CN106467487B - A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer and preparation method thereof and the application in the sterilizing of light power - Google Patents

A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer and preparation method thereof and the application in the sterilizing of light power Download PDF

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CN106467487B
CN106467487B CN201510510732.XA CN201510510732A CN106467487B CN 106467487 B CN106467487 B CN 106467487B CN 201510510732 A CN201510510732 A CN 201510510732A CN 106467487 B CN106467487 B CN 106467487B
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photosensitizer
soluble cationic
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CN106467487A (en
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吴飞鹏
方艳艳
赵榆霞
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Technical Institute of Physics and Chemistry of CAS
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Abstract

The present invention discloses a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer and its synthetic method and the application in the sterilizing of light power.Photosensitizer molecule structure of the invention is simple, matches with determining chemical structure, and with suitable rouge moisture, has the characteristics that rouge water amphiphilic, while reaction condition of its synthesis is mild, easily prepared and purifying is easy to operate.The photosensitizer of the invention biology photodynamic activity with higher in 350~600nm wave-length coverage, it is capable of the light power inactivation of pathogenic microorganism of selectivity and avoids damage to host cell and tissue as far as possible, with broad spectrum antibacterial, there is application prospect well in terms of light power sterilizing.

Description

A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer and preparation method thereof with Application in the sterilizing of light power
Technical field
The present invention relates to field of photodynamic.More particularly, to a kind of water-soluble cationic benzal cycloalkane ketone The preparation method of photosensitizer and its application in the sterilizing of light power.
Background technique
The discovery of antibiotic once made the mankind once think that the epoch of microorganism infection will be taken leave of.But with antibiotic Commonly used and continuous upgrading, clinical bacteria infection is not fully controlled, in contrast, many pathogenic bacteria or condition For pathogenic bacteria under the pressure of living environment, the multi-drug resistant bacteria of antibiotic killing resistance mechanism is effectively resisted in variation at possessing. High mortality caused by the microbial infection of multidrug resistant and high payment for medical care make the work of anti-microbial infection be faced with sternness Test.2010, British Medical Journal《Lancet》Carrying " New Delhi metalloproteinases -1 (NDM-1) " gene of announcement " superbacteria " can almost be resistant to all antibiotic, but clinically common anti-infectives and method are to such at present The curative effect of infection is extremely limited.Therefore, once occurring having the general drug-fast bacteria infection of regional infection ability, consequence will be very tight Weight.
Optical dynamic therapy (photodynamic therapy, PDT) be it is a kind of can be under the action of light using photosensitizer The active material for eliminating sick cell or bacterium is generated, to reach the treatment means of therapeutic purposes.
For photodynamic therapy anti-microbial infection among research, in vitro study, which is proved the method, can effectively antagonize micro- life Object (including drug-fast bacteria), and natural and artificial synthesized photosensitizer can be used.In the recent period, Demidova and Hamblin et al. exist “Photodynamic inactivation of Bacillus spores mediated by phenothiazinium It is also demonstrated in the article of dyes ", Appl Environ Microbiol, 2005, vol.71, pp6918-6925, in phenthazine It, can using red light irradiation bacterial spore (having drug resistance to most of antibacterial agents) cultivating system under temperate condition existing for class dyestuff Inactivate bacillus.Jori G. et al. is in " Photodynamic therapy in the treatment of microbial infections:basic principles and perspective applications”,Lasers in It is pointed out under physiological ph in the article of Surgery and Medicine, 2006, vol.38, pp468-481, cationic light Quick dose of such as phenothiazine derivative, phthalocyanine derivates, derivatives of porphyrin can effectively cause Gram-negative and Gram-positive thin The inactivation of bacterium, in addition it also has good smooth power curative effect to saccharomycete, fungi, mycoplasma and pathogenic protozoon.Resist with traditional Raw extract for treating is compared, and the sterilizing of light power has following main advantage:(1), extensive antimicrobial spectrum, to bacterium, fungi, virus, original Worm etc. is effectively, equally effective to multiple antibiotic resistant strain；(2), it is capable of the killing pathogenic microorganism of selectivity, without damaging host Tissue；(3), the drug resistance of bacterial strain is not will lead to；(4), the toxic side effect of photosensitizer is small, small to the damage of hepatic and renal function.
Realizing that PDT is preferably minimized the damage of host cell and tissue by effective inactivation of pathogenic microorganism simultaneously is that light moves The desired result of power inactivation of pathogenic microorganism.Friedberg et al. is in " Antibody-Targeted Photolysis: Bacteriocidal Effects of Sn(IV)Chlorin e6-Dextran-Monoclonal Antibody Conjugates”,Annals of the New York Academy of Sciences,1991,vol.66,pp383-393 Article in propose on antibacterial agent connection targeting thallus chemical molecular method, achieve preferable effect.But this Class method can be such that the broad spectrum activity of antibacterial agent significantly reduces.Therefore, realize that the more dominant strategy of PDT selectivity still needs to explore.Early period grinds Studying carefully the ingredient for showing the cell membrane of mammalian cell membrane and microorganism and structure, there are significant differences, wherein microbial cell Film outer layer is in elecrtonegativity, and the intimate electroneutral of mammalian cell membrane outer layer.Based on the above feature, design is synthesized in physiological pH The lower electropositive photosensitizer (cationic photosensitizer) of presentation of value is most important for the selectivity for realizing the inactivation of light power.In addition, Cationic photosensitizer, can also be by upsetting and interrupting microorganism other than it can utilize reactive oxygen species inactivation of pathogenic microorganism Orderly membrane structure plays antibacterial effect.Due to the special antibacterial mechanisms of cationic photosensitizer, it is considered to have Broad-spectrum antibacterial property.
Clinical optical dynamic therapy photosensitizer such as hematoporphyrin derivative HpD, photofrin existing at present, Verteporfin etc., it is unclear to there is different degrees of active princlple in these photosensitizers, and the intracorporal Absorption And Metabolism mechanism of biology is not It is clear, it is metabolized the problems such as poor.And it is used for the photosensitizer phenothiazines dyestuff methylenum careuleum (methylene in clinical practice stage Blue, MB), dimer is easily formed in bacterium surface, has seriously affected the efficiency of light power inactivation.
Based on problem above, needs to design, synthesizes that some chemical structures are clear, dissolubility is good and has to pathogenic microorganism The novel photosensitive agent of effective lethal effect.
Summary of the invention
It is an object of the present invention to provide a kind of water-soluble cationic benzal cycloalkane ketone photosensitizers.Such is photosensitive Agent has determining chemical structure and molecular structure is simple, and solubility is good in water, and there is suitable rouge moisture to match, and There is stronger absorption in 350~600nm wave-length coverage, can quickly generate reactive oxygen species under light source irradiation, it is dynamic to can be used for light Power sterilizing.
Second object of the present invention is to provide a kind of preparation of water-soluble cationic benzal cycloalkane ketone photosensitizer Method.Providing one kind can water-soluble cationic benzal of the light power selective inactivation pathogenic microorganism without damaging host cell The mentality of designing of cycloalkane ketone photosensitizer.This method is easy to operate, reaction condition is mild, purification process is easy, product purity The characteristics of can reach drug requirement.
Third object of the present invention is to provide a kind of purposes of water-soluble cationic benzal cycloalkane ketone photosensitizer.
In order to achieve the above first purpose, the present invention adopts the following technical solutions：
A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, which is characterized in that including with following general formula C1, C2 Or the compound of C3 structure：
Wherein：
R2, R3And R4It is identical or different, R2、R3And R4Selected from methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl or-(CH2)n-R1X；Preferably, R2, R3And R4Selected from methyl, ethyl or-(CH2)n-R1X；
R5And R6It is identical or different, R5And R6Selected from N or P；Preferably, R5And R6For N；
X is anion Cl-、Br-Or I-；
N=1,2,3 or 4；Preferably, n is 1 or 2；
N1 and n2=0,1,2,3 or 4；Preferably, n1 and n2 is 0,1 or 2；
R1For quaternary ammonium salt cationic；Preferably, R1It is selected from
A is selected from N or P；Preferably, A N；
A1, A2And A3It is identical or different, A1、A2And A3Selected from methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl or phenyl；Preferably, A1, A2And A3Selected from methyl, ethyl or phenyl；
Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
To reach above-mentioned second purpose, a kind of preparation of water-soluble cationic benzal cycloalkane ketone photosensitizer of the present invention Method, the compound with general formula C1 structure includes following synthesis step：
1) after phosphorus pentachloride being reacted with dimethylformamide, then with general formula Q1 compound
Reaction, collection obtain general formula Q2 intermediate product
It 2), will under the conditions of the basic catalyst of ethanol-dichloromethane solutionIt is anti-with gained general formula Q2 intermediate product It answers, collection obtains general formula Q3 intermediate product,
3) under the conditions of the basic catalyst of ethanol-dichloromethane solution, by gained general formula Q3 intermediate product and general formula Q4 Compound
Reaction；
Alternatively, under the conditions of the basic catalyst of ethanol-dichloromethane solution, it willIt is anti-with gained general formula Q2 compound It answers；
Collect obtained general formula Q5 intermediate product
4) under the conditions of solvent is dimethylformamide (DMF), by gained general formula Q5 intermediate product and tertiary amine or azacyclo- Compound reaction, collection obtain the compound of general formula C1 structure；
Wherein：
N3 and n4 are identical or different, n3, n4=1,2,3 or 4；Preferably, n3, n4 are 1 or 2；
N5 and n6 are identical or different, n5, n6=1,2,3 or 4；Preferably, n5 and n6 is 1 or 2；
B1And B2It is identical or different, B1And B2Selected from-H ,-OH ,-Cl ,-Br or-I；
B3Selected from N or P；Preferably, B3For N；
B4、B5Selected from-H ,-Cl ,-Br or-I；B4、B5It is identical or different, but at least one is selected from-Cl ,-Br or-I；
B6Selected from N or P；Preferably, B6For N；
B7And B8Selected from-H ,-Cl ,-Br or-I；B7And B8It is identical or different, but at least one is selected from-Cl ,-Br or-I；
Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
Preferably, with general formula C1 structure compound synthesis step 2), 3) described in basic catalyst be hydroxide The group of one or more of lithium, sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum, Anhydrous potassium carbonate, pyridine or hexahydropyridine It closes.
To reach above-mentioned second purpose, a kind of preparation of water-soluble cationic benzal cycloalkane ketone photosensitizer of the present invention Method, the compound with general formula C2 structure includes following synthesis step：
1) after phosphorus pentachloride being reacted with dimethylformamide, then with general formula S1 compound
Reaction, collection obtain general formula S2 intermediate product
It 2), will under the conditions of the basic catalyst of ethanol-dichloromethane solutionIt is anti-with gained general formula S2 intermediate product It answers, collection obtains general formula S3 intermediate product
3) under the conditions of the basic catalyst of ethanol-dichloromethane solution, by gained general formula S3 intermediate product and general formula Q2 Compound
Reaction；
Alternatively, under the conditions of the basic catalyst of ethanol-dichloromethane solution, by gained general formula S2 compound and general formula Q3 Compound
Reaction, the general formula S4 intermediate product collected
4) under the conditions of solvent is dimethylformamide (DMF), by gained general formula S4 intermediate product and tertiary amine or azacyclo- Compound reaction, collection obtain the compound of general formula C2 structure；
Wherein：
N1=0,1,2,3 or 4；Preferably, 0,1 or 2 n1；
N3 and n4 are identical or different, n3, n4=1,2,3 or 4；Preferably, n3, n4 are 1 or 2；
D1Selected from-H ,-OH ,-Cl ,-Br or-I；
D2Selected from-H ,-Cl ,-Br or-I；
B3Selected from N or P；Preferably, B3For N；
B4、B5Selected from-H ,-Cl ,-Br or-I；B4、B5It is identical or different, but at least one is selected from-Cl ,-Br or-I；
Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
Preferably, with general formula C2 structure compound synthesis step 2), 3) described in basic catalyst be hydroxide The group of one or more of lithium, sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum, Anhydrous potassium carbonate, pyridine or hexahydropyridine It closes.
To reach above-mentioned second purpose, a kind of preparation of water-soluble cationic benzal cycloalkane ketone photosensitizer of the present invention Method, the compound with general formula C3 structure includes following synthesis step：
1) by general formula S3 compound
With general formula S5 compound
It is reacted under the conditions of the basic catalyst of ethanol-dichloromethane solution；
Alternatively, by general formula S2
With general formulaIt is reacted under the conditions of the basic catalyst of ethanol-dichloromethane solution；
Collection obtains general formula T1 intermediate product
2) under the conditions of solvent is dimethylformamide (DMF), by gained general formula T1 intermediate product and tertiary amine or azacyclo- Compound reaction, collection obtain the compound of general formula C3 structure；
Wherein：
N1=0,1,2,3 or 4；Preferably, 0,1 or 2 n1；
N2=0,1,2,3 or 4；Preferably, 0,1 or 2 n2；
D2Selected from-H ,-Cl ,-Br or-I；
D3Selected from-H ,-Cl ,-Br or-I；D3And D2It is identical or different, but at least one is selected from-Cl ,-Br or-I；
Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
Preferably, with general formula C3 structure compound synthesis step 1) described in basic catalyst be lithium hydroxide, The combination of one or more of sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum, Anhydrous potassium carbonate, pyridine or hexahydropyridine.
To reach above-mentioned third purpose, water-soluble cationic benzal cycloalkane ketone photosensitizer of the invention is applied in light Power inactivation of bacterial, fungi and virus.
Preferably, the bacterium includes the gram-positive bacteria and Gram-negative bacteria classified according to Gram's staining；More Preferably, the gram-positive bacteria includes staphylococcus aureus, streptococcus, Diplococcus pneumopniae, bacillus anthracis, corynebacterium diphtheriae Or clostridium tetani；The Gram-negative bacteria includes Escherichia coli, shigella dysenteriae, typhoid bacillus, proteus or pertussis Bacillus.
Preferably, the fungi include mould, saccharomycete, Candida albicans, beer mother bacterium, monascin, Candida, Aspergillus flavus, geotrichum candidum or antibiotic bacteria.
Preferably, the virus includes bacterial virus, the plant virus, animal virus according to host types classification；It is preferred that Ground, the bacterial virus include bacteriophage；Preferably, the plant virus includes tobacco mosaic virus (TMV)；Preferably, the animal Virus includes HIV, variola virus, hepatitis A virus, hepatitis type B virus or rubella virus.
Water-soluble cationic benzal cycloalkane ketone photosensitizer of the invention is applied in light power inactivation of bacterial, fungi and disease Poison mechanism be cationic antimicrobial mechanism, special electrostatic interaction between cationic photosensitizer and thallus, thus interrupt and Upsetting bacterium membrane structure is the pith in its antibacterial mechanisms.
Beneficial effects of the present invention are as follows：
1. water-soluble cationic benzal cycloalkane ketone photosensitizer structure in the present invention is simple, molecular weight is small, have true Fixed chemical structure, easily prepared, purifying and further modification, meets the basic demand of clinical application.
2. the water-soluble cationic benzal cycloalkane ketone photosensitizer in the present invention has the characteristics that rouge water parents, rouge water Distribution ratio can satisfy the requirement of clinical optical dynamic therapy.
3. the synthetic method of the water-soluble cationic benzal cycloalkane ketone photosensitizer in the present invention has easy to operate, production High, the with high purity feature of product yield, can high-volume synthesize.
4. the water-soluble cationic benzal cycloalkane ketone photosensitizer in the present invention has in 350~600nm wave-length coverage Higher biology photodynamic activity has good application prospect as photo-dynamical medicine inactivation of pathogenic microorganism aspect.
5. the water-soluble cationic benzal cycloalkane ketone photosensitizer in the present invention can be realized bacterium, fungi and virus Effective light inactivation, has broad spectrum antibacterial, supplemented with the very big blank in benzal cycloalkane ketone antibacterial field.
6. the micro- life of inactivation cause of disease that the water-soluble cationic benzal cycloalkane ketone photosensitizer in the present invention is capable of selectivity Object and reduce the damage to host cell as far as possible, this effect is strong to be demonstrated such cationic photosensitizer and is applied to Clinical the bright outlook.
Detailed description of the invention
Specific embodiments of the present invention will be described in further detail with reference to the accompanying drawing.
It is slow in dimethylformamide (DMF) and phosphate buffered saline solution (PBS) that Fig. 1 shows photosensitizer C1-1 in embodiment 1 Absorption spectrum in fliud flushing.
Fig. 2 shows in the presence of photosensitizer C1-1 in embodiment 1,1,3- dimethyl isobenzofuran (DPBF) is in DMF The down ratio of absorbance at any time.
Fig. 3 shows absorption spectrum of the photosensitizer C1-2 in DMF and PBS buffer solution in embodiment 7.
Fig. 4 is shown in embodiment 7 in the presence of photosensitizer C1-2, the down ratio of absorbance of the DPBF in DMF at any time.
Fig. 5 shows absorption spectrum of the photosensitizer C1-3 in DMF and PBS buffer solution in embodiment 12.
Fig. 6 is shown in embodiment 12 in the presence of photosensitizer C1-3, the suppression ratio of absorbance of the DPBF in DMF at any time Example.
Fig. 7 shows the bacterium plate photosensitizer concentration schematic diagram of light power inactivation staphylococcus aureus, Escherichia coli.
Fig. 8 shows the experimental result of embodiment 40：Photosensitizer obtained inactivates golden yellow Portugal for light power in embodiment 2 The experiment of grape coccus.
Fig. 9 shows the experimental result of embodiment 41：Photosensitizer obtained is used for light power colibacillus deactivating in embodiment 2 Experiment.
Figure 10 shows the experimental result of embodiment 42：Photosensitizer obtained is read for light power inactivation white in embodiment 2 The experiment of pearl bacterium.
Figure 11 shows the experimental result of embodiment 43：Photosensitizer obtained is golden yellow for the inactivation of light power in embodiment 8 Staphylococcic experiment.
Figure 12 shows the experimental result of embodiment 44：Photosensitizer obtained inactivates large intestine bar for light power in embodiment 8 The experiment of bacterium.
Figure 13 shows the experimental result of embodiment 45：Photosensitizer obtained inactivates white beads for light power in embodiment 8 The experiment of bacterium.
Figure 14 shows the experimental result of embodiment 46：In embodiment 13 photosensitizer obtained for observe cellular uptake sun from The experiment of sub- photosensitizer.
Specific embodiment
In order to illustrate more clearly of the present invention, the present invention is done further below with reference to preferred embodiments and drawings It is bright.Similar component is indicated in attached drawing with identical appended drawing reference.It will be appreciated by those skilled in the art that institute is specific below The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
Embodiment 1
A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, synthetic method are as follows：
(I) preparation of midbody compound Q2-1：
52.06 grams of (0.25mol) phosphorus pentachlorides are slowly added in the DMF of the 150mL cooling to ice bath, continues ice bath 30 and divides Zhong Hou, then be stirred at room temperature 15 minutes.It is slowly added to 20 grams of N- ethyl-N hydroxyethyl aniline (0.12mol) into above-mentioned system, controls After the stirring 12 hours of 45 DEG C of temperature, restore to room temperature and with sodium bicarbonate solution neutralization reaction liquid.Reaction solution is extracted with dichloromethane Three times, it is dry that anhydrous magnesium sulfate is added after dichloromethane extract is washed with water to neutrality, filtered, rotate removing methylene chloride, Obtain 24.9 grams of corresponding intermediate product Q2-1 (yield 98%).
(II) preparation of midbody compound Q3-1：
10.58 grams of (0.05mol) Q2-1,3.52 grams of (0.05mol) ring fourths are added into 100 milliliters of three-necked flasks Ketone, 40 milliliters of methylene chloride and 20 milliliters of ethyl alcohol are added at one time 0.03 gram of sodium hydroxide after stirring to dissolve uniformly, and 20 DEG C Lower reaction 10 hours, reaction solution remove solvent through revolving and obtain crude product, obtain 5.9 grams (yields 44%) with chromatographic column separating-purifying Orange solids Q3-1.
(III) preparation of midbody compound Q5-1：
2.4 grams of (0.01mol) Q3-1 are added into 100 milliliters of three-necked flasks, 1.8 grams (0.01mol) commercially available 4- (N, N- lignocaine) benzaldehyde, 40 milliliters of methylene chloride and 10 milliliters of ethyl alcohol are disposable after stirring to dissolve uniformly 0.06 gram of sodium hydroxide is added, stirs 12 hours at room temperature, removes solvent through revolving and obtains crude product, with chromatographic column separating-purifying Obtain 1.5 grams of Q5-1 solid (yield 35%).
(IV) preparation of target product C1-1：
0.23 gram of (0.5mmol) Q5-1 of addition into 100 milliliters of three-necked flasks, 1.96 grams of pyridines, 10 milliliters of DMF, It is reacted 12 hours for 100 DEG C of heating after stirring to dissolve uniformly.After reaction system is cooled to room temperature, obtained using re crystallization from toluene To 80 milligrams of C1-1 solid (yield 30%).HR-MS(ESI):[M]+:Calcd for[C31H36N3O]+466.2852；found 466.2861。
(V) (referred to as with the phosphate buffer of pH value 7.4：PBS buffer solution) target photosensitizer C1-1 is detected in aqueous systems In solubility, 25 DEG C of its solubility are greater than 4mg/mL；Target photosensitizer C1-1 is dissolved in DMF and PBS buffer solution respectively, is surveyed Try its absorption spectrum, it was demonstrated that photosensitizer C1-1 has compared with strong absworption peak in 350~600nm wave-length coverage, sees Fig. 1.
(VI) above-mentioned target photosensitizer C1-1 is dissolved in DMF, makes it in the absorbance 0.1 of 473nm, with Phthalocyanine Zinc (singlet oxygen quantum yield ΦΔ=0.56) it is reference, is the capturing agent of active oxygen using DPBF, under conditions of the saturation of the air The measurement of active oxygen quantum yield is completed, as a result as shown in Figure 2.Illustrate that photosensitizer C1-1 is produced under 473nm laser excitation condition Reactive oxygen species are given birth to.
Embodiment 2
Embodiment 1 is repeated, difference is,For cyclooctanone, catalyst is natrium carbonicum calcinatum, with (2,2- bipyridyl) replaces pyridine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal cycloalkanes Hydrocarbon ketone photosensitizer, yield 34%.
Embodiment 3
Embodiment 1 is repeated, difference is,For cycloheptanone, catalyst is Anhydrous potassium carbonate, with (2- benzyl pyridine) replaces pyridine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal cycloalkanes Hydrocarbon ketone photosensitizer, yield 45%.
Embodiment 4
Embodiment 1 is repeated, difference is,For cyclohexanone, catalyst is potassium hydroxide, with (dipyridyl ethane) replaces pyridine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal basic ring Alkane ketone photosensitizer, yield 24%.
Embodiment 5
Embodiment 1 is repeated, difference is, with(7,8- benzoquinoline) replaces pyridine former as reaction Material, other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer, yield 55%.
Embodiment 6
Embodiment 1 is repeated, difference is, with(4,7- phenanthroline) replaces pyridine former as reaction Material, other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer, yield 33%.
Embodiment 7
A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, synthetic method are as follows：
(I) preparation of midbody compound Q2-2：
Referring to the operation of (I) in embodiment 1, with mole 1：3 N, N- dihydroxy ethyl aniline and vilsmeier reagent are anti- It answers, obtains intermediate product Q2-2 (yield 97%).
(II) preparation of midbody compound Q3-2：
It is 1 with mole referring to the operation of (II) in embodiment 1：1 Q2-2 is reacted with cyclobutanone, and catalyst is hydrogen-oxygen Change potassium, obtains intermediate product Q3-2 (yield：39%).
(III) preparation of midbody compound Q5-2：
Referring to the operation of (III) in embodiment 1, with mole 1:1 Q3-2 and 4- (N, N- lignocaine) benzaldehyde is anti- It answers, catalyst is potassium hydroxide, obtains intermediate product Q5-2 (yield 62%).
(IV) preparation of target product C1-2：
It is 1 with mass ratio referring to the operation of (IV) in embodiment 1：10 Q5-2 is reacted with pyridine, obtains target photosensitizer C1-2 (yield：90%).HR-MS(ESI):[M]+:Calcd for[C36H40ClN4O]+579.2885；found 579.2889.
(IV) referring to the operation of (V) in embodiment 1, it was demonstrated that C1-2 solubility is greater than 5mg/mL；And in 350~600nm wave Long range has compared with strong absworption peak, sees Fig. 3.
(V) referring to the operation of embodiment 1 (VI), as a result it has been also demonstrated that target photosensitizer C1-2 in 473nm laser irradiation Under can generate reactive oxygen species, see Fig. 4.
Embodiment 8
Embodiment 7 is repeated, difference is,For cyclohexanone, catalyst is natrium carbonicum calcinatum, with (quinoline) replaces pyridine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone light Quick dose, yield 88%.
Embodiment 9
Embodiment 7 is repeated, difference is,For cycloheptanone, catalyst is natrium carbonicum calcinatum, with (diphenyl -2- phridyl methane) replaces pyridine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 77%.
Embodiment 10
Embodiment 7 is repeated, difference is, with(2,2- diquinoline) replaces pyridine conduct Reaction raw materials, other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer, yield 47%.
Embodiment 11
Embodiment 7 is repeated, difference is, replaces pyridine as reaction raw materials using triethylamine, other conditions are constant.It obtains Product water-soluble cationic benzal cycloalkane ketone photosensitizer, yield 87%.
Embodiment 12
A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, synthetic method are as follows：
(I) preparation of intermediate product Q5-3：
It is 1 with mole referring to the operation of (III) in embodiment 1：2 cyclobutanone is reacted with Q2-1, and catalyst is pyrrole Pyridine obtains intermediate product Q5-3 (yield：85%).
(II) preparation of target product C1-3：
It is 1 with mass ratio referring to the operation of (IV) in embodiment 1：10 Q5-3 is reacted with pyridine, obtains target photosensitizer C1-3 (yield：50%).HR-MS(ESI):[M]+:Calcd for[C36H40ClN4O]+579.2885；found 579.2886.
(III) referring to the operation of (V) in embodiment 1, it was demonstrated that C1-3 solubility is greater than 5mg/mL；And in 350~600nm wave Long range has compared with strong absworption peak, sees Fig. 5.
(IV) referring to the operation of embodiment 1 (VI), as a result it has been also demonstrated that target photosensitizer C1-3 in 473nm laser irradiation Under can generate reactive oxygen species, see Fig. 6.
Embodiment 13
Embodiment 12 is repeated, difference is,For cycloheptanone, catalyst is Anhydrous potassium carbonate, with (2- pyridyl group Benzophenone) replaces pyridine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 44%.
Embodiment 14
Embodiment 12 is repeated, difference is,For cyclooctanone, catalyst is hexahydropyridine, with (acridine) replaces pyridine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone light Quick dose, yield 29%.
Embodiment 15
A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, synthetic method are as follows：
(I) preparation of midbody compound S2-1：
Referring to the operation of (I) in embodiment 1, with mole 1：2 commercially available chlorobenzene and vilsmeier reagent is anti- It answers, obtains intermediate product S2-1 (yield 96%).
(II) preparation of midbody compound Q2-3：
Referring to the operation of (I) in embodiment 1, with mole 1：3 commercially available N, N- bis- (2- bromoethyl) aniline and The reaction of vilsmeier reagent, obtains intermediate product Q2-3 (yield 98%).
(III) preparation of midbody compound S3-1：
It is 1 with mole referring to the operation of (II) in embodiment 1：1 S2-1 and hexamethylene reactive ketone, catalyst is hydrogen-oxygen Change sodium, obtains intermediate product S3-1 (yield：50%).
(IV) preparation of midbody compound S4-1：
Referring to the operation of (III) in embodiment 1, with mole 1:1 S3-1 and Q2-3 reaction, catalyst is hydroxide Sodium obtains intermediate product S4-1 (yield 88%).
(V) preparation of target product C2-1：
It is 1 with mass ratio referring to the operation of (IV) in embodiment 1：30 S4-1 is reacted with commercially available triethylamine, is obtained To target photosensitizer C2-1 (yield：50%).HR-MS(ESI):[M]+:Calcd for[C42H69Br2N4O]+803.3833； found 803.3847。
Embodiment 16
Embodiment 15 is repeated, difference is,For cyclopentanone, catalyst is potassium hydroxide, with (2- benzyl pyridine) replaces triethylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal basic ring Alkane ketone photosensitizer, yield 45%.
Embodiment 17
Embodiment 15 is repeated, difference is, with(pyridine) replaces triethylamine as reaction raw materials, other conditions It is constant.Obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer, yield 78%.
Embodiment 18
Embodiment 15 is repeated, difference is, with(2,2- bipyridyl) replaces triethylamine as reaction Raw material, other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer, yield 38%.
Embodiment 19
Embodiment 15 is repeated, difference is,For cycloheptanone, catalyst is natrium carbonicum calcinatum, with (quinoline) replaces triethylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone Photosensitizer, yield 65%.
Embodiment 20
Embodiment 15 is repeated, difference is,For cyclobutanone, catalyst is natrium carbonicum calcinatum, with (2- pyridyl group Benzophenone) replaces triethylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 67%.
Embodiment 21
A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, synthetic method are as follows：
(I) preparation of midbody compound Q2-4：
Referring to the operation of (I) in embodiment 1, with mole 1：2 commercially available N- (2- bromoethyl)-methylphenylamine It is reacted with vilsmeier reagent, obtains intermediate product Q2-4 (yield 98%).
(II) preparation of midbody compound S2-2：
Referring to the operation of (I) in embodiment 1, with mole 1：2 commercially available 2- (chloroethyl) benzene and vilsmeier Reagent reaction, obtains intermediate product S2-2 (yield 98%).
(III) preparation of midbody compound S3-2：
It is 1 with mole referring to the operation of (II) in embodiment 1：1 Q2-4 and hexamethylene reactive ketone, catalyst is hexahydro Pyridine obtains intermediate product S3-2 (yield：45%).
(IV) preparation of midbody compound S4-2：
Referring to the operation of (III) in embodiment 1, with mole 1:1 S2-2 and S3-2 reaction, catalyst are hexahydro pyrrole Pyridine obtains intermediate product S4-2 (yield 60%).
(V) preparation of target product C2-2：
It is 1 with mass ratio referring to the operation of (IV) in embodiment 1：40 S4-2 is reacted with commercially available triphenylamine, is obtained To target photosensitizer C2-2 (yield：50%).HR-MS(ESI):[M]+:Calcd for[C61H57BrN3O]+926.3680； found 926.3677。
Embodiment 22
Embodiment 21 is repeated, difference is,For cyclobutanone, catalyst is potassium hydroxide, with (dipyridyl ethane) replaces triphenylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 35%.
Embodiment 23
Embodiment 21 is repeated, difference is,For cyclopentanone, catalyst is Anhydrous potassium carbonate, with (2,2- diquinoline) replaces triphenylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal basic ring Alkane ketone photosensitizer, yield 57%.
Embodiment 24
Embodiment 21 is repeated, difference is,For cyclobutanone, catalyst is natrium carbonicum calcinatum, with (acridine) replaces triphenylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal cycloalkane ketone Photosensitizer, yield 67%.
Embodiment 25
Embodiment 21 is repeated, difference is,For cycloheptanone, catalyst is Anhydrous potassium carbonate, with (7,8- benzoquinoline) replaces triphenylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 77%.
Embodiment 26
Embodiment 21 is repeated, difference is,For cyclopentanone, catalyst is potassium hydroxide, with (4,7- phenanthroline) replaces triphenylamine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 47%.
Embodiment 27
Embodiment 21 is repeated, difference is,For cyclooctanone, catalyst is sodium hydroxide, with (diphenyl -2- phridyl methane) replaces triphenylamine as reaction raw materials, and other conditions are constant.It is sub- to obtain product water-soluble cationic Benzyl rings alkane ketone photosensitizer, yield 55%.
Embodiment 28
A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, synthetic method are as follows：
(I) preparation of midbody compound S2-3：
Referring to the operation of (I) in embodiment 1, with mole 1：2 commercially available 2- iodoethyl benzene and vilsmeier Reagent reaction, obtains intermediate product S2-3 (yield 96%).
(II) preparation of midbody compound S3-3：
It is 1 with mole referring to the operation of (II) in embodiment 1：1 S2-3 and cycloheptyl reactive ketone, catalyst is carbonic acid Potassium obtains intermediate product S3-3 (yield：40%).
(III) preparation of midbody compound T1-1：
Referring to the operation of (III) in embodiment 1, with mole 1:1 S3-3 and S2-1 reaction, catalyst is potassium carbonate, Obtain intermediate product T1-1 (yield 78%).
(IV) preparation of target product C3-1：
It is 1 with mass ratio referring to the operation of (IV) in embodiment 1：30 T1-1 is reacted with commercially available triphenylphosphine, Obtain target photosensitizer C3-1 (yield：50%).HR-MS(ESI):[M]+:Calcd for[C59H52IOP2]+965.2533； found 965.2539。
Embodiment 29
Embodiment 28 is repeated, difference is,For cyclopentanone, catalyst is sodium hydroxide, with (7,8- benzoquinoline) replaces triphenylphosphine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 56%.
Embodiment 30
Embodiment 28 is repeated, difference is,For cyclobutanone, catalyst is sodium hydroxide, with (4,7- phenanthroline) replaces triphenylphosphine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic benzal Cycloalkane ketone photosensitizer, yield 44%.
Embodiment 31
Embodiment 28 is repeated, difference is,For cyclohexanone, catalyst is sodium carbonate, with (diphenyl -2- phridyl methane) replaces triphenylphosphine as reaction raw materials, and other conditions are constant.Obtain product water-soluble cationic Benzal cycloalkane ketone photosensitizer, yield 28%.
Embodiment 32
Embodiment 28 is repeated, difference is, with(pyridine) replaces triphenylphosphine as reaction raw materials, and other Part is constant, obtains product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 33
Embodiment 28 is repeated, difference is, with(bipyridyl) replaces triphenylphosphine former as reaction Material, other conditions are constant, obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 34
Embodiment 28 is repeated, difference is, with(quinoline) replaces triphenylphosphine as reaction raw materials, Its condition is constant, obtains product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 35
Embodiment 28 is repeated, difference is, with(2- pyridyl group Benzophenone) is made instead of triphenylphosphine For reaction raw materials, other conditions are constant, obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 36
Embodiment 28 is repeated, difference is, with(acridine) replaces triphenylphosphine former as reaction Material, other conditions are constant, obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 37
Embodiment 28 is repeated, difference is, with(2- benzyl pyridine) replaces triphenylphosphine as anti- Raw material is answered, other conditions are constant, obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 38
Embodiment 28 is repeated, difference is, with(dipyridyl ethane) replaces triphenylphosphine As reaction raw materials, other conditions are constant, obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 39
Embodiment 28 is repeated, difference is, with(2,2- diquinoline) replaces triphenylphosphine As reaction raw materials, other conditions are constant, obtain product water-soluble cationic benzal cycloalkane ketone photosensitizer.
Embodiment 40
Photosensitizer obtained in embodiment 2 is used for the experiment of light power inactivation staphylococcus aureus
(I) bacterium is recovered in broth bouillon, determines the concentration of bacterium by measuring the absorbance value of 600nm.
(II) using sterile 96 orifice plates carry out minimal inhibitory concentration (minimum inhibitory concentration, MIC measurement).See per four adjacent holes in 7,96 orifice plate of schematic diagram, such as photosensitizer concentration added by C1, C2, D1 and D2 is It is identical.According to concentration shown in schematic diagram, the Broth solution of 100 microlitres of different photosensitizer concentrations is added in every hole.Wherein, negative right It is B+B group (10 microlitres of bacterium is added in 100 microlitres of meat soups) according to group, positive controls are that (100 microlitres of meat soups are added GM group 1% gentamicin), blank control group is Broth group (10 microlitres of PBS are added in 100 microlitres of meat soups).In above-mentioned 96 orifice plate Bacterial concentration is about 5 × 105Every milliliter of CFU.
(III) laser (the 30J cm of 532nm is utilized-2, 10min) after above-mentioned 96 orifice plate of irradiation, be put into bacteriological incubator after Continuous culture 18 hours.Then it is developed the color using 0.0675% resazurin sodium salt solution.
(IV) pass through 4 hours chromogenic reactions, it is minimum antibacterial that photosensitizer concentration corresponding to concentration is outlined in 96 orifice plates Concentration.See Fig. 8.
Embodiment 41
Referring to the operation in embodiment 40, photosensitizer obtained in embodiment 2 is used for light power colibacillus deactivating Experiment, is shown in Fig. 9.
Embodiment 42
Photosensitizer obtained in embodiment 2 is used for the experiment of light power inactivation candida albicans.
(I) it takes appropriate bacterium solution to be inoculated into Sabouraud dextrose broth bouillon, cultivates 48~72 hours.
(II) photosensitizer that various concentration is added in the fungi solution of suitable concentration is taken, the ultimate density 25 of photosensitizer is made Micromole, 50 micromoles and 100 micromoles.After intake 1 hour, illumination is carried out to above-mentioned mixed liquor using the laser of 532nm (30J cm-2,10min).And it is cultivated 24 hours in dark place.
(III) using coating bacterium plate method, the colony count under various concentration is observed, the antibacterial activity of photosensitizer is measured.See Figure 10.
Embodiment 43
Photosensitizer obtained in embodiment 8 is used for the experiment of light power inactivation staphylococcus aureus, sees Figure 11.
Embodiment 44
Photosensitizer obtained in embodiment 8 is used for the experiment of light power colibacillus deactivating, sees Figure 12.
Embodiment 45
Photosensitizer obtained in embodiment 8 is used for the experiment of light power inactivation candida albicans, sees Figure 13.
Embodiment 46
Photosensitizer obtained in embodiment 13 is used to observe the experiment of the such photosensitizer of cellular uptake.
(I) by cell with 105In every hole implantation culture vessel with glass bottom (35 millimeters of diameter), changes into after 24 hours and micro- rub containing 10 The culture solution of your photosensitizer continues culture 4 hours；
(II) 100 nanomole fluorescence probes are added into culture solution and continue culture 20 minutes, are visited so that PBS cleaning removal is free Needle；
(III) 1 milliliter of PBS solution is added, with confocal microscope observation photosensitizer in the positioning figure of cell.See figure 14。
Embodiment 47
Photosensitizer obtained in embodiment 15 is used for the measurement experiment of rouge moisture proportion
A certain amount of photosensitizer is dissolved in 2mL PBS, 2mL n-octyl alcohol is then added, mixed solution is shaked into 3min, then It is placed in ultrasonic wave and vibrates 5min, be then centrifuged 5 minutes under 5000 turns of speed per minute, make two-phase laminated flow.Measure two-phase In photosensitizer abosrption spectrogram, concentration of the photosensitizer in two-phase, rouge water are calculated by Lambert-beer law Distribution ratio (Log PC) is concentration proportion of the photosensitizer in two-phase.It is shown in Table 1.
Embodiment 48
Photosensitizer obtained in embodiment 21 is used for the measurement experiment of rouge moisture proportion, is shown in Table 1.
Embodiment 49
Photosensitizer obtained in embodiment 28 is used for the measurement experiment of rouge moisture proportion, is shown in Table 1.
Embodiment 50
Photosensitizer obtained in embodiment 31 is used for light power inactivation tobacco mosaic virus (TMV).
100 μ L various concentration (0.125,0.25,0.5,1.0,2.0,4.0,8.0,16.0,32.0 and into 96 orifice plates 64.0 μM) photosensitizing agent solution in be added suitable tobacco mosaic virus (TMV) and guarantee virus final concentration of 2x1011Pfu/mL, Shake culture 30 minutes in dark, the 91192 solar simulator (5mW/cm of Oriel for being 550nm or so with wavelength2, After 50min) irradiating, the mixed solution in 96 orifice plates is transferred in the agar disks containing culture medium, is calculated with colony counting method The survival rate of tobacco mosaic virus (TMV).Wherein, the bacteria suspension of the same concentration without photosensitizer is used as control group.
Table 1
Photosensitizer title Log PC
C2-1 -2.66
C2-2 5.72
C3-1 4.58
Obviously, the above embodiment of the present invention be only to clearly illustrate example of the present invention, and not be pair The restriction of embodiments of the present invention may be used also on the basis of the above description for those of ordinary skill in the art To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is all to belong to this hair The obvious changes or variations that bright technical solution is extended out are still in the scope of protection of the present invention.

Claims (27)

1. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer, which is characterized in that including with following general formula C1, C2 or The compound of C3 structure：
Wherein：
R2, R3And R4It is identical or different, R2、R3And R4Selected from methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl Or-(CH2)n-R1X；
R5And R6It is identical or different, R5And R6Selected from N or P；
X is anion Cl-、Br-Or I-；
N=1,2,3 or 4；
N1 and n2=0,1,2,3 or 4；
R1For quaternary ammonium salt cationic；Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
2. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 1, which is characterized in that R2, R3 And R4Selected from methyl, ethyl or-(CH2)n-R1X。
3. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 1, which is characterized in that R5With R6For N.
4. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 1, which is characterized in that n 1 Or 2.
5. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 1, which is characterized in that n1 and N2 is 0,1 or 2.
6. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 1, which is characterized in that R1Choosing From
A is selected from N or P；
A1, A2And A3It is identical or different, A1、A2And A3Selected from methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl Or phenyl.
7. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 6, which is characterized in that A is N。
8. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 6, which is characterized in that A1, A2 And A3Selected from methyl, ethyl or phenyl.
9. a kind of preparation method of water-soluble cationic benzal cycloalkane ketone photosensitizer as described in claim 1, feature It is, the compound with general formula C1 structure includes following synthesis step：
1) after phosphorus pentachloride being reacted with dimethylformamide, then with general formula Q1 compound
Reaction, collection obtain general formula Q2 intermediate product
It 2), will under the conditions of the basic catalyst of ethanol-dichloromethane solutionIt reacts, receives with gained general formula Q2 intermediate product Collection obtains general formula Q3 intermediate product
3) under the conditions of the basic catalyst of ethanol-dichloromethane solution, by gained general formula Q3 intermediate product and general formula Q4 chemical combination Object
Reaction；
Alternatively, under the conditions of the basic catalyst of ethanol-dichloromethane solution, it willIt is reacted with gained general formula Q2 compound；
Collect obtained general formula Q5 intermediate product
4) under the conditions of solvent is dimethylformamide (DMF), by gained general formula Q5 intermediate product and tertiary amine or azacyclo- chemical combination Object reaction, collection obtain the compound of general formula C1 structure；
Wherein：
N3 and n4 are identical or different, n3, n4=1,2,3 or 4；
N5 and n6 are identical or different, n5, n6=1,2,3 or 4；
B1And B2It is identical or different, B1And B2Selected from-H ,-OH ,-Cl ,-Br or-I；
B3Selected from N or P；
B4、B5Selected from-H ,-Cl ,-Br or-I；B4、B5It is identical or different, but at least one is selected from-Cl ,-Br or-I；
B6Selected from N or P；
B7And B8Selected from-H ,-Cl ,-Br or-I；B7And B8It is identical or different, but at least one is selected from-Cl ,-Br or-I；
Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
10. preparation method according to claim 9, which is characterized in that n3, n4 are 1 or 2.
11. preparation method according to claim 9, which is characterized in that n5 and n6 is 1 or 2.
12. preparation method according to claim 9, which is characterized in that B3For N.
13. preparation method according to claim 9, which is characterized in that B6For N.
14. a kind of preparation method of water-soluble cationic benzal cycloalkane ketone photosensitizer as described in claim 1, feature It is, the compound with general formula C2 structure includes following synthesis step：
1) after phosphorus pentachloride being reacted with dimethylformamide, then with general formula S1 compound
Reaction, collection obtain general formula S2 intermediate product
It 2), will under the conditions of the basic catalyst of ethanol-dichloromethane solutionIt reacts, receives with gained general formula S2 intermediate product Collection obtains general formula S3 intermediate product
3) under the conditions of the basic catalyst of ethanol-dichloromethane solution, by gained general formula S3 intermediate product and general formula Q2 chemical combination Object
Reaction；
Alternatively, under the conditions of the basic catalyst of ethanol-dichloromethane solution, by gained general formula S2 compound and general formula Q3 chemical combination Object
Reaction, the general formula S4 intermediate product collected
4) under the conditions of solvent is dimethylformamide (DMF), by gained general formula S4 intermediate product and tertiary amine or azacyclo- chemical combination Object reaction, collection obtain the compound of general formula C2 structure；
Wherein：
N1=0,1,2,3 or 4；
N3 and n4 are identical or different, n3, n4=1,2,3 or 4；
D1Selected from-H ,-OH ,-Cl ,-Br or-I；
D2Selected from-H ,-Cl ,-Br or-I；
B3Selected from N or P；
B4、B5Selected from-H ,-Cl ,-Br or-I；B4、B5It is identical or different, but at least one is selected from-Cl ,-Br or-I；
Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
15. preparation method according to claim 14, which is characterized in that n1 0,1 or 2.
16. preparation method according to claim 14, which is characterized in that n3, n4 are 1 or 2.
17. preparation method according to claim 14, which is characterized in that B3For N.
18. a kind of preparation method of water-soluble cationic benzal cycloalkane ketone photosensitizer as described in claim 1, feature It is, the compound with general formula C3 structure includes following synthesis step：
1) by general formula S3 compound
With general formula S5 compound
It is reacted under the conditions of the basic catalyst of ethanol-dichloromethane solution；
Alternatively, by general formula S2
With general formulaIt is reacted under the conditions of the basic catalyst of ethanol-dichloromethane solution；
Collection obtains general formula T1 intermediate product
2) under the conditions of solvent is dimethylformamide (DMF), by gained general formula T1 intermediate product and tertiary amine or azacyclo- chemical combination Object reaction, collection obtain the compound of general formula C3 structure；
Wherein：
N1=0,1,2,3 or 4；
N2=0,1,2,3 or 4；
D2Selected from-H ,-Cl ,-Br or-I；
D3Selected from-H ,-Cl ,-Br or-I；D3And D2It is identical or different, but at least one is selected from-Cl ,-Br or-I；
Selected from cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone or cyclooctanone.
19. preparation method according to claim 18, which is characterized in that n1 0,1 or 2.
20. preparation method according to claim 18, which is characterized in that n2 0,1 or 2.
21. a kind of preparation method of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 9, special Sign is, the synthesis step 2 of the compound with general formula C1 structure), 3) described in basic catalyst be lithium hydroxide, hydroxide The combination of one or more of sodium, potassium hydroxide, natrium carbonicum calcinatum, Anhydrous potassium carbonate, pyridine or hexahydropyridine.
22. a kind of preparation method of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 14, Be characterized in that, with general formula C2 structure compound synthesis step 2), 3) described in basic catalyst be lithium hydroxide, hydrogen-oxygen Change the combination of one or more of sodium, potassium hydroxide, natrium carbonicum calcinatum, Anhydrous potassium carbonate, pyridine or hexahydropyridine.
23. a kind of preparation method of water-soluble cationic benzal cycloalkane ketone photosensitizer according to claim 18, Be characterized in that, with general formula C3 structure compound synthesis step 1) described in basic catalyst be lithium hydroxide, hydroxide The combination of one or more of sodium, potassium hydroxide, natrium carbonicum calcinatum, Anhydrous potassium carbonate, pyridine or hexahydropyridine.
24. a kind of water-soluble cationic benzal cycloalkane ketone photosensitizer a method as claimed in any one of claims 1-8 is inactivated in preparation Application in the photo-dynamical medicine of bacterium, fungi or virus.
25. application according to claim 24, which is characterized in that the bacterium includes the leather classified according to Gram's staining Lan Shi positive bacteria and Gram-negative bacteria；The gram-positive bacteria includes staphylococcus aureus, streptococcus, the double balls of pneumonia Bacterium, bacillus anthracis, corynebacterium diphtheriae or clostridium tetani；The Gram-negative bacteria includes Escherichia coli, shigella dysenteriae, typhoid fever bar Bacterium, proteus or Bordetella pertussis.
26. application according to claim 24, which is characterized in that the fungi includes mould, saccharomycete, Candida albicans Bacterium, beer mother bacterium, monascin, Candida, aspergillus flavus, geotrichum candidum or antibiotic bacteria.
27. application according to claim 24, which is characterized in that the virus includes the bacterium classified according to host types Virus, plant virus, animal virus；The bacterial virus includes bacteriophage；The plant virus includes tobacco mosaic virus (TMV)；Institute Stating animal virus includes HIV, variola virus, hepatitis A virus, hepatitis type B virus or rubella virus.
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