CN103664867A - Acylhydrazone derivatives containing 1,4-benzodioxane, and preparation method and antibacterial activity thereof - Google Patents
Acylhydrazone derivatives containing 1,4-benzodioxane, and preparation method and antibacterial activity thereof Download PDFInfo
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- benzodioxan
- nitrae
- isosorbide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 230000000844 anti-bacterial effect Effects 0.000 title claims description 7
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 title abstract 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 235000019441 ethanol Nutrition 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 229940088710 antibiotic agent Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 235000014469 Bacillus subtilis Nutrition 0.000 abstract description 2
- 241000588724 Escherichia coli Species 0.000 abstract description 2
- 229940124350 antibacterial drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 11
- 241000894006 Bacteria Species 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical compound FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 2
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 235000015278 beef Nutrition 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 108010079058 casein hydrolysate Proteins 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 1
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 230000010748 Photoabsorption Effects 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 239000012773 agricultural material Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- -1 alkaloid compound Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses acylhydrazone derivatives containing 1,4-benzodioxane, of which the general formula is disclosed in the specification, wherein R is disclosed in the specification. The acylhydrazone derivatives containing 1,4-benzodioxane have different inhibiting actions on B. subtilis, S. aureus, E. coli and P. aeruginosa, and thus, can be used in preparing antibacterial drugs. The invention also discloses a preparation method of the acylhydrazone derivatives containing 1,4-benzodioxane.
Description
Technical field
The present invention relates to novel acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan of a class and preparation method thereof and purposes as antibacterials.
Background technology
In the past few decades, the problem of multidrug resistance microorganism has reached thrilling degree in the whole world.Therefore the novel drugs of, finding the anti-microbial infection of efficient, low side effect becomes an important and urgent task.
Isosorbide-5-Nitrae-benzodioxan derivative is structural unit common in many medicines and natural product, and has important biological activity, and they can be used as clinical treatment retarding agent, are playing the part of the role who becomes more and more important in the therapies such as hypertension, hyperglycemia.And in recent years, have bibliographical information, Isosorbide-5-Nitrae-benzodioxan derivative has certain antibacterial, anti-inflammatory activity.
Acylhydrazone is the class Schiff alkaloid compound being formed by hydrazides and aldehydes or ketones condensation, under the environment of one's own thing, show good biological activity, stronger coordination ability and various coordination mode, therefore at aspects such as medicine, agricultural chemicals, material and analytical reagents, received concern widely.In recent years, researchist finds, the multiple biological activitys such as that acylhydrazone has is antibacterial, anti-inflammatory and weeding, and some acylhydrazone also has antitumous effect.Therefore, Isosorbide-5-Nitrae-benzodioxan structure is modified, form acylhydrazone structure, can strengthen its anti-microbial activity.
Summary of the invention
The object of this invention is to provide novel acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan of a class and its production and use.Technical scheme of the present invention is as follows:
The acylhydrazone analog derivative of Isosorbide-5-Nitrae-benzodioxan that one class is novel, it has following general formula:
In formula, R is:
A method of preparing the acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan claimed in claim 1, is characterized in that it is comprised of the following step:
Step 1. adds 10g Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid to dissolve in 50ml ethanol, slowly splashes into the 3ml vitriol oil, 80 ℃ of backflows, reaction 10h.After reaction finishes, solvent evaporated, adds 20ml ethyl acetate, saturated sodium-chloride washing 3 times, and anhydrous sodium sulfate drying, rapid column chromatography, obtains colourless transparent oil liquid Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid, ethyl ester.
20ml dissolve with ethanol Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid, ethyl ester for step 2., then adds hydrazine hydrate (85%) 30ml, 80 ℃ of backflows, reaction 24h.After reaction finishes, be cooled to a large amount of white solids after room temperature and separate out, saturated nacl aqueous solution washing 3 times, washing with alcohol is removed hydrazine hydrate 3 times, and in ethanol, recrystallization obtains white needles solid, filters, dry, obtains Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid hydrazides 6g.
The hydrazides obtaining in 20ml dissolve with ethanol step 2 for step 3., then adds several Glacial acetic acid, then to the ketone that adds equimolar amount in reaction solution, 80 ℃ of backflows, reaction 12h.After reaction finishes, be cooled to room temperature, have a large amount of white or yellow solid to separate out, filter and obtain product crude product, by crude product ethyl alcohol recrystallization, obtain product, the acylhydrazone analog derivative of Isosorbide-5-Nitrae-benzodioxan.
Experimental result shows, the novel acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan of the present invention has obvious restraining effect to bacterium.Therefore the acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan of the present invention can be applied to prepare antibacterials.
By following examples, further describe the present invention, but scope of the present invention is not subject to any restriction of these embodiment.
Embodiment 1:N '-(1-(4-fluorophenyl)-ethylidene)-2, the preparation of 3-dihydro [b] [Isosorbide-5-Nitrae] benzodioxan-5-acylhydrazone
With 20ml dissolve with ethanol Isosorbide-5-Nitrae-benzodioxan-5-hydrazides, then add several Glacial acetic acid, then to add in reaction solution equimolar amount to fluoro acetophenone, 80 ℃ of backflows, reaction 12h.After reaction finishes, be cooled to room temperature, have a large amount of white or yellow solid to separate out, filter and obtain product crude product, by crude product ethyl alcohol recrystallization, obtain target compound.Obtain white or buff powder, productive rate 75%, mp:210-211 ℃;
1h NMR (300MHz, DMSO-d
6, δ ppm): 2.32 (s, 3H); (4.16-4.19 d, J=17.04Hz, 2H); (4.41-4.45 d, J=17.04Hz, 2H); 6.95-6.98 (m, 1H); (7.04-7.06 d, J=4.74Hz, 1H); 7.25-7.29 (m, 2H); (7.35-7.38 d, J=4.56Hz, 1H); 7.89-7.91 (m, 2H); 10.74 (s, 1H) .MS (ESI): 314.31 (C
17h
15fN
2o
3, [M
+h]
+) .Anal.Calcd for C
17h
14fN
2o
3: C, 64.96; H, 4.81; N, 8.91%.Found:C, 64.84; H, 4.83; N, 8.88%.
Embodiment 2:N '-(1-(4-chloro-phenyl-)-ethylidene)-2, the preparation of 3-dihydro [b] [Isosorbide-5-Nitrae] benzodioxan-5-acylhydrazone
Preparation method is with embodiment 1.With parachloroacetophenone, replace fluoro acetophenone, obtain target compound.White powder, productive rate 83%, mp:207-208 ℃;
1h NMR (300MHz, DMSO-d
6, δ ppm): 2.36 (s, 3H); (4.33-4.35 d, J=11.58Hz, 2H); (4.40-4.42 d, J=17.07Hz, 2H); 6.73-6.75 (m, 1H); (6.97-7.02 d, J=4.74Hz, 1H); 7.19-7.22 (m, 2H); (7.33-7.35 d, J=4.59Hz, 1H); 7.87-7.90 (m, 2H); 10.78 (s, 1H) .MS (ESI): 330.77 (C
17h
15clN
2o
3, [M
+h]
+) .Anal.Calcd for C
17h
14clN
2o
3: C, 61.73; H, 4.57; N, 8.47%.Found:C, 61.56; H, 4.56; N, 8.45%.
Embodiment 3:N '-(1-(4-bromophenyl)-ethylidene)-2, the preparation of 3-dihydro [b] [Isosorbide-5-Nitrae] benzodioxan-5-acylhydrazone
Preparation method is with embodiment 1.With parabromoacetophenone, replace fluoro acetophenone, obtain target compound.White powder, productive rate 79%, mp:213-215 ℃;
1h NMR (300MHz, DMSO-d
6, δ ppm): 2.29 (s, 3H); (4.41-4.46 d, J=14.28Hz, 2H); (4.45-4.49 d, J=12.84Hz, 2H); 6.62-6.64 (m, 1H); (7.07-7.08 d, J=4.63Hz, 1H); 7.23-7.25 (m, 2H); (7.38-7.40 d, J=4.50Hz, 1H); 7.84-7.87 (m, 2H); 10.72 (s, 1H) .MS (ESI): 375.22 (C
17h
15brN
2o
3, [M
+h]
+) .Anal.Calcd for C
17h
14brN
2o
3: C, 54.42; H, 4.03; N, 7.47%.Found:C, 54.38; H, 4.58; N, 7.44%.
Embodiment 4:N '-(1-(p-aminomethyl phenyl)-ethylidene)-2, the preparation of 3-dihydro [b] [Isosorbide-5-Nitrae] benzodioxan-5-acylhydrazone
Preparation method is with embodiment 1.With p-methyl aceto phenone, replace fluoro acetophenone, obtain target compound.White powder, productive rate 86%, mp:203-205 ℃;
1h NMR (300MHz, DMSO-d
6, δ ppm): 2.31 (s, 3H); 2.35 (s, 3H); 4.34 (s, 2H); 4.46 (s, 2H); 6.95-6.99 (m, 1H); 7.05-7.08 (m, 1H); (7.24-7.27 d, J=8.04Hz, 2H); (7.37-7.40 d, J=7.50Hz, 1H); (7.75-7.77 d, J=8.25Hz, 2H); 10.71 (s, 1H) .MS (ESI): 310.35 (C
18h
18n
2o
3, [M
+h]
+) .Anal.Calcd for C
18h
17n
2o
3: C, 69.66; H, 5.85; N, 9.03%.Found:C, 69.73; H, 5.82; N, 9.04%.
Embodiment 5:N '-(1-styroyl)-2, the preparation of 3-dihydro [b] [Isosorbide-5-Nitrae] benzodioxan-5-acylhydrazone
Preparation method is with embodiment 1.To replace fluoro acetophenone without substituted acetophenone, obtain target compound.White powder, productive rate 80%, mp:201-202 ℃;
1h NMR (300MHz, DMSO-d
6, δ ppm): 2.31 (s, 3H); (4.37-4.40 d, J=14.28Hz, 2H); (4.67-4.72 d, J=14.61Hz, 2H); 6.63-6.65 (m, 1H); (7.09-7.13 d, J=7.29Hz, 1H); 7.17-7.21 (m, 2H); (7.25-7.29 d, J=8.91Hz, 1H); 7.78-7.81 (m, 2H); 10.76 (s, 1H) .MS (ESI): 296.32 (C
17h
16n
2o
3, [M
+h]
+) .Anal.Calcd for C
17h
15n
2o
3: C, 68.91; H, 5.44; N, 9.45%.Found:C, 68.84; H, 5.46; N, 9.41%.
Embodiment 6:N '-(1-(4-p-methoxy-phenyl)-ethylidene)-2, the preparation of 3-dihydro [b] [Isosorbide-5-Nitrae] benzodioxan-5-acylhydrazone
Preparation method is with embodiment 1.With p-methoxy-acetophenone, replace fluoro acetophenone, obtain target compound.White powder, productive rate 82%, mp:197-199 ℃;
1h NMR (300MHz, DMSO-d
6, δ ppm): 2.51 (s, 3H); 3.85 (s, 3H); 4.35 (s, 2H); 4.46 (s, 2H); 6.94-7.07 (m, 4H); (7.37-7.41 d, J=7.68Hz, 1H); (7.80-7.83 d, J=8.76Hz, 2H); 10.68 (s, 1H) .MS (ESI): 326.35 (C
18h
18n
2o
4, [M+H]+) .Anal.Calcd for C
18h
17n
2o
4: C, 66.25; H, 5.56; N, 8.58%.Found:C, 66.17; H, 5.58; N, 8.55%.
Embodiment 7: containing the acylhydrazone analog derivative anti-microbial activity research of Isosorbide-5-Nitrae-benzodioxan
1. experiment material and method
1.1 medicines and reagent
Mueller-Hinton substratum (beef extract powder 5g, casein hydrolysate 17.5g, starch 1.5g, agar 12.5g, adds in 1000mL distilled water), kantlex, penicillin, DMSO, MTT (3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt, commodity are called tetrazolium bromide), Virahol, hydrochloric acid, be analytical reagent, synthetic compound 1-6, PBS damping fluid (phosphate buffered saline buffer 0.01mol/L, pH7.4, Na
2hPO
4.12H
2o 2.9g, KH
2pO
40.2g, NaCl 8.0g, KCl 0.2g, distilled water 1000mL).
1.2 bacterial classification
Intestinal bacteria (E.coli), streptococcus aureus (S.aureus), subtilis (B.subtilis), Pseudomonas aeruginosa (P.aeruginosa)
1.3 experimental technique
1.3.1 the preparation of substratum
Get beef extract powder 5g, casein hydrolysate 17.5g, starch 1.5g, agar 12.5g, adds in 1000mL distilled water, and heated and boiled is dissolved, packing, 121 ℃ of autoclavings 15 minutes are standby.
1.3.2 the cultivation of test organisms
In sterilisable chamber, get intestinal bacteria, streptococcus aureus, four kinds of test strains of subtilis and Pseudomonas aeruginosa, under spirit lamp with inoculating needle respectively on four kinds of test strain inclined-planes, scrape the inclined-plane lawn that takes a morsel, with a certain amount of sterilized water, make bacteria suspension, then get a certain amount of being added to and melt and be cooled in the MH substratum of 50 ℃ of left and right, shake up, at once pour in sterile petri dish, after abundant condensation with after plug sealing, in 37 ℃ cultivate 18-24 hour standby.Draw bacterium liquid 1mL, with MH substratum, by dilution in 1: 1000, make bacterial concentration be about 10
5cfu/mL.
1.3.3 antibacterial experiment:
Medicine to be measured is dissolved in to the solution that is mixed with 2mg/mL in DMSO, then with doubling dilution, medicine is diluted in finite concentration gradient (50 μ g/mL, 25 μ g/mL, 12.5 μ g/mL, 3.125 μ g/mL) and DMSO.The substratum that adds respectively 100 μ L in sterilizing microtiter plate article one, the positive contrast of second, adds 100 μ L bacteria suspensions.In remaining hole, add the bacteria suspension of 90 μ L and the drug solution of 10 μ L.Parallel 3 times of each drug solution concentration.In microtiter plate bottom, indicate bacteria name.The culture dish of handling is cultivated to 24h, observation in 37 ℃.
1.3.4 the mensuration of MIC
After each microtiter plate can be measured its MIC value intuitively, in each hole of plate, add 50 μ L PBS damping fluid (phosphate buffered saline buffer 0.01mol/L, pH7.4, Na
2hPO
4.2H
2o 2.9g, KH
2pO
40.2g, NaCl 8.0g, KCl 0.2g, distilled water 1000mL), wherein comprise 2mg MTT/mL.At room temperature continue to hatch 4-5h.Material in hole is shifted out and added the Virahol that 100 μ L contain 5%1mol/L HCl and extract dyestuff.Continue at room temperature to hatch 12h, by microplate reader, measure each hole photoabsorption (OD value), measure wavelength 550nm.According to each hole OD value, calculate the minimum inhibition concentration of medicine to bacterial growth.
Minimum inhibition concentration (minimum inhibitory concentration, MIC): under specific environment, hatch 24 hours, can suppress certain microorganism and occur that the lowest drug concentration rising appreciably is minimum inhibition concentration, according to the optical density(OD) (OD value) of measuring, make the typical curve of bacterial growth inhibiting rate, on typical curve, try to achieve its corresponding drug level.
The MIC recording is shown in Table 1
2. experimental result
The inhibition MIC value (μ g/mL) of the listed acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan of table 1 the present invention to bacterium
Kanamycin; Penicillin: positive control.
Claims (3)
1. a class, containing the acylhydrazone analog derivative of 4-benzodioxan, is characterized in that it has following general formula:
In formula, R is:
2. a method of preparing the acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan claimed in claim 1, is characterized in that it is comprised of the following step:
Step 1. adds 10g Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid to dissolve in 50ml ethanol, slowly splashes into the 3ml vitriol oil, 80 ℃ of backflows, reaction 10h.After reaction finishes, solvent evaporated, adds 20ml ethyl acetate, saturated sodium-chloride washing 3 times, and anhydrous sodium sulfate drying, rapid column chromatography, obtains colourless transparent oil liquid Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid, ethyl ester.
20ml dissolve with ethanol Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid, ethyl ester for step 2., then adds hydrazine hydrate (85%) 30ml, 80 ℃ of backflows, reaction 24h.After reaction finishes, be cooled to a large amount of white solids after room temperature and separate out, saturated nacl aqueous solution washing 3 times, washing with alcohol is removed hydrazine hydrate 3 times, and in ethanol, recrystallization obtains white needles solid, filters, dry, obtains Isosorbide-5-Nitrae-benzodioxan-5-carboxylic acid hydrazides 6g.
The hydrazides obtaining in 20ml dissolve with ethanol step 2 for step 3., then adds several Glacial acetic acid, then to the ketone that adds equimolar amount in reaction solution, 80 ℃ of backflows, reaction 12h.After reaction finishes, be cooled to room temperature, have a large amount of white or yellow solid to separate out, filter and obtain product crude product, by crude product ethyl alcohol recrystallization, obtain product, the acylhydrazone analog derivative of Isosorbide-5-Nitrae-benzodioxan.
3. the application of the acylhydrazone analog derivative containing Isosorbide-5-Nitrae-benzodioxan according to claim 1 in preparation antibacterials.
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| WO2010083307A2 (en) * | 2009-01-14 | 2010-07-22 | Dow Agrosciences Llc | Synergistic fungicidal compositions including hydrazone derivatives and copper |
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| Title |
|---|
| 王钦荣，: "羟基苯甲酰腙类化合物的合成及其活性研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
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