CN109843289A - A kind of diaryl chalcogenide of anti-candida albicans and its preparation and application - Google Patents
A kind of diaryl chalcogenide of anti-candida albicans and its preparation and application Download PDFInfo
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Abstract
The invention discloses a kind of diaryl chalcogenide of anti-candida albicans and its preparations and application.Shown in the structure such as formula (I) of the diaryl chalcogenide:
Description
The invention belongs to biomedicine technical fields.More particularly, to a kind of diaryl chalcogenide of anti-candida albicans and its preparation and application.
Candida albicans (Candida albicans) is the fungal disease of the wide-scale distribution in the mankind; it is a kind of important opportunistic fungus; it would generally cause acute, subacute or chronic infection, and one of most important cause of disease of hospital acquired infections now.In healthy human body mucous membrane surface, such as oral cavity, enteron aisle, Candida albicans will not usually cause disease, but it is damaged or inhibits in patient body in immune system, in chemotherapy patients, organ transplant patients or aids patient, serious systemic infection can be caused, lethality is up to 40%.
Clinically antifungal species are limited at present, and wherein azole drug (Fluconazole) is widely used, and Fluconazole is by inhibiting fungi duplication to play antibacterial effect, but with the abuse of antibiotic, the phenomenon that drug resistance is increasingly severe.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the defects and deficiency of existing anti-candida albicans drug, utilize the compound of Novel antibacterial strategy design anti-candida albicans, start with from the distinctive yeast of Candida albicans-mycelia dimorphism, new compound that is efficient, less toxic, being not likely to produce drug resistance is pointedly had devised, there is important scientific meaning and application prospect.
The object of the present invention is to provide a kind of diaryl chalcogenides of anti-candida albicans.
Another object of the present invention is to provide the preparation method of the diaryl chalcogenide.
Another object of the present invention is to provide the application of the diaryl chalcogenide.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of diaryl chalcogenide of anti-candida albicans, shown in structure such as formula (I):
Wherein, Y is S or Se.
The diaryl chalcogenide the preparation method comprises the following steps: will hydrogenation nitrogen-containing heterocycle compound and diaryl sulphur/
The mixing of selenide compound is added dimethyl sulfoxide as solvent and elemental iodine as promotor, is cooled to room temperature after being stirred to react, with ethyl acetate dilute reaction solution, it is washed out drying, evaporating solvent under reduced pressure obtains crude product, most obtains the diaryl chalcogenide through column Chromatographic purification afterwards.
Wherein it is preferred to which the molar ratio of the hydrogenation nitrogen-containing heterocycle compound, diaryl sulphur/selenide compound and elemental iodine is 0.5~1.5:0.5~1.5:1~2.
It is highly preferred that the molar ratio of the hydrogenation nitrogen-containing heterocycle compound, diaryl sulphur/selenide compound and elemental iodine is 1:1:1.5.
Preferably, the hydrogenation nitrogen-containing heterocycle compound is indoline.
Preferably, the diaryl sulphur/selenide compound is diphenyl sulfide or hexichol selenide.
Preferably, the amount ratio of the solvent dimethyl sulfoxide and elemental iodine is 1~2mL:1~2mmol.
It is highly preferred that the amount ratio of the solvent dimethyl sulfoxide and elemental iodine is 2mL:1.5mmol.
Preferably, the condition being stirred to react is to be stirred to react at 100 DEG C 4~20 hours.
Preferably, the washing is to be washed with water several times.
Preferably, it is washed with water 3 times.
Yeast-mycelia dimorphism is the distinctive characteristic of Candida albicans.Free yeast state during infection for host be do not have it is virose, it is main to exercise the effect for being adhered to receptor tissue, it then carries out promoting to invade to the transformation of mycelia state from yeast state, enters infected tissue by cause of disease of mycelia state later, further play toxic effect.Yeast-mycelia Morphological Transitions are the significant process that Candida albicans plays virulence.Therefore, the present invention is started with using the compound of Novel antibacterial strategy design anti-candida albicans from the distinctive yeast of Candida albicans-mycelia dimorphism, pointedly designs efficient, low toxicity, the new compound for being not likely to produce drug resistance.It then is for trying object with Candida albicans (Candida albicans), influence of the diaryl chalcogenide to the adhesiveness of Candida albicans, mycelia formation rate, cytotoxicity and mouse survival rate of design synthesis of the invention is investigated, purpose is the interference by detection compound to Candida albicans virulence formative factor, further influences Candida albicans in toxic effect in the mammalian body.The results show that the compound converts the adhesiveness of Candida albicans, hypha form and pathogenic has good inhibiting effect.Moreover, compound toxicity itself is smaller, Candida albicans and the growth of human cell are not influenced.
Therefore, application of the above-mentioned diaryl chalcogenide in the drug for preparing anti-candida albicans infection, and the application in the drug of preparation prevention and/or the treatment microbial infectious diseases of Candida albicans, should all be within protection scope of the present invention.
Specifically, the anti-candida albicans refer to inhibit Candida albicans adhesiveness, hypha form conversion,
Toxicity action pathogenic and/or to cell.
A kind of drug of anti-candida albicans containing the diaryl chalcogenide or the drug for preventing and treating the microbial infectious diseases of Candida albicans, also should be within protection scope of the present invention.
The invention has the following advantages:
The present invention provides a kind of new diaryl chalcogenide, the adhesiveness of Candida albicans, hypha form are converted and pathogenic with good inhibiting effect.Moreover, compound toxicity itself is smaller, the growth of human cell is not influenced, is had a good application prospect in terms of the exploitation of the exploitation of novel antifungal drugs, especially anti-candida albicans infection medicine.
The present invention also studies discovery, the diaryl chalcogenide only has certain inhibiting effect to the growth of Candida albicans, show the compound to the effect of albicans strain not mainly by kill bacterium, but by inhibiting the adhesiveness of bacterium, hypha form conversion and pathogenic, therefore it is not likely to produce drug resistance.
Fig. 1 is the synthesis process figure of diaryl chalcogenide.
Fig. 2 is the nucleus magnetic hydrogen spectrum of No. 3 compounds.
Fig. 3 is the carbon spectrum of No. 3 compounds.
Fig. 4 is the nucleus magnetic hydrogen spectrum of No. 8 compounds.
Fig. 5 is the carbon spectrum of No. 8 compounds.
Fig. 6 is influence of the diaryl chalcogenide to Candida albicans adhesiveness；Wherein, 13 kinds of compounds that figure (A) is final concentration of 100 μM are adhered to the influence result figure on polystyrene to albicans cell；Scheme the result figure that (B) is 1,2,3, No. 8 inhibiting rate of totally 4 kinds of compounds under 6.25 μM to 100 μM of various concentration；DMSO is as control；8 duplicate average results of biology are shown in data, and error bar reflects standard deviation.
Fig. 7 is the influence result figure that diaryl chalcogenide forms Candida albicans mycelia；Wherein, figure (A) is the measurement result figure of inhibiting rate that is formed to Candida albicans mycelia of diaryl chalcogenides of 13 kinds of final concentration of 100 μM synthesis；Scheming (B) is 1,2,3, No. 8 inhibitory effect figure of the compound under 6.25 μM to 100 μM of various concentration；Figure (C) is DMSO, Fluconazole, the micro- sem observation picture figure that 1,2,3, No. 8 compound inhibits mycelia generation at final concentration of 100 μM；The average result of 3 secondary pollutants experiment is shown in this data, and error bar reflects standard deviation.
Fig. 8 is influence result figure of the diaryl chalcogenide to Candida albicans growth rate；DMSO is as control；3 duplicate average results of biology are shown in data, and error bar reflects standard deviation.
Fig. 9 be diaryl chalcogenide to Candida albicans the pathogenic aspect of A549 cell influence；(A) cytotoxicity of final concentration of 100 μM of the 13 kinds of diaryl chalcogenides to A549 cell；(B) final concentration of 100 μM of 13 kinds of diaryl chalcogenides are to the influence after Candida albicans infected cell；(C) 1,2,3, No. 8 compound is under 6.25 μM to 100 μM of various concentration to the influence after Candida albicans infected cell.The toxicity of cell is detected by detecting the burst size of LDH, when detecting the cytotoxicity of Candida albicans, we will joined the LDH burst size of DMSO group as 100%, and thus carry out the LDH releasing ratio of other addition diaryl chalcogenide groups of specification.4 duplicate average results of biology are shown in data, and error bar reflects standard deviation.
The present invention is further illustrated below in conjunction with Figure of description and specific embodiment, but embodiment does not limit in any form the present invention.Unless stated otherwise, the present invention uses reagent, method and apparatus is the art conventional reagents, method and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are commercially available.
The synthesis of 1 diaryl chalcogenide of embodiment
1, diaryl chalcogenide synthesis schematic diagram as shown in Figure 1, specific synthetic method the following steps are included:
(1) in the reactor, 1mmol hydrogenation nitrogen-containing heterocycle compound (compound A-1~A-6) and 1mmol diaryl sulphur/selenide compound (compound B-1~B-6) is added, it is promotor that 2mL dimethyl sulfoxide, which is added, as the elemental iodine of solvent and 1.5mmol, is stirred to react at 100 DEG C 4~20 hours；
Wherein, compound A-1~A-6 is respectively as follows: tetrahydroquinoline, indoline, 4- cyano indoline, 6- indoline quinoline acid methyl esters, 7- azepine indoline, 7,8- benzo tetrahydroquinoline (structural formula is shown in Fig. 1)；
Compound B-1~B-6 is respectively as follows: 2,2 '-diphenyl sulfide ether acid methyl esters, 2,2 '-two pyridine thioethers, diphenyl sulfide, 4,4 '-dimethyl diphenyl sulfide ethers, hexichol selenide, 4,4 '-dimethoxy hexichol selenides (structural formula is shown in Fig. 1).
(2) above-mentioned to be cooled to room temperature after reaction, it with ethyl acetate dilute reaction solution, then washes three times, dry, evaporating solvent under reduced pressure obtains crude product, most obtains diaryl chalcogenide 1-10 compound through column Chromatographic purification afterwards.
2, wherein, the nucleus magnetic hydrogen spectrum and carbon of compound 3 and compound 8 are composed respectively as shown in figs. 2 to 4.
The effect detection of 2 diaryl chalcogenide of embodiment
1, test method:
(1) activation of albicans strain: Candida albicans reference culture SC5314 is activated into (tryptone 10g/L, yeast extract 5g/L, NaCl 10g/L, agar 15g/L) in LB culture medium, is placed in 30 DEG C of incubator overnight incubations.
(2) influence of the compound to albicans strain SC5314 adhesiveness:
SC5314 bacterial strain on picking LB solid plate is inoculated in YNB culture solution (0.2% glucose is added before use in 6.7g/L), and 30 DEG C, 200rpm shaken cultivation is stayed overnight, and measures bacterium solution OD600.Bacterium solution is then diluted to OD with GMM600=0.5, it takes 1mL bacterium solution in 1.5ml EP pipe, sequentially adds final concentration of 100 μM of compound, concussion mixing respectively takes 200 μ L to be added in 96 orifice plates, and 4 repetitions are arranged in each processing, while the processing for only adding DMSO is arranged.96 orifice plates are statically placed in 37 DEG C and are incubated for, bacterium solution is discarded after 4h, 50 μ L, 0.5% crystal violet is added, room temperature acts on 45min.Crystal violet is discarded, and with ice ddH2O is washed 10 times, and 200 μ L, 75% ethyl alcohol is added, is placed at room temperature for 30 minutes, measures OD590, with GraphPad Prism6 software data processing.
(3) influence of the compound to albicans strain SC5314 mycelia:
SC5314 bacterial strain on picking LB solid plate, is inoculated in GMM culture solution, and 30 DEG C, 200rpm shaken cultivation is stayed overnight, and measures bacterium solution OD600, bacterium solution is diluted to OD with GMM600=0.1.Take 500 μ L
Bacterium solution is in 1.5mL EP pipe, it is separately added into final concentration of 100 μM of compounds, it is respectively positive, negative control that DMSO, BDSF (B.cenocepacia diffusible signal factor, be formed with good inhibiting effect to SC5314 mycelia) is arranged simultaneously.Concussion mixes, and is placed in 37 DEG C of water-baths and is incubated for, and after 6h, is centrifuged 5000rpm, 10min, abandons supernatant, 40 μ L GMM culture solutions is added, thallus is resuspended, and in the formation of Zeiss Axioplan2 microscopically observation mycelia, takes different visual field shooting photos.
(4) measurement of the compound to albicans strain SC5314 growth effect:
Picking bacterial strain SC5314 single colonie is inoculated in GMM culture solution, and 30 DEG C, 200rpm shaken cultivation is stayed overnight, and measures bacterium solution OD600, bacterium solution is diluted to OD with GMM600=0.05.It takes 1mL bacterium solution in 1.5mlEP pipe, sequentially adds final concentration of 100 μM of compound, concussion mixing respectively takes 300 μ L to be added in 100 orifice plates, and 4 repetitions are arranged in each processing, while the processing for only adding DMSO plus Fluconazole is arranged.It is placed in growth curve analyzer, 30 DEG C, 200rpm, every 2h measures an OD600It is worth, observation experiment after 2d is as a result, GraphPad Prism 6 handles data.
(5) influence of the compound to albicans strain SC5314 cytotoxicity:
(a) recovery and culture of A549 cell: the A549 cell of freeze thawing is transferred in the DMEM culture medium containing 10%FBS (Gioco company), 37 DEG C, 5%CO2Under the conditions of be incubated overnight.
(b) A549 cell prepares: A549 cell is in the high glucose medium DMEM containing 10% fetal calf serum, with 1.5 × 104The cell concentration in a/hole overnight incubation in 96 orifice plates.When being covered with 96 orifice plate bottom 80% to cell, culture solution is discarded, is cleaned cell 3 times with 1 × PBS.
(c) Candida albicans prepares: the fresh SC5314 of picking is inoculated in GMM culture solution, and in 30 DEG C, shaken cultivation is stayed overnight under the conditions of 200rpm；OD is adjusted to the DMEM cell maintenance medium containing 1%FBS600=1.0, then 10 times of (≈ 10 are diluted with DMEM (1%FBS)8Cfu/mL) stand-by.
(d) cytotoxicity bioassay: final concentration of 100 μM of compounds are added in bacteria-containing cell maintenance medium, are taken 100 μ L to be added in ready A549 cell, are placed in 37 DEG C, 5%CO28h is cultivated in cell incubator, 4 repetitions of every processing, while setting only adds DMSO plus BDSF and Fluconazole to be used as the toxicity action for compareing, while measuring compound on intracellular itself, final concentration of 100 μM of compounds are added in not bacteria-containing cell maintenance medium, are ibid handled.Referring to Promega company CytoToxNonRadioactive Cytotoxicity Assay operating method measures cell LDH activity, then handles data with GraphPad Prism 6.
(6) influence of the compound to albicans strain SC5314 mouse intramatrical infection:
(a) mouse is raised: the male BALB/c that will be purchased from 6-8 week old of Guangdong Province's Experimental Animal Center is small
Mouse is raised in Agricultural University Of South China's Experimental Animal Center.It is randomly assigned 8/group, weighing is recorded and marked to every mouse.
(b) Candida albicans prepares: the fresh SC5314 of picking is inoculated in GMM culture solution, and in 30 DEG C, shaken cultivation is stayed overnight under the conditions of 200rpm, and thalline were collected by centrifugation by 5000rpm, 5min, is cleaned thallus 3 times with 1 × PBS, with 5 × 108The concentration of cfu/mL is dispersed in containing in PBS.
(c) mouse tail vein injection: final concentration of 100 μM of compounds 3,8 are added in bacteria-containing PBS, are mixed stand-by.This test is the nursing of experimental animal in the health guidance according to National Institutes of Health and is carried out using regulations (No. 8023 publications of NIH are revised for 1978).Mouse weighing, tail vein injection, 100 μ L/10g, while 1 × PBS is injected, 100 μM of Fluconazoles are respectively as control.Continuous observation mouse survival situation records, statistical data after 20d, handles data with GraphPad Prism 6.
2, experimental result
(1) compound inhibits the adhesiveness of albicans strain SC5314
As shown in A figure in attached drawing 6, using the adhesiveness of Candida albicans in DMSO group as reference, the results show that in 10 compounds, treated that cell adhesion is reduced 35% or so for No. 3 and No. 8 compounds, plays the role of the adhesiveness for significantly inhibiting Candida albicans SC5314.
Bioactivity of the binding compounds in terms of mycelia formation rate and cytotoxicity, we select No. 1, No. 2, No. 3 and No. 8 compound to carry out concentration gradient test.As the result is shown (B figure) in attached drawing 6, the Adhesion inhibiyive effect that No. 3 and No. 8 compounds present dependence concentration gradient can also decrease the adhesion inhibiting effect of Candida albicans with the reduction of compound concentration.
(2) compound inhibits the formation of albicans strain SC5314 mycelia
Using the processed mycelia formation rate of DMSO and BDSF as control, as shown in A figure in attached drawing 7, there are 6 to have significant inhibiting effect for Candida albicans SC5314 in 10 compounds, mycelia formation rate is reduced 35% or less.C figure shows that the mycelia observed under the microscope forms result in attached drawing 7.
Equally, in conjunction with otherwise activity, we have detected 1,2,3, No. 8 compound under 6.25 μM to 100 μM concentration gradients, the mycelia formation rate of albicans strain SC5314.As the result is shown (in attached drawing 7 B scheme), four kinds of compounds show the characteristic of concentration dependant to the Mycelial growth effect of Candida albicans, and No. 8 compounds are at 6.25 μM, it is also possible that mycelia formation rate is reduced 40% or so.
(3) compound has certain influence to the growth of albicans strain SC5314
It as a result is control with DMSO and Fluconazole as shown in A figure in attached drawing 8,100 μM of 1,2,3, No. 8 compound has certain inhibiting effect to the growth of albicans strain SC5314.Meanwhile we survey
The influence of examination 3 and No. 8 compound various concentration gradients to Candida albicans.(B figure and C figure in attached drawing 8) as the result is shown, No. 3 compounds affects are smaller, and No. 8 compound relative effects are larger, have certain inhibiting effect to the growth of SC5314.
(4) compound can inhibit albicans strain SC5314 to the toxicity action of cell
Cytotoxicity experimental result shows (A schemes in such as attached drawing 9), is compareed with DMSO, under conditions of no bacterium, in 10 compounds, does not have toxicity to cell.
Under conditions of adding Candida albicans SC5314; with DMSO; BDSF treated cytotoxicity is control; B figure and C figure are shown in attached drawing 9; compound 1,2,3,8 with protective effect the virulence of Candida albicans can reduce below 30% infecting for cell in inhibition bacterial strain SC5314.
(5) compound has protective effect to the albicans strain SC5314 mouse infected
Comprehensive diaryl chalcogenide various aspects performance results, we pick out various aspects and show preferable 1,2,3, No. 8 progress mouse experiment, and Therapy lasted observes 20d.
The results show that No. 1 and No. 2 compounds test no protective effect in vivo, and No. 3 and No. 8 compounds treated mouse survival rate is 100%, as shown in table 1.
The compound influence pathogenic to Candida albicans in 1 mouse infection model of table
| Compound | Survival rate (%) |
| DMSO | 0 |
| Fluconazole | 100 |
| No. 3 | 100 |
| No. 8 | 100 |
To sum up experimental result can be seen that No. 3 and No. 8 compounds are the candidate new persons of anti-candida albicans drug.Generally speaking, the present invention has synthesized a series of diaryl chalcogenides, and has screened their abilities to resistant to fungal pathogens.Some compounds in them are shown inhibits albicans cell adherency, mycelia formation and pathogenic characteristic well；Although they, without toxicity, do not have toxicity to human body cell simultaneously to albicans cell itself yet.Experimental result shows that some compounds in these compounds may be developed as the drug of novel anti-candida albicans infection.
The above embodiment is a preferred embodiment of the present invention; but embodiment of the present invention are not limited by the above embodiments; other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention; it should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
- A kind of diaryl chalcogenide of anti-candida albicans, which is characterized in that shown in its structure such as formula (I):Wherein, Y is S or Se.
- The preparation method of diaryl chalcogenide described in claim 1, it is characterized in that, the following steps are included: nitrogen-containing heterocycle compound and diaryl sulphur/selenide compound mixing will be hydrogenated, dimethyl sulfoxide is added as solvent and elemental iodine as promotor, it is cooled to room temperature after being stirred to react, with ethyl acetate dilute reaction solution, is washed out drying, evaporating solvent under reduced pressure obtains crude product, most obtains the diaryl chalcogenide through column Chromatographic purification afterwards.
- Preparation method according to claim 2, which is characterized in that the molar ratio of the hydrogenation nitrogen-containing heterocycle compound, diaryl sulphur/selenide compound and elemental iodine is 0.5~1.5:0.5~1.5:1~2.
- Preparation method according to claim 2, which is characterized in that the hydrogenation nitrogen-containing heterocycle compound is indoline, and the diaryl sulphur/selenide compound is diphenyl sulfide or hexichol selenide.
- Preparation method according to claim 2, which is characterized in that the condition being stirred to react is to be stirred to react at 100 DEG C 4~20 hours.
- Preparation method according to claim 2, which is characterized in that the washing is to be washed with water several times.
- Application of the diaryl chalcogenide in the drug for preparing anti-candida albicans described in claim 1.
- Application according to claim 7, which is characterized in that the anti-candida albicans refer to the adhesiveness for inhibiting Candida albicans, hypha form conversion, pathogenic and/or to cell toxicity action.
- Application of the diaryl chalcogenide described in claim 1 in the drug of preparation prevention and/or the treatment microbial infectious diseases of Candida albicans.
- A kind of drug of anti-candida albicans or the drug for preventing and treating the microbial infectious diseases of Candida albicans, which is characterized in that contain diaryl chalcogenide described in claim 1.
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| CN112494483A (en) * | 2020-11-13 | 2021-03-16 | 兰州大学 | Application of dithiolethiones compound in antibacterial aspect |
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| CN110003080A (en) * | 2019-04-30 | 2019-07-12 | 成都大学 | A kind of selenium-containing compound and preparation method thereof and purposes |
| CN112494483A (en) * | 2020-11-13 | 2021-03-16 | 兰州大学 | Application of dithiolethiones compound in antibacterial aspect |
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| WO2019071395A1 (en) | 2019-04-18 |
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