CN106588911B - A kind of novel thiazole class compound XQH-3-6 of Streptococcus mutans and its application - Google Patents
A kind of novel thiazole class compound XQH-3-6 of Streptococcus mutans and its application Download PDFInfo
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Abstract
The invention discloses a kind of novel thiazole class compound that can inhibit streptococcus mutans, which is XQH-3-6, molecular formula C16H16ClN5O4S, molecular weight 409.85, Chinese N1(3- chlorphenyl-N4(5- nitrothiazole -2- base)) piperidines -1,4- diformamide.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 97% or more is reached to the inhibiting rate of streptococcus mutans biomembrane when compound XQH-3-6 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, main pathogenic bacteria-the growth of streptococcus mutans planktonic cells and the formation of biomembrane of dental caries can be significantly inhibited, potentiality with anticaries can be used as the novel targeted drug candidate of 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 compounds of Streptococcus mutans
XQH-3-6 and its application.The compound can inhibit the growth of oral cavity periodontal bacterium, can be used for preventing and treating saprodontia, belong to oral cavity
Disease prevention and cure field of medicine preparing technology.
Background technique
Dental caries (Dental caries) are commonly called as decaying tooth, and are the common chronic diseases in one of oral cavity.Dental caries chronic progression into
And irreversible damage is caused to dental hard tissue, and distribution is extensive, and disease incidence is high, pain not only is brought to individual,
Cause huge medical resource waste, it has also become threaten the global problem of Human Oral Cavity health, the World Health Organization (WHO)
Be classified as one of three big non-communicable diseases (cardiovascular disease, cancer and dental caries) of mankind's keypoint control (Petersen.,
2003)。
Generally acknowledged etiology of dental caries theory is " tetrad factor theory " at present, i.e. bacterium, oral environment, host and four kinds of the time
Factor results in dental caries jointly.Oral temperature is suitable for that, containing alkalescent saliva, swill etc. is the procreation of flora in oral cavity
Provide suitable environment (Loesche., 1986).Bacterium is the pathogenetic necessary factor of dental caries, bacterium and swill in oral cavity
And saliva mixing, it is firmly adhered in dental surface and nest ditch, forms plaque bio-film, it is pathogenetic initial to become dental caries
Condition.Many scholars at home and abroad have confirmed that deformation bacterium (Streptococcus mutans) of practising a ball game is to cause saprodontia most important
Pathogen.Streptococcus mutans are a kind of Gram-positive anaerobic bacterias, and cariogenicity and its adherency produce sour, acidproof and born of the same parents
The processes such as exo polysaccharides synthesis are related (Hamad and Slade., 1980).Streptococcus mutans generate glucanotransferase metabolism sugar
And glucose and fructose are aggregated into glucan and levulan, dextran molecule amount is high, viscosity is big, is adsorbed on tooth and is situated between
It leads other floras in streptococcus mutans and oral cavity and assembles and be adhered to dental surface formation bacterial plaque, deform hammer in bacterial plaque environment
Bacterium generates organic acid, reduces the pH value of oral environment, make enamel and decalcification of dentine to formed dental caries (Lemos et al.,
2013).Meanwhile streptococcus mutans still can survive in low ph environment and be metabolized carbohydrate, relative in oral cavity
Other bacteriums have growth vigor.
From the twentieth century middle period, fluoride is just used to preventing decayed tooth, and fluoride can be promoted again by reducing enamel decalcification
Secondary mineralising generates the mechanism such as inhibition and killing effect to microorganism and carrys out pre- anti-caries.Therefore fluoride is widely used in dental caries
Clinical treatment, but result in the selective growth of F resistant Strain.The production acid and acid-fast ability of streptococcus mutans F resistant Strain
All stronger than parental strain, cariogenic potential also enhances (Van Loveren et al., 1993).The appearance of F resistant Strain is to fluoride
Prophylactic treatment saprodontia proposes new problem, prevents and the research and development of the New Measure and drug for the treatment of saprodontia become very urgent.
Summary of the invention
For the demand of the prior art, the object of the present invention is to provide the novel thiazoles that one kind can inhibit streptococcus mutans
Class compound and its application.
The thiazole compound XQH-3-6 of Streptococcus mutans of the present invention, it is characterised in that: the compound chemistry point
Minor is C16H16ClN5O4S, Chinese N1(3- chlorphenyl-N4(5- nitrothiazole -2- base))-two formyl of piperidines-Isosorbide-5-Nitrae
Amine, English name are N1- (3-chlorophenyl)-N4- (5-nitrothiazol-2-yl) piperidine-1,4-
Dicarboxamide, molecular weight 409.85, 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-3-6 is shown in following reaction formula
Wherein: (a) I-hydroxybenzotriazole (HOBT), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
(EDCI), triethylamine, room temperature；(b) ethyl acetate hydrogen chloride saturated solution, room temperature；Or trifluoroacetic acid/dichloromethane；(d) three
Phosgene, anhydrous ethyl acetate, 0 DEG C to reflux；(e) triethylamine, anhydrous tetrahydro furan, 0 DEG C is arrived room temperature.
Thiazole compound XQH-3-6 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-3-6 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-3-6 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-3-6 of the present invention in the targeted drug of preparation prevention and treatment saprodontia.
Thiazole compound XQH-3-6 of the present invention is preparing toothpaste, mouthwash or disinfection as antibacterial adding ingredient
Application in liquid.
By powdered compound XQH-3-6 dmso solution, and it is made into the mother liquor of final concentration of 1024mg/L
Storage.
The present invention determines compound XQH-3-6 to the inhibitory effect of streptococcus mutans type strain and clinical strains.
The results show that compound XQH-3-6 has good bacteriostatic activity to the streptococcus mutans under floating state and kills
Bacterium activity, the minimal inhibitory concentration (MIC) to streptococcus mutans UA159 bacterial strain is 4mg/L, and minimum bactericidal concentration (MBC) is
8mg/L, half maximum suppression concentration (IC50) it is 0.963mg/L.When compound XQH-3-6 final concentration reaches 4mg/L in culture medium
When be 97.69% to the inhibiting rate of streptococcus mutans UA159 bacterial strain biomembrane.Compound XQH-3-6 is to streptococcus mutans UA246
The minimal inhibitory concentration (MIC) of bacterial strain is 4mg/L, and minimum bactericidal concentration (MBC) is 32mg/L, half maximum suppression concentration
(IC50) it is 1.505mg/L.When compound XQH-3-6 final concentration reaches 4mg/L in culture medium to streptococcus mutans UA246 bacterium
The inhibiting rate of strain biomembrane is 97.93%.
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
UA246 bacterial strain is the clinical strains being 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), at 37 DEG C, Anaerobic culturel it is most suitable
Stationary culture under the conditions of preferably.
Thiazole compound XQH-3-6 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 main pathogenic bacteria of dental caries --- streptococcus mutans planktonic cells
Growth and biomembrane formation, with anticaries potentiality, can be used as the novel targeted drug candidate of pre- anti-caries.
Specific embodiment
Below with reference to a kind of novel thiazole class compound of Streptococcus mutans provided by the invention, further describe its
Application during killing, inhibition streptococcus mutans planktonic cells and its biofilm formation.The content is to solution of the invention
It releases rather than limits.
Embodiment 1: the preparation of compound XQH-3-6
The synthetic route of compound XQH-3-6 is shown in following reaction formula:
Wherein: (a) I-hydroxybenzotriazole (HOBT), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
(EDCI), triethylamine, room temperature；(b) ethyl acetate hydrogen chloride saturated solution, room temperature；Or trifluoroacetic acid/dichloromethane；(d) three
Phosgene, anhydrous ethyl acetate, 0 DEG C to reflux；(e) triethylamine, anhydrous tetrahydro furan, 0 DEG C is arrived room temperature.
Solvent involved in reaction process is then dried according to common standard drying method if you need to drying.
Specific reaction process:
(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), 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).
Method 1: chloroacetic chloride slowly being instilled in dehydrated alcohol (v:v, 4:5), generates HCl and ethyl acetate, then by upper one
Step intermediate is dissolved in wherein, is stirred 15 minutes at normal temperature, detects fully reacting with TLC, solvent evaporated obtains yellow solid, slightly
Product yield 100%, it is unprocessed directly to carry out in next step.
Method 2: under ice bath, previous step intermediate is dissolved in a small amount of anhydrous methylene chloride, trifluoroacetic acid is added dropwise dropwise
Solution (2eq), after which warms naturally to room temperature, the reaction was continued 3 hours, until TLC monitoring reaction has finished.Divide exactly organic
Solvent, resulting crude product is unprocessed to be directly thrown into next step.
(3)N1(3- chlorphenyl-N4The preparation of (5- nitrothiazole -2- base) piperidines -1,4- diformamide (XQH-3-6).
Intermediate 3 (1eq) and triethylamine (1.2eq) are dissolved in anhydrous tetrahydro furan at 0 DEG C, add dropwise 3- chlorine
Phenyl isocyanate (1.2eq) stirs 3h, is detected and is reacted with TLC, steams tetrahydrofuran, and the distillation of 50ml is added into reaction solution
Water, water phase are extracted with ethyl acetate (3 × 50ml) three times, merge organic phase with saturated sodium chloride solution and wash (2 × 50ml) twice,
Anhydrous magnesium sulfate is 30 minutes dry, then obtains crude product through vacuum evaporation.Crude product is pure through silica gel chromatographic column (200~300 mesh)
Change separation, (methylene chloride: methanol=50:1) is used as eluant, eluent, obtains off-white powder, yield 67%,1H NMR(400MHz,
DMSO-d6): δ 13.15 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 7.66 (s, 1H), 7.40 (d, J=8.2Hz, 1H),
7.25 (t, J=8.1Hz, 1H), 6.97 (d, J=7.8Hz, 1H), 4.16 (d, J=13.3Hz, 2H), 2.95-2.77 (m, 3H),
1.91 (d, J=11.3Hz, 2H), 1.59 (m, 2H) .ESI-MS:409.9 [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 phosphate2.5g/L, pH 7.4 ± 0.2.If you need to solid medium, then need to add again
Add 1.5% agar powder.115 DEG C of moist heat sterilization 30min, it is stand-by after cooling.
(2) culture medium for cultivating streptococcus mutans biomembrane is brain heart infusion-sucrose culture medium.Preparation method is by sucrose
It is made into 20% storage liquid and with 0.22 μm of sterile filters filtration sterilization, final concentration of 1% is added in brain-heart infusion medium
Sucrose.
(3) bacterium solution of streptococcus mutans type strain UA159 and clinical strains UA246 are inoculated in the training of brain heart infusion solid
It supports on base and crosses, in 37 DEG C, anaerobism is inverted culture 24 hours, apparent single colonie occurs.
(4) single colonie of streptococcus mutans UA159 and UA246 a bacterial strain is picked them separately with sterile oese, is inoculated with
Into the test tube equipped with brain heart infusion fluid nutrient medium, the anaerobism static gas wave refrigerator at 37 DEG C, until examination liquid in pipe is muddy.
(5) streptococcus mutans UA159 and UA246 is measured respectively with ultra-violet and visible spectrophotometer in 600nm wavelength
Absorption value (OD600).
(6) compound XQH-3-6 assay balance accurate weighing is added dimethyl sulfoxide and is dissolved, and being made into concentration is
The storage liquid of 1024mg/L deposits in -20 DEG C for use using 0.22 μm of sterile filters filtration sterilization.
Embodiment 3: Activity determination of the compound XQH-2-92 to streptococcus mutans planktonic cells
(1) prepare streptococcus mutans bacterium solution and compound XQH-3-6 according to method described in embodiment 2, culture is made
Logarithmic phase (OD600=0.8~1.0) streptococcus mutans UA159 and UA246 bacterium solution is diluted to brain heart infusion fluid nutrient medium
Final concentration of 5 × 105Cfu/ml is stand-by.
(2) detection of the compound XQH-3-6 to the minimal inhibitory concentration of streptococcus mutans UA159 and UA246 planktonic cells
Using micro broth dilution method.Streptococcus mutans bacterium solution final concentration of 5 × 10 in each hole of sterile 96 orifice plate5Cfu/ml,
The storage liquid of the compound XQH-3-6 prepared according to the above method is added in the first hole and is adjusted to final concentration of 256mg/L, mixes
It is even, 150 μ l to the 2nd hole are then drawn, draw 150 μ l to the 3rd hole after mixing again, so continuous doubling dilution to the 11st hole, and
150 μ l are drawn from the 11st hole to discard.So far, the 1st to the 11st hole is plus the experimental group of medical fluid, the 12nd hole are not dosing as life
Long control group.1st hole to the 12nd hole drug concentration is respectively 256,128,64,32,16,8,4,2,1,0.5,0.25,0 μ g/ml.
Minimal inhibitory concentration (MIC) is positioned to completely inhibit the minimum concentration of bacterial growth in aperture.
(3) after taking on the bacterium solution even spread to brain heart infusion agar solid medium in hole, 37 DEG C of anaerobism are inverted culture
24 hours, minimum bactericidal concentration (MBC) is positioned with the minimum concentration of not bacterial growth.
(4) each interior absorbance value under 600nm wavelength of 96 orifice plates is detected with microplate reader, calculates each drug concentration item
The inhibiting rate of cell under part, calculation formula are inhibiting rate=(1- experimental group/growth control group) × 100%, and the data obtained uses
SPSS statistical software calculates half maximum suppression concentration (IC50), experimental result is as shown in table 1.
Activity determination of the 1. compound XQH-3-6 of table to streptococcus mutans UA159 and UA246 planktonic cells
In table 1, MIC: minimal inhibitory concentration；MBC: minimum bactericidal concentration；IC50: half maximum suppression concentration
From table 1 it will be seen that compound XQH-3-6 has very streptococcus mutans UA159 and UA246 planktonic cells
Good sterilization and bacteriostatic activity.Compound XQH-3-6 will be significantly better than deformation to the activity of streptococcus mutans UA159 planktonic cells
Streptococcus UA246.
Embodiment 4: inhibitory activity of the compound XQH-2-92 to streptococcus mutans biomembrane
(1) prepare streptococcus mutans bacterium solution and compound XQH-3-6 according to method described in Examples 1 and 2, 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-3-6 is added (eventually
Concentration 4mg/L) it is used as experimental group, the hole of compound XQH-3-6 is not added as a control group.It is small in 37 DEG C of anaerobism stationary cultures 40
When.
(3) planktonic cells in each hole of 96 orifice plates are removed, and is rinsed with a large amount of water to remove unadsorbed cell.
(4) crystal violet solution that 200 μ l 0.1% are added into each hole is dyed at room temperature, is stood 5min and is moved back
Crystal violet solution is walked, and is rinsed out with a large amount of water and removes unadsorbed crystal violet solution.
(5) acetic acid solution of 200 μ l 33% is added into each hole to dissolve the crystal violet of absorption, then uses enzyme mark
Instrument detects the absorbance value under 590nm wavelength, calculates the inhibiting rate of biomembrane, calculation formula is the same as embodiment 1.
The results show that when compound XQH-2-6 reaches 4mg/L in culture medium to streptococcus mutans UA159 bacterial strain biology
The inhibiting rate of film is 97.93%, and the inhibiting rate to streptococcus mutans UA246 bacterial strain biomembrane is 97.69%.
Claims (6)
1. a kind of thiazole compound XQH-3-6 of Streptococcus mutans, it is characterised in that: the compound chemical molecular formula is
C16H16ClN5O4S, Chinese N1(3- chlorphenyl-N4(5- nitrothiazole -2- base)) piperidines-Isosorbide-5-Nitrae-diformamide, English
Entitled N1- (3-chlorophenyl)-N4- (5-nitrothiazol-2-yl) piperidine-1,4-
Dicarboxamide, molecular weight 409.85, shown in chemical structure such as formula (1):
2. thiazole compound XQH-3-6 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-3-6 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-3-6 described in claim 1
With.
5. application of the thiazole compound XQH-3-6 described in claim 1 in the targeted drug of preparation prevention and treatment saprodontia.
6. thiazole compound XQH-3-6 described in claim 1 is preparing toothpaste, mouthwash or disinfection as antibacterial adding ingredient
Application in liquid.
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| CN108078822B (en) * | 2018-01-17 | 2020-06-26 | 山东大学 | Special white and black toothpaste |
| CN108210385B (en) * | 2018-01-17 | 2020-08-18 | 山东大学 | A jelly-like collutory with effects of preventing dental caries, resisting bacteria, strengthening root and consolidating teeth |
| CN108685911B (en) * | 2018-08-14 | 2020-06-26 | 山东大学 | Application of 2- [ (4-tert-butylthiazole-2-yl) imino ] thiazoline-4-one in pharmacy |
| CN109503569B (en) * | 2019-01-03 | 2021-01-15 | 山东大学 | Thiazole derivative and preparation method and application thereof |
| CN109503510B (en) * | 2019-01-03 | 2020-07-03 | 山东大学 | Antibacterial thiazole compound for preventing caries and preparation method thereof |
| CN112174943A (en) * | 2019-07-03 | 2021-01-05 | 四川大学 | Application of indole-2-ketone compound in preparation of oral bacteria prevention and treatment product |
| CN116440077A (en) * | 2023-03-15 | 2023-07-18 | 山东大学 | Oral spray for preventing and rapidly diagnosing and treating caries and preparation method thereof |
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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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