CN107033134A - Bisamide class compound containing pyridiniujm and 1,3,4 oxadiazolyls and preparation method and application - Google Patents

Abstract

Contain pyridiniujm and 1, the bisamide class compound of 3,4 oxadiazolyls and preparation method and application the invention discloses one kind, the compound has the structure as shown in formula (I)：

Description

Bisamide class compound containing pyridiniujm and 1,3,4- oxadiazolyls and preparation method thereof And application

Technical field

It is especially a kind of to contain pyridiniujm and 1, the bisamide of 3,4- oxadiazolyls the present invention relates to field of pharmaceutical chemistry technology Class compound and preparation method and application.

Background technology

In recent years, with the continuous change of ecological condition, kind and cropping system, (such as paddy rice is white for bacterial diseases of plants Leaf blight and citrus bacterial canker disease etc.) and virosis (such as tobacco mosaic disease) occur on a large scale and popular in China, and in the whole nation Have further diffusion spreading trend, the scope that causes harm is wide, and preventing and treating is difficult, existing commercial antimicrobial agent (such as Yekuzuo, Thiodiazole-copper, Can kill to wait) and antivirotic (Ningnanmycin, virazole etc.) preventive effect it is low, be badly in need of finding the efficiently anti-work for planting sick bacterium or virus Property compound, formulates out the green novel pesticide of independent intellectual property right on this basis, is that crops are bacillary and Disease Prevention and control provide drug candidate.

Bisamide class compound is ground because having extensive bioactivity in terms of antibacterium and virus as researcher One of focus studied carefully, the bisamide class compound of commercialization have insecticide (such as chlorantraniliprole (chlorantraniliprole), Flubendiamide (flubendiamide) etc.), bactericide (such as benzene pyrrole bacterium ketone (fenpyrazamine)).Meanwhile, containing pyridiniujm The thio-ether type compounds of group or 1,3,4- oxadiazole groups also show extensive bioactivity in terms of agricultural chemicals.In order to find Efficient sterilizing, antiviral reactive compound, the present invention is based on bisamide class compound, it would be possible to improve target compound The pyridinium group of bioactivity and 1,3,4- oxadiazole groups are incorporated into this system, synthesize it is a series of contain pyridiniujm and 1,3, The bisamide class compound of 4- oxadiazolyls, investigates its bioactivity, and the research and development and initiative for novel pesticide provide important science Basis.

The bioactivity research progress of bisamide class compound is as follows：

[Wu, the J. such as Wu in 2013；Kang,S.H.；Luo,L.J.；Shi,Q.C.；Ma,J.；Yin,J.；Song,B.A.； Hu,D.Y.；Yang,S.Synthesis and antifungal activities of novel nicotinamide Derivatives containing 1,3,4-oxadiazole.Chem.Cent.J.2013,7,64] synthesize a series of The bisamide analog derivative of the oxadiazolyl containing 1,3,4-.Such compound is to fusarium graminearum, capsicum wilt bacterium and apple Rotten pathogenic bacteria shows certain inhibitory activity.

[Z.B.Yang, D.Y.Hu, S.Zeng, B.A.Song, the Novel hydrazone such as Yang in 2016 derivatives containing pyridine amide moiety:Design,synthesis,and Insecticidal activity.Bioorg.Med.Chem.Lett.2016,26,1161-1164] synthesize a series of containing acyl The bisamide class compound of hydrazone structure, biological activity test result shows target compound to brown plant-hopper, diamondback moth and sharp and rounded sounds Culex has insecticidal activity, wherein, compound 5j shows most strong insecticidal activity to northern house, its LC₅₀And LC₉₅Respectively For 2.44 and 5.76mg/L.

[J.A.Good, J.Silver, the C. such as Good in 2016W.Bahnan,K.S.Krishnan, O.Salin,P.R.Svensson,P.Artursson,Gylfe,S.F.Almqvist, Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity.J.Med.Chem.2016,59,2094-2108] report a series of thiazoles and 2- pyridone amide-type chemical combination Thing, biological activity test result shows that partial target compound shows preferable inhibitory activity to chlamydia trachomatis.

The bioactivity research progress of the group devicative of oxadiazolyl containing 1,3,4- is as follows：

, [W.M.Xu, S.Z.Li, M.He, S.Yang, X.Y.Li, the P.Li.Synthesis and such as Xu in 2013 bioactivities of novel thioether/sulfone derivatives containing 1,2,3- thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety.Bioorg.Med.Chem.Lett., 2013,23,5821-5824] design thioether, the sulfone compound for having synthesized the group of oxadiazole containing 1,3,4-.Preliminary is antiviral Biological activity test shows, under 500 μ g/mL concentration, and such compound shows preferable suppression to tobacco mosaic virus (TMV) Activity, wherein compound 7a, 7c, 7d, 8a and 9a show higher inhibitory activity.

, [W.N.Wu, Q.Chen, A.Q.Tai, G.Q.Jiang, G.P.Ouyang, the Synthesis and such as Wu in 2015 antiviral activity of 2-substituted methylthio-5-(4-amino-2-methylpyrimidin- 5-yl) -1,3,4-oxadiazole derivatives.Bioorg.Med.Chem.Lett.2015,25,2243-2246] close Join 1,3,4- oxadiazole class compounds into a series of pyrimidines.Antiviral activity test shows that target compound is to Tobacco mosaic Virus has preferable inhibitory activity, wherein, compound 8i shows higher therapeutic activity to tobacco mosaic disease, its EC₅₀For 246.48μg/mL。

2016, Khalilullah etc. [H.Khalilullah, S.Khan, M.S.Nomani, B.Ahmed, Arab.J.Chem.2016,9, S1029-S1035] report some benzodioxane classes for arranging the groups of oxadiazole containing 1,3,4- Derivative.Biological activity test shows that partial target compound is to bacterium (such as staphylococcus aureus, Escherichia coli, withered grass bud Spore bacillus etc.) and fungi (aspergillus niger, aspergillus flavus, Candida albicans etc.) show preferable inhibitory activity.

The bioactivity research progress of amphipathic molecule based on pyridiniujm is as follows：

[M.Messali, Eco-Friendly Synthesis of a New the Class of such as Messali in 2015 Pyridinium-Based Ionic Liquids with Attractive Antimicrobial Activity, Molecules 2015,20,14936-14949] synthesize a series of ionic liquids containing pyridiniujm.Such compound pair Gram- (+) such as streptococcus pneumonia (Streptococcus pneumonia) and hay bacillus (Bacillus subtilis) and Gram- (-) such as Pseudomonas aeruginosa (Pseudomonas aeruginosa) and Escherichia coli (Escherichia coli.) show Certain inhibitory activity.

[R.X.Jia, Y.F.Duan, Q.Fang, X.Y.Wang, J.Y.Huang, the Pyridine- such as Jia in 2016 grafted chitosan derivative as an antifungal agent.Food Chem.2016,196,381- 387] pyridiniujm is grafted onto on chitosan, synthesizes the chitosan derivatives containing pyridiniujm.The compound is to Fulvia fulva MIC and minimum fungicidal concentration be respectively 0.13 and 1.0mg/mL, MIC to ash arrhizus bacteria and Minimum fungicidal concentration is respectively 0.13 and 4.0mg/mL.

The content of the invention

The purpose of the present invention is：A kind of bisamide class compound and its system containing pyridiniujm and 1,3,4- oxadiazolyls are provided Preparation Method and application, it has good inhibition, and the very economical letter of its synthetic method to infective pathogen bacterium and virus Just.

What the present invention was realized in：One kind contains pyridiniujm and 1, the bisamide class compound of 3,4- oxadiazolyls, its spy Levy and be：The compound has the structure as shown in formula (I)：

In formula, the R on phenyl ring₁For hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, propylene Amide groups, C_1-3Alkylamino, nitro or halogen atom；R₂For hydrogen, C_1-4Alkyl or different substituted benzyls, wherein, difference substitution Substituent on benzyl is more than one, and substituent is hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, Acrylic, acrylamido, C_1-3Alkylamino, nitro or halogen atom；R on pyridine salt cation₃For hydrogen, C_1-4Alkyl, three Methyl fluoride, hydroxyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, acrylamido, amino, C_1-3Alkylamino, nitro or halogen Atom；X is oxygen atom or sulphur atom；N is the natural number more than 1.

2nd, a kind of preparation of the bisamide class compound as claimed in claim 1 containing pyridiniujm and 1,3,4- oxadiazolyls Method, it is characterised in that：Its synthetic route is as follows；

In formula, the R on phenyl ring₁For hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, propylene Amide groups, C_1-3Alkylamino, nitro or halogen atom；R₂For hydrogen, C_1-4Alkyl or different substituted benzyls, wherein, difference substitution Substituent on benzyl is more than one, and substituent is hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, Acrylic, acrylamido, C_1-3Alkylamino, nitro or halogen atom；R on pyridine salt cation₃For hydrogen, C_1-4Alkyl, three Methyl fluoride, hydroxyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, acrylamido, amino, C_1-3Alkylamino, nitro or halogen Atom；X is oxygen atom or sulphur atom；N is the natural number more than 1.

Bisamide class compound containing pyridiniujm and 1,3,4- oxadiazolyls is preparing anti-infective pathogen bacterium and virus Application in medicine.

By using above-mentioned technical proposal, the present invention is possible to improve target based on aryl bisamide class compound The pyridine salt cation of chemical combination microbic activity and 1,3,4- oxadiazolyls are incorporated into this system, synthesize a series of containing pyridiniujm With 1, the bisamide class compound of 3,4- oxadiazolyls, and it is good to find that the compound has to infective pathogen bacterium and virus Inhibitory action, for pathogenetic bacteria [such as rice leaf spot bacteria (Xanthomonas oryzae pv.oryzae, Xoo), citrus Ulcer bacteria (Xanthomonas axonopodis pv.citri, Xac) etc.] and plant virus [such as tobacco mosaic virus (TMV) (Tobacco Mosaic Virus, TMV) etc.] good inhibition is respectively provided with, the research and development and initiative for novel pesticide provide weight The scientific basic wanted.

Embodiment

Embodiments of the invention 1：Target compound 5- (2- (2- methyl -5- (methyl sulfide base) -1,3,4- oxadiazoles) benzene first Amide groups) amino) -5- valeryls) and -1- pyridinium bromide salt preparation

5- bromines valeric chloride (0.45mmol) is added to dissolved with 2- amino-N- (2- methyl -5- (methyl sulfide base) -1,3,4- Oxadiazole) benzamide (0.45mmol) and triethylamine (0.91mmol) 10mL dry methylene chloride solution in, normal-temperature reaction 5 Stop reaction after hour, precipitation adds 50mL ethyl acetate, washes molten again after 20mL × 3 time, anhydrous sodium sulfate drying, precipitation Solution is in 5mL pyridines, after 50 DEG C are reacted 12 hours, precipitation, column chromatography (eluant, eluent CH₂Cl₂:CH₃OH=6:1) yellow oily is obtained Thing, yield 41.2%.

The synthesis of other target compounds is with reference to embodiment 1.

The structure and hydrogen nuclear magnetic resonance of bisamide class compound of the part of synthesis containing pyridiniujm and 1,3,4- oxadiazolyls As shown in table 1, physico-chemical property is as shown in table 2 for spectrum and carbon modal data.

The proton nmr spectra and carbon modal data of the part of compounds of table 1

The physicochemical property of the partial target compound of table 2

Pharmacological Examples 1：

Using inhibiting rate of the nephelometry test target compound to phytopathogen, subjects are rice leaf spot bacteria And citrus processing (Xac) (Xoo).DMSO is dissolved in the medium as blank control.By rice leaf spot bacteria (paddy rice Bacterial leaf-blight opportunistic pathogen is in M210 solid mediums) it is put into NB culture mediums, shaken cultivation is arrived in 28 DEG C, 180rpm constant-temperature tables Exponential phase is standby；Citrus processing (on M210 solid mediums) is put into NB culture mediums, in 28 DEG C, 180rpm Shaken cultivation is standby to exponential phase in constant-temperature table.Medicament (compound) is configured to various concentrations (example：100,50μg/ ML toxic NB fluid nutrient mediums 5mL) is added in test tube, is separately added into 40 μ L and is contained the NB fluid nutrient mediums for planting sick bacterium, Vibrated in 28-30 DEG C, 180rpm constant-temperature tables, its bacterial blight of rice opportunistic pathogen culture 36h, citrus processing culture 48h. The bacterium solution of each concentration is determined into OD on spectrophotometer₅₉₅Value, and the toxic sterile NB liquid of corresponding concentration is determined in addition The OD of culture medium₅₉₅Value.

EC₅₀(median effective concentration) is the weight for evaluating phytopathogen to compound responsive Index is wanted, while when being also to target compound study on mechanism, the important parameter that compound concentration is set.In concentration gradient In experiment, suitable 5 concentration is set using doubling dilution, it is finally that medicament is dense to inhibiting rate, the medicament of phytopathogen Degree is converted into logarithm value, obtains virulence curve by SPSS software regression analyses, calculates EC₅₀。

Using median effective concentration EC of the nephelometry test target compound to phytopathogen₅₀, subjects are that paddy rice is white Leaf spoting bacteria (Xoo) and citrus processing (Xac).DMSO is dissolved in the medium as blank control.By paddy rice bacterial leaf spot Germ (bacterial blight of rice opportunistic pathogen is in M210 solid mediums) is put into NB culture mediums, in 28 DEG C, 180rpm constant-temperature tables Shaken cultivation is standby to exponential phase；Citrus processing (on M210 solid mediums) is put into NB culture mediums, 28 DEG C, shaken cultivation is standby to exponential phase in 180rpm constant-temperature tables.Medicament (compound) is configured to various concentrations (example：80,40,20,10,5 μ g/mL) toxic NB fluid nutrient mediums 5mL be added in test tube, be separately added into 40 μ L contain plant disease The NB fluid nutrient mediums of bacterium, vibrate, its bacterial blight of rice opportunistic pathogen culture 36h in 28-30 DEG C, 180rpm constant-temperature tables, Citrus processing culture 48h.The bacterium solution of each concentration is determined into OD on spectrophotometer₅₉₅Value, and correspondence is determined in addition The OD of the toxic sterile NB fluid nutrient mediums of concentration₅₉₅Value.

Correct the OD values=values of OD containing bacterium culture medium-aseptic culture medium OD values

Inhibiting rate %=[(after correction control medium bacterium solution OD values-correct toxic culture medium OD values)/

Control medium bacterium solution OD values after correction] × 100

The embodiment of the present invention is aided with explanation technical scheme, but the content of embodiment is not limited thereto, part Target compound experimental result is as shown in Tables 3 and 4.

Inhibitory activity of bisamide class compound of the table 3 containing pyridiniujm and 1,3,4- oxadiazolyls to plant pathogenetic bacteria

" NT " represents not test

EC of bisamide class compound of the table 4 containing pyridiniujm and 1,3,4- oxadiazolyls to plant pathogenetic bacteria₅₀

From table 3 and 4 as can be seen that in isolated test, target compound is to plant pathogenic pathogen (the white leaf of such as paddy rice Rot bacterium and citrus processing) show preferable inhibitory activity.Wherein, compound 7,8,9 and 10 is dense in 100 μ g/mL It is respectively 90.5,74.0,99.7 and 86.8% to the inhibitory activity of rice leaf spot bacteria under degree, compound 9 is in 50 μ g/mL It is 98.3% to the inhibitory activity of rice leaf spot bacteria under concentration；Compound 1,3,8 and 10 is under 100 μ g/mL concentration to mandarin orange The inhibiting rate of tangerine ulcer bacteria is respectively 67.6,70.0,71.5 and 99.8%, and compound 9 is burst under 50 μ g/mL concentration to citrus The inhibitory activity of ulcer germ is 99.8%.Further test result shows EC of the compound 9 to both germs₅₀Respectively 0.7 With 5.9 μ g/mL, available for preparing anti-plant pathogenic pathogenetic bacteria agricultural chemicals.

Pharmacological Examples 2：The antiviral activity experiment (resisting tobacco mosaic virus) of partial target compound

The anti-phytoviral activity of compound is determined using half tikka method.Accurately 3mg test compounds are weighed in measuring cup In, adding the μ L of solvent DMSO 60 makes it fully dissolve.It is made into 500mg/L's with the redistilled water containing 1%Tween 20 Compound solution.It is another to take the Ningnanmycin aquas of 250 μ L 2%, add the μ L of solvent DMSO 60, the secondary steaming containing 1%Tween 20 Distilled water 10mL, is made into 500mg/L Ningnanmycin solution.

The live body therapeutic activity that medicament infects to TMV.The consistent Nicotiana glutinosa of growing way is chosen, first virus liquid is dipped with parallelism (concentration is 6 × 10^-3Mg/mL), blade face (full leaf) along its artificial frictional inoculation in offshoot direction on the blade sprinkled with diamond dust, The inoculation dynamics of left and right blade, which is tried one's best, to be consistent, and is supported below blade with smooth plank.After virus liquid is dry, rinsed with flowing water Fall the diamond dust above blade.After blade is dry, medicament is spread in Zuo Banye, right half leaf spreads aqua sterilisa and compared.Per medicament Processing sets 3 plants, and plant is then placed on moisturizing culture in illumination box by every plant of 3-4 piece leaf, controls 23 DEG C of temperature, illumination The number for producing withered spot is observed and recorded after 10000LuX, 2-4d.3 repetitions are carried out per medicament as stated above, calculates and suppresses Rate.

The live body protection activity that medicament infects to TMV.The consistent Nicotiana glutinosa of growing way is chosen, is gently applied with writing brush in Zuo Banye Dispenser agent, right half leaf spreads aqua sterilisa and compared, virus inoculation after 24 hours.Viral juice is dipped with spread pen, and (concentration is 6x10^{- 3}Mg/mL), blade face (full leaf) along its artificial frictional inoculation in offshoot direction on the blade sprinkled with diamond dust, left and right blade connects The dynamics of kind, which is tried one's best, to be consistent, and is supported below blade with smooth plank.After virus liquid is dry, rinsed out with flowing water above blade Diamond dust.3 plants are set per chemicals treatment, plant is then placed on moisturizing culture in illumination box, control temperature by every plant of 3-4 piece leaf The number for producing withered spot is observed and recorded after 23 DEG C of degree, illumination 10000Lux, 2-4d.3 weights are carried out per medicament as stated above It is multiple, calculate inhibiting rate Y (%)=(R-L)/R × 100%.

Wherein：Y is compound to the inhibiting rate to tobacco mosaic virus (TMV)；R is control group (right half leaf) withered spot number, and L is Treatment group (Zuo Banye) withered spot number.The embodiment of the present invention is aided with explanation technical scheme, but embodiment content simultaneously This is not limited to, experimental result is as shown in table 5.

Inhibitory activity of bisamide class compound of the table 5 containing pyridiniujm and 1,3,4- oxadiazolyls to plant virus

As can be seen from Table 5, in the case where concentration is 500 μ g/mL, live body test result shows, the series compound has necessarily Antiviral activity, wherein compound 3, the therapeutic activity of 5 and 9 pairs of tobacco mosaic virus (TMV)s are respectively 50.6,60.0 and 51.9%； Compound 1 is 51.2% to the protection activity of tobacco mosaic virus (TMV), it is seen that compound of the invention can be used for preparing anti-phytopathy Malicious agricultural chemicals.

Claims (3)

1. a kind of bisamide class compound containing pyridiniujm and 1,3,4- oxadiazolyls is characterized in that：The compound has as logical Structure shown in formula (I)：

In formula, the R on phenyl ring₁For hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, acrylamide Base, C_1-3Alkylamino, nitro or halogen atom；R₂For hydrogen, C_1-4Alkyl or different substituted benzyls, wherein, the benzyl of difference substitution On substituent be more than one, and substituent be hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, propylene Base, acrylamido, C_1-3Alkylamino, nitro or halogen atom；R on pyridine salt cation₃For hydrogen, C_1-4Alkyl, fluoroform Base, hydroxyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, acrylamido, amino, C_1-3Alkylamino, nitro or halogen atom； X is oxygen atom or sulphur atom；N is the natural number more than 1.

2. a kind of preparation side of the bisamide class compound as claimed in claim 1 containing pyridiniujm and 1,3,4- oxadiazolyls Method, it is characterised in that：Its synthetic route is as follows：

In formula, the R on phenyl ring₁For hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, acrylamide Base, C_1-3Alkylamino, nitro or halogen atom；R₂For hydrogen, C_1-4Alkyl or different substituted benzyls, wherein, the benzyl of difference substitution On substituent be more than one, and substituent be hydrogen, C_1-4Alkyl, trifluoromethyl, C_1-3Alkoxy, trifluoromethoxy, propylene Base, acrylamido, C_1-3Alkylamino, nitro or halogen atom；R on pyridine salt cation₃For hydrogen, C_1-4Alkyl, fluoroform Base, hydroxyl, C_1-3Alkoxy, trifluoromethoxy, acrylic, acrylamido, amino, C_1-3Alkylamino, nitro or halogen atom； X is oxygen atom or sulphur atom；N is the natural number more than 1.

3. the bisamide class compound as claimed in claim 1 containing pyridiniujm and 1,3,4- oxadiazolyls is preparing anti-disease of causing a disease The application of indigenous bacteria and antiviral drug.