CN109111405A - A kind of Aromatic Sulfide class compound and its pesticide and medical usage - Google Patents
A kind of Aromatic Sulfide class compound and its pesticide and medical usage Download PDFInfo
- Publication number
- CN109111405A CN109111405A CN201811226569.4A CN201811226569A CN109111405A CN 109111405 A CN109111405 A CN 109111405A CN 201811226569 A CN201811226569 A CN 201811226569A CN 109111405 A CN109111405 A CN 109111405A
- Authority
- CN
- China
- Prior art keywords
- compound
- class compound
- aromatic sulfide
- agricultural
- sulfide class
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/38—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/66—1,3,5-Triazines, not hydrogenated and not substituted at the ring nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pest Control & Pesticides (AREA)
- Dentistry (AREA)
- Plant Pathology (AREA)
- Agronomy & Crop Science (AREA)
- Environmental Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Aromatic Sulfide class compound and pesticides and medical usage.Aromatic Sulfide class compound of the invention has inhibits medicine Candida albicans activity well, Aromatic Sulfide class compound of the invention has good inhibitory activity to sars coronavirus main protease, and Aromatic Sulfide class compound of the invention has good insecticidal activity, anti-agricultural disease fungi activity, anti-agricultural plant virus activity.It can be used for preparing agricultural insecticide, disinfectant use in agriculture or agricultural antivirotic and medical antifungal drug or medical antiviral.
Description
Technical field
The present invention relates to a kind of Aromatic Sulfide class compound and its pesticides and medical usage, and in particular to a kind of Aromatic Sulfide
Class compound and its purposes in terms of preparing disinfectant use in agriculture, the purposes in terms of preparing agricultural antivirotic, in preparation agriculture
With the purposes in terms of insecticide, in the purposes for preparing medical antifungal drug and in terms of SARS coronary virus resistant infection medicine
Purposes.
Technical background
Acetolactate synthestase (acetohydroxyacid synthase, AHAS, E.C.2.2.1.6) is catalysis branch
Amino acid valine, leucine and isoleucine biosynthesis by way of first key enzyme, which is not present in feeding
In newborn animal body, therefore the inhibitor on human body for targeting AHAS has biological safety (Duggleby, R.G., et
Al.J.Biochem.Mol.Biol. 2000,33,1-36).In the eighties in last century, scientists confirmed that acetolactic acid closes
After the target that can be used as herbicide at enzyme, every country releases one after another a series of AHAS inhibitor, within the scope of our times
There are sulfonylurea (SU), imidazolone type (IMI), triazolo pyrimidine class (TP), pyrimidine bigcatkin willow by the inhibitor of target of AHAS
Acids (PTB), sulfonamide carbonyltriazolinone (SCT), these herbicides generally have low toxicity, broad weed-killing spectrum and selectivity
High feature.Wherein pyrithiobac-sodium herbicide substantially belongs to one kind of pyrimidine salicylic acid compounds.Pyrithiobac-sodium is Japan
Combinatorial chemistry company develops, by combinatorial chemistry company, An Yuan company and DuPont Corporation's joint development, the nineties in last century
The broad-spectrum herbicide of new generation of listing is mainly used to prevent and treat cotton weeds at present to include herba digitariae, barnyard grass, herba eleusines indicae and herba setariae viridis
Etc. a variety of common weeds.Pyrithiobac-sodium is by 4, a 6- dimethoxypyridin ring and salicylic acid two parts with sulphur atom phase
Even composition (Nezu, Y., et al.J. Pesticide Sci.1999,24,217-229).
Certain compounds containing pyrimidine ring show good insecticidal activity, such as Pyramat (Xu Ying etc., pesticide, 2011,
50,474-478)；Certain compounds containing pyrimidine ring also show good bactericidal activity, such as methyl mepanipyrim (Chen Meihang
Deng pesticide, 2017,474-477)；We are before this study found that certain disulfide compounds containing pyrimidine ring are shown
As compound 3-32 shows inhibitory effect (Wang, the J.G.et of good sars coronavirus main protease
Al.Eur.J.Med. Chem.2017,137,450-461).
The above is it turns out that Aromatic Sulfide class compound may show sterilization, desinsection, antiviral activity.
Pyrithiobac-sodium, Pyramat, the structural formula of methyl mepanipyrim and compound 3-32 are as follows.
Summary of the invention
The purpose of the present invention is to provide a kind of Aromatic Sulfide class compound and its pesticides and medical usage, especially its
Prepare the related pesticide of fungicide, insecticide and antivirotic purposes and its preparing SARS coronary virus resistant infection, anti-
The purposes of the related pharmaceutical of candida albicans infection.
Aromatic Sulfide class compound of the invention are as follows:
Aromatic Sulfide class compound of the invention is obtained by following reaction equation
For condition A, refer to that the benzenethiol class that phenyl ring contains cyano (- CN) substitution is raw material.In this case, will contain
The benzenethiol (1) for thering is cyano to replace in being dissolved in acetonitrile, under conditions of the catalysis of appropriate triethylamine with chloro- 4, the 6- dimethoxy of 2-
Base triazine (2) is stirred at room temperature overnight, and extraction rear pillar chromatography obtains target compound (3),.
For condition B, refer to that the substitution benzenethiol that phenyl ring contains carboxyl (- COOH) is raw material.In this case, will contain
The benzenethiol (1) for having carboxyl to replace, chloro- 4, the 6- dimethoxy-triazine (2) of 2- and sodium methoxide are dissolved in methanol, and it is small to be heated to reflux 5
When, extraction rear pillar obtains target compound (3) after chromatographing.
For condition C, refer to that heterocyclic moiety is pyrimidine ring.In this case, benzenethiol (1) will be replaced, 2- methylsulfonyl
The tetrabutylammonium bromide of base -4,6- dimethoxypyridin (2), catalytic amount is reacted in 95% ethanol solution, passes through saturated carbon
Sour hydrogen sodium solution adjusts pH > 7, is heated to reflux 15 hours, obtains target compound (3) after extraction rear pillar chromatography.
It is studied by activity in vivo, Aromatic Sulfide class compound of the invention shows to inhibit medicine Candida albicans very well
Effect.
Show the Aromatic Sulfide class compound of the invention SARS under to 20 μM of concentration by the experiment of in vitro enzyme inhibition activity
The inhibitory effect of coronavirus proteolytic is fairly obvious.
It is studied by agricultural insecticidal activity experiment, Aromatic Sulfide class compound of the invention is under 600 μ g/mL concentration to viscous
Worm has good control efficiency.
It is made internal disorder or usurp by inhibiting agricultural disease fungi activity to grind, Aromatic Sulfide class compound of the invention is under 50 μ g/mL concentration
To rape sclerotium, Phytophthora capsici, apple synthetic fibre line, wheat line be withered, watermelon anthrax and rice bakanae disease have good control efficiency.
It is studied by agriculture antiviral activity, Aromatic Sulfide class compound of the invention is under 500 μ g/mL concentration to tobacco
Mosaic virus has good living body passivation.
The present invention also provides a kind of agricultural insecticides, and under effective dose, which can prevent and kill off agricultural pests, especially
Mythimna separata.
The present invention also provides a kind of disinfectant use in agriculture, and under effective dose, the agriculture pathogeny bacterium of fungicide energy has well
Preventive effect, especially rape sclerotium, Phytophthora capsici, apple synthetic fibre line, wheat line be withered, watermelon anthrax and rice bakanae disease have it is anti-well
Effect.
The present invention also provides a kind of agricultural antivirotics, and under effective dose, which has tobacco mosaic virus (TMV)
Good preventive effect.
The agricultural insecticide, disinfectant use in agriculture or agricultural antivirotic can containing with it is above-mentioned with Aromatic Sulfide class compound with
And one or more agriculturally acceptable carriers and salt.Its dosage form is missible oil, wettable powder, soluble powder, water and milk
Agent, microemulsion, aqua, suspending agent, microcapsule formulations or water dispersion granule.Its usage mode is cauline leaf process or soil treatment.
The present invention also provides a kind of for preventing and/or the drug of human or animal's fungal infection, especially Candida albicans
(Candida albicans) is killed very to a effective amount of above-mentioned Aromatic Sulfide class compound of fungi or its environmental applications with this
Bacterium or control fungi growth.
The present invention also provides a kind of for preventing and treating the drug of SARS virus infection, and the drug is by inhibiting SARS hat
Shape virus main protease has effect.
The medical antifungal drug or medical antiviral can containing above-mentioned Aromatic Sulfide class compound and one kind or
A variety of pharmaceutically acceptable carriers.The carrier include the diluent of pharmaceutical field routine, excipient, filler, adhesive,
Wetting agent, disintegrating agent, sorbefacient, surfactant, absorption carrier, lubricant and synergist etc..The drug can be made
It is used at the form of injection, tablet, pill, capsule, suspending agent or emulsion.Its administration route can be oral, percutaneous, vein or
Intramuscular injection.
Detailed description of the invention
Fig. 1 is the mono-crystalline structures figure of compound JGW6.
Specific embodiment
Substantive distinguishing features of the present invention can be embodied from the following examples, but these embodiments are only used as explanation, and
It does not limit the invention.
Raw material 2- sulfydryl -6- fluorobenzonitrile, 2- sulfydryl -6- 6-chlorophenyl nitrile, the 2- sulfydryl -6- Brominal, 2- mercapto that the present invention uses
Base -6- ioxynil, 2- sulfydryl -5- fluorobenzonitrile, 2- sulfydryl -5- 6-chlorophenyl nitrile, 2- sulfydryl -5- Brominal, the fluoro- 4- sulfydryl cyanophenyl of 3-,
The chloro- 4- sulfydryl cyanophenyl of 3-, the bromo- 4- sulfydryl cyanophenyl of 3-, 2- sulfydryl -4- 6-chlorophenyl nitrile, 2- sulfydryl -4- 4-trifluoromethylbenzonitrile, 2- sulfydryl -
5- 4-trifluoromethylbenzonitrile, 2- trifluoromethyl -4- sulfydryl cyanophenyl, 2,4,6- trichlorine cyanophenyls, 3- trifluoromethyl -4- sulfydryl cyanophenyl, 2-
Mesyl -4,6- dimethoxypyridin, 2- chlorine-4,6-dimethoxy-1,3,5-triazine, 2- sulfydryl -5- fluobenzoic acid, 2- mercapto
The fluoro- 4- mercaptobenzoic acid of base -5- bromobenzoic acid, 3-, the chloro- 4- mercaptobenzoic acid of 3-, the bromo- 4- mercaptobenzoic acid of 3-, 2- sulfydryl -4-
Fluobenzoic acid, 2- sulfydryl -4- chlorobenzoic acid, 2- sulfydryl -4- bromobenzoic acid, 2- sulfydryl -4,6- dichlorobenzoic acid, sulfydryl -2 4-,
6- dichlorobenzoic acid, 2- trifluoromethyl -4- mercaptobenzoic acid, 2- sulfydryl -4- trifluoromethylbenzoic acid and 4- sulfydryl -1,3- hexichol
The reaction raw materials such as formic acid are purchased from U.S. Aldrich chemical company, U.S.'s Aurora chemical company, Latvia FCH chemistry
Product company, Shanghai Chemhere chemical company, Shanghai Apichemical chemical company, Jiangsu HE Chemical chemistry
Product company, remaining raw materials and reagents are that Tianjin is commercially available.
The synthesis of 1. compound JGW1 of embodiment
2- sulfydryl -6- fluorobenzonitrile 0.48g (2.94mmol) is added in the round-bottomed flask of 100mL, 40mL acetonitrile is added will
It is dissolved, and chloro- 4, the 6- dimethoxy-triazine of lower addition 0.77g (4.4mmol) 2- is stirred at room temperature, is stirred overnight.Post-processing: will be anti-
System is answered to be spin-dried for.Reaction system ethyl acetate and water phase are mutually extracted, ethyl acetate layer is extracted, silica white is added and is spin-dried for.Instead
It answers the polarity of object and product to be closer to, carried out column using the eluent of 80: 1 (petroleum ethers: ethyl acetate).Obtain final product
JGW1 is white solid, quality 0.19g, yield 22%.
Likewise, compound JGW2, JGW3, JGW4, JGW5, JGW6, JGW7, JGW8, JGW9, JGW10 can be synthesized,
JGW22, JGW32 and JGW33.
The synthesis of 2. compound JGW11 of embodiment
0.28g (1.60mmol) 2- sulfydryl -5- chlorobenzoic acid, chloro- 4, the 6- dimethoxy-triazine 0.42g of 2- is added
(2.40mmol) and 0.26g (4.78mmol) sodium methoxide is in methanol, reaction reflux 5h.Post-reaction treatment: reaction system is revolved
It after dry, mutually extracted three times with NaOH aqueous solution and ethyl acetate, extracts water layer, adjust pH between 3-4 with HCl, solution becomes
At white emulsion.The water layer is washed twice with ethyl acetate later, collects organic phase ethyl acetate, and silica white is added and is spin-dried for.
Column is crossed with the eluent of 80: 1 (methylene chloride: methanol).Obtaining final product JGW11 is white solid, quality 0.08g, yield
18%.
Likewise, compound JGW12, JGW13, JGW14, JGW15, JGW16, JGW25 and JGW30 can be synthesized.
The synthesis of 3. compound JGW17 of embodiment
0.48g (2.66mmol) 2- sulfydryl -5- fluobenzoic acid, 2- mesyl -4,6- dimethoxypyridin 0.87g is added
(4.0mmol), 0.1g (0.3mmol) tetrabutylammonium bromide in 95% ethyl alcohol, surveyed every two hours by reaction reflux 15h, reaction
A fixed pH value utilizes saturation NaHCO3Aqueous solution adjusts pH value, and the pH value of reaction system is made to be maintained at 7 or more.After reaction
Reason: reaction system is spin-dried for, and is mutually extracted three times using NaOH aqueous solution and ethyl acetate, is extracted water layer, adjusts pH using HCl
Value is to 3-4, and aqueous solution becomes milky suspension at this time.The water layer is extracted with ethyl acetate later, silica white is added and is spin-dried for
Column is crossed, crosses column using the eluent of 80: 1 (methylene chloride: methanol).Obtain product 0.15g, yield 18%.
Likewise, compound JGW18, JGW19, JGW20, JGW21, JGW23, JGW24, JGW26 can be synthesized,
JGW27, JGW28, JGW29 and JGW31.
The physicochemical data and structural characterization data of compound JGW1-JGW33 is shown in Table 1.
Table 1, the physicochemical data of compound JGW1-JGW33 and spectroscopic characterization
Measurement of 4. compound of embodiment to Candida albicans minimum inhibitory concentration MIC
The fungal bacterial strain (type strain sc5314, clinical strain g5 and 17#) used in experiment is ground by Chinese Academy of Sciences microorganism
Study carefully and is provided.
First by disk diffusion method come the antifungal activity of Preliminary Determination solsonylurea compounds.By 10 μ L volume 1nM's
Untested compound is placed on inoculation plate, is cultivated 24 hours, 48 hours and 72 hours at 35 DEG C, is read and is inhibited band.
Again using broth dilution method determination compound to the minimum inhibitory concentration MIC of Candida albicans (Ghannoum,
M.A.et. Al.J.Clin.Microbiol.1992,30,2881-2886).It is female that compound is prepared using sterile DMSO as solvent
Liquid, be allowed to ultimate density in YNB (Yeast Nitrogen Base without Amino Acids) culture medium be in
A series of existing concentration gradients.Final concentration of 0.5% glucose and the ammonium sulfate of 100mM is added in YNB culture medium.From culture 48
1 fungi strain of picking measures turbidity at 530nm, using 0.5% wheat in the degerming water of 5mL on the culture dish of hour
Turbidity is modulated 1x10 by family name's standard pipe6-5x106CFU/mL, then the turbidity of inoculation liquid is diluted to about 10 with YNB culture medium4CFU/
ML, 96 orifice plates are cultivated 72 hours at 35 DEG C.Respectively in 24 hours, 48 hours and 72 hours reading turbidity values, inhibit fungi
The concentration of 90% growth is calculated.Each concentration is measured in parallel three times.
As control, the survey of conditions of similarity is also carried out to the bacteriostatic activity of compound using RPMI1640 standard medium
It is fixed, due to containing branched-chain amino acid in RPMI1640 culture medium, branched-chain amino acid can be evaluated to compound bacteriostatic activity
It influences.
Table 2 gives partial target compound and control compound ethoxysulfuron under different experimental conditions to fungi
The inhibitory activity of bacterial strain.
Minimum inhibitory concentration MIC value (μ g/mL) of 2. target compound of table to the Candida albicans of separate sources
As can be seen that the compound of the present invention has good inhibition for the Candida albicans of separate sources, trained in YNB
It is different to support the activity showed under base and 1640 culture medium conditions, it is active higher in YNB.Compound JGW1 is to 17#'s
Inhibition is comparable with comparison medicine ethoxysulfuron.
The insecticidal activity assay of embodiment 5, compound
Leaf dipping method, after postponing required concentration, into the liquid 5-6 seconds of blade leaching for being about 5-6cm diameter is taken out, is put
It dries, is placed in specified culture dish on blotting paper, access 10 3 instar larvaes of mythimna separata, be put into 27 ± 1 DEG C of insectary Zhong Guan
Inspection result after examining 3-4 days.Death rate formula are as follows:
The insecticidal effect of target compound is shown in Table 3.
Table 3, partial target compound are under 600 μ g/mL concentration to the insecticidal effect (%) of mythimna separata
| Number | Insecticidal effect | Number | Insecticidal effect | Number | Insecticidal effect |
| JGW1 | 20 | JGW2 | 5 | JGW3 | 75 |
| JGW4 | 45 | JGW5 | 20 | JGW6 | 0 |
| JGW7 | 20 | JGW8 | 0 | JGW9 | 30 |
| JGW10 | 30 | JGW11 | 80 | JGW12 | 40 |
| JGW13 | 45 | JGW14 | 30 | JGW15 | 20 |
| JGW16 | 10 | JGW18 | 65 | JGW19 | 30 |
| JGW20 | 50 | JGW21 | 50 | JGW22 | 25 |
| JGW23 | 65 | JGW24 | 30 | JGW25 | 80 |
| JGW26 | 60 |
As can be seen that the compound of the present invention has good insecticidal effect to mythimna separata under 600 μ g/mL concentration, wherein changing
The insecticidal activity for closing object JGW11 and JGW25 is up to 80%.
Embodiment 6, compound inhibit the measurement of agricultural disease fungi activity
By taking Sclerotinia sclerotiorum as an example, other agricultural disease fungies can be changed into.
In vitro test method: Sclerotinia sclerotiorum is connected in PDA culture medium and is cultivated 7 days, with punch in colony edge
The bacterium dish for producing diameter 4cm, which is inoculated into the PDA culture medium containing 50 μ g/mL and without medicament, to be cultivated 4 days, and it is straight to measure bacterium colony
Diameter, and compares the inhibition percentage for calculating medicament.
Table 4 gives the effect that part of compounds inhibits plant difference agricultural disease fungi.
Table 4, target compound are under 50 μ g/mL concentration to the inhibitory effect (%) of agricultural disease fungi
As can be seen that most compounds of the invention have good inhibitory effect for corps diseases fungi, there is part
Sterilizing rate > 80% of the compound under 50 μ g/mL concentration.
Further determine the EC that part high-activity compound inhibits wheat rust50Value, control compound is pyrithiobac-sodium,
It the results are shown in Table 5.
The EC of 5. part high-activity compound of table inhibition wheat rust50It is worth (μ g/mL)
| Wheat line is withered | EC50Value | Wheat line is withered | EC50Value |
| JGW10 | 12.4483 | JGW20 | 9.2004 |
| JGW19 | 11.7896 | JGW21 | 11.3503 |
Embodiment 7, compound resisting tobacco mosaic virus (TMV) active measurement
Virus purification and concentration mensuration are given birth to survey room establishment tobacco mosaic virus (TMV) SOP specification referring to Nankai University's element and are held
Row.Viral crude extract measures concentration after 2 polyethylene glycol centrifugal treatings, and 4 DEG C of refrigerations are spare.It is former after weighing target compound
DMF dissolution is added in medicine, is made 1 × 105μ g/mL mother liquor, it is rear to be diluted to required concentration with containing 1 ‰ Tween 80 aqueous solutions；Ningnan is mould
Plain preparation is directly watered dilution.The uniform western cigarette of 3-5 leaf phase coral of growing way is selected, medicament is mixed with isometric viral juice
After passivation 30 minutes, frictional inoculation, 20 μ g/mL of virus concentration is rinsed with flowing water after inoculation, is repeated 3 times, if 1 ‰ Tween 80s
Aqueous solution control.Number scab number after 3 days, calculates living body passivation effect.
Inhibiting rate (%)=[(control withered spot number-processing withered spot number)/control withered spot number] × 100%
The anti-TMV Activity Results of target compound and comparison medicament virazole and Ningnanmycin are shown in Table 6.
Table 6, partial target compound are passivated control efficiency (%) to the living body of TMV
As can be seen that the compound of the present invention has good living body to be passivated control efficiency tobacco mosaic virus (TMV) TMV,
Middle compound JGW17, JGW19 and JGW25 preventive effect under 500 μ g/mL concentration are better than commodity medicament virazole.
The measurement of embodiment 8, target compound SARS coronary virus resistant main protease inhibitory activity
The methods of the expression of the sars coronavirus main protease that the present invention uses, purifying step bibliography method
(Rao, Z.H. et al., PNAS, 2003,100,13190-13195), screening technique are Rao Zi and equal in CN101418334A
Disclosed in screening technique.The determination of activity of sars coronavirus main protease is using fluorogenic substrate MCA-AVLQSGFR-Lys
(Dnp) -Lys-NH2Come what is completed.The amino acid sequence of the fluorogenic substrate derives from the N-terminal of sars coronavirus main protease
Self cleavage sequence.Instrument for fluorescent strength determining is Fluoraskan Ascent luminoscope (Thermo), exciting light and hair
The wavelength for penetrating light is respectively 320nm and 405nm.
Buffer system for enzyme reaction is 50mM Tris-HCl (pH 7.3), and 1mM EDTA (is free of DTT), with buffering
Liquid configures coronavirus proteolytic (1 μM of total concentration), and alternative sample DMSO dissolved matter (final concentration of 10 μM), 303k is added
10min is placed, fluorogenic substrate MCA-AVLQ ↓ SGFR-Lys (Dnp)-Lys-NH2 is rapidly added, concentration of substrate is 20 μM.Every 5s
First order fluorescence reading is recorded, measures 200 points altogether.1200rpm shakes 5s, detects fluorescent value.Alternative sample is not added, remaining experiment
Condition is all the same.
Using the time as X-axis, fluorescent value is that Y-axis can obtain enzyme activity kinetic curve.Pass through the phase for the enzyme reaction that microplate reader records
Parameter is closed, according to fluorescence intensity and reaction time, the enzymatic reaction of 10s before being analyzed using 5 software of GraphPad Prism
Rate.Set V0For the initial velocity of the enzymatic reaction of without inhibitor, ViFor the initial velocity of the enzymatic reaction of inhibiting.According to
Enzyme's reaction speeding calculates residual activity Ra (Residual Activity, Ra) (V of each compoundi/V0) and inhibit
Rate Ir (Inhibition Rate, Ir) (1-Vi/V0)。
Secondary screening is carried out for the compound of residual activity < 20%, excludes the possibility of false positive.Residual activity is lower than
15% compound, design fluorescent quenching experiment.The residual activity percentage and fluorescent quenching rate for comprehensively considering compound can
To judge compound to the inhibiting effect of sars coronavirus main protease.
Because the system is mainly to be screened by fluorescence intensity, as the compound for having fluorescence or and MCA
Similar compound all can generate interference to system.In addition, many Dnp similar structures can be quenched the fluorescence of system and cause vacation
The positive, in order to exclude false positive results, we allow system fluorescence using first reacting with fluorogenic substrate main protease for a period of time
Reach maximum value Q1, then the compound with experimental group equivalent is added in system, and the fluorescent value size of detection architecture is Q2.It will
Fluorescent quenching rate Qr (Qr=(Q1-Q2)/Q2*100%) is calculated according to formula in the fluorescent value of the two.When fluorescent quenching rate is high
It needs to exclude for false positive results in 20%, is positive findings when fluorescent quenching rate is lower than 20%, next step research can be carried out.
Target compound is shown in Table 7 to the inhibiting rate of the main albumen of sars coronavirus.
Table 7, part of compounds are under 20 μM of concentration to the inhibiting rate (%) of the main albumen of sars coronavirus
| Number | Inhibiting rate | Number | Inhibiting rate | Number | Inhibiting rate |
| JGW1 | 90.8 | JGW2 | 76.6 | JGW3 | 96.3 |
| JGW4 | 98.4 | JGW5 | 100 | JGW6 | 85.1 |
| JGW7 | 100 | JGW11 | 94.5 | JGW12 | 24.2 |
| JGW13 | 48.8 | JGW14 | 89.5 | JGW15 | 25.5 |
| JGW16 | 25 | JGW19 | 26.8 | JGW22 | 29.9 |
| JGW24 | 84.7 | JGW25 | 21.7 | Pyrithiobac-sodium | 9.1 |
As can be seen that the compound of the present invention has very strong inhibition to the main albumen of sars coronavirus, under 20 μM of concentration,
The equal > 90% of inhibiting rate of these compounds of compound JGW1, JGW3, JGW4, JGW5, JGW7, JGW11.
Claims (11)
1. a kind of Aromatic Sulfide class compound, it is characterised in that the compound is
2. a kind of purposes of the Aromatic Sulfide class compound described in claim 1 in terms of preparing agricultural insecticide.
3. thin purposes of the ether compound in terms of preparing disinfectant use in agriculture of a kind of fragrance described in claim 1.
4. a kind of purposes of the Aromatic Sulfide class compound described in claim 1 in terms of preparing agricultural antivirotic.
5. a kind of use of the Aromatic Sulfide class compound described in claim 1 in terms of preparing medical anti-candida albicans drug
On the way.
6. a kind of use of the Aromatic Sulfide class compound described in claim 1 in terms of preparing medical anti-SARS virus infection medicine
On the way.
7. the application of compound according to claim 6, wherein the compound is the small of sars coronavirus main protease
Molecule inhibitor.
8. a kind of agricultural insecticide, disinfectant use in agriculture or agricultural antivirotic, it is characterised in that it contains described in claim 1
A kind of Aromatic Sulfide class compound and agriculturally acceptable carrier.
9. agricultural insecticide according to claim 8, disinfectant use in agriculture or agricultural antivirotic, it is characterised in that its dosage form
For missible oil, wettable powder, soluble powder, aqueous emulsion, microemulsion, aqua, suspending agent, microcapsule formulations or water dispersible granular
Agent.
10. a kind of medical antibiotic or medical antiviral, it is characterised in that it contains a kind of thioether described in claim 1
Class compound and one or more pharmaceutically acceptable carriers；The carrier includes the diluent of pharmaceutical field routine, assigns
Shape agent, filler, adhesive, wetting agent, disintegrating agent, sorbefacient, surfactant, absorption carrier, lubricant or synergy
Agent.
11. medical antibiotic according to claim 10 or medical antiviral, it is characterised in that it is containing described
Injection, tablet, pill, capsule, suspending agent or the emulsion of antibacterials.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811226569.4A CN109111405B (en) | 2018-10-22 | 2018-10-22 | Aromatic thioether compound and pesticide and medical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811226569.4A CN109111405B (en) | 2018-10-22 | 2018-10-22 | Aromatic thioether compound and pesticide and medical application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109111405A true CN109111405A (en) | 2019-01-01 |
| CN109111405B CN109111405B (en) | 2021-07-30 |
Family
ID=64854955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811226569.4A Active CN109111405B (en) | 2018-10-22 | 2018-10-22 | Aromatic thioether compound and pesticide and medical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109111405B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115385917A (en) * | 2022-08-09 | 2022-11-25 | 贵州大学 | Tryptanthrin 7-position or 9-position substituted aromatic thioether derivative, and preparation method and application thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0346789A2 (en) * | 1988-06-16 | 1989-12-20 | BASF Aktiengesellschaft | Salicylic-acid derivatives and their sulfur analogues |
| CN1052852A (en) * | 1989-12-28 | 1991-07-10 | 库米阿依化学工业株式会社 | Pyrimidine or pyrrolotriazine derivatives and contain the herbicidal composition of such material |
| EP0493321A1 (en) * | 1990-12-21 | 1992-07-01 | Ciba-Geigy Ag | Pyrimidinyl- and triazinyl-salicylamides, their use and their preparation |
| WO1993003017A1 (en) * | 1991-07-31 | 1993-02-18 | Kumiai Chemical Industry Co., Ltd. | Pyrimidine or triazine derivative and herbicide |
| US5360913A (en) * | 1990-10-26 | 1994-11-01 | Basf Aktiengesellschaft | Salicyclic acid derivatives |
| WO2009075691A1 (en) * | 2007-04-18 | 2009-06-18 | Acadia Pharmaceuticals Inc. | Cb-1 modulating compounds and their use |
| CN105837480A (en) * | 2016-03-31 | 2016-08-10 | 南京理工大学 | Preparation method for asymmetric aromatic thioether |
-
2018
- 2018-10-22 CN CN201811226569.4A patent/CN109111405B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0346789A2 (en) * | 1988-06-16 | 1989-12-20 | BASF Aktiengesellschaft | Salicylic-acid derivatives and their sulfur analogues |
| KR900012909A (en) * | 1988-06-16 | 1990-09-03 | 바스프 악티엔게젤샤프트 | Salicylic acid derivatives and their sulfur-containing analogs |
| CN1052852A (en) * | 1989-12-28 | 1991-07-10 | 库米阿依化学工业株式会社 | Pyrimidine or pyrrolotriazine derivatives and contain the herbicidal composition of such material |
| US5360913A (en) * | 1990-10-26 | 1994-11-01 | Basf Aktiengesellschaft | Salicyclic acid derivatives |
| EP0493321A1 (en) * | 1990-12-21 | 1992-07-01 | Ciba-Geigy Ag | Pyrimidinyl- and triazinyl-salicylamides, their use and their preparation |
| WO1993003017A1 (en) * | 1991-07-31 | 1993-02-18 | Kumiai Chemical Industry Co., Ltd. | Pyrimidine or triazine derivative and herbicide |
| WO2009075691A1 (en) * | 2007-04-18 | 2009-06-18 | Acadia Pharmaceuticals Inc. | Cb-1 modulating compounds and their use |
| CN105837480A (en) * | 2016-03-31 | 2016-08-10 | 南京理工大学 | Preparation method for asymmetric aromatic thioether |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115385917A (en) * | 2022-08-09 | 2022-11-25 | 贵州大学 | Tryptanthrin 7-position or 9-position substituted aromatic thioether derivative, and preparation method and application thereof |
| CN115385917B (en) * | 2022-08-09 | 2024-01-19 | 贵州大学 | Tryptanthrin 7-or 9-substituted aromatic thioether derivative, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109111405B (en) | 2021-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liu et al. | Design, synthesis, and pesticidal activities of pyrimidin-4-amine derivatives bearing a 5-(trifluoromethyl)-1, 2, 4-oxadiazole moiety | |
| CN108271339A (en) | Seed endophyte, compositions related and its application method between cultivar and species | |
| US20080200461A1 (en) | Modulators of acetyl-coenzyme a carboxylase and methods of use thereof | |
| EP2301925A1 (en) | A methoxyl acrylic ester fungicide, the preparation method and uses thereof | |
| WO2006081759A1 (en) | N-(2-substituted phenyl)-n-methoxycarbamates and their preparation as well as use | |
| CN101250167B (en) | Heterocyclic compounds containing thiadiazole as well as synthesis and uses thereof | |
| CN102276596A (en) | Thiadiazole compound as well as preparation and application thereof | |
| CN104488901B (en) | A kind of complex composition and preparation of the azoles of bacterium containing methylsulfonyl and antibioticses bactericide | |
| Liu et al. | The discovery of 3-(1-aminoethylidene) quinoline-2, 4 (1 H, 3 H)-dione derivatives as novel PSII electron transport inhibitors | |
| Cao et al. | Bioisosterism and scaffold hopping in modern nematicide research | |
| CN107033098B (en) | 1,3,4- oxadiazoles sulphur/oxygen ether compound of amide bond and preparation method and application | |
| CN109942540A (en) | A kind of 1,4- pentadiene -3- ketones derivant, preparation method and the application of the ester containing thiophene-sulfonic acid | |
| Basak et al. | Halogenated quinolines bearing polar functionality at the 2-position: Identification of new antibacterial agents with enhanced activity against Staphylococcus epidermidis | |
| CN101885724B (en) | Heterocyclic ketone-containing N-substituted phenyl pyrazole compound, preparation method thereof and application thereof in prevention and control of plant diseases and insect pests | |
| Yang et al. | Design, synthesis and nematicidal activitives of trifluorobutene amide derivatives against Meloidogyne incognita | |
| CN109111405A (en) | A kind of Aromatic Sulfide class compound and its pesticide and medical usage | |
| Veignie et al. | Design of new antifungal dithiocarbamic esters having bio-based acrylate moiety | |
| CN107089975B (en) | The thiazole salt compounds and preparation method and application of the base of oxadiazoles containing 1,3,4- | |
| Tang et al. | Morpholine derivatives in agrochemical discovery and development | |
| CN104542625B (en) | Compound composition containing methanesulfonyl bacteria oxazole and oxazole bactericide and preparation | |
| CN108117528B (en) | 2, 5-substituent-1, 3, 4-oxadiazole sulfone derivative, preparation method and application thereof | |
| CN103641824B (en) | A kind of furan nucleus 2,5-bis-that contains replaces-1,3,4-thiadiazole compound and its preparation method and application | |
| CN107698525A (en) | A kind of substituted benzene oxygen sulfonyl urea compound and its production and use | |
| CN107098869B (en) | Bisamide class compound of the base of oxadiazoles containing 1,3,4- and preparation method and application | |
| CN100569764C (en) | A kind of substituted benzene formyl amido methyl-formiate compounds and preparation method thereof and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20211207 Address after: 071000 West Unit 3 Floor, Building 12, Zhongguancun Innovation Base, 369 Huiyang Street, Baoding City, Hebei Province Patentee after: Baoding Norway Technology Co.,Ltd. Address before: 300071 Tianjin City, Nankai District Wei Jin Road No. 94 Patentee before: NANKAI University |