent, solvent, stablizer, absorption agent, water for injection and isotonic agent.
Described said composition can be made oral administration form or drug administration by injection form.
[1] Zong Yongli etc., the time precious traditional Chinese medical science traditional Chinese medicines, 2006,17,2068;
[2]Slavik J.et al.，Collection Czechoslov.Chem.Commun.，1965，30，3697；1968，33，635；1977，42，2686；
[3]Paul J.Scheuer，et al.，J.Nat.Prod.，1962，42，1472；
[4]Tanahashi，T.et al.，J.Nat.Prod.，1990，53，579；
[5] Li Dingxiang etc., Chinese natural drug, 2004,2,285.
[6] Ke Min jade-like stone etc., Botany Gazette, 1982,24,124.
But, do not have document to point out these compounds to have the antimicrobial agent effect based on benzo [C] phenanthridine alkaloid and protopine and derivative thereof.
Description of drawings
Fig. 1 is the extraction separation flowchart text of haplont alkali 1～4 in the acid alcohol extract of pilewort herb among the present invention.
Embodiment
Be used for that alkaloid of the present invention and derivative thereof can be purchased or by the method preparation of existing document prompting.Illustrated as table 1 is the chemical structure of part benzo [C] phenanthridine alkaloid and protopine and derivative thereof.But these enforcements only provide with way of example, and do not play the qualification effect.
The chemical structure of table 1. benzo [C] phenanthridine alkaloid and protopine 1 to 8
To by embodiment method and the pharmacological action thereof for preparing benzo [C] phenanthridine alkaloid and derivative thereof among the present invention be described in more detail below.But these enforcements only provide with way of example, and do not play the qualification effect.
Embodiment 1: extraction separation haplont alkali 1-4 from pilewort.
Get pilewort (Chelidonium majus) herb and press reference [2,3] method of introducing in adjusts slightly carries out: the 5kg medicinal material is with 70% alcohol reflux that contains 5% acetic acid three times, united extraction liquid, concentrating under reduced pressure boils off most of ethanol, acid water extracting liquid is the acid-alkali treatment method routinely, add 5% hydrochloric acid earlier to PH2, use petroleum ether extraction, gained sour water layer (S-1) gets 23g (L-1) with chloroform extraction, through silica gel column chromatography, sherwood oil: chloroform (10: 0～10: 1.5) gradient elution gets Stylophorine (4=1.86g) and dihydrochelerythrine (2=45mg).
The sour water layer (S-2) that above-mentioned chloroform extraction is crossed leaves standstill back leaching precipitation, separates obtaining Sanguinarine chloride (3=0.72g) with 5% hydrochloric acid-ethanol (PH1) recrystallization; Supernatant liquor adds ammoniacal liquor again and transfers to PH10, get 48g (L-2) with chloroform extraction, again in sherwood oil: chloroform: methyl alcohol: diethylamine=10: 2: 0.5: 0～0: get white chelerythrine (1=0.94g), sanguinarine(e) (3=0.83g) through silica gel column chromatography repeatedly under 10: 3: 1 the condition.
Embodiment 2: be converted into tertiary amine-type benzo [C] phenanthridine alkaloid from quaternary ammonium type benzo [C] phenanthridine alkaloid.
Press the method for reference [4], get white chelerythrine hydrochloride (20mg, 0.052mM) be dissolved in the dilute hydrochloric acid of 15ml10%, add zinc powder 0.3g under the stirring at room, continue to stir and spend the night, reaction mixture chloroform extraction (60ml * 3), with a small amount of sour water (10% dilute hydrochloric acid) washing extraction liquid, be washed to neutrality again, reclaim chloroform, residue gets dihydrochelerythrine 14mg (yield 77%) with ethyl alcohol recrystallization.The products therefrom physicochemical constant is consistent with extraction separation gained dihydrochelerythrine with spectral data.
Other quaternary ammonium type benzo [C] phenanthridine alkaloids are converted into tertiary amine-type benzo [C] phenanthridine alkaloid and can make with similar approach.
Embodiment 3: the physics and chemistry of monomeric compound and spectral data.
White chelerythrine hydrochloride (1): [C
21H
18NO
4]
+, yellow needle, mp 201-202 ℃, bismuth potassium iodide reacting positive.IR KBr max(cm
-1)：3380，2920，2824，1642(C≡N
+)，1575，1450，1364，1250，1100，1035(C-O-C)，970，875，825；UV(nm，logε)：228(4.49)，274sh(4.54)，282(4.62)，320(4.26)，346sh(3.55)；EIMS：m/z 348[M]
+(100)，333(12)，318(5)，307(6)，290(5)，167(4)，154(38)，136(31)，124(4)。
1H-NMR(400MHz，DMSO-d
6)：4.07(3H，s，OMe)，4.13(3H，s，3H，s，OMe)，4.93(3H，s，3H，s，N-Me)，6.22(2H，s，2H，s，-OCH
2O-)，7.83(1H，s，1H，s，H-1)，8.24(1H，d，J＝9.0Hz，H-9)，8.26(1H，s，H-4)，8.29(1H，d，J＝9.0Hz，H-9)，8.80(2H，d，J＝9.0Hz，H-11)，10.06(1H，s)。
Dihydrochelerythrine (2): off-white color crystal, C
21H
19NO
4, mp164-165 ℃, the bismuth potassium iodide reacting positive.EIMS：349[M]
+(100)，348(80)，334[M-Me]
+(15)，333(12)，332(14)，319(15)，304(11)，290(19)，276(9)，174(10)；UVλMeOH max(nm)226，278；IR KBr max(cm
-1)2920，2850，1600，1460，1247cm
1。
1H NMR(400MHz)：7.67，s(H-1)，7.11，s(H-4)，7.48，d，8.5Hz(H-5)，7.70，d，8.6Hz(H-6)，4.29，s(H-8)，6.94，d，8.5Hz(H-11)，7.51，d，8.5Hz(H-12)，6.05，s(H-15)，2.60，s(7-NC
H 3)，3.88，s(9-OC
H 3)，3.93，s(10-OC
H 3)；
13C NMR(100MHz)：100.8(C-1)，149.3(C-2)，147.2(C-3)，104.0(C-4)，131.0(C-5a)，125.5(C-5)，120.4(C-6)，124.3(C-13)，118.1(C-12)，111.2(C-11)，151.8(C-10)，147.2(C-9)，126.3(C-8a)，48.8(C-8)，40.4(NCH
3)，126.4(C-1a)，102.6(C-15)，63.1(9-OMe)，56.9(10-OMe)。
Sanguinarine(e) (3): [C
20H
14NO
4]
+, free alkali crystallization (H
2O), mp243～244 ℃ (dec.), bismuth potassium iodide reacting positive.IR KBr max(cm
-1)：2940，2882，1604，1460，1350，1323，1240，1080，1030，940，860，820，800；UV MeOH max nm(log)：323(4.09)，282(4.52)，228(4.47)，207(4.52)；EIMS：m/z 204(2)，122(36)，94(100)，93(22)，91(10)，79(18)，55(21)，41(30)。
1HNMR(400Mz，DMSO-d
6)：7.62(1H，s，H-1)，8.14(1H，s，H-4)，10.21(1H，s，H-6)，8.70(1H，d，J＝8.6Hz，H-9)，8.09(1H，d，J＝8.6Hz，H-10)，8.56(1H，d，J＝9.1Hz，H-11)，8.25(1H，d，J＝9.1Hz，H-12)，4.91(3H，s，5-Me)，6.36(2H，s，3-OCH
2O-)，6.61(2H，s，7，8-OCH
2O-)。
Stylophorine (4): (±)-Stylophorine: C
20H
19NO
5, white crystals (EtOH), 215～216 ℃ of mp, bismuth potassium iodide reacting positive.
1H-NMR(400MHz，CDCl
3)：6.76(1H，d，J＝7.9Hz，H-9)，6.73(1H，d，J＝7.9Hz，H-10)，6.66(1H，s，H-4)，6.64(1H，s，H-1)，5.99(1H，d，J＝1.5Hz，C
2，3-OCH
2O)，5.95(1H，d，J＝1.3Hz，C
2，3-OCH
2O)，5.92(1H，d，J＝1.8Hz，C
7，8-OCH
2O)，5.93(1H，d，J＝1.5Hz，C
7，8-OCH
2O)，4.23(1H，br s，H-11)，4.08(1H，d，J＝15.7Hz，H-6)，3.57(1H，br s，H-H)，3.43(1H，d，J＝15.6Hz，H-6)，3.21(1H，d，J＝17.5Hz，H-12)，3.08(1H，dd，J＝16.5，4.3Hz，H-12)，2.98(1H，t，J＝2.8Hz，H-13)，2.27(3H，s，N-CH
3)；
13C-NMR(CDCl
3)：107.4(C-1)，145.3CC-2)，145.6(C-3)，111.9(C-4)，128.9(C-4a)，53.9(C-6)，117.1(C-6a)，143.1(C-7)，148.2(C-8)，109.6(C-9)，120.4(C-10)，131.4(C-10a)，72.4(C-11)，39.7(C-12)，125.8(C-12a)，42.1(C-13)，62.9(C-14)，42.4(N-CH
3)，101.1(2，3-OCH
2O)，101.4(7，8-OCH
2O)。
Embodiment 4: be used as the screening of the clinical drug-resistant bacterial strain MRSA of drug sensitive test
1. test materials
Antibiotic drug sensitive test paper (Nat'l Pharmaceutical ﹠ Biological Products Control Institute), MH agar (sky, Hangzhou and microorganism reagent company limited).
2. sample is originated
Separation screening 5 strain MRSA bacteriums from the clinical infectious sample of my institute are numbered and are MRSA45, MRSA55, MRSA63, MRSA82, MRSA92, and 1 strain is produced the ESBLs Klebsiella Pneumoniae and is numbered KZF047, and it is standby that refrigerator-20 ℃ is preserved down.
3. Bacteria Identification
According to " national Clinical Laboratory working specification " and well known to a person skilled in the art that method for determining bacteria separates, cultivates above-mentioned bacterium, through being accredited as streptococcus aureus (SA), and by known antibiotic susceptibility conventionally test method (K-B paper disk method), carrying out resistant organism with reference to U.S. clinical laboratory standard committee (NCCLS) standard in 2004 identifies, cefoxitin to the inhibition zone of this sample all≤19mm, so be considered as resistance SA bacterial strain (MRSA).Producing the evaluation strictness of ESBLs bacterial strain adopts two paper disk methods to carry out (Zhao builds equality, Chinese journal of medical examination, 2002,25,112) by standard.
4. drug sensitive test
Further use the K-B paper disk method, according to China Ministry of Health in " the paper disk method antibacterials sensitization test standard " of on May 1st, 2000 issuing and implementation (SAST) routine operation, in 35 ℃ of cultivations 24 hours, measure the susceptibility of 5 strain MRSA with the MH nutrient agar, the results are shown in Table 2 antibiotic commonly used.
Table 2.MRSA bacterial strain is to the drug susceptibility test result of antibiotic commonly used
| Bacterial strain | Resistance (R) | Intermediary (M) | Responsive (S) |
| MRSA45 | Penicillin, Ampicillin Trihydrate, Oxazacillin, erythromycin, clarithromycin, clindamycin, cephalofruxin, Kefzol, cephalo sulphur miaow, piperacillin/Tazobactam Sodium, amoxicillin/clavulanate | Gatifloxacin | Vancomycin |
| MRSA55 | Penicillin, Oxazacillin, Ampicillin Trihydrate, Azythromycin, clindamycin, clarithromycin, erythromycin, Kefzol, cephalo sulphur miaow, cephalofruxin | Gatifloxacin | Vancomycin |
| MRSA63 | Penicillin, Prostaphlin, Ampicillin Trihydrate, clindamycin, cephalofruxin, cephalo sulphur miaow, Kefzol, erythromycin, Rifampin | Gatifloxacin | Piperacillin/Tazobactam Sodium |
| MRSA82 | Penicillin, Prostaphlin, Ampicillin Trihydrate, cephalofruxin, Kefzol, Azythromycin, clindamycin, clarithromycin, erythromycin | / | Vancomycin, Gatifloxacin Rifampin, SMZ |
| MRSA92 | Penicillin, Azythromycin, clindamycin, clarithromycin, levofloxacin, Prostaphlin, cefoxitin | / | Phosphonomycin, Rifampin, Gatifloxacin, piperacillin/Tazobactam Sodium |
Embodiment 5: the anti-microbial activity of 1 to 8 pair of Resistant strain of compound is measured
1. test materials
Substratum: MH meat soup (sky, Hangzhou and microorganism reagent company limited); Be subjected to reagent: compound 1 to 8 sample (obtaining), solvent: DMSO (analytical pure), distilled water by extraction separation in the pilewort; Standard bacterium: streptococcus aureus (MSSA) ATCC25923, escherichia coli ATCC25922, pseudomonas aeruginosa ATCC27853 (Nat'l Pharmaceutical ﹠ Biological Products Control Institute); Resistant organism: MRSA 5 strains are produced ESBLs escherichia coli ATCC35218 (Nat'l Pharmaceutical ﹠ Biological Products Control Institute), Klebsiella Pneumoniae KZF047; Contrast medicine: Ampicillin Trihydrate and vancomycin.
2. soup preparation
Take by weighing with electronic analytical balance and respectively to be subjected to reagent product 5mg, be made into 5mg/ml solution as former drug solns with aseptic DMSO.
3. the preparation of bacterium liquid
With transfering loop inoculation on nutrient agar plate, place 35 ℃ of thermostat containers to cultivate 24h, with transfering loop bacterial strain is transferred in the test tube again, be made into 10 with stroke-physiological saline solution
6Cfu/ml makes to measure MIC and uses.
4. measure the minimal inhibitory concentration (MIC) that medicine suppresses bacterium
Adopt known doubling dilution, getting 10 sterile test tube numbers and places on the test-tube stand, in every test tube, add the 1mlMH broth culture, get original liquid 1ml and first test tube shakes up, draw 1ml then and add in second test tube, and the like be diluted to the tenth pipe, discard 1ml, remove the tenth pipe and do not add bacterium liquid, do outside the negative control, all the other all add the 0.1ml dilution is 10
6CFU/ml bacterium liquid shakes up, and puts in the incubator in 35 ℃ and cultivates 24 hours, is subjected to reagent thing activity rating by method as well known to those skilled in the art, makes positive control simultaneously, and the concrete measurement result of gained is shown in table 3 and table 4.
The activity explanation of the MSSA of the external antimicrobial agent of table 3. monomeric compound 1-8 and the MIC of MRSA and MBC.[μg/ml，Mean±SEM(n)]
| Compound | MIC | MBC | ||
| MSSA | | MSSA | MRSA | |
| 3 | 0.45±0.05(2) | 0.64±0.19(5) | 6.00±2.00(2) | 21.60±3.99(5) |
| 1 | 0.13±0.00(2) | 2.98±1.14(5) | 23.00±8.00(2) | 36.00±9.34(5) |
| 5 | 72.50±24.50(2) | 145.50±0.00(1) | 2325.00±775.00(2) | 2325.00±0.00(1) |
| 6 | 28.50±10.50(2) | 205.00±97.06(4) | 937.50±312.50(2) | 1875.00±0.00(4) |
| 2 | 30.00±10.00(2) | 316.70±91.18(5) | 487.50±162.50(2) | 1096.00±132.53(5) |
| 8 | 93.75±31.250(2) | 400.25±176.42(4) | 312.50±187.50(2) | 1445.25±546.46(4) |
| 7 | 1000.00±0.00(2) | 1600.00±100.00(5) | 3000.00±1000.00(2) | 3000.00±0.00(5) |
| 4 | 400.00±133.00(2) | 2004.00±129.00(2) | 2133.00±0.00(2) | 2004.00±129.00(2) |
| The Ampicillin Trihydrate | 40.00±0.00(2) | / | 160.00±0.00(2) | / |
| Vancomycin | 78.00±0.00(2) | 2.19±0.94(4) | 313.00±0.00(2) | 57.50±47.50(4) |
The MIC of external anti-other resistant organism of table 4. monomeric compound 1,3 and the activity explanation of MBC.[μg/ml，Mean±SEM(n＝2)]
| Compound | Active | Escherichia coli | Klebsiella Pneumoniae | Pseudomonas aeruginosa | |
| The standard bacterium | Resistant organism | Resistant organism | The |
||
| 3 | MIC | 142.50±47.50 | 142.50±47.50 | 567.00±189.00 | 284.00±94.00 |
| MBC | 142.50±47.50 | 284.00±94.00 | 756.00±0.00 | 756.00±0.00 | |
| 1 | MIC | 18.75±6.25 | 300.00±100.00 | 400.00±0.00 | 300.00±100.00 |
| MBC | 37.50±12.50 | 400.00±0.00 | 400.00±0.00 | 400.00±0.00 | |
Claims (10)
1. the new purposes of protopine in the preparation drug-resistance bacteria medicine that has benzo [C] phenanthridines and the general formula I I of general formula I,
Wherein, R
1To R
10, R
12To R
15For hydrogen, hydroxyl, chain or cycloalkyl, alkoxyl group or acyloxy, benzyloxy, chlorine and other halogen atoms, amino, methylol, aldehyde radical, carbonyl, acetonyl, carboxyl, sulfonyloxy, 4-methyl-phenylsulfonyloxy, aryl-sulfonyl oxygen, diphenylphosphine acyloxy with 1～12 carbon atom and-OCONH
2, R
11Be hydrogen or methyl or Sauerstoffatom, the N atom is uncle or season N form.
2. purposes according to claim 1 is characterized in that: the monomer of the compound that is comprised and contain these monomer combination and pharmaceutically acceptable salt or carrier compositions as the application of preparation in the drug-resistance bacteria medicine.
3. purposes according to claim 1 is characterized in that: R
5With R
6Or the R in the general formula I
15Form two keys.
4. purposes according to claim 1 is characterized in that: R
12Or R
13Form two keys with adjacent N atom.
5. purposes according to claim 1 is characterized in that: the N atom in the general formula can be because of substituent R
11To R
14Cause being uncle or season N atomic form.
6. purposes according to claim 1 is characterized in that: R
1To R
10The luxuriant structure of substituting group Wei Er Evil on the adjacent carbons.
7. purposes according to claim 1 is characterized in that in the general formula I: R
14With R
15Form two keys.
8. purposes according to claim 1 is characterized in that among the general formula I I: R
14With R
15Be carbonyl independently of one another.
9. purposes according to claim 1 and 2 is characterized in that: this pharmaceutically acceptable carrier is selected from following at least a: vehicle, tackiness agent, lubricant, disintegrating agent, Drug coating, emulsifying agent, suspension agent, solvent, stablizer, absorption agent, water for injection and isotonic agent.
10. purposes according to claim 1 and 2 is characterized in that: said composition is made oral administration form or drug administration by injection form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100664977A CN101195627B (en) | 2007-12-27 | 2007-12-27 | New application of benzo [C] phenanthridine and protopine in producing overriding resistant bacterium medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100664977A CN101195627B (en) | 2007-12-27 | 2007-12-27 | New application of benzo [C] phenanthridine and protopine in producing overriding resistant bacterium medicament |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101195627A true CN101195627A (en) | 2008-06-11 |
| CN101195627B CN101195627B (en) | 2010-11-24 |
Family
ID=39546269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100664977A Expired - Fee Related CN101195627B (en) | 2007-12-27 | 2007-12-27 | New application of benzo [C] phenanthridine and protopine in producing overriding resistant bacterium medicament |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101195627B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105820119A (en) * | 2015-07-06 | 2016-08-03 | 盐城工学院 | 5,6-dihydrobenzophenanthridines derivative and preparation method thereof |
| CN109942592A (en) * | 2019-05-09 | 2019-06-28 | 江西中医药大学 | A kind of new protopine alkaloids and its preparation method and application |
| CN111000845A (en) * | 2020-01-06 | 2020-04-14 | 陕西科技大学 | Application of chelerythrine in inhibition of growth of multidrug-resistant providencia rettgeri |
| CN111135173A (en) * | 2019-12-10 | 2020-05-12 | 陕西科技大学 | Application of chelerythrine in inhibition and removal of multiple-drug-resistant providencia rettgeri biofilm |
| CN114555189A (en) * | 2018-07-25 | 2022-05-27 | 美国政府健康及人类服务部 | Xanthophyllone derivatives as inhibitors of topoisomerase IB (TOP1) and/or tyrosyl-DNA phosphodiesterase 1(TDP1) |
| CN114667288A (en) * | 2019-10-17 | 2022-06-24 | 成都安泰康赛生物科技有限公司 | Benzophenanthridine alkaloids and methods of use thereof |
-
2007
- 2007-12-27 CN CN2007100664977A patent/CN101195627B/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105820119A (en) * | 2015-07-06 | 2016-08-03 | 盐城工学院 | 5,6-dihydrobenzophenanthridines derivative and preparation method thereof |
| CN105820119B (en) * | 2015-07-06 | 2019-04-02 | 盐城工学院 | One kind 5,6- dihydrobenzo phenanthridine derivatives and preparation method thereof |
| CN114555189A (en) * | 2018-07-25 | 2022-05-27 | 美国政府健康及人类服务部 | Xanthophyllone derivatives as inhibitors of topoisomerase IB (TOP1) and/or tyrosyl-DNA phosphodiesterase 1(TDP1) |
| CN109942592A (en) * | 2019-05-09 | 2019-06-28 | 江西中医药大学 | A kind of new protopine alkaloids and its preparation method and application |
| CN114667288A (en) * | 2019-10-17 | 2022-06-24 | 成都安泰康赛生物科技有限公司 | Benzophenanthridine alkaloids and methods of use thereof |
| CN111135173A (en) * | 2019-12-10 | 2020-05-12 | 陕西科技大学 | Application of chelerythrine in inhibition and removal of multiple-drug-resistant providencia rettgeri biofilm |
| CN111135173B (en) * | 2019-12-10 | 2022-01-14 | 陕西科技大学 | Application of chelerythrine in inhibition and removal of multiple-drug-resistant providencia rettgeri biofilm |
| CN111000845A (en) * | 2020-01-06 | 2020-04-14 | 陕西科技大学 | Application of chelerythrine in inhibition of growth of multidrug-resistant providencia rettgeri |
| CN111000845B (en) * | 2020-01-06 | 2023-04-07 | 陕西科技大学 | Application of chelerythrine in inhibition of growth of multidrug-resistant providencia rettgeri |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101195627B (en) | 2010-11-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101195627B (en) | New application of benzo [C] phenanthridine and protopine in producing overriding resistant bacterium medicament | |
| Zhu et al. | Design, synthesis, and antifungal evaluation of neocryptolepine derivatives against phytopathogenic fungi | |
| DE69834923T2 (en) | HIGH GRADE LIPOPHILIC CAMPTOTHECINE DERIVATIVES | |
| Li et al. | Toxoflavin produced by Burkholderia gladioli from Lycoris aurea is a new broad-spectrum fungicide | |
| Akhtar et al. | Proceragenin, an antibacterial cardenolide from Calotropis procera | |
| Pejović et al. | Antimicrobial ferrocene containing quinolinones: Synthesis, spectral, electrochemical and structural characterization of 2-ferrocenyl-2, 3-dihydroquinolin-4 (1H)-one and its 6-chloro and 6-bromo derivatives | |
| CN102977082B (en) | Isocoumarin compound as well as preparation method and application thereof | |
| CN101428026A (en) | New use of 8-substituted dihydrobenzene-[C]phenanthridine alkaloids in producing anti-drug-fast bacteria medicament | |
| CN103627772B (en) | The preparation method of a kind of triptolide alcohol derivative and product thereof and application | |
| CN102093357B (en) | Novel indoletriazole alkaloid as well as preparation method and antifungal application thereof | |
| CN109810017B (en) | Amazonia sparsa acid derivative and preparation method and application thereof | |
| CN101804064B (en) | Application of dihydroquercetin and glucoside compounds to preparing drug-resistance bacteria medicine | |
| CN101665491A (en) | Synthetic method of berberine 13-bit derivant and berberrubine 13-bit derivant | |
| CN107936009B (en) | Berberine derivative and application | |
| CN106749213B (en) | A kind of indole derivatives and preparation method with 1,2,4- oxadiazoles structure and the application in preparation antibacterials | |
| Hong et al. | Antimicrobial activity of 9-O-acyl-and 9-O-benzoyl-substituted berberrubines | |
| Yuan et al. | Isolation of an antibacterial substance from Mahonia fortunei and its biological activity against Xanthomonas oryzae pv. oryzicola | |
| CN105622492B (en) | Chalcone derivative with antimicrobial agent activity | |
| CN115300519B (en) | Application of cyclocarya paliurus glycoside I in preparation of antibacterial drugs and/or antibacterial agents | |
| Khwaza et al. | Synthesis, antibacterial, and cytotoxicity evaluation of oleanolic acid-4-aminoquinoline based hybrid compounds | |
| CN102218047B (en) | Medicament for treating drug-resistant bacteria infection, and application of active ingredient thereof in pharmacy | |
| Naureen et al. | Iron (III) and zinc (II) metal alkaloid complexes: Synthesis, characterization and biological activities | |
| CN102038676B (en) | Medicament for treating drug-resistant bacteria infection and application of active ingredient thereof in pharmacy | |
| Liao et al. | Identification of ruthenium (II) complexes with furan‐substituted ligands as possible antibacterial agents against Staphylococcus aureus | |
| DE3586469T2 (en) | CRISAMICIN ANTIBIOTIC, ITS PRODUCTION AND USE AND A MICROORGANISM THAT CAN PRODUCE THIS. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101124 Termination date: 20131227 |