CN106699751B - A kind of new compound XQH-3-7 and its in Streptococcus mutans and inhibit application in its biofilm formation - Google Patents
A kind of new compound XQH-3-7 and its in Streptococcus mutans and inhibit application in its biofilm formation Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
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Abstract
The invention discloses a kind of novel thiazole class compound, which is XQH-3-7, molecular formula C16H17N5O4S2, molecular weight 391.47, Chinese is N- (5- nitrothiazole -2- base) -1- (phenyl first sulphamide) piperidines -4- formamide.Experiment confirm the compound of the present invention under floating state streptococcus mutans type strain and clinical strains show good bacteriostatic activity and bactericidal activity.Meanwhile 96% or more is reached to the inhibiting rate of streptococcus mutans biomembrane when compound XQH-3-7 final concentration reaches 4mg/L in culture medium.Compound molecular weight of the present invention is small, structure is relatively easy, bacteriostatic experiment confirmation has the characteristics that strong inhibition capability, fragmentation effect are good, the formation that streptococcus mutans planktonic cells and biomembrane can be significantly inhibited is expected to the novel targeted drug candidate as pre- anti-caries.
Description
Technical field
The present invention relates to a kind of thiazole compound more particularly to a kind of novel thiazole class compound XQH-3-7 and its
Streptococcus mutans and inhibit application in its biofilm formation.The compound can inhibit the growth of oral cavity periodontal bacterium,
It can be used for preventing and treating saprodontia, belong to oral disease prevention and control field of medicine preparing technology.
Background technique
Compared to the growth pattern of (planktonic) of swimming, most of bacterium is more likely to adopt in the natural environment
The mode of biomembrane (biofilm) is taken to be grown.So-called biomembrane (being also referred to as biofilm) refers to that bacterium utilizes
Own cells are wrapped up and are attached to the one of life or lifeless object surface by the macromolecular extracellular matrix of itself secretion
The organized cell colony of class height.In biomembrane there are macromolecular substances include protein, polysaccharide, DNA, RNA, peptide glycan,
The substances such as rouge and phosphatide.There is also a large amount of microorganisms in human oral cavity, they utilize remaining carbohydrate in oral cavity
The surface of human teeth is resided in the form of biomembrane with saliva.Under normal circumstances, the microorganism in oral cavity is in dental surface
In a kind of metastable physiological equilibrium state, once this balance be broken will cause saprodontia (Selwitz et al.,
2007)。
Saprodontia is commonly called as decayed tooth, decayed tooth, is a kind of chronic disease that can lead to enamel, dentine demineralization decomposition that bacterium induces
Disease.Disease disease incidence is high for this, it is wide to dabble range, especially relatively common in teenager and children.Eurodonticus is to cold and hot sour-sweet
Equal stimulations become quite sensitive and along with pain (Fejerskov and Kidd, 2009).Serious person can cause dental pulp disease, root
A series of complication such as sharp disease, or even lose entire tooth and then influence health and quality of life.Saprodontia has become tight
One of main oral disease of human health (Pitts, 2004) is endangered again.In the forming process of saprodontia, hammer is deformed
Bacterium (Streptococcus mutans) plays a crucial role.
Streptococcus mutans are the gram-positive bacterias of a kind of amphimicrobian, be in human oral cavity main cariogenic hedgehog fungus it
One.Streptococcus mutans can not only generate a large amount of acidic materials by metabolism and corrode enamel, but also can be by generating Portugal
Sucrose remaining in oral cavity is changed into glucan by glycan transferase.Glucan is difficult to be removed after adhering to tooth, and energy
It is enough selectively to adsorb other bacteriums in oral cavity, form bacterial plaque.Bacterial metabolism in bacterial plaque generate acid product long term in
Tooth can make tooth demineralization generate tooth hole, will form saprodontia (Lemos et al., 2013) over time.
Therefore, searching is able to suppress streptococcus mutans planktonic cells and the new compound of biofilm formation will be helpful to people
Develop the remedy measures and related drugs of new anticaries.
Summary of the invention
For the demand of the prior art, the object of the present invention is to provide a kind of novel thiazole class compound XQH-3-7 and its
In Streptococcus mutans and inhibit application in its biofilm formation.
Thiazole compound XQH-3-7 of the present invention, it is characterised in that: the compound chemical molecular formula is
C16H17N5O4S2, Chinese is N- (5- nitrothiazole -2- base) -1- (phenyl first sulphamide) piperidines -4- formamide, English name
Referred to as N- (3-bromophenyl) -4- (2- ((5-nitrothiazol-2-yl) amino) -2-oxoethyl)
Piperazine-1-carboxamide, molecular weight 391.47, shown in chemical structure such as formula (1):
Above compound is soluble in dimethyl sulfoxide (DMSO), is insoluble in water.
The synthetic route of above compound XQH-3-7 is shown in following reaction formula:
Wherein: (a) HOBT, EDCI, triethylamine, room temperature；(b) ethyl acetate hydrogen chloride saturated solution, room temperature；(d) three light
Gas, anhydrous ethyl acetate, 0 DEG C to reflux；(e) triethylamine, anhydrous tetrahydro furan, 0 DEG C is arrived room temperature.It is dry according to common standard
The dry used various solvents of method.
Thiazole compound XQH-3-7 of the present invention inhibits and kills streptococcus mutans (Streptococcus in preparation
Mutans) the application in type strain and the planktonic cells drug of clinical strains.
Thiazole compound XQH-3-7 of the present invention inhibits streptococcus mutans (Streptococcus in preparation
Mutans) the application of type strain and clinical strains biomembrane formed in drug.
Thiazole compound XQH-3-7 of the present invention is in preparation oral cavity streptococcus mutans (Streptococcus
Mutans) the application in bioflm inhibiting agents.
Application of the thiazole compound XQH-3-7 of the present invention in the targeted drug of preparation prevention and treatment saprodontia.
Thiazole compound XQH-3-7 of the present invention is preparing toothpaste, mouthwash or disinfection as antibacterial adding ingredient
Application in liquid.
Compound XQH-3-7 is dissolved with DMSO when test, is made into the mother liquor storage of final concentration of 1024mg/L.
The present invention determines compound XQH-3-7 to the inhibitory effect of streptococcus mutans type strain and clinical strains.
The results show that compound XQH-3-7 has good bacteriostatic activity to the streptococcus mutans under floating state and kills
Bacterium activity, the minimal inhibitory concentration to streptococcus mutans UA159 bacterial strain are 4mg/L, minimum bactericidal concentration 32mg/L, half
Maximum suppression concentration (IC50) it is 0.918mg/L.When compound XQH-3-7 final concentration reaches 4mg/L in culture medium to deformation chain
The inhibiting rate of coccus UA159 bacterial strain biomembrane is 96.62%.Compound XQH-3-7 to streptococcus mutans 6715-13 bacterial strain most
Small Mlc is 4mg/L, minimum bactericidal concentration 32mg/L, half maximum suppression concentration (IC50) it is 0.546mg/L.Work as training
It supports when compound XQH-3-7 final concentration reaches 4mg/L in base and is to the inhibiting rate of streptococcus mutans 6715-13 bacterial strain biomembrane
96.18%.
Wherein, used streptococcus mutans UA159 bacterial strain be type strain, ncbi database (http: //
Www.ncbi.nlm.nih.gov/ the reference gene group # in) is NC_004350.Streptococcus mutans used in the present invention
6715-13 bacterial strain is clinical strains, is isolated from the oral cavity with saprodontia patient.Its preferred brain heart infusion of most suitable culture medium
(Brain Heart Infusion) culture medium (Brain infusion solids 12.5g/L, Beef heart
Infusion solids 5.0g/L, Proteose peptone 10.0g/L, Glucose 2.0g/L, Sodium
Chloride 5.0g/L, Di-sodium phosphate 2.5g/L, pH 7.4 ± 0.2), most suitable condition of culture is preferably detested
Oxygen, 37 DEG C of stationary cultures.
Thiazole compound XQH-3-7 molecular weight disclosed by the invention is small, structure is relatively easy, and bacteriostatic experiment confirmation has
The features such as strong inhibition capability, fragmentation effect are good can significantly inhibit the formation of streptococcus mutans planktonic cells and biomembrane, have pre-
The potentiality of anti-dental caries are expected to the novel targeted drug candidate as pre- anti-caries.
Specific embodiment
It is further described in killing, suppression below with reference to a kind of novel thiazole class compound XQH-3-7 provided by the invention
Application during streptococcus mutans planktonic cells and its biofilm formation processed.The content be explanation of the invention rather than
It limits.
Embodiment 1: the preparation of compound XQH-3-7
The synthetic route of compound XQH-3-7 is shown in following reaction formula:
Wherein: (a) HOBT, EDCI, triethylamine, room temperature；(b) ethyl acetate hydrogen chloride saturated solution, room temperature；(d) three light
Gas, anhydrous ethyl acetate, 0 DEG C to reflux；(e) triethylamine, anhydrous tetrahydro furan, 0 DEG C is arrived room temperature.It is dry according to common standard
The dry used various solvents of method.
Specific reaction process is described as follows:
(1) the intermediate 4- tert-butyl-(preparation of (5- nitrothiazole -2- base) carbamyl -1- carboxylic acid (1).
1-Boc-4- piperidinecarboxylic acid (1eq) is dissolved in n,N dimethylformamide, then be separately added into HOBt (1.2eq) and
EDCI (1.2eq) is added dropwise triethylamine (1.2eq).It is added dropwise, adds 5- nitro thiazolamine (1.2eq), at normal temperature
Overnight, into reaction solution plus the distilled water of 200ml, water phase are extracted with ethyl acetate (3 × 200ml) three times for reaction, merge organic
It is mutually washed (2 × 100ml) twice with saturation NaCl, anhydrous magnesium sulfate is dry, is then concentrated by evaporation to obtain crude product with Rotary Evaporators.Slightly
Product obtain yellow solid, yield 75% through silica gel chromatographic column column purification separation (methylene chloride: methanol=v:v, 200:1).
(2) preparation of intermediate 2- (4- amino -1- base)-N- (5- nitrothiazole -2- base) piperidines -4- formamide (2)
Chloroacetic chloride is slowly instilled in dehydrated alcohol (v:v, 4:5), generates HCl and ethyl acetate, then will be among previous step
Body is dissolved in wherein, is stirred 15 minutes at normal temperature, detects fully reacting with TLC, solvent evaporated obtains yellow solid, and crude product produces
Rate 100%, it is unprocessed directly to carry out in next step.
(3) preparation of N- (5- nitrothiazole -2- base -) -1- (phenyl formyl sulfydryl) piperidines -4- acyl (XQH-3-7)
Intermediate 3 (1eq) and triethylamine (1.2eq) are dissolved in anhydrous tetrahydro furan at 0 DEG C, add dropwise phenyl
Isothiocyanates (1.2eq) stirs 3h, is detected and is reacted with TLC, steams tetrahydrofuran, and the distilled water of 50ml is added into reaction solution,
Water phase is extracted with ethyl acetate (3 × 50ml) three times, merges organic phase with saturated sodium chloride solution and washes (2 × 50ml) twice, nothing
Water magnesium sulfate is 30 minutes dry, then obtains crude product through vacuum evaporation.Crude product is through silica gel chromatographic column (200-300 mesh) purifying point
From (methylene chloride: methanol=v:v, 50:1) is used as eluant, eluent, obtains off-white powder, yield 61%.
1H NMR(400MHz,DMSO-d6): δ 13.19 (s, 1H), 9.31 (s, 1H), 8.64 (s, 1H), 7.29 (d, J=
6.0Hz, 4H), 7.10 (d, J=2.6Hz, 1H), 4.72 (d, J=13.3Hz, 2H), 3.20 (t, J=11.7Hz, 2H), 2.92
(t, J=12.9Hz, 1H), 1.94 (d, J=11.2Hz, 2H), 1.74-1.60 (m, 2H) .ppm；ESI-MS:390.1[M-H].
Embodiment 2: the preparation of streptococcus mutans
(1) culture medium for cultivating streptococcus mutans is brain heart infusion (Brain Heart Infusion) culture medium (brand
OXOID, article No. CM1135), culture medium main component is Brain infusion solids 12.5g/L, Beef heart
Infusion solids 5.0g/L, Proteose peptone 10.0g/L, Glucose 2.0g/L, Sodium
Chloride 5.0g/L, Di-sodium phosphate 2.5g/L, pH 7.4 ± 0.2.If you need to be configured to solid, need to add
Add agar powder 15g/L.115 DEG C of sterilizing 30min, it is stand-by after cooling.
(2) culture medium for cultivating streptococcus mutans biomembrane is brain heart infusion-sucrose culture medium, i.e., in brain heart infusion culture
Final concentration of 1% sucrose is added in base.Sucrose need to be made into 20% storage liquid in advance and be crossed with 0.22 μm of sterile filters and be filtered out
Bacterium.
(3) with aseptic inoculation ring by streptococcus mutans type strain UA159 and the deformation that is isolated from saprodontia patient's mouth
Strains of streptococcus 6715-13 crosses on the plate containing brain heart infusion agar solid medium, is inverted in 37 DEG C and detests
Culture in oxygen incubator is until there is apparent single colonie.
(4) it with sterile inoculation shovel scraping streptococcus mutans UA159 and 6715-13 bacterial strain, is transferred to respectively equipped with the brain heart
It in the test tube of immersion liquid fluid nutrient medium, is stood in 37 DEG C of anaerobic culture box, culture to liquid muddiness.
(5) absorbance value (OD with ultraviolet-uisible spectrophotometer detection streptococcus mutans at 600nm600nm)。
(6) assay balance accurate weighing compound XQH-3-7 is used, DMSO is added and is dissolved, is then 0.22 μ with aperture
The sterile filters filtration sterilization of m is made into the storage liquid of final concentration of 1024mg/L, deposits in -20 DEG C for use.
Embodiment 3: Activity determination of the compound XQH-3-7 to streptococcus mutans planktonic cells
(1) prepare streptococcus mutans bacterium solution and compound XQH-3-7 according to method described in embodiment 2, culture is made
The streptococcus mutans UA159 and 6715-13 bacterium solution (OD of logarithmic phase600nm=0.8~1.0) end is diluted to brain-heart infusion medium
Concentration is 5 × 105Cfu/ml is stand-by.
(2) it is swum using micro broth dilution method detection compound XQH-3-7 to streptococcus mutans UA159 and 6715-13
The minimal inhibitory concentration of cell.The compound XQH-3-7 solution of various concentration after doubling dilution is added separately to sterile 96
In orifice plate, the 1st to the 11st hole is plus the experimental group of medical fluid, the 12nd hole are that not dosing is used as growth control group, deforms in each hole
Streptococcus bacterium solution final concentration of 5 × 105Cfu/ml, at this point, the 1st hole to the 12nd hole drug concentration is respectively 256,128,64,32,
16,8,4,2,1,0.5,0.25,0μg/ml.It is minimum antibacterial dense with the minimum concentration positioning for completely inhibiting bacterial growth in aperture
It spends (MIC).
(3) by after on the bacterium solution even spread to brain heart infusion agar solid medium in aperture, in 37 DEG C of Anaerobic culturels
It is inverted culture 24 hours in case, minimum bactericidal concentration (MBC) is positioned with the minimum concentration of no bacterium production.
(4) absorbance value in each aperture at 600nm is detected with microplate reader, calculated thin under the conditions of each drug concentration
The inhibiting rate of born of the same parents, calculation formula are inhibiting rate=(1- experimental group/growth control group) × 100%, and the data obtained is united using SPSS
It counts software and calculates half maximum suppression concentration (IC50), experimental result is as shown in table 1.
Activity determination of the 1. compound XQH-3-7 of table to streptococcus mutans UA159 and 6715-13 planktonic cells
MIC: minimal inhibitory concentration；MBC: minimum bactericidal concentration；IC50: half maximum suppression concentration
From table 1 it will be seen that compound XQH-3-7 has streptococcus mutans UA159 and 6715-13 planktonic cells
Good bacteriostatic activity and killing activity.Compound XQH-3-7 is obvious good to the activity of streptococcus mutans UA159 planktonic cells
In streptococcus mutans 6715-13.
Embodiment 4: inhibitory activity of the compound XQH-3-7 to streptococcus mutans biomembrane
(1) prepare streptococcus mutans bacterium solution and compound XQH-3-7 according to method described in embodiment 2 and 3, with the brain heart
Streptococcus mutans in logarithmic phase are diluted to final concentration of 5 × 10 by immersion liquid-sucrose culture medium5Cfu/ml is stand-by.
(2) the 150 μ l of bacterium solution in (1) is added, and into 96 sterile orifice plates the hole of compound XQH-3-7 is added (eventually
Concentration 4mg/L) it is used as experimental group, the hole of compound XQH-3-7 is not added as a control group.It is put in quiet in 37 DEG C of anaerobic culture boxes
Set culture 40 hours.
(3) planktonic cells in each hole are removed, and rinses unadsorbed cell with a large amount of water.
(4) 0.1% 200 μ l of crystal violet solution is added into each hole, stands 5min at room temperature and is contaminated
Then color removes crystal violet solution, and is rinsed out with a large amount of water and remove unadsorbed crystal violet.
(5) crystal violet of 33% 200 μ l of acetic acid solution dissolution absorption is added into each hole, is then examined using microplate reader
The absorbance value under 590nm is surveyed, calculates the inhibiting rate of biomembrane, calculation formula is the same as embodiment 1.
The results show that when compound XQH-3-7 final concentration reaches 4mg/L in culture medium to streptococcus mutans UA159 bacterium
The inhibiting rate of strain biomembrane is 96.62%, and the inhibiting rate to streptococcus mutans 6715-13 bacterial strain biomembrane is 96.18%.
Claims (6)
1. a kind of thiazole compound XQH-3-7, it is characterised in that: the compound chemical molecular formula is C16H17N5O4S2, Chinese name
Referred to as N- (5- nitrothiazole -2- base) -1- (phenyl first sulphamide) piperidines -4- formamide, English name are N- (3-
bromophenyl)-4-(2-((5-nitrothiazol-2-yl)amino)-2-oxoethyl)piperazine-1-
Carboxamide, molecular weight 391.47, shown in chemical structure such as formula (1):
2. thiazole compound XQH-3-7 described in claim 1 inhibits and kills streptococcus mutans type strain in preparation and faces
Application in the planktonic cells drug of bed bacterial strain.
3. thiazole compound XQH-3-7 described in claim 1 inhibits streptococcus mutans type strain and clinical strains in preparation
The application of biomembrane formed in drug.
4. the answering in preparation oral cavity streptococcus mutans bioflm inhibiting agents of thiazole compound XQH-3-7 described in claim 1
With.
5. application of the thiazole compound XQH-3-7 described in claim 1 in the targeted drug of preparation prevention and treatment saprodontia.
6. thiazole compound XQH-3-7 described in claim 1 is preparing toothpaste, mouthwash or disinfection as antibacterial adding ingredient
Application in liquid.
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| WO1998005332A1 (en) * | 1996-08-01 | 1998-02-12 | Isis Pharmaceuticals, Inc. | Novel heterocycle compositions |
| WO2014179144A1 (en) * | 2013-04-29 | 2014-11-06 | E. I. Du Pont De Nemours And Company | Fungicidal heterocyclic compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005332A1 (en) * | 1996-08-01 | 1998-02-12 | Isis Pharmaceuticals, Inc. | Novel heterocycle compositions |
| WO2014179144A1 (en) * | 2013-04-29 | 2014-11-06 | E. I. Du Pont De Nemours And Company | Fungicidal heterocyclic compounds |
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