CN104798808B - Application of 2-quinazoline diselenide derivatives in preparing phytopathogen resisting medicine - Google Patents
Application of 2-quinazoline diselenide derivatives in preparing phytopathogen resisting medicine Download PDFInfo
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- CN104798808B CN104798808B CN201510223872.9A CN201510223872A CN104798808B CN 104798808 B CN104798808 B CN 104798808B CN 201510223872 A CN201510223872 A CN 201510223872A CN 104798808 B CN104798808 B CN 104798808B
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- Prior art keywords
- diselenide
- bis
- pathogenic bacteria
- quinazoline
- compound
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
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- 150000003957 organoselenium compounds Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
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- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of 2-quinazoline diselenide derivatives in preparing phytopathogen resisting medicine. The 2-quinazoline diselenide derivatives are compound shown by a structural formula (I). According to the application of the 2-quinazoline diselenide derivatives in preparing the phytopathogen resisting medicine, the compound or pharmaceutically acceptable salt of the compound has good phytopathogen resisting activity on treating and preventing various kinds of phytopathogen and especially has excellent antibacterial effects on gibberella zeae, fusarium oxysporum and cytospora mandshurica.
Description
Technical Field
The invention belongs to organic selenium nitrogen heterocyclic quinazoline medicines, and particularly relates to antibacterial bioactivity of a plant pathogenic bacteria resistant medicine bisquinazoline diselenide compound.
Background
In recent years, a great deal of research data show that quinazoline compounds show good biological activity, and a great deal of documents, patents, articles and the like report every year. Oxadiazole-containing quinazoline oxime ether derivatives were found to have anti-TMV activity as early as 1984 (Srivastava, N.; Bahadur, S.; Verma, H. N.; et al Synthesis of new 5, 3/5-and 2-substitated (1,3,4) -oxadiazoles and related products as potential inhibitors and inhibitors, Current science, 1984, 53 (5), 235-239.); the quinazoline oxime ether compounds also have activity against Tobacco Mosaic Virus (TMV), Cucumber Mosaic Virus (CMV) and other plant pathogens (Liu Xin, Huang run, Li Hui Ying, etc.. the synthesis and biological activity of O- (4-quinazoline) hydroximic acid thioester (amide) compounds, application chemistry, 1999, 16 (2), 23-26; Huang run, Li Hui Ying, Ma military, etc.. the synthesis of 4-oxime ether quinazoline compounds and the activity against plant virus TMV. advanced chemical reports, 1996, 17 (4), 571-; leistner et al, 1991, disclose a quinazolinone derivative antiviral patent that inhibits Potato Virus X (PVX) replication on tobacco sheets (Leistner, S.; Siegling, A.; Strohscheid, T.; et al, Preparation of 3- (alkylthioalkyl) -2, 4-dioxol-1, 2,3,4-tetrahydroquinazolines. DD 293816 (1991), [ chem. Abst. 1991, 117, 48587)]) (ii) a In recent years, quinazolinones have been found to have antimalarial and anticoccidial activity (McLaughlin N P, EvansP. hydrolysis of vinyl sulfates (+) -and (-) -febrifugine and halofuginone. The Journal of Organic chemistry, 2010, 75(2), 518-); 2-thioether-substituted quinazolinones also have excellent antibacterial activity against gram-positive and gram-negative bacteria (Fatmah A M, Al-Omary, Ghada S, et Al. Nonclasic antifilerates, part 3: Synthesis, biological evaluation and molecular modeling test of spatial 2-heterocyclic thio-quinazolin-4-ones. European Journal of medicinal chemistry, 2013, 63, 33-45.); quinazolinyl-4-carbonyl quinazolines have certain anti-inflammatory and anti-ulcer activities (Gineinah, M.; EI-Sherbeny, M. A.; Nasr, M. N.; et al. synthetic anti-inflammatory sc)rening of sodium quinazoline and quinazoline-4-oxoquinazoline derivatives, Archiv der Pharmazie (Weinheim, Germany) chem.,2002, 335 (11), 556-562); quinazoline oximeters have acaricidal activity (Lamberth, C.; Hillesheim, E.; Bassan, D.; et al. Synthesis and acrylic activity of 4-pyrimidinyloxy-and 4-pyrimidinylaminophenyldioxides and oximeter. Pest. Manag. Sci., 2000, 56 (1), 94-100.); the 4-aminoquinazoline compounds have good antibacterial activity (Shalaby, A.; EI-Khamry, A. M.; Shiba, S. A.; et al. Synthesis and anti-inactivation of sodium new quinazoline and benzoxazinone derivatives. Archiv der Pharmazie (Weinheim, Germany). 2000,333(11) 365-; liu gang, Song Bao' an, sang Wei Jun, etc. the synthesis and biological activity research of N-substituted aromatic ring-4-amino quinazoline compounds, organic chemistry, 2004, 24 (10), 1296-one-well 1299. Quinazoline compounds possess such a wide range of agricultural biological activities that they have attracted great interest to medical researchers and chemists.
Selenium is a trace element necessary for human bodies, is a constituent component of various enzymes, and has the functions of resisting diseases, delaying senility and enhancing the immunity of the organisms in the human bodies, thereby achieving the effect of balancing the environment in the organisms. More than forty human diseases related to selenium are found, in particular to a plurality of frequently encountered diseases and common diseases which seriously affect the human health, such as cardiovascular and cerebrovascular diseases, cancers, diabetes, inflammation, immune system dysfunction and the like, and endemic selenium deficiency diseases, such as keshan disease, Kashin-Beck disease and the like in China. Selenium has a wide range of biological functions, is an important component of erythrocyte glutathione peroxidase, and can participate in the synthesis of coenzyme A and coenzyme Q. In recent years, organic selenium compounds such as selenium chitosan selenide, selenium-containing protein, selenium polysaccharide, selenium methionine, selenium carrageenan, selenium tea polyphenol and other selenium micromolecular or biological macromolecule compounds are obviously higher than those of corresponding compounds which are not selenylated in terms of biological activities such as tumor resistance, cardiovascular disease treatment, aging resistance, organism immunity improvement and the like. Representative drugs currently under clinical investigation, such as Ebselen (Ebselen) as an anti-inflammatory and anti-oxidant drug (Schewe T. Gen. Pharmacol-Vasc. S., 1995, 26 (6), 1153-1169; Azad G K, Balkrishna S J, Sathish N, et al, biochem. Pharmacol., 2012, 83 (2), 296-303) and the highly effective anti-viral, anti-neoplastic drug Selenazolofuran (selezofurin) (Franchetti P, Cappelluci L, Griffinii M, et al. Inosine Monophosphate Dehydrogene, Chapter 11, pp 212-230, Acssypium Series, Vol. 839, 2003-03-03R.; SidWer W, Huffman J, Anffe W, Call. 353, 1986, 343). The development of new drugs by using the unique chemical and biological properties of selenium has attracted increasing attention of scientists, and the synthesis of various bioactive organic selenium compounds is still a hot spot of current drug research (Ninomiya M, Garud D R, Koketsu M, et al.
In recent years, scientists have found that oxygen, sulfur and selenium are the same group elements of group VI, and that selenium and sulfur behave very similarly and have unique degradability, biological oxidation resistance and radical scavenging activity, and at the same time, are not as odorous as sulfur atoms. Gradually becomes a hotspot of researches on chemistry, biology, medicine and pharmacology, environmental science, medicine and pharmacology and the like, and is widely applied to agriculture, food and medicine. In the field of Agricultural chemicals, research on the activity of selenium element introduced into the molecules of chemical compounds, such as selenoyltriazole amide compounds (Liu Rui, Li Cheng, Huang Qing, etc.. research on the synthesis and activity of selenium-containing compounds, Shanghai: university of eastern China, 2004.), selenium-bis-azole compounds (Zhao Wei Guang, Liu Xuan, Li Zheng name. 1,2, 3-selenadiazole-5-methanphthalein amide compounds, organic Chemistry, 23 (supplement): 17.), selenium-morpholine derivatives (von Ju hong., heteroatom organic compound research (II) having biological activity, Shanghai: university of Mediterranean China, 2002.), 3- (substituted phenylselenoyl) -1-ribosyl/deoxyribose-1H-1, 2, 4-triazole compounds (Pravin K. Singh. Agricuicural and Chemistry, 2011, 60 (23), 5813-. Scientists use the successful experience and method in medicine for reference, research the synthesis and activity of selenium-containing compounds by the principle of bioisostery and the active group splicing, and find out organic selenium compounds with high bactericidal, insecticidal and herbicidal activities.
Chemists have shown a great interest in organoselenium compounds containing Se-Se bonds, firstly because of the high specificity of such compounds in terms of selectivity of organic synthesis; furthermore, in some important biological processes, such compounds are important intermediates. Diselenide compounds have been one of the research hotspots of active drugs, and Fischer et al found that bis (o-carbamoylphenyl) diselenide has significant antioxidant activity and is superior to Ebselen (Fischer H, Dereu N, Kuhl P, et al, DE 3513071, 1986). Wilson et al found that diaryl diselenides also have activity mimicking GSH-Px, and found that the introduction of ammonium salt groups ortho to the selenium atom greatly enhanced activity (Wilson S R, Zucker P A, Huang R R C, et al, J. Am. chem. Soc., 1989, 111 (15): 5936-5939.). Wang et al applied a phase transfer catalyst PEG-400 to design and synthesize a series of substituted diphenyl diselenide compounds by one-step method, and developed the synthesis method of diaryl diselenide compounds (Wang J X, Wang C H, Cui W F, et al, J.chem. Soc. Perkin Trans. 1, 1994, 2341-. Chinese patent CN 102627614 applied by the subject group discloses a preparation method and anticancer activity of a class of bis-quinazoline diselenide compounds, and activity tests show that the compounds in the local part have proliferation inhibition effect on breast cancer cells MDA-MB-435 and show good anticancer activity (Liu gang, Liu Chun Lian, Xu Sheng Guang. CN 102627614, 2012-08-08). Subsequently, an invention patent (Liu gang, Huang Yin Jiu, Sulin, etc. CN 103191121A, 2013-07-10) about the application of the di (quinazoline-4-yl) diselenide compound in preparing anticancer drugs is applied, and excellent activity of the di (quinazoline-4-yl) diselenide compound on anticancer activity is disclosed. A series of quinazoline diselenide compounds are synthesized by carrying out diselenide reaction on anthranilic acid or substituted anthranilic acid as a starting material by people like Liu gang and the like in the 6 th meeting place abstract of the 28 th academic annual meeting of the Chinese chemical society, sequentially carrying out solvent-free reaction and ring closure on the anthranilic acid or substituted anthranilic acid, chlorination on phosphorus oxychloride or thionyl chloride and reaction on potassium diselenide, wherein the activity test of a target compound is in progress (Liu gang, Marvin spring, King, and the like. the 6 th meeting place abstract of the 28 th academic annual meeting of the Chinese chemical society is in the process of 2012.04.14).
The diquinazoline diselenide compounds related to the application are all reported compounds, and are obtained by reacting 4-chloroquinazoline or substituted 4-chloroquinazoline raw materials with sodium diselenide in an alcohol solvent.
The research of the invention finds that the bis-quinazoline diselenide compound has excellent anti-plant pathogenic bacteria activity, probably as a result of dual action of quinazoline ring and bis-selenide and different action sites, selenol or selenol can be generated in the degradation process of the compound, and the compound also has anti-plant pathogenic bacteria activity, so that the activity is improved or further maintained. The activity test shows that the inhibition activity of partial compounds under lower concentration is superior to that of a commercial contrast medicament hymexazol, and the bacteriostatic effect is excellent.
Disclosure of Invention
The application of the bis-quinazoline diselenide compound in preparing the anti-phytopathogen medicament is characterized in that the molecular structural formula of the bis-quinazoline diselenide derivative is a compound represented by the following general formula (I):
（I）
wherein,
R1、R2、R3、R4and R5Each is hydrogen, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a phenyl group.
The application of the compound in preparing the anti-phytopathogen medicine is characterized in that the medicine is a medicine composition and comprises an effective amount of the compound shown as the formula (I) or pharmaceutically acceptable salt thereof.
The application of the composition in preparing the anti-phytopathogen medicine is characterized in that the pharmaceutically acceptable salt comprises inorganic acid salt or organic acid salt.
The application of the compound in preparing the anti-phytopathogen medicine is characterized in that the compound in the formula (I) is used for treating and preventing various phytopathogens.
The application of the plant pathogenic bacteria in preparing the anti-plant pathogenic bacteria medicine is characterized in that the plant pathogenic bacteria comprise wheat scab original bacteria (A), (B), (C) and (C)Gibberella zeae) Pathogenic bacteria of pepper wilt: (Fusarium oxysporum) Pathogenic bacteria of apple rot: (Cytospora mandshurica) Pinellia Ternate Fusarium (B.F.)Rhizoctonia solani) Pathogenic bacteria of rice sheath blight (A)Thanatephorus cucumeris) Sclerotium pathogenic bacterium of colza: (Sclerotina sclerotiorum) Cucumber Botrytis cinerea (a)Botrytis cinerea) Late blight of potatoPhytophthora infestans) Pathogenic bacteria of apple anthrax: (Colletotrichum gloeosporioides)。
The pharmaceutical compositions comprise as active ingredient at least a compound of formula (I) as such or in admixture with one or more pharmaceutically acceptable inert non-toxic excipients or carriers.
The application in the preparation of the anti-phytopathogen medicament can be a medicinal composition, characterized in that it comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises a salt of an inorganic acid, such as a hydrohalic acid salt, a sulfate salt, a hydrogen sulfate salt, a phosphate salt, a monohydrogen phosphate salt, a dihydrogen phosphate salt, a nitrate salt, a carbonate salt, or a hydrogen carbonate salt, or salts of organic acids such as acetate, trifluoroacetate, trichloroacetate, citrate, maleate, fumarate, oxalate, monohydroxy oxalate, phosphonate, alkylsulfonate, arylsulfonate, benzoate, fumarate, succinate, lactate, tartrate, malate, citrate, ascorbate, salicylate, caffeate, nicotinate and 2-chloronicotinate.
In the context of the present invention, the halogen atom may be a fluorine, chlorine, bromine or iodine atom.
In the present invention, the hydrohalic acid salt may be a hydrofluoride salt, a hydrochloride salt, a hydrobromide salt, or a hydroiodide salt atom.
The preparation method of the drug for resisting phytopathogen is characterized in that 4-chloroquinazoline, sodium diselenide or potassium diselenide or lithium diselenide is taken as raw material, and water, ethanol, isopropanol, ethanol, water, ethanol, sodium, potassium, lithium, potassium, sodium, potassium, lithium, potassium, sodium, potassium,N,N-dimethylformamide, dioxane, dimethylsulfoxide or a mixture thereof as a solvent, and reacting to synthesize: adding 4-chloroquinazoline in batches at 20-120 ℃ into the prepared solution of sodium diselenide, potassium diselenide or lithium diselenide, performing reflux reaction for 3-36h, cooling, performing suction filtration to obtain a brownish red solid, and using the brownish red solidN,NRecrystallizing dimethyl formamide and water to obtain orange to brownish red crystals, namely the product of the bis-quinazoline diselenide compound. The synthetic chemical reaction equation is as follows:
the method is suitable for synthesizing all the above bis-quinazoline diselenide compounds.
Description of the drawings:
FIG. 1 shows the change of spore germination after treatment of wheat scab original fungi with the compound bis (6-chloroquinazolin-4-yl) diselenide.
Detailed Description
The following examples will better illustrate the invention, but it should be emphasized that the invention is in no way limited to what is shown in these examples.
The following examples show different aspects of the invention, and the data given include specific operating and reaction conditions and products whose purity confirms their structure by infrared, hydrogen and carbon nuclear magnetic resonance spectroscopy.
Example 1 Synthesis of bis (6-chloroquinazolin-4-yl) diselenide.
0.3 g (3.8 mmol) of selenium, 0.1 g (2.6 mmol) of sodium borohydride and 15 mL of absolute ethyl alcohol are sequentially added into a 150 mL three-necked bottle provided with a reflux condenser tube, the temperature of an ice water bath is controlled to be below 3 ℃, the solution turns brown from black, the solution turns reddish brown after about 10min, the ice bath is removed, and the solution is heated, stirred and refluxed for 1.5 h and turns dark brown. Adding 2.5 mmol 4, 6-dichloroquinazoline in batches, adding for about 1h, changing the solution into dark brick red, refluxing for 24 h, cooling to room temperature, adjusting pH of the reaction system to =5-6 with glacial acetic acid, removing solvent under reduced pressure to obtain solid in earthy yellow color, and recrystallizing with DMF and water (V)DMF/H2O= 5: 1) to obtain orange crystals, namely the product bis (6-chloroquinazoline-4-yl) diselenide, wherein the yield is 29.0 percent, and the melting point is 255.2-257.9 ℃. IR (KBr) v 3083.3 (v)Ar-H), 1615.4-1450.9 (quinazoline skeleton vibration), 825.7, 681.7 (Ar-H),647.7 (vC-Cl) cm-1;1H NMR (DMSO-d 6 , 600 MHz) : 8.55 (d,J= 1.8 Hz, 2H,quinazoline H-5, 5’), 8.20 (s, 2H, quinazoline H-2, 2’), 8.00 (dd,J H7-H8 = 8.4Hz,J H7-H5 = 1.8 Hz, 2H, quinazoline H-7, 7’), 7.78 (d,J= 8.4 Hz, 2H,quinazoline H-8, 8’);13C NMR (DMSO-d 6 , 150 MHz) : 186.9 (2C, quinazoline C-4, 4’), 145.2 (2C, quinazoline C-2, 2’), 142.6 (2C, quinazoline C-9, 9’),136.1 (2C, quinazoline C-6, 6’), 133.9 (2C, quinazoline C-7, 7’), 133.6 (2C,quinazoline C-8, 8’), 131.3 (2C, quinazoline C-10, 10’), 130.9 (2C,quinazoline C-5, 5’).
Example 2, bis (6-chloroquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: weighing the compound according to the required dosage, putting the compound into a 10 mL volumetric flask, adding a small amount of solvent (0.5mL) to fully dissolve the compound, and then using sterilized distilled water containing 0.5% Tween 20 to make the volume of the solution to be 10 mL to prepare a compound solution with the corresponding concentration.
(2) Bacteriostatic activity assay of compounds: an ex vivo growth rate method was used. Heating potato glucose agar culture medium (PDA culture medium: 200 g of potato, 20 g of agar, 20 g of glucose and 1000 mL of distilled water) to molten state (40-60 deg.C), pouring 10 mL of medicinal liquid (10 times of the final concentration of medicinal liquid) into 90 mL of PDA culture medium, shaking thoroughly, pouring into culture dish with diameter of 9 cm, standing horizontally, and cooling to solidify. A bacterial dish with the diameter of 5 mm is punched at the edge of a fresh pathogenic bacterium colony cultured for 4 d by a puncher, the bacterial dish is placed in the center of a PDA (personal digital assistant) plate containing a medicament in an inverted mode, then the bacterial dish is placed in a constant-temperature constant-humidity incubator at 27 ℃ for inverted culture, when a solvent control bacterial colony grows to be close to two thirds of the position of the plate, observation is started, the diameter (cm) of the bacterial colony is measured by a cross method, and an average value is obtained. The control was free of agent, but contained the same concentration of solvent and 0.5% Tween 20. Each treatment was repeated three times. The inhibition rate of the agent on the growth of hyphae is calculated by the following formula:
whereinIIn order to achieve the suppression rate,Cthe diameter of the blank is the diameter of the blank,Tto process the diameter.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: preliminary screening is carried out on the in vitro bacteriostatic activity of the compound di (6-chloroquinazoline-4-yl) diselenide to discover (Table 1), the compound di (6-chloroquinazoline-4-yl) diselenide has good inhibitory activity on three plant pathogenic bacteria when the concentration is 50 mug/mL, wherein the inhibitory rate on wheat scab original bacteria reaches 96.3%, which is far higher than the inhibitory rate (53.68%) of a commercial medicament hymexazol on wheat scab original bacteria, and the method is worthy of further research and development.
TABLE 1 bacteriostatic activity of the compound bis (6-chloroquinazolin-4-yl) diselenide at 50 μ g/mL against three phytopathogenic fungi
Example 3 regression equation for Di (6-chloroquinazolin-4-yl) diselenide virulence and EC50And (4) measuring the value.
The test method comprises the following steps: on the basis of a preliminary screening experiment, 6 concentrations are designed from the range that the inhibition rate of a compound bis (6-chloroquinazolin-4-yl) diselenide on pathogenic bacteria reaches about 10-90%, a medicament is prepared into a series of concentrations by a solvent by adopting a double dilution method, the inhibition rate of each concentration is determined by adopting a growth rate method, and each treatment is repeated three times. Converting the inhibition rate data into a probability value (y), converting the medicament concentration (mug/mL) into a logarithm value (x), performing regression analysis in SPSS11.5 software to obtain a virulence regression equation (y = ax + b) and a correlation coefficient (r), and calculating the concentration (EC) of the medicament in inhibiting pathogenic bacteria50) And the commercial drug hymexazol is used as a positive control.
And (3) test results: the compound di (6-chloroquinazoline-4-yl) diselenide has good bacteriostatic activity, so that the compound is subjected to activity test for resisting various plant pathogenic fungi, and regression analysis is performed on the bacteriostatic activity of the compound by taking the commercial medicament hymexazol as a contrast, and the activity result is shown in table 2.
TABLE 2 bacteriostatic regression analysis of the compound bis (6-chloroquinazolin-4-yl) diselenide
The antibacterial regression analysis (Table 2) of the compound bis (6-chloroquinazolin-4-yl) diselenide and the commodity medicament hymexazol shows that the compound bis (6-chloroquinazolin-4-yl) diselenide inhibits the medium concentration (EC) of wheat scab pathogenic bacteria, apple rot pathogenic bacteria, potato late blight pathogenic bacteria and pinellia ternate damping-off pathogenic bacteria50) All are lower than the inhibition medium concentration of hymexazol, and have better broad-spectrum antibacterial activity.
Example 4 Effect of bis (6-chloroquinazolin-4-yl) diselenide on spore germination.
The test method comprises the following steps: weighing compounds to prepare a toxic culture medium, enabling final concentrations to be 0 (control), 20, 40, 60, 80 and 100 mug/mL respectively, repeatedly treating three times, diluting a pathogen microspore suspension to about 50 spores per visual field, uniformly coating the pathogen microspore suspension on the toxic flat culture medium, carrying out dark culture at the temperature of 27 ℃, observing and counting under a microscope (taking the sum of three visual fields per dish) when the control germination rate is more than 90%, and calculating the germination rate.
And (3) test results: from the experimental results (FIG. 1), it can be seen that the germination rate of wheat scab original fungus microspores is lower and lower with the increase of the concentration of the compound bis (6-chloroquinazolin-4-yl) diselenide and the control agent hymexazol, and the germination rate of the wheat scab original fungus microspores treated with the compound bis (6-chloroquinazolin-4-yl) diselenide is always lower than that of the wheat scab original fungus microspores treated with the control agent hymexazol. When the concentration reaches 100 mug/mL, the germination rate of the spores treated by the compound bis (6-chloroquinazolin-4-yl) diselenide is only 2 percent and is lower than that of the control medicament by 23 percent. Therefore, the inhibition effect of the di (6-chloroquinazoline-4-yl) diselenide on the growth of wheat scab primary fungus hypha can be explained.
Example 5 bis (6, 8-dichloroquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6, 8-dichloroquinazolin-4-yl) diselenide following the preparation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6, 8-dichloroquinazolin-4-yl) diselenide according to the test for determining bacteriostatic activity described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: as can be seen from the results in Table 3, the inhibition rate of the compound bis (6, 8-dichloroquinazolin-4-yl) diselenide on wheat scab zymogen reaches 83.67% when the concentration is 50 mug/mL, and the inhibition rate is far higher than that of a commercial medicament hymexazol on wheat scab zymogen (53.68%), so that the bacteriostasis effect is excellent.
TABLE 3 bacteriostatic activity of the compound bis (6, 8-dichloroquinazolin-4-yl) diselenide at 50 μ g/mL against three phytopathogenic fungi
Example 6 bis (6-bromoquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6-bromoquinazolin-4-yl) diselenide by the preparation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6-bromoquinazolin-4-yl) diselenide as per the bacteriostatic activity assay described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: from the results in Table 4, the inhibition rate of the compound bis (6-bromoquinazoline-4-yl) diselenide on wheat scab pathogenic bacteria reaches 76.33%, the inhibition rate on pepper wilt pathogenic bacteria reaches 64.71%, the inhibition rate on apple rot pathogenic bacteria reaches 70.87% when the concentration is 50 mug/mL, and the inhibition rates are higher than the inhibition rates of the commodity medicament hymexazol on wheat scab pathogenic bacteria (53.68%), pepper wilt pathogenic bacteria (52.11%) and apple rot pathogenic bacteria (52.02%), and the bacteriostasis effect is excellent.
TABLE 4 bacteriostatic activity of the compound bis (6-bromoquinazolin-4-yl) diselenide at 50 μ g/mL against three phytopathogenic fungi
Example 7 bis (6-iodoquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6-iodoquinazolin-4-yl) diselenide following the preparation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6-iodoquinazolin-4-yl) diselenide as per the bacteriostatic activity assay described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: as can be seen from the results in Table 5, the inhibition rate of the compound di (6-iodoquinazolin-4-yl) diselenide on wheat scab zymogen reaches 62.86% when the concentration is 50 mug/mL, which is higher than the inhibition rate of the commercial medicament hymexazol on wheat scab zymogen (53.68%); the inhibition rate of the pesticide on pepper wilt pathogenic bacteria reaches 53.78 percent, which is equivalent to the inhibition rate of the pesticide hymexazol on pepper wilt pathogenic bacteria (52.11 percent); the inhibition rate of the pesticide on apple rot pathogenic bacteria reaches 57.39 percent, and is equivalent to the inhibition rate of the pesticide hymexazol on apple rot pathogenic bacteria (52.02 percent).
TABLE 5 antibacterial Activity of the Compound bis (6-iodoquinazolin-4-yl) diselenide on three phytopathogenic fungi at 50 μ g/mL
Example 8 bis (2-methylquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2-methylquinazolin-4-yl) diselenide following the preparation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2-methylquinazolin-4-yl) diselenide as per the bacteriostatic activity assay described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: from the results in Table 6, it can be seen that the compound bis (2-methyl quinazolin-4-yl) diselenide has an inhibition rate of 21.20% on wheat scab pathogenic bacteria, an inhibition rate of 21.09% on pepper wilt pathogenic bacteria and an inhibition rate of 26.85% on apple rot pathogenic bacteria when the concentration is 50 mug/mL, and has certain bacteriostatic activity which is lower than that of a commercial medicament hymexazol on three types of pathogenic bacteria.
TABLE 6 antibacterial Activity of the Compound bis (2-methyl quinazolin-4-yl) diselenide on three phytopathogenic fungi at 50 μ g/mL
Example 9 bis (2-phenylquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2-phenylquinazolin-4-yl) diselenide following the preparation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2-phenylquinazolin-4-yl) diselenide following the bacteriostatic activity assay described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: as can be seen from the results in Table 7, the inhibition rate of the compound di (2-phenylquinazolin-4-yl) diselenide on the wheat scab zymogen reaches 17.96 percent at the concentration of 50 mug/mL, which is far lower than the inhibition rate of the commercial medicament hymexazol on the wheat scab zymogen (53.68 percent); the inhibition rate of the pesticide on the pepper wilt pathogenic bacteria reaches 57.14 percent, which is equivalent to the inhibition rate (52.11 percent) of the commercial pesticide hymexazol on the pepper wilt pathogenic bacteria; the inhibition rate of the pesticide on apple rot pathogenic bacteria reaches 44.35 percent, and is slightly lower than the inhibition rate (52.02 percent) of the pesticide hymexazol on the apple rot pathogenic bacteria. The di (2-phenylquinazoline-4-yl) diselenide has better antibacterial activity.
TABLE 7 antibacterial Activity of the Compound bis (2-phenylquinazolin-4-yl) diselenide on three phytopathogenic fungi at 50 μ g/mL
Example 10, bis (2-chloroquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2-chloroquinazolin-4-yl) diselenide following the formulation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2-chloroquinazolin-4-yl) diselenide as per the bacteriostatic activity assay described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: from the results in Table 8, it can be seen that the inhibition rate of the compound bis (2-chloroquinazolin-4-yl) diselenide on wheat scab pathogenic bacteria reaches 26.94%, the inhibition rate on pepper wilt pathogenic bacteria reaches 5.88%, the inhibition rate on apple rot pathogenic bacteria reaches 6.09%, the inhibition rate is lower than that of the commodity medicament hymexazol on three types of pathogenic bacteria, and the antibacterial activity is weaker.
TABLE 8 antibacterial Activity of the Compound bis (2-chloroquinazolin-4-yl) diselenide on three phytopathogenic fungi at 50 μ g/mL
Example 11, bis (2, 6-dichloroquinazolin-4-yl) diselenide bacteriostatic activity assay.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2, 6-dichloroquinazolin-4-yl) diselenide following the preparation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (2, 6-dichloroquinazolin-4-yl) diselenide according to the test for determining bacteriostatic activity described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: from the results in Table 9, it can be seen that the compound bis (2, 6-dichloroquinazolin-4-yl) diselenide has an inhibition rate of 25.14% on wheat scab pathogenic bacteria, an inhibition rate of 14.23% on pepper wilt pathogenic bacteria and an inhibition rate of 11.22% on apple rot pathogenic bacteria when the concentration is 50 mug/mL, and the inhibition rates are lower than that of a commercial medicament hymexazol on three types of pathogenic bacteria, and the bacteriostatic activity is weaker.
TABLE 9 antibacterial Activity of the Compound bis (2, 6-dichloroquinazolin-4-yl) diselenide on three phytopathogenic fungi at 50 μ g/mL
Example 12 determination of the bacteriostatic activity of bis (6, 7-dimethoxyquinazolin-4-yl) diselenide.
(1) Preparing a solution: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6, 7-dimethoxyquinazolin-4-yl) diselenide following the preparation of the solution described in example 2.
(2) Bacteriostatic activity assay of compounds: only bis (6-chloroquinazolin-4-yl) diselenide was replaced by bis (6, 7-dimethoxyquinazolin-4-yl) diselenide according to the test for determining bacteriostatic activity described in example 2.
(3) Test results of inhibiting the activity of plant pathogenic bacteria: as can be seen from the results in Table 10, the inhibition rate of the compound bis (6, 7-dimethoxyquinazolin-4-yl) diselenide on wheat scab zymogen reaches 31.43 percent at the concentration of 50 mug/mL, which is lower than the inhibition rate of the commercial medicament hymexazol on wheat scab zymogen (53.68 percent); the inhibition rate of the pesticide on pepper wilt pathogenic bacteria reaches 10.08 percent, the inhibition rate on apple rot pathogenic bacteria reaches 11.30 percent, is far lower than the inhibition rate (52.11 percent) of the pesticide hymexazol on pepper wilt pathogenic bacteria and the inhibition rate (52.02 percent) on apple rot pathogenic bacteria, and has certain bacteriostatic activity.
TABLE 10 antibacterial activity of the compound bis (6, 7-dimethoxyquinazolin-4-yl) diselenide at 50 μ g/mL against three phytopathogenic fungi
Claims (3)
1. An application of the bisquinazoline diselenide derivative in preparing the medicines for resisting the pathogenic bacteria of plant is characterized in that the pathogenic bacteria of plant specifically include wheat scab primary bacteria (B)Gibberella zeae) Pathogenic bacteria of pepper wilt: (Fusarium oxysporum) Pathogenic bacteria of apple rot: (Cytospora mandshurica) Pinellia Ternate Fusarium (B.F.)Rhizoctonia solani) Pathogenic bacteria of rice sheath blight (A)Thanatephorus cucumeris) Sclerotium pathogenic bacterium of colza: (Sclerotina sclerotiorum) Cucumber Botrytis cinerea (a)Botrytis cinerea) Late blight of potatoPhytophthora infestans) Pathogenic bacteria of apple anthrax: (Colletotrichum gloeosporioides) The molecular structural formula of the bis-quinazoline diselenide derivative is a compound represented by the following general formula (I):
（I）
wherein,
R1is hydrogen, R2Is hydrogen, halogen atom, C1-6 alkyl and C1-6 alkoxy, R3Are hydrogen, C1-6 alkyl and C1-6 alkoxy, R4Is hydrogen or halogen atom, R5Hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy and phenyl.
2. The use of a bis-quinazoline diselenide derivative according to claim 1 in the manufacture of a medicament against phytopathogens comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
3. The use of a bis-quinazoline diselenide derivative according to claim 2 in the manufacture of a medicament for combating phytopathogens, wherein said pharmaceutically acceptable salt comprises a salt of an inorganic acid, or a salt of an organic acid.
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