CN108727332A - A kind of propylene ties Ciprofloxacin-isatin hybrid and its preparation method and use - Google Patents
A kind of propylene ties Ciprofloxacin-isatin hybrid and its preparation method and use Download PDFInfo
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- CN108727332A CN108727332A CN201810428517.9A CN201810428517A CN108727332A CN 108727332 A CN108727332 A CN 108727332A CN 201810428517 A CN201810428517 A CN 201810428517A CN 108727332 A CN108727332 A CN 108727332A
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- ciprofloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The invention discloses a kind of people's propylene to tie Ciprofloxacin-isatin hybrid and its preparation method and use.Ciprofloxacin produced by the present invention-isatin hybrid 3d is to all for examination gram-positive bacteria and Gram-negative bacteria（Go out the pathogen of very strong drug resistance including clinical signs）Very strong resistance is all had, effect is suitable with parent Ciprofloxacin and lavo-ofloxacin or more effective；And hybrid 3b（MIC:0.10 and 0.5 μ g/mL）Antibacterial activity to Mycobacterium tuberculosis H37Rv bacterial strain is respectively Ciprofloxacin（MIC：0.78μg/mL）And rifampin（MIC：0.39μg/mL）4 times and 8 times, and it is respectively three kinds of reference drugs --- Ciprofloxacin to multiple-drug resistance tuberculosis antibacterial ability（MIC:2.0μg/mL）, rifampin（MIC:32μg/mL）The isoniazid and（>128μg/mL）4->256 times.With relatively low cell toxicant（CC50:64 and 256 μ g/mL）Hybrid 3b and 3d show acceptable metabolic stability and Internal pharmacokinetics（PK）Feature.
Description
Technical field
This patent belongs to medicinal chemistry arts more particularly to a kind of propylene ties Ciprofloxacin-isatin hybrid
And its preparation method and use.
Background technology
The bacterium infection caused by gram-positive bacteria and Gram-negative bacteria and mycobacterial pathogen is that hospital obtains
The main reason for obtaining sexy dye, this kind of infection leads to a large amount of cases deaths, and global medical system is made to bear huge burden.
The poly- World Health Organization（WHO）Newest report estimation, there are about 10,000,000 people to die of infectious disease every year（Account for all death tolls
15% or more）, and tuberculosis（TB）It is the ninth-largest cause of the death in the whole world, while is also the main reason for coming from Simple infection source.In recent years
Come, such as methicillin-resistant staphylococcus aureus（MRSA）, methicillin-resistance staphylococcus epidermis（MRSE）, it is resistance to through the ages
Mycin staphylococcus aureus（VRSA）, extended spectrum β lactamases（ESBL）Produce Escherichia coli and resistant tuberculosis（DR-TB）
The appearance of equal drug-resistant microorganisms and spread speed are to reach stunning level, and these drug-fast bacterias also result in phase
When the big death rate.Therefore, exploitation has the new of antibacterial activity simultaneously to drug susceptibility-types bacterium infection and drug-fast bacteria infection
Type antibiotic preparation is imperative.
Fluoroquinolones is a kind of synthetic spectrum antibiotic, they are in clinic for treating various bacterium infections
（Including the infection of the upper respiratory tract and lower respiratory tract infection）The second major class antibiotic, and they treatment bacterium infection effect
Also constantly increasing with value.Fluoroquinolones mainly by with two kinds of II type bacterium topoisomerase biochemical enzymes, i.e. DNA
Gyrase（The major target class of Gram-negative bacteria）With topoisomerase I V（The major target class of Gram-negative bacteria）Be combined and
Its antibacterial action is played, and DNA gyrases are considered as that a kind of unique II type bacterium topologys that can have among MTB are different
Therefore structure biochemical enzymes are fluoroquinolones（FQs）Unique action target spot.Other than there is typical antibacterial activity,
Fluoroquinolones also shows anti-malarial, antitumor and treating tuberculosis（TB）Etc. atypia biological characteristics, and these characteristics
Can then it play the role of during new drug development vital.
However, as other kinds of antibacterials, bacterial pathogens are also fast to the drug resistance of fluoroquinolones
Speed is formed, and the main reason for causing this severe situation is since people are to the long-term, extensive, improper using very of such drug
To abuse, this all makes it to the therapeutic effect of bacterium infection worse and worse.Therefore, the drug effect of fluoroquinolones is improved
Become extremely urgent.
Isatin is a kind of endogenous compound being present among many organisms, with various biological spy
Property, such as antibacterial, anticancer, AntiHIV1 RT activity, anti-malarial and anti-tubercular, and these above-mentioned bioactivity then may be by its into
Row non-covalent interaction（Such as electrostatic interaction and hydrogen bond etc.）Come what is realized.In addition to this, the western Buddhist nun of such as Saimaa and
Nitre has been approved for clinical treatment for Buddhist nun's cloth etc. is many with the relevant compound of isatin.Therefore, isatin portion
Dividing will be particularly effective in antibacterial field.
Either in vitro, still in vivo, the fluoroquinolones to be formed is tied from different attachments（FQs）- Yin
Diindyl expires diketone hybrid and different microbial organisms is shown with excellent lethality.Past correlative study shows to deposit
It is fluoroquinolones（FQs）Attachment between isatin plays most important in terms of its anti-tubercular
Effect, therefore, it is necessary to carry out further optimization to this attachment to improve its antibacterial activity.
Invention content
To solve the above problems, the invention discloses a kind of people's propylene tie Ciprofloxacin-isatin hybrid and
Its preparation method and use.Ciprofloxacin produced by the present invention-isatin hybrid 3d is to all for examination gram sun
Property bacterium and Gram-negative bacteria（Go out the pathogen of very strong drug resistance including clinical signs）Very strong resistance is all had,
Effect is suitable with parent Ciprofloxacin and lavo-ofloxacin or more effective；And hybrid 3b（MIC:0.10 and 0.5 μ g/
mL）Antibacterial activity to Mycobacterium tuberculosis H37Rv bacterial strain is respectively Ciprofloxacin（MIC：0.78μg/mL）And rifampin
（MIC：0.39μg/mL）4 times and 8 times, and it is respectively three kinds of reference drugs to multiple-drug resistance tuberculosis antibacterial ability ---
Ciprofloxacin（MIC: 2.0 μg/mL）, rifampin（MIC: 32 μg/mL）The isoniazid and（>128 μg/mL）4->256 times.
With relatively low cell toxicant（CC50:64 and 256 μ g/mL）Hybrid 3b and 3d show acceptable metabolic stability with
And Internal pharmacokinetics（PK）Therefore feature can carry out them further optimization to filter out optimal hybrid.
To achieve the above object, the technical scheme is that：
A kind of propylene ties Ciprofloxacin-isatin hybrid, it is miscellaneous that the propylene ties Ciprofloxacin-isatin
The chemical combination formula of compound is chemical combination formula one or chemical combination formula two or chemical combination formula three；Chemical combination formula one is as follows：
Chemical combination formula two is as follows：
Chemical combination formula three is as follows：
Wherein R1=H or Me；R2=NoMe or NOEt.
Further to improve, it is chemical combination formula one or two that the propylene, which ties Ciprofloxacin-isatin hybrid,.
Further to improve, it is chemical combination formula one, wherein R that the propylene, which ties Ciprofloxacin-isatin hybrid,1=
Me。
Further to improve, it is chemical combination formula two, wherein R that the propylene, which ties Ciprofloxacin-isatin hybrid,1=
Me；R2=NoMe。
A kind of propylene ties the synthetic method of Ciprofloxacin-isatin hybrid, the following chemical equation of synthetic method
Shown in formula：
Wherein, wherein R1=H or Me；R2=NoMe or NOEt.
Further to improve, synthetic method is as follows：
。
It is further to improve, R1=Me；R2=NoMe.
Above-mentioned propylene ties Ciprofloxacin-isatin hybrid for resisting gram-positive bacteria and/or gram-negative
Property bacterium.
Above-mentioned propylene ties Ciprofloxacin-isatin hybrid for Ad tuberculosis, and wherein propylene ties
The chemical combination formula of Ciprofloxacin-isatin hybrid is chemical combination formula one.
Above-mentioned propylene ties Ciprofloxacin-isatin hybrid and is used to prepare liquid preparation or tablet or capsule.
Description of the drawings
Fig. 1 is the synthetic route chart of mono-/bis-- isatin-Ciprofloxacin hybrid 3a-f and 4a-f.
Specific implementation mode
Embodiment 1
Fig. 1 gives the synthetic route that propylene ties isatin-Ciprofloxacin hybrid 3a-f and 4a-f.Replace through C-5
Isatin 1a, b be alkylated reacted to generate N- (3- bromines third with 1,3- dibromopropanes in the presence of potassium carbonate
Base) isatin 2a, b, among these intermediate products are then incorporated into CPFX cores, and then it can be obtained by expected mesh
Mark product 3a, b and double-isatin-Ciprofloxacin hybrid 4a, b.Then, in the presence of sodium bicarbonate, hybrid
With methyl hydroxylamine or ethylhydroxyl amine hydrochloride condensation reaction occurs for 3a, b or 4a, b to generate other conjugated bodies 3c-f and 4c-
f。
This research ties isatin-Ciprofloxacin hybrid 3a-f and 4a-f to clinically typical to all propylene
Gram-positive bacteria, Gram-negative bacteria carried out antibacterial activity in vitro in terms of assessment, and also to MTB H37Rv and
The anti-mycobacteria activity of MDR-TB bacterial strains is evaluated.Wherein, minimum inhibitory concentration（MIC）Be defined as to 90% it is thin
Bacterium growth course realizes the minimum concentration of compound needed for inhibiting effect.Table 1,2 and 3 lists the minimum of classes of compounds respectively
Mlc（MIC）.
Antibacterial activity in vitro of the 1. hybrid 3a-f and 4a-f of table to gram positive bacterial strain
Initialism：MSSE, methicillin-sensitivity staphylococcus epidermis ATCC 12228；MRSE, methicillin-resistant epidermis grape ball
Bacterium 13-3；MSSA, Methicillin Sensitive Staphylococcus aureus ATCC 29213；MRSA, methicillin-resistant staphylococcus grape ball
Bacterium ATCC 33591；E.fa.1, enterococcus faecalis ATCC 29212；E.fa.2, enterococcus faecalis ATCC 51299；E.fm.1, dung intestines
Coccus ATCC 700221；E.fm.2, enterococcus faecium 13-7.
As it can be seen from table 1 all mono- isatin-Ciprofloxacin hybrid 3a-f are to the gram sun for examination
Property bacterium shows preferable antibacterial activity, their minimum inhibitory concentration（MIC）Between 0.06 to 64 μ g/mL.Wherein,
Most the hybrid 3d of antibacterial activity all has very strong biocidal properties to all gram positive bacterial strains for examination, particularly with
Clinical important pathogen body MSSE, MRSA, MSSA, MRSA and enterococcus faecalis, antibacterial ability are more prominent（Minimum inhibitory concentration
（MIC）The μ g/mL of respectively 0.06,0.06,0.06 and 0.5）, with reference drug Ciprofloxacin（MIC：0.125-64μg/mL）With
Lavo-ofloxacin（MIC：0.125-4μg/mL）It compares, the antibacterial ability of composition 3d is eager to excel 2-64 times.
Antibacterial activity in vitro of the 2. hybrid 3a-f and 4a-f of table to gram negative strain
Initialism：25922 ESBLs (-) of E.co.1, Escherichia coli ATCC；35218 ESBLs of E.co.2, Escherichia coli ATCC
(+)；700603 ESBLs (+) of K.p.1, klebsiella pneumobacillus ATCC；K.p.2, thunder Bai Shi Bacillus pneumonia bars
Bacterium 15-2 ESBLs (-)；P.a., Pseudomonas aeruginosa ATCC 27853；A.c., calcoacetious acinetobacter calcoaceticus ATCC
19606；E.c., enterobacter cloacae ATCC 43560；E.a., clostridium perfringen ATCC 13048；S.m.1, serratia marcescens
ATCC 21074；M.m., morganella morganii ATCC 25830；P.r., Providentia rettgeri ATCC 31052；
P.v., proteus vulgaris ATCC 29905；P.m., proteus mirabilis 13-1；S.m.2, thermophilic malt addiction oligotrophy eat unit cell
Bacterium ATCC 13636；C.f., Citrobacter freundii ATCC 43864.ESBLs(+)：Extended spectrumβ-lactamase-generation.
From table 2 it can be seen that all mono- isatin-Ciprofloxacin hybrid 3a-f are to the gram-negative for examination
Property bacterium shows excellent antibacterial activity, and their minimum inhibitory concentration（MIC）Between 0.03-2 μ g/mL.Interesting
It is that the most hybrid 3d of antibacterial activity is also the same to the Gram-negative bacteria that all gram positive bacterial strains for examination are all
Show highest bacterium biocidal properties, and its minimum inhibitory concentration（MIC）Between 0.03-0.5 μ g/mL, and with reference to medicine
Object Ciprofloxacin（MIC：0.03-2μg/mL）And lavo-ofloxacin（MIC： 0.03-2μg/mL）It compares, the antibacterial of composition 3d
Activity is suitable with the former or is slightly above the former.
Structure-activity relationship（SAR）Show mono- isatin-Ciprofloxacin hybrid 3a-f to all for trying Gram-positive
The antibacterial activity of bacterial strain and gram negative strain obviously higher than double-isatin-Ciprofloxacin hybrid 4a-f, this
Show that the carboxylic acid on the positions C-3 is necessary for gyrase combination and bacterial membrane transport process；In isatin portion
The positions C-3 divided, which introduce imine group, can improve its antibacterial activity, and be-NOME to the relative contribution size order to antibacterial>-
NOEt>-O；Substitution on the positions C-5 of isatin part has a strong influence to its activity, and with to replace
The compound of reaction is compared, with electron donor --- the antibacterial activity of the hybrid of-Me wants higher.
The anti-mycobacteria activity and cytotoxicity of table 3. hybrid 3a-f and 4a-f
aMDR-TB：To INH, RIF and EMB, there are drug resistances
bCC50：50% cytotoxic concentration in mammal VERO cell strains
Above-mentioned anti-mycobacteria the result shows that, all hybrids are to MTB H37Rv shows related excellent to MDR-TB
Antibacterial activity, their minimum inhibitory concentration（MIC）Between 0.1-64 μ g/mL, and other than 3f, other are all
The antibacterial activity of mono- isatin-Ciprofloxacin is superior to parent Ciprofloxacin.Structure-activity relationship（SAR）The results show that mono-
Isatin-Ciprofloxacin hybrid all has stronger compared with corresponding double-isatin-Ciprofloxacin hybrids
Antibacterial activity, this is consistent with the result that previous correlative study is obtained.For mono- isatin-Ciprofloxacin hydridization
For object, imine group and C-5 power supply bases --- the introducing of-Me reduces it at the positions C-3 of isatin part
To the antibacterial activity of strains tested.Especially, the most hybrid 3b of antibacterial activity（MIV：0.1 and 0.5 μ g/mL）To MTB
H37The antibacterial activity of Rv is parent Ciprofloxacin respectively（MIC: 0.78 μg/mL）And rifampin（RIF,MIC: 0.39 μg/
mL）4 times and 8 times, and it is three kinds to the antibacterial activity of MDR-TB and refers to drug Ciprofloxacin（MIC: 2.0 μg/mL）, profit
Good fortune is flat（MIC: 32 μg/mL）The isoniazid and（INH, >128 μg/mL）4->256 times.
This research then also ties isatin-Ciprofloxacin hybrid 3a-f and 4a-f in mammal to propylene
Toxicity in VERO cell lines（CC50）It is detected.After exposure 72 hours, in MTT（3-（4,5- dimethylthiazoles-
2- bases）- 2,5- diphenyltetrazolium bromides）Through cell transformation be formazan products on the basis of, cell viability is carried out
Related evaluation, the results are shown in Table 3.As can be seen from the table, all hybrids show acceptable cytotoxicity,
Simultaneously fortunately, the most hybrid 3b of antibacterial activity（CC 50：64μg/mL）And 3d（CC50: 256 μg/mL）Cell toxicant
Property is suitable with CPFX（CC50: 128 μg/mL）.
Metabolic stability and internal pharmacokinetics value of table 4.3c and the 3d heterocomplex in Mice Body
After the gastric infusion for carrying out hybrid 3b and 3d to mouse with the dosage of 50mg/kg, this research is respectively metabolized it
Stability and internal pharmacokinetics（PK）It is evaluated.As shown in table 4, in 1.5 hours after gastric infusion, two
The plasma concentration of kind hybrid reaches a peak value；And the elimination half-life period of two kinds of hybrids is good（Respectively 4.1 Hes
3.3 hour）, while area under the curve（AUG）Respectively 4988 and 2865.Under normal conditions, the metabolism of above two hybrid
Stability and internal pharmacokinetics（PK）It is not so good as parent Ciprofloxacin, so needing further to be optimized.
To sum up, this research, which has synthesized a series of new propylene, ties Ciprofloxacin-isatin hybrid, and divide
Not with regard to them to MTB H37The external anti-mycobacteria activity and cytotoxicity of Rv and MDR-TB is evaluated.Research knot
Fruit shows that all hybrids show strains tested great inhibitory activity, and at the same time having very low cell toxicant
The hybrid 3b of property and most highly active is to MTB H37The antibacterial activity of Rv and MDR-TB will be significantly stronger than parent Ciprofloxacin, because
This this aspect is worth carrying out the research of next step.
Antibacterial minimum inhibitory concentration（MIC）It measures
This research uses agar medium, and by two times of serial dilutions of standard come blue to typical case's leather to above-mentioned all hybrids
Family name's positive bacteria and Gram-negative bacteria（Chinese control and prevention of disease center）Antibacterial activity in vitro screened.By hybrid
（10.0mg）It is dissolved in the sodium hydroxide solution and water of a concentration of 0.1N respectively（10mL）Among.Use the Ma-Xin family after thawing
Agar carries out two times of serial dilutions to obtain testing required concentration（128,64,32,16,8,4,2,1,0.5,0.25,
0.125,0.06,0.03,0.015 and 0.008 mg/mL）.By culture dish and 104 colony forming units（cfu）It carries out common
It is incubated, incubation temperature and incubation time are respectively 35 DEG C and 18-24 hours.
Anti- mycobacteria minimum inhibitory concentration（MIC）It measures
Hybrid 3a-f, 4a-f are dissolved among DMSO together together with CPFX, RIF and INH, and tried by quick Susceptibility Testing
The technology of testing is come to its external anti-MTB H37Rv and MDR-TB activity is evaluated.Use experiment chemical combination of the 100mL through doubling dilution
Object and 100ml MTB H containing 4*10^-3mg cells37Rv or MDR-TB suspension fills out the hole of sterile 48 orifice plate
It fills.The positive control that the compound after two Kong Zhongjing dilutions is used as growth is substituted using pure culture base, and at other two
Kong Zhong substitutes culture using as the negative control of growth using deionized water.The orifice plate is covered and sealed, then at one
It is incubated in wet box, incubation temperature is 37 DEG C.After being incubated 3 days, more significant difference should be shown in positive and negative control wells.
By using continuous range estimation high power lens system come to cell in each experimental port quantity and state observed to determine it most
Low Mlc（MIC）, and after 7 days, it is redeterminated.The definition of MIC is can completely inhibit bacterial growth institute
Need the minimum concentration of compound.
Cytotoxicity
Among this research synthesized hybrid 3a-f and 4a-f are dissolved into DMSO, and in the model of a concentration of 1000-4 μ g/mL
Enclose the interior toxicity to respectively to each hybrid in mammal VERO cell lines（CC50）It is detected.The VERO is thin
Born of the same parents cultivate in the environment of containing 5% carbon dioxide（Culture medium is the minimum essential medium for containing Earle ' s balance salt
（Added with 10% fetal calf serum）, cultivation temperature is 37 DEG C）.Cell is inoculated among 96 orifice plates, wherein containing in each hole
1*10^4 cell, and allow in the medium to restore 24 hours.Using containing test compound or without drug will be carried out
The analysis culture medium of ingredient carrys out substitutive medium.After exposure 72 hours, cell is collected, and by MTT analytic approach come to thin
Born of the same parents' vigor is detected.The value of CC50 is calculated finally by using Bliss analytic approach.
Pharmacokinetic properties
This research uses SPF Female ICR mices（Weight is 20-25g）To be carried out to the pharmacokinetic properties of above-mentioned hybrid
It probes into.A night before administration needs to carry out fasting to mouse.Each treatment（Processing）Group includes 3 mouse.It will need to survey
The compound of examination carries out gastric infusion according to the dosage of 50mg/kg together with CPFX suspension to mouse.By compound and 0.5
CMC be configured to suspension so that mouse to be administered orally.And 0.25,0.5,1,2,4,6,8,24 hour upon administration is right
Every mouse carries out jugular vein blood collection.All blood samples are centrifuged 10 minutes with the rotating speed of 3000r/min, then by it
It is preserved, the serum of 150 μ L is added in the acetonitrile of 500 μ L, then by the mixture with 13000 r/min at -20 DEG C
Rotating speed centrifuge 10 minutes to remove protein.The supernatant that centrifugation obtains is dried, and is dissolved into the acetonitrile of 100 μ L
Among, which is centrifuged 10 minutes under the rotating speed of 13000 r/min.Supernatant is moved in sample bottle to carry out efficient liquid
Phase chromatography（HPLC）Analysis.The gross area under sample concentration-time graph（AUC）, eliminate half-life period（t1/2）, peak concentration
（Cmax）And reach time of peak concentration can by using WinNonlin V6.2.1 from experimental data directly really
It is fixed.
Although the embodiments of the present invention have been disclosed as above, but it is not restricted to listed fortune in specification and embodiment
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily real
Now other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is not limited to
Specific details and the legend herein shown with description.
Claims (10)
1. a kind of propylene ties Ciprofloxacin-isatin hybrid, which is characterized in that the propylene ties Ciprofloxacin-
The chemical combination formula of isatin hybrid is chemical combination formula one or chemical combination formula two or chemical combination formula three；Chemical combination formula one is as follows：
Chemical combination formula two is as follows：
Chemical combination formula three is as follows：
Wherein R1=H or Me；R2=NoMe or NOEt.
2. propylene as described in claim 1 ties Ciprofloxacin-isatin hybrid, which is characterized in that the propylene
It is chemical combination formula one or two to tie Ciprofloxacin-isatin hybrid.
3. propylene as claimed in claim 2 ties Ciprofloxacin-isatin hybrid, which is characterized in that the propylene
It is chemical combination formula one, wherein R to tie Ciprofloxacin-isatin hybrid1=Me。
4. propylene as claimed in claim 2 ties Ciprofloxacin-isatin hybrid, which is characterized in that the propylene
It is chemical combination formula two, wherein R to tie Ciprofloxacin-isatin hybrid1=Me；R2=NoMe。
5. a kind of propylene ties the synthetic method of Ciprofloxacin-isatin hybrid, which is characterized in that synthetic method is as follows
Shown in chemical equation：
Wherein, wherein R1=H or Me；R2=NoMe or NOEt.
6. propylene as claimed in claim 5 ties the synthetic method of Ciprofloxacin-isatin hybrid, feature exists
In synthetic method is as follows：
。
7. the propylene as shown in claim 6 ties the synthetic method of Ciprofloxacin-isatin hybrid, feature exists
In R1=Me；R2=NoMe.
8. a kind of any propylene of claim 2-4 ties Ciprofloxacin-isatin hybrid for anti-gram
Positive bacteria and/or Gram-negative bacteria.
9. propylene as claimed in claim 8 ties Ciprofloxacin-isatin hybrid and is used for Ad tuberculosis,
The chemical combination formula that middle propylene ties Ciprofloxacin-isatin hybrid is chemical combination formula one.
10. a kind of any propylene of claim -4 ties Ciprofloxacin-isatin hybrid and is used to prepare liquid
Medicament or tablet or capsule.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112870196A (en) * | 2019-11-11 | 2021-06-01 | 山东畜牧兽医职业学院 | Composition for treating drug-resistant microbial bacteria |
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2018
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112870196A (en) * | 2019-11-11 | 2021-06-01 | 山东畜牧兽医职业学院 | Composition for treating drug-resistant microbial bacteria |
| CN112939860A (en) * | 2019-11-11 | 2021-06-11 | 山东畜牧兽医职业学院 | Compound for treating drug-resistant gram-negative positive bacteria and preparation method thereof |
| CN112939860B (en) * | 2019-11-11 | 2022-11-11 | 山东畜牧兽医职业学院 | Compound for treating drug-resistant gram-negative positive bacteria and preparation method thereof |
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