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
- quinazoline
- diselenide
- compound
- pathogen
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- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003224 coccidiostatic agent Substances 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical class C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 description 1
- 229950010152 halofuginone Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 235000013902 inosinic acid Nutrition 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 230000003447 ipsilateral effect Effects 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- AOCTZXQONZALCQ-UHFFFAOYSA-N phenol;selenium Chemical compound [Se].OC1=CC=CC=C1 AOCTZXQONZALCQ-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical class C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 1
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 150000003958 selenols Chemical class 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-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
- 229940035936 ubiquinone Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 238000009333 weeding Methods 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 ring quinazoline ditosylate salt medicine, the specifically quinoline azoles of anti-phytopathogen medicine two
The antibacterial biologically active of quinoline diselenide class compound.
Background technology
In recent years numerous studies data shows that quinazoline compounds show good biologically active, there is a large amount of every year
The report such as document, patent, paper.The quinazoline oxime ethers containing oxadiazoles has been found that early in Srivastava in 1984 et al.
Derivative has anti-TMV active（Srivastava, N.; Bahadur, S.; Verma, H. N.; et al.
Synthesis of new 5,3/5- and 2-substituted (1,3,4)-oxadiazoles and their
related products as potential antifungal and antiviral agents. Current
Science, 1984, 53 (5), 235-239.）；Quinazoline oximido ether compound also has resisting tobacco mosaic virus（TMV）、
Cucumber mosaic virus（CMV）And the activity of other phytopathogens（Liu Xin, Huang Runqiu, Li Huiying, etc. O- (4- quinazolines)
The synthesis of hydroximic acid monothioester (acid amides) class compound and biologically active. applied chemistry, 1999,16 (2), 23-26;It is yellow
The profit autumn, Li Huiying, Ma Junan, etc. the synthesis of 4- oximidoether quinazoline compounds and its Antiphytoviral TMV are active.
SCI, 1996,17 (4), 571-574.）；Leistner in 1991 et al. discloses quinazolinone and spreads out
Biological antiviral patent, can suppress the potato virus X on tobacco sheet（PVX）Replicate（Leistner, S.; Siegling,
A.; Strohscheidt, T.; et al. Preparation of 3-(alkylthioalkyl)- 2,4-dioxo-1,
2,3,4-tetrahydroquinazolines. DD 293816 (1991), [Chem. Abst. 1991, 117,
48587]）；In recent years, it is found that quianzolinones have antimalarial and coccidiostat activity（McLaughlin N P, Evans
P. Dihydroxylation of vinyl sulfones: stereoselective synthesisof (+)- and
(-)-febrifugine and halofuginone. The Journal of Organic chemistry, 2010, 75
(2), 518-521.）；The quianzolinones that 2- thioethers replace also have Zhuo to gram-positive bacteria and Gram-negative bacteria
Antibacterial activity more（Fatmah A M, Al-Omary, Ghada S, et al. Nonclassical antifolates,
part 3: Synthesis, biological evaluation and molecular modeling study of some
new 2-heteroarylthio-quinazolin-4-ones. European Journal of Medicinal
Chemistry, 2013, 63, 33-45.）；Quinazolyl -4- carbonyl quinazoline compounds have certain anti-inflammatory and resist
Ulcer activities（Gineinah, M. M.; EI-Sherbeny, M. A.; Nasr, M. N.; et al. Synthesis
and antiinflammatory screening of some quinazoline and quinazolyl-4-
oxoquinazoline derivatives. Archiv der Pharmazie (Weinheim, Germany) Chem.,
2002, 335 (11), 556-562.）；Quinazoline oxime ester compound has acaricidal activity（Lamberth, C.;
Hillesheim, E.; Bassand, D.; et al. Synthesis and acaricidal activity of 4-
pyrimidinyloxy- and 4-pyrimidinylaminoethylphenyl dioxolanes and oxime
ethers. Pest. Manag. Sci., 2000, 56 (1), 94-100.）；4- amino-quinazoline compounds have compared with
Good bacteriostatic activity（Shalaby, A. A.; EI-Khamry, A. M.; Shiba, S. A.; et al. Synthesis
and antifungal activity of some new quinazoline and benzoxazinone
derivatives. Archiv der Pharmazie (Weinheim, Germany). 2000, 333 (11), 365-
372.；Liu Gang, Song Baoan, Sang Weijun, etc. N- replaces the synthesis of aromatic ring -4- amino-quinazoline compounds and biology living
Journal of Sex Research. organic chemistry, 2004,24 (10), 1296-1299.）.Quinazoline compounds have so extensive agricultural
Biologically active, causes the great interest of medical research personnel and chemist.
Selenium is the necessary trace element of human body, is the constituent of various enzymes, plays in human body and resists disease, delays to decline
Always, body's immunity is strengthened, so as to reach the effect of balance organismic internal environment.Have now found that the human diseases relevant with selenium has
Kind more than 40, more especially has a strong impact on frequently-occurring disease, the common disease of human health, such as cardiovascular and cerebrovascular disease, cancer, glycosuria
Disease, inflammation and immune system dysfunction etc. and region lack Keshan disease and Kaschin-Beck disease of selenium disease such as China etc..Selenium has wide
General biological function, is the important component part of erythrocyte glutathion peroxidase, may participate in coacetylase and ubiquinone
Synthesis.The Organic Selenium class compound for synthesizing in recent years, such as selenium chitosan, Selenonic protein, selenium polysaccharide, selenizing methionine, selenizing
The small molecule or large biological molecule compound of the selenium such as carragheen, selenizing Tea Polyphenols is in antitumor, treatment angiocardiopathy, anti-aging
And the biologically actives such as immunity of organisms aspect is improved apparently higher than the respective compound without selenizing.Currently carry out clinic to grind
The representative drugs studied carefully, such as anti-inflammatory, anti-oxidation medicine ebselen (Ebselen) (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 it is highly efficient anti-virus, anti-
Tumour medicine selenazofurin (selenazofurin) (Franchetti P, Cappellacci L, Grifantini M, et
al. Inosine Monophosphate Dehydrogenase, Chapter 11, pp 212–230, ACS
Symposium Series, Vol. 839, 2003-03-03.; Sidwell R W, Huffman J H, Call E W,
et al. Anti. Res., 1986, 6 (6), 343-353).Developed using the unique chemistry and biology property of selenium new
Medicine increasingly caused the concern of scientists, the organic selenium compounds for synthesizing multiple biological activities are still that current medicine grinds
Study carefully a big focus (Ninomiya M, Garud D R, Koketsu M, et al. Coordin. Chem. Rev.,
2011, 255 (23-24), 2968-2990; Plano D, Ibáñez E, Palop J A, et al. Struct.
Chem., 2011, 22 (6), 1233-1240.)。
In recent years, scientists found the congeners of oxygen, sulphur and Xi Doushi VI races, the selenium and sulphur unusual phase in performance
Seemingly, and with unique readily degradable, antioxidation and free radical scavenging activity, meanwhile, it is also unlike sulphur atom
With different smell.The focus of the researchs such as chemistry, biology, medicine and pharmacology, environmental science and medicine and pharmacology is increasingly becoming, in agricultural, food
Product and medicine aspect are widely used.In terms of agricultural chemicals, someone is introduced into selenium element in compound molecule and carries out activity
Research, such as selenium acyl triazolylamide compound（Liu Runhui, Li Zhong, the yellow youth, etc. the synthesis of selenium-containing compound and pesticide activity
Research. Shanghai:East China University of Science, 2004.）, selenium diazoles compound（Zhao Weiguang, Liu Zhengxiao, Li Zhengming. 1,2,3-
The synthesis of selenium diazole -5- first phthalein aminated compounds and bioactivity research. organic chemistry, 23 (supplementary issues): 17.）, seleno
Beautiful jade derivative（Feng Juhong. the research of the heteroatomic organic compounds with biologically active (II). Shanghai:Central China Normal University,
2002.）, 3- (substituted-phenyl selenonyl) -1- ribosyls/deoxyribose -1H-1,2,4- triazole class compounds（Pravin K.
Singh. Agricultural and Food Chemistry, 2011, 60 (23), 5813-5818.）, containing selenium neighbour benzene two
First phthalein aminated compounds（Li Yufeng, Yang Haiyu, Feng Meili, etc. synthesis, the structure of the phthalein amine noval chemical compound of O-phthalic containing selenium
Characterize and insecticidal activity. agricultural chemicals, 2012,51 (3), 175-178.）.Scientists use for reference pharmaceutically successful experience and side
Method, splices principle etc. and the synthesis of selenium-containing compound and activity is ground by bioisosterism and active group
Study carefully, and find that some compounds there are the organic selenium compounds of higher sterilization, desinsection, activity of weeding.
Chemist shows keen interest to the organic selenium compounds containing Se-Se keys, firstly because this kind of chemical combination
Thing has high specificity in terms of the selectivity of organic synthesis；Furthermore, in some important bioprocess, this kind of compound
It is a kind of critically important intermediate.Diselenide class compound is always one of study hotspot of active medicine, Fischer etc. and sends out
Existing double (adjacent Carbamoylphenyl) diselenides have significant antioxidation activity, and better than Ebselen（Fischer H,
Dereu N, Kuhl P, et al. DE 3513071, 1986）.Wilson etc. has found that diaryl diselenide equally has
Simulation GSH-Px activity, and it was found that selenium atom ortho position introduce ammonium salt groups, activity greatly improve (Wilson S R,
Zucker P A, Huang R R C, et al. J. Am. Chem. Soc., 1989, 111 (15) : 5936-
5939.).Wang etc. has designed and synthesized a series of substituted diphenylamine base diselenides using phase transfer catalyst PEG-400 one-step method
Class compound, has expanded the synthetic method of diaryldiselenides class compound（Wang J X, Wang C H, Cui W F, et
al. J.Chem. Soc. Perkin Trans. 1, 1994, 2341-2343）.The Chinese invention patent of this seminar application
CN 102627614, discloses the preparation method and active anticancer of the quinazoline diselenide class compound of a class two, active testing table
Bright part of compounds has proliferation inhibiting effect to breast cancer cell MDA-MB-435, shows good active anticancer（Liu Gang, Liu
Spring duckweed, Xu Shengguang. CN 102627614,2012-08-08）.It is follow-up to have applied with regard to " two (quinazoline -4- bases) diselenides again
The patent of invention of purposes of the compound in cancer therapy drug is prepared "（Liu Gang, Huang Yinjiu, Sun Lin, etc. CN 103191121A,
2013-07-10）, disclose two (quinazoline -4- bases) excellent activities of diselenide compound on active anticancer.Chemistry In China
Can the 28th sub-venue of Annual Conference the 6th summary concentrate Liu Gang et al. with ortho-aminobenzoic acid or replace ortho-aminobenzoic acid for
Beginning raw material, sequentially passes through and formamide solvent-free reaction closed loop and POCl3 or thionyl chloride chlorination and two selenizing nak responses
Two selenizings have synthesized series of quinazoline diselenide class compound, and the active testing of target compound is underway（Liu Gang, Marvin's
Spring, Wang Bing, etc. the 28th sub-venue of Annual Conference the 6th summary collection of Chinese Chemical Society, 2012.04.14）.
Two quinazoline diselenide class compounds involved by present patent application are and report compound, with 4- chloro-quinazolines
Or replacement 4- reacts in alcoholic solvent with sodium diselenide for chloro-quinazoline raw material and obtains.
Present invention research finds that two quinazoline diselenide class compounds have excellent anti-phytopathogen activity, it may be possible to
Due to quinazoline ring and the result of diselenide double action and different action sites, selenol can be produced during degradation
Or selenium phenol, it may have anti-phytopathogen activity so that activity is improved or further maintained.Active testing shows, part chemical combination
Inhibitory activity of the thing under low concentration is better than the comparison medicament hymexazol of commercialization, and fungistatic effect is excellent.
The content of the invention
A kind of purposes of two quinazolines diselenide class compound in anti-phytopathogen medicine is prepared, is characterized in that two quinolines
Oxazoline diselenide derivative molecular structural formula is by general formula（I）The compound of expression：
（I）
Wherein,
R1、R2、R3、R4And R5Individually hydrogen, halogen atom, C1-6 alkyl, C1-6 alkoxyls, phenyl.
The above-described purposes in anti-phytopathogen medicine is prepared, it is characterised in that described medicine is a kind of medicine
Compositions, the formula comprising effective dose（I）Compound or its pharmaceutically acceptable salt.
The above-described purposes in anti-phytopathogen medicine is prepared, it is characterised in that described is pharmaceutically acceptable
Salt including inorganic acid salt, or the salt of organic acid.
The above-described purposes in anti-phytopathogen medicine is prepared, it is characterised in that formula（I）The purposes of compound
It is for treating and preventing various phytopathogens.
The above-described purposes in anti-phytopathogen medicine is prepared, it is characterised in that described pathogenic bacterium bag
Include gibberella saubinetii pathogen (Gibberella zeae), Fusarium oxysporum (Fusarium oxysporum), apple decay
Pathogen (Cytospora mandshurica), tuber of pinellia damping-off opportunistic pathogen (Rhizoctonia solani), rice banded sclerotial blight cause of disease
Bacterium (Thanatephorus cucumeris), sclerotinia rot of colza opportunistic pathogen (Sclerotina sclerotiorum), cucumber grey mold
Pathogen (Botrytis cinerea), late blight of potato opportunistic pathogen (Phytophthora infestans), apple anthracnose
Opportunistic pathogen (Colletotrichum gloeosporioides)。
Described pharmaceutical composition, containing at least formula as active component（I）Compound itself or its with one or more
The mixture of pharmaceutically useful inert non-toxic excipient or carrier.
The above-described purposes in anti-phytopathogen medicine is prepared, can be a kind of pharmaceutical composition, and its feature exists
In the formula comprising effective dose（I）Compound or its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt includes nothing
The salt of machine acid, such as halogen acid salt, sulfate, disulfate, phosphate, dibasic alkaliine, dihydric phosphate, nitrate, carbon
Hydrochlorate or bicarbonate, or the salt of organic acid, such as acetate, trifluoroacetate, trichloroacetate, citrate, Malaysia
Hydrochlorate, fumarate, oxalates, oxalic acid monohydric salt, phosphonate, alkylsulfonate, arylsulphonate, benzoate, corydalis tuber
Hydrochlorate, succinate, lactate, tartrate, malate, citrate salt, ascorbate, salicylate, caffeiate,
Nicotinate and 2- chlorine apellagrin salt.
In present invention, halogen atom can be fluorine, chlorine, bromine, atomic iodine.
In present invention, halogen acid salt can be hydrofluoride, hydrogen chlorate, hydrobromate, hydriodate atom.
Above-described a kind of preparation method for anti-phytopathogen medicine, it is characterised in that with 4- chloro quinoline azoles
Quinoline, sodium diselenide or two potassium selenides or two lithium selenides are raw material, with water, ethanol, isopropanol,N,N- dimethylformamide, dioxy
Six rings, dimethyl sulfoxide or its mixture are solvent, are synthesized：In the sodium diselenide for preparing or two potassium selenides or two lithium selenides
Solution in, be dividedly in some parts 4- chloro quinazoline derivatives at 20-120 DEG C, back flow reaction 3-36h, cooling, suction filtration obtains brown-red solid,
WithN,N- dimethylformamide and water are recrystallized, and obtain orange colour to brownish red crystal, as the quinazoline diselenide class of product two
Compound.Synthesis chemical equation is as follows：
This step is applied to the synthesis of all above-mentioned two quinazolines diselenide class compounds.
Description of the drawings：
Fig. 1 compounds two (6- chloro-quinazoline -4- bases) diselenide processes the change of spore germination after gibberella saubinetii pathogen
Change.
Specific embodiment
Following enforcement example will better illustrate the present invention, but it is emphasized that the present invention is by no means limited to these
Implement the content represented by example.
Following examples show the not ipsilateral of the present invention, given data include concrete operations and reaction condition and
Product, product purity confirms its structure by infrared spectrum, proton nmr spectra and carbon-13 nmr spectra.
The synthesis of embodiment 1, two (6- chloro-quinazoline -4- bases) diselenide.
0.3 g is sequentially added in the 150 mL there-necked flasks equipped with reflux condensing tube（3.8 mmol）Selenium, 0.1 g
（2.6mmol）Sodium borohydride, 15 mL absolute ethyl alcohols, below 3 DEG C of ice-water bath temperature control, solution is brown by blacking, after about 10min
Solution is changed into rufous, removes ice bath, and intensification is stirred at reflux 1.5 h solution and is changed into dark-brown.It is dividedly in some parts 2.5 mmol 4,6-
Dichloroquinazoline, about 1 h is added, and solution is changed into latericeous, and the h of back flow reaction 24 is cooled to room temperature, is adjusted with glacial acetic acid and is reacted
System pH=5-6, decompression precipitation obtains khaki solid, is recrystallized with DMF and water（VDMF/H2O=5：1）, orange crystals are obtained, as
Product two (6- chloro-quinazoline -4- bases) diselenide, yield 29.0%, fusing point 255.2-257.9 C.IR (KBr) v: 3083.3
(vAr-H), 1615.4-1450.9 (quinazoline skeleton vibration), 825.7, 681.7 (δAr-H),
647.7 (vC-Cl) cm-1; 1H NMR (DMSO-d 6 , 600 MHz) δ: 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 = 8.4
Hz, 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) δ: 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’).
Embodiment 2, two (6- chloro-quinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By required dosage Weigh Compound in 10 mL volumetric flasks, and add a small amount of solvent (0.5
ML) it is fully dissolved, be then settled to 10 mL with the sterile purified water containing 0.5% Tween 20, be made into the change of respective concentration
Polymer solution.
（2）The Antibacterial Activity experiment of compound：Using isolated growth performance rate method.Heating potato dextrose agar training
Foster base (PDA culture medium：The g of potato 200, the g of agar 20, the g of glucose 20, the mL of distilled water 1000) culture medium is to molten state
(40-60 DEG C), 10 mL liquids (liquid of 10 times of final concentrations) are poured in 90 mL PDA culture mediums, are fully shaken up, and are uniformly fallen
Enter in the culture dish of the cm of diameter 9, horizontal positioned, solidification to be cooled.Use in the fresh pathogen colony edge for having cultivated 4 d
Card punch plays the bacterium dish for taking a diameter of 5 mm, and bacterium dish is inverted in into the central authorities of PDA plate containing medicament, is subsequently placed in 27 DEG C of constant temperature and humidities
Culture is inverted in incubator, observation, crossing method are started when at solvent control colony growth to close plate 2/3rds
Measurement colony diameter (cm), averages.Compare not adding medicine, but the solvent containing same concentration and 0.5% Tween 20.Often
Process in triplicate.Inhibiting rate of the medicament to mycelial growth is calculated by below equation：
WhereinIFor inhibiting rate,CFor blank diameter,TTo process diameter.
（3）Suppressing phytopathogens active testing result：By to compound two (6- chloro-quinazoline -4- bases) diselenide
Antifungal Activity in Vitro carries out preliminary screening discovery (table 1), and (6- chloro-quinazoline -4- bases) diselenide of compound two is 50 in concentration
There is preferable inhibitory activity to three kinds of phytopathogens during g/mL, wherein reaching to the inhibiting rate of gibberella saubinetii pathogen
96.3%, far above inhibiting rate of the commodity medicament hymexazol to gibberella saubinetii pathogen（53.68%）, it is worth further research and opens
Send out.
Compound two (6- chloro-quinazoline -4- bases) diselenide of table 1 is in 50 g/mL to the suppression of three kinds of plant pathogenic fungis
Bacterium activity
(6- chloro-quinazoline -4- bases) the diselenide virulence regression equation of embodiment 3, two and EC50The measure of value.
Test method：On the basis of primary dcreening operation experiment, from compound two (6- chloro-quinazoline -4- bases) diselenide to pathogen
6 concentration are designed in the range of the big about 10-90% of inhibiting rate, medicament solvent is configured to by series using doubling dilution dense
Degree, using growth rate method each concentration inhibiting rate is determined, and is often processed in triplicate.By inhibiting rate data conversion into probit value
Y (), drug concentration (g/mL) are converted into logarithm value (x), in SPSS11.5 softwares regression analysis is carried out, and obtain toxicity regression
Equation (y=ax+b) and coefficient correlation (r), calculate medicament to concentration (EC in pathogen suppression50), and with commodity medicament hymexazol
As positive control.
Result of the test：The bacteriostatic activity of compound two (6- chloro-quinazoline -4- bases) diselenide preferably, therefore is carried out to it
Anti- various plants disease fungus active testing, and with commodity medicament hymexazol as control, their bacteriostatic activity has been carried out time
Return analysis, its Activity Results is shown in Table 2.
The antibacterial regression analysis of compound two (6- chloro-quinazoline -4- bases) diselenide of table 2
By carrying out antibacterial regression analysis to (6- chloro-quinazoline -4- bases) diselenide of compound two and commodity medicament hymexazol
(table 2) finds that compound two (6- chloro-quinazoline -4- bases) diselenide is to gibberella saubinetii pathogen, apple decay pathogen, Ma Ling
Concentration (EC in the suppression of potato late blight pathogen and tuber of pinellia damping-off opportunistic pathogen50) it is below concentration in the suppression of hymexazol effect, tool
There is preferable broad spectrum antibiotic activity.
Embodiment 4, two (6- chloro-quinazoline -4- bases) impact of the diselenide to spore germination.
Test method：Weigh Compound prepares poisonous culture medium, make final concentration be respectively 0 (control), 20,40,60,80,
100 g/mL, often process three repetitions, pathogen microspore suspension are diluted to into about 50, every visual field spore, then uniformly
Coat on poisonous plating medium, dark culturing at a temperature of 27 DEG C, when germination rate is compareed more than 90%, see under microscope
Counting (taking three visual field sums per ware) is examined, germination rate is calculated.
Result of the test：From experimental result（Fig. 1）As can be seen that with compound two (6- chloro-quinazoline -4- bases) diselenide
With the increase of comparison medicament hymexazol concentration, the germination rate of gibberella saubinetii pathogen sporidiole is more and more lower, and Jing compounds
The germination rate of the gibberella saubinetii pathogen sporidiole of two (6- chloro-quinazoline -4- bases) diselenides process is always below disliked to Jing according to medicine
The germination rate of the gibberella saubinetii pathogen sporidiole that mould spirit is processed.When concentration reaches 100 g/mL, (the 6- chlorine of Jing compounds two
Quinazoline -4- bases) spore germination rate that processed of diselenide only has 2%, less than comparison medicament 23%.Thus two (6- chlorine can be explained
Quinazoline -4- bases) inhibitory action of the diselenide to gibberella saubinetii pathogen mycelial growth.
Embodiment 5, two (6,8- dichloroquinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (6,8- dichloroquinazoline -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (6,8- dichloroquinazoline -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 3, (6, the 8- bis- chloroquine azoles of compound two
Quinoline -4- bases) diselenide reaches 83.67% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, far above commodity
Medicament hymexazol is to gibberella saubinetii pathogen（53.68%）Inhibiting rate, fungistatic effect is excellent.
Compound two (6,8- dichloroquinazoline -4- bases) diselenide of table 3 is in 50 g/mL to three kinds of plant pathogenic fungis
Bacteriostatic activity
Embodiment 6, two (6- bromine quinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (6- bromine quinazoline -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (6- bromine quinazoline -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 4, compound two (6- bromine quinazolines-
4- yls) diselenide reaches 76.33% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, to capsicum wilt
The inhibiting rate of opportunistic pathogen reaches 64.71%, and to the inhibiting rate of apple decay pathogen 70.87% is reached, and is above commodity medicament evil mould
Spirit is to gibberella saubinetii pathogen（53.68%）, to Fusarium oxysporum（52.11%）, to apple decay pathogen（52.02%）
Inhibiting rate, fungistatic effect is excellent.
Compound two (the 6- bromine quinazoline -4- bases) diselenide of table 4 is in 50 g/mL to the suppression of three kinds of plant pathogenic fungis
Bacterium activity
Embodiment 7, two (6- iodine quinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (6- iodine quinazoline -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (6- iodine quinazoline -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 5, compound two (6- iodine quinazolines-
4- yls) diselenide reaches 62.86% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, higher than commodity medicament
Hymexazol is to gibberella saubinetii pathogen（53.68%）Inhibiting rate；53.78% is reached to the inhibiting rate of Fusarium oxysporum, with
Commodity medicament hymexazol is to Fusarium oxysporum（52.11%）Inhibiting rate it is suitable；The inhibiting rate of apple decay pathogen is reached
To 57.39%, with commodity medicament hymexazol to apple decay pathogen（52.02%）Inhibiting rate it is suitable.
Compound two (the 6- iodine quinazoline -4- bases) diselenide of table 5 is in 50 g/mL to the suppression of three kinds of plant pathogenic fungis
Bacterium activity
Embodiment 8, two (2- methylquinazolin -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (2- methylquinazolin -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (2- methylquinazolin -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 6, (the 2- methyl quinoline azoles of compound two
Quinoline -4- bases) diselenide reaches 21.20% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, withered to capsicum
The inhibiting rate of pathogen reaches 21.09%, and to the inhibiting rate of apple decay pathogen 26.85% is reached, and is below commodity medicament evil
Inhibiting rate of the mould spirit to three class pathogens, there is certain bacteriostatic activity.
Compound two (2- methylquinazolin -4- bases) diselenide of table 6 is in 50 g/mL to three kinds of plant pathogenic fungis
Bacteriostatic activity
Embodiment 9, two (2- phenylquinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (2- phenylquinazoline -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (2- phenylquinazoline -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 7, (the 2- phenyl quinazoline azoles of compound two
Quinoline -4- bases) diselenide reaches 17.96% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, far below commodity
Inhibiting rate of the medicament hymexazol to gibberella saubinetii pathogen（53.68%）；The inhibiting rate of Fusarium oxysporum is reached
57.14%, with inhibiting rate of the commodity medicament hymexazol to Fusarium oxysporum（52.11%）Quite；To apple decay pathogen
Inhibiting rate reach 44.35%, slightly less than inhibiting rate of the commodity medicament hymexazol to apple decay pathogen（52.02%）.Two (2-
Phenylquinazoline -4- bases) diselenide has preferable bacteriostatic activity.
Compound two (2- phenylquinazoline -4- bases) diselenide of table 7 is in 50 g/mL to three kinds of plant pathogenic fungis
Bacteriostatic activity
Embodiment 10, two (2- chloro-quinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (2- chloro-quinazoline -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (2- chloro-quinazoline -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 8, compound two (2- chloro-quinazolines-
4- yls) diselenide reaches 26.94% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, to capsicum wilt
The inhibiting rate of opportunistic pathogen reaches 5.88%, and to the inhibiting rate of apple decay pathogen 6.09% is reached, and is below commodity medicament hymexazol
Inhibiting rate to three class pathogens, bacteriostatic activity is weaker.
Compound two (2- chloro-quinazoline -4- bases) diselenide of table 8 is in 50 g/mL to the suppression of three kinds of plant pathogenic fungis
Bacterium activity
Embodiment 11, two (2,6- dichloroquinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (2,6- dichloroquinazoline -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (2,6- dichloroquinazoline -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 9, (2, the 6- bis- chloroquine azoles of compound two
Quinoline -4- bases) diselenide reaches 25.14% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, withered to capsicum
The inhibiting rate of pathogen reaches 14.23%, and to the inhibiting rate of apple decay pathogen 11.22% is reached, and is below commodity medicament evil
Inhibiting rate of the mould spirit to three class pathogens, bacteriostatic activity is weaker.
Compound two (2,6- dichloroquinazoline -4- bases) diselenide of table 9 is in 50 g/mL to three kinds of plant pathogenic fungis
Bacteriostatic activity
Embodiment 12, two (6,7- dimethoxyquinazoline -4- bases) diselenide Antibacterial Activity.
（1）The preparation of solution：By the preparation of solution described in embodiment 2, only two (6- chloro-quinazoline -4- bases) diselenides
Change two (6,7- dimethoxyquinazoline -4- bases) diselenides into.
（2）The Antibacterial Activity experiment of compound：Test by Antibacterial Activity described in embodiment 2, only two (6-
Chloro-quinazoline -4- bases) diselenide changes two (6,7- dimethoxyquinazoline -4- bases) diselenides into.
（3）Suppressing phytopathogens active testing result：As can be seen from Table 10, (6, the 7- dimethoxies of compound two
Base quinazoline -4- bases) diselenide reaches 31.43% when concentration is 50 g/mL to the inhibiting rate of gibberella saubinetii pathogen, it is less than
Inhibiting rate of the commodity medicament hymexazol to gibberella saubinetii pathogen（53.68%）；The inhibiting rate of Fusarium oxysporum is reached
10.08%, 11.30% is reached to the inhibiting rate of apple decay pathogen, it is former to capsicum wilt far below commodity medicament hymexazol
The inhibiting rate of bacterium（52.11%）, inhibiting rate to apple decay pathogen（52.02%）, with certain bacteriostatic activity.
Compound two (6,7- dimethoxyquinazoline -4- bases) diselenide of table 10 is in 50 g/mL to three kinds of phytopathies
The bacteriostatic activity of fungal pathogenses
Claims (3)
1. a kind of purposes of two quinazolines diselenide derivative in anti-phytopathogen medicine is prepared, is characterized in that pathogenic
Bacterium specifically include gibberella saubinetii pathogen (Gibberella zeae), Fusarium oxysporum (Fusarium oxysporum)、
Apple decay pathogen (Cytospora mandshurica), tuber of pinellia damping-off opportunistic pathogen (Rhizoctonia solani), paddy rice
Sheath blight the original bacterium (Thanatephorus cucumeris), sclerotinia rot of colza opportunistic pathogen (Sclerotina sclerotiorum)、
Gray mold of cucumber opportunistic pathogen (Botrytis cinerea), late blight of potato opportunistic pathogen (Phytophthora infestans), apple
Fruit anthrax pathogen (Colletotrichum gloeosporioides), two quinazoline diselenide derivative molecular structural formulas are
General formula（I）The compound of expression：
（I）
Wherein,
R1For hydrogen, R2For hydrogen, halogen atom, C1-6 alkyl and C1-6 alkoxyls, R3For hydrogen, C1-6 alkyl and C1-6 alkoxyls, R4For
Hydrogen and halogen atom, R5For hydrogen, halogen atom, C1-6 alkyl, C1-6 alkoxyls and phenyl.
2. use of a kind of two quinazolines diselenide derivative according to claim 1 in anti-phytopathogen medicine is prepared
On the way, it is characterised in that described medicine be a kind of pharmaceutical composition, the formula comprising effective dose（I）Compound or its pharmaceutically can connect
The salt received.
3. use of a kind of two quinazolines diselenide derivative according to claim 2 in anti-phytopathogen medicine is prepared
On the way, it is characterised in that described pharmaceutically acceptable salt includes the salt of inorganic acid, or the salt of organic acid.
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| CN103191121A (en) * | 2013-04-22 | 2013-07-10 | 鲁东大学 | Anti-cancer biological activity of di(quinazoline-4-group)diselenide compound |
| CN104000828A (en) * | 2014-06-16 | 2014-08-27 | 鲁东大学 | Quinazoline diselenide salt compound, preparation method thereof and biological activity |
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| CN103191121A (en) * | 2013-04-22 | 2013-07-10 | 鲁东大学 | Anti-cancer biological activity of di(quinazoline-4-group)diselenide compound |
| CN104000828A (en) * | 2014-06-16 | 2014-08-27 | 鲁东大学 | Quinazoline diselenide salt compound, preparation method thereof and biological activity |
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