CN115304624A - Enoxacin-azobenzene antibacterial compound with photoresponse and preparation method thereof - Google Patents
Enoxacin-azobenzene antibacterial compound with photoresponse and preparation method thereof Download PDFInfo
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 229960002549 enoxacin Drugs 0.000 claims abstract description 27
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 claims abstract description 17
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical compound C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229940124350 antibacterial drug Drugs 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 29
- 239000007788 liquid Substances 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 16
- 238000002390 rotary evaporation Methods 0.000 claims description 16
- 238000007710 freezing Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- -1 alkynyl enoxacin Chemical compound 0.000 claims description 10
- 230000008014 freezing Effects 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- PTBDIHRZYDMNKB-UHFFFAOYSA-N 2,2-Bis(hydroxymethyl)propionic acid Chemical compound OCC(C)(CO)C(O)=O PTBDIHRZYDMNKB-UHFFFAOYSA-N 0.000 claims description 5
- PEKKGQPDLDUTKH-UHFFFAOYSA-N 2-azido-n-(2-azidoethyl)ethanamine Chemical compound [N-]=[N+]=NCCNCCN=[N+]=[N-] PEKKGQPDLDUTKH-UHFFFAOYSA-N 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 5
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 claims description 5
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 5
- RYMHZBAYPLCCAC-UHFFFAOYSA-N 4-phenyldiazenylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1N=NC1=CC=CC=C1 RYMHZBAYPLCCAC-UHFFFAOYSA-N 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- GAUZCKBSTZFWCT-UHFFFAOYSA-N azoxybenzene Chemical compound C=1C=CC=CC=1[N+]([O-])=NC1=CC=CC=C1 GAUZCKBSTZFWCT-UHFFFAOYSA-N 0.000 claims description 2
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 230000004298 light response Effects 0.000 claims 1
- 230000004043 responsiveness Effects 0.000 abstract description 8
- 241000894006 Bacteria Species 0.000 abstract description 3
- 230000002147 killing effect Effects 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000002105 nanoparticle Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003504 photosensitizing agent Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 229910000859 α-Fe Inorganic materials 0.000 description 2
- 208000037088 Chromosome Breakage Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- 108010041052 DNA Topoisomerase IV Proteins 0.000 description 1
- 210000003578 bacterial chromosome Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CIZVQWNPBGYCGK-UHFFFAOYSA-N benzenediazonium Chemical group N#[N+]C1=CC=CC=C1 CIZVQWNPBGYCGK-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000005886 chromosome breakage Effects 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
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- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 238000007626 photothermal therapy Methods 0.000 description 1
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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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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- 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
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Abstract
The invention relates to an enoxacin-azobenzene antibacterial compound with photoresponse and a preparation method thereof. The enoxacin-azobenzene combines enoxacin medicine with better killing effect on gram-negative bacteria and azobenzene with photostimulation responsiveness, and the combined product can play an antibacterial effect with photostimulation responsiveness. The method has simple preparation process, and provides a new idea and method for the research and development of novel photoresponse antibacterial drugs.
Description
Technical Field
The invention belongs to the field of material synthesis, and relates to an enoxacin-azobenzene antibacterial compound with photoresponse and a preparation method thereof.
Background
Enoxacin (Enoxacin) is a third-generation fluoroquinolone antibiotic and has broad-spectrum and strong bactericidal action. It exerts its antibacterial action by inhibiting bacterial nucleic acid synthesis by destroying topoisomerase IV and DNA gyrase, and causing bacterial chromosome breakage. On the other hand, azobenzene has good photostimulation responsiveness due to its unique cis-trans isomerism.
Document 1 discloses a hemoglobin-functionalized Copper Ferrite nanoparticle combining nanocatalysis Antibacterial Therapy and Photothermal Therapy, and experimental results prove that the hemoglobin-functionalized Copper Ferrite nanoparticle has excellent synergistic bactericidal effect. However, the uncertain biocompatibility of the inorganic nanoparticles limits further clinical applications.
Document 2A photosensive orthogonal synergistic complex on host-guest interactions [ J ]. Chemistry-A European Journal,2017,23,2628-2634 "discloses a tetrao-isopropoxy substituted azobenzene with photoresponse and forms a supramolecular complex with γ -cyclodextrin, which shows a bactericidal action sensitive to photoresponse. However, the dynamic nature of supramolecular interactions leads to uncertainty in the structure of supramolecular complexes, limiting their further application in biomedicine.
Document 3, "supervisory molecular Reversible On-Off Switch for Singlet oxy Using Cucurbit n ] uril addition Complexes [ J ]. Phys. Chem.C. 2017,121,39,21782-21789. However, the photosensitizer used in the material preparation is expensive, so that the application of the photosensitizer in the clinical aspect is limited.
Disclosure of Invention
Technical problem to be solved
In order to avoid the defects of the prior art, the invention provides an enoxacin-azobenzene antibacterial compound with photoresponse and a preparation method thereof.
Technical scheme
An enoxacin-azobenzene antibacterial compound with photoresponse, which is characterized by the structural formula:
a preparation method of the enoxacin-azobenzene antibacterial compound with photoresponse is characterized by comprising the following steps:
step 1: under ice bath conditions, 4- (phenylazo) benzoyl chloride and bis (2-azidoethyl) amine in a molar ratio of 1: 2.0-3.0 react with dichloromethane serving as a solvent at 20-30 ℃ for 5-10 min under stirring, 2,2-dimethylolpropionic acid in a molar ratio of 1: 2.5-3.5 is dissolved in dichloromethane and dropwise added into a reaction system, and the reaction system reacts at 20-30 ℃ for 24-28 h after the dropwise addition is finished; quenching the reaction by using a saturated sodium chloride solution, concentrating the filtrate by using an organic phase through rotary evaporation, and separating by using column chromatography to obtain a yellow liquid, namely azoxybenzene bis;
step 2: enoxacin, cesium carbonate and propargyl bromide in a molar ratio of 1: 2.0 to 4.0 are reacted with N, N-dimethylformamide as a solvent for 4 hours at room temperature with stirring; after the reaction is finished, quenching the reaction by adopting a saturated sodium bicarbonate solution, extracting by using a dichloromethane solution, concentrating the filtrate by using an organic phase through rotary evaporation, passing through a silica gel column, taking the filtrate, and evaporating the solvent by using a rotary evaporator to obtain a white solid, namely the alkynyl enoxacin;
and step 3: adding bis azide azobenzene, alkynyl enoxacin and pentamethyl diethylenetriamine into a Schlenk tube according to a mole ratio of 1: 3.0-4.0: 3.0-5.0, taking dry N, N-dimethylformamide as a solvent, and removing dissolved oxygen in the reaction tube by using a Schlenk technology after complete dissolution; then cuprous bromide with the molar weight of 5 percent of the diazide azobenzene is added under the protection of nitrogen, and the mixture is heated and stirred to react for 16 to 20 hours at the temperature of between 45 and 65 ℃; and after the reaction is finished, evaporating the solvent by rotary evaporation, dissolving the solvent in dichloromethane, concentrating the filtrate by rotary evaporation, and separating by column chromatography to obtain the enoxacin-azobenzene antibacterial drug with two enoxacin drugs at the tail end.
The heating of the reaction solution in the steps 1, 2 and 3 is carried out under the condition of a constant-temperature oil bath.
The extraction operation in the step 1, the step 2 and the step 3 refers to that the solution is fully mixed in a separating funnel, then the solution is kept stand for layering, the organic phase is collected, and the steps are repeated for three times.
The Schlenk technology in the step 3 refers to: after the reaction raw materials and the solvent were added to a dried Schlenk tube, liquid nitrogen freezing was performed first, vacuum-pumping was performed in a nitrogen atmosphere, nitrogen gas was introduced again, and then liquid nitrogen freezing was performed again, and thus the freezing-thawing-freezing operation was repeated 3 times.
Advantageous effects
The invention provides an enoxacin-azobenzene antibacterial compound with photoresponse and a preparation method thereof. The enoxacin-azobenzene combines enoxacin medicine with better killing effect on gram-negative bacteria and azobenzene with photostimulation responsiveness, and the combined product can play an antibacterial effect with photostimulation responsiveness. The method has simple preparation process, and provides a new idea and method for the research and development of novel photoresponse antibacterial drugs.
The invention has the beneficial effects that: the antibiotic raw medicine enoxacin reacts with azobenzene with photoresponse to generate a novel enoxacin-azobenzene drug molecule with two enoxacin at the tail end. Because the enoxacin medicine with better killing effect on gram-negative bacteria and the azobenzene component with photostimulation responsiveness are simultaneously added into the components, the obtained compound can have the antibacterial effect with photostimulation responsiveness. If the azobenzene component is changed, the compound does not have specific photostimulation responsiveness. The preparation method is simple, and the price of the used raw materials is low; meanwhile, the method provides ideas and methods for the construction of novel anti-photoresponse antibacterial drugs.
Drawings
FIG. 1 is a schematic diagram of the structure of enoxacin-azobenzene molecules prepared by the method of the present invention.
FIG. 2 is a mass spectrum of enoxacin-azobenzene molecule prepared by the method of the present invention
Detailed Description
The invention will now be further described with reference to the following examples and drawings:
the first embodiment is as follows:
in a 250ml dry one-necked flask, 2.5g of 4- (phenylazo) benzoyl chloride was added under ice-bath conditions, and after dissolving with 50ml of dichloromethane, 0.85g of bis (2-azidoethyl) amine was added thereto and stirred. Then 2.5g of 2,2-dimethylolpropionic acid is dissolved in dichloromethane and is dripped into the reaction system, and the reaction is carried out for 24 hours at room temperature after the dripping is finished; the reaction was quenched with saturated sodium chloride solution, the organic phase was concentrated by rotary evaporation and separated by column chromatography to give 2.2g of yellow bisazide azobenzene liquid.
To a dry 250ml single-necked flask, 1.1g of enoxacin, 8.5g of cesium carbonate and 2.5g of propargyl bromide were added, 70ml of N, N-dimethylformamide was added as a solvent, and the reaction was carried out for 4 hours with stirring at room temperature; after the reaction is finished, quenching the reaction by adopting a saturated sodium bicarbonate solution, extracting by using a dichloromethane solution, concentrating the filtrate by using an organic phase through rotary evaporation, passing through a silica gel column, taking the filtrate, and evaporating the solvent by using a rotary evaporator to obtain 1.2g of white alkynyl enoxacin solid.
Transferring the obtained 0.12g alkynyl enoxacin solid into a dry Schlenk bottle, adding 0.04g bisazidobenzene and 0.04g pentamethyldiethylenetriamine, measuring 50ml N, N-dimethylformamide as a solvent, dissolving the substances, freezing the substances by liquid nitrogen under the Schlenk technical condition, vacuumizing, introducing nitrogen gas into the system for about 30s, freezing the solution by liquid nitrogen again, and repeating the steps for three times. Adding 15mg of cuprous bromide under the protection of nitrogen, and heating and stirring at 50 ℃ to react for 24 hours. After the reaction is finished, the solvent is evaporated by rotation, then dichloromethane is used for dissolving, saturated sodium chloride solution is added, the organic phase after liquid separation is subjected to rotary evaporation to concentrate the liquid, the liquid passes through a silica gel column, filtrate is taken, and the solvent is evaporated by a rotary evaporator to obtain 1.2g of enoxacin-azobenzene product with two enoxacin at the tail end.
As can be seen from the nuclear magnetic spectrum of fig. 2, the enoxacin-azobenzene product prepared in this example is consistent with the designed expected product structure.
Example two:
under ice bath conditions, to 250ml dry single-neck flask adding 1.25g 4- (benzene azo) benzoyl chloride, adding 25ml dichloromethane dissolved, then adding 0.425g bis (2-azidoethyl) amine continuously stirring. Then 1.25g of 2,2-dimethylolpropionic acid is dissolved in dichloromethane and is dripped into a reaction system, and the reaction is carried out for 24 hours at room temperature after the dripping is finished; the reaction was quenched with saturated sodium chloride solution, the organic phase was concentrated by rotary evaporation and separated by column chromatography to give 1.08g of yellow bisazide azobenzene liquid.
To a dry 250ml single-necked flask, 0.55g of enoxacin, 4.25g of cesium carbonate and 1.25g of propargyl bromide were added, and 35ml of N, N-dimethylformamide as a solvent was added and reacted for 4 hours with stirring at room temperature; after the reaction is finished, quenching the reaction by adopting a saturated sodium bicarbonate solution, extracting by using a dichloromethane solution, concentrating the filtrate by using an organic phase through rotary evaporation, passing through a silica gel column, taking the filtrate, and evaporating the solvent by using a rotary evaporator to obtain 0.63g of white alkynyl enoxacin solid. .
Transferring 0.06g of the obtained alkynyl enoxacin solid into a dried Schlenk bottle, adding 0.02g of bisazidoazobenzene and 0.02g of pentamethyldiethylenetriamine, measuring 25ml of N, N-dimethylformamide as a solvent, dissolving the substances, freezing the substances by liquid nitrogen under the Schlenk technical condition, vacuumizing the system, introducing nitrogen into the system for about 30s, freezing the solution by liquid nitrogen again, and repeating the steps for three times. 7.5mg of cuprous bromide is added under the protection of nitrogen, and the mixture is heated and stirred to react for 24 hours at the temperature of 50 ℃. After the reaction is finished, the solvent is evaporated by rotation, then dichloromethane is used for dissolving, saturated sodium chloride solution is added, the organic phase is subjected to rotary evaporation after liquid separation to concentrate the liquid, the organic phase is subjected to silica gel column, filtrate is taken, and the solvent is evaporated by a rotary evaporator to obtain 0.61g of enoxacin-azobenzene product with two enoxacin at the tail end.
Example three:
in a 250ml dry one-necked flask, 5.0g of 4- (phenylazo) benzoyl chloride was added under ice-bath conditions, and dissolved in 100ml of methylene chloride, followed by addition of 1.7g of bis (2-azidoethyl) amine and continuous stirring. Then 5.0g of 2,2-dimethylolpropionic acid is dissolved in dichloromethane and is dripped into the reaction system, and the reaction is carried out for 24 hours at room temperature after the dripping is finished; the reaction was quenched with saturated sodium chloride solution, the organic phase was concentrated by rotary evaporation and separated by column chromatography to give 4.1g of yellow bisazide azobenzene liquid.
Adding 2.2g of enoxacin, 17g of cesium carbonate and 5g of propargyl bromide into a dry 250ml single-neck flask, adding 140ml of N, N-dimethylformamide as a solvent, and reacting for 4 hours at room temperature under stirring; after the reaction is finished, quenching the reaction by adopting a saturated sodium bicarbonate solution, extracting by using a dichloromethane solution, concentrating the filtrate by using an organic phase through rotary evaporation, passing through a silica gel column, taking the filtrate, and evaporating the solvent by using a rotary evaporator to obtain 2.2g of white alkynyl enoxacin solid.
Transferring the obtained 0.24g alkynyl enoxacin solid into a dried Schlenk bottle, adding 0.08g bisazidobenzene and 0.08g pentamethyldiethylenetriamine, measuring 100ml N, N-dimethylformamide as a solvent, dissolving the substances, freezing the substances by liquid nitrogen under the Schlenk technical condition, vacuumizing, introducing nitrogen into the system for about 30s, freezing the solution by liquid nitrogen again, and repeating the steps for three times. Adding 30mg of cuprous bromide under the protection of nitrogen, and heating and stirring at 50 ℃ to react for 24 hours. After the reaction is finished, the solvent is evaporated by rotation, then dichloromethane is used for dissolving, saturated sodium chloride solution is added, after liquid separation, the organic phase is concentrated by rotation evaporation, the liquid passes through a silica gel column, filtrate is taken, and the solvent is evaporated by a rotation evaporator to obtain 2.6g of enoxacin-azobenzene product with two enoxacin at the tail end.
Claims (5)
1. An enoxacin-azobenzene antibacterial compound with light response is characterized in that the structural formula is as follows:
2. a method for preparing the enoxacin-azobenzene antibacterial compound having a photoresponse according to claim 1, characterized by the following steps:
step 1: under ice bath conditions, 4- (phenylazo) benzoyl chloride and bis (2-azidoethyl) amine in a molar ratio of 1: 2.0-3.0 react with dichloromethane serving as a solvent at 20-30 ℃ for 5-10 min under stirring, 2,2-dimethylolpropionic acid in a molar ratio of 1: 2.5-3.5 is dissolved in dichloromethane and dropwise added into a reaction system, and the reaction system reacts at 20-30 ℃ for 24-28 h after the dropwise addition is finished; quenching the reaction by using a saturated sodium chloride solution, concentrating the filtrate by using an organic phase through rotary evaporation, and separating by using column chromatography to obtain a yellow liquid, namely azoxybenzene bis;
and 2, step: enoxacin, cesium carbonate and propargyl bromide in a molar ratio of 1: 2.0 to 4.0 are reacted with N, N-dimethylformamide as a solvent for 4 hours at room temperature with stirring; after the reaction is finished, quenching the reaction by adopting a saturated sodium bicarbonate solution, extracting by using a dichloromethane solution, concentrating the filtrate by using an organic phase through rotary evaporation, passing through a silica gel column, taking the filtrate, and evaporating the solvent by using a rotary evaporator to obtain a white solid, namely the alkynyl enoxacin;
and step 3: adding bis azide azobenzene, alkynyl enoxacin and pentamethyl diethylenetriamine into a Schlenk tube according to a mole ratio of 1: 3.0-4.0: 3.0, taking dry N, N-dimethylformamide as a solvent, and removing dissolved oxygen in the reaction tube by using a Schlenk technology after complete dissolution; then cuprous bromide with the molar weight of 5 percent of the diazide azobenzene is added under the protection of nitrogen, and the mixture is heated and stirred to react for 16 to 20 hours at the temperature of between 45 and 65 ℃; and after the reaction is finished, evaporating the solvent by rotary evaporation, dissolving the solvent in dichloromethane, concentrating the filtrate by rotary evaporation, and separating by column chromatography to obtain the enoxacin-azobenzene antibacterial drug with two enoxacin drugs at the tail end.
3. The method of claim 2, wherein: the heating of the reaction solution in the steps 1, 2 and 3 is carried out under the condition of a constant-temperature oil bath.
4. The method of claim 2, wherein: the extraction operation in the step 1, the step 2 and the step 3 refers to that the solution is fully mixed in a separating funnel, then the solution is kept stand for layering, the organic phase is collected, and the steps are repeated for three times.
5. The method of claim 2, wherein: the Schlenk technology in the step 3 refers to: after the reaction raw materials and the solvent were added to a dried Schlenk tube, liquid nitrogen freezing was first performed, vacuum pumping was performed in a nitrogen atmosphere, nitrogen gas was then introduced, and then liquid nitrogen freezing was performed again, and thus the freezing-thawing-freezing operation was repeated 3 times.
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| JP2005314261A (en) * | 2004-04-28 | 2005-11-10 | National Institute Of Advanced Industrial & Technology | Azobenzene compound and gelatinizer comprising the same and method for producing the gelatinizer |
| AU2012211514A1 (en) * | 2006-10-24 | 2012-09-27 | Aradigm Corporation | Concentrated, inhalable ciprofloxacin formulation |
| CN109820854A (en) * | 2019-03-27 | 2019-05-31 | 中国科学院化学研究所 | A kind of supermolecule photoresponse drug and preparation method thereof and regulation method |
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| JP2005314261A (en) * | 2004-04-28 | 2005-11-10 | National Institute Of Advanced Industrial & Technology | Azobenzene compound and gelatinizer comprising the same and method for producing the gelatinizer |
| AU2012211514A1 (en) * | 2006-10-24 | 2012-09-27 | Aradigm Corporation | Concentrated, inhalable ciprofloxacin formulation |
| CN109820854A (en) * | 2019-03-27 | 2019-05-31 | 中国科学院化学研究所 | A kind of supermolecule photoresponse drug and preparation method thereof and regulation method |
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| CHENGFEI LIU，ET AL.: "Light controlled drug-based supramolecular polymer self-assemblies for efficient antibacterial manipulation", 《SUPRAMOLECULAR MATERIALS》, vol. 1, 23 April 2022 (2022-04-23), pages 100014 * |
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