CN110776548B - Acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure as well as preparation method and application thereof - Google Patents
Acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN110776548B CN110776548B CN201911058407.9A CN201911058407A CN110776548B CN 110776548 B CN110776548 B CN 110776548B CN 201911058407 A CN201911058407 A CN 201911058407A CN 110776548 B CN110776548 B CN 110776548B
- Authority
- CN
- China
- Prior art keywords
- compound
- substructure
- ursolic acid
- isopropanolamine
- acetoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
Abstract
The invention relates to acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure, and a preparation method and application thereof. The compound has a structure shown as a general formula (I):
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a 3 beta-acetoxy ursolic acid-28-piperazine compound containing an isopropanolamine substructure, and a preparation method and application thereof.
Background
In recent years, plant bacteria and fungi seriously affect the yield and quality of crops all over the world, and bring huge economic loss to farmers. For example, rice bacterial blight (Xanthomonas oryzae, oryzae) is a rod-shaped gram-negative bacterium that causes withering and whitening of rice leaves, which causes at least 10-50% reduction in yield per year in rice-growing countries. In addition, citrus canker (Xanthomonas axonopodis pv. Citri) can cause citrus rot, affecting citrus yield on a global scale. In the agricultural production process, due to the long-term use of traditional medicaments, phytopathogens generate certain resistance to the traditional medicaments. Therefore, the method has very important significance for creating novel, efficient, low-toxicity and safe green pesticide.
The natural product is an important resource for creating new pesticides. Ursolic acid belongs to pentacyclic triterpenes natural products, exists in various natural medicinal plants, and has wide development potential. The ursolic acid has been reported in the literature to have a wide range of biological activities, such as antibacterial, antiviral, anti-inflammatory, anticancer, etc. In order to search for high-efficiency antibacterial active compounds, the invention takes an ursolic acid structure as a basis, takes isopropanol as a connecting chain, introduces a series of nitrogen-containing saturated aliphatic heterocycles or aliphatic secondary amine groups into the system, synthesizes a series of 3 beta-acetoxy ursolic acid-28-piperazine compounds containing isopropanolamine substructure, inspects the bioactivity of the compounds, and provides an important scientific basis for the research and development of new pesticides.
The research on the biological activity of ursolic acid compounds progresses as follows:
in 2008, tanachatcharaana et al [ tanachatcharaana, t., brenner, j.b.,
chokchai, R, suksamarn, A.Antichronogenic activity of cinamate-based esters of the tribeppens betulinic, oleanic and ursic acids [ J ]. Chem.pharm.Bull.,2008, 56, 194-198 ] reported that introducing p-hydroxycinnamic acid at position 3 of ursolic acid, the bioactivity test results showed that Compound 17a has better bioactivity against Mycobacterium tuberculosis, and the Minimum Inhibitory Concentration (MIC) was: 6.25. Mu.g/mL.
In 2010, cunha et al [ Cunha, W.R., de materials, G.X., souza, M.G.M., tozatti, M.G., silva, M.L.A.E., martins, C.H.G., da Silva, R.D., da Silva, A.A.evaluation of the antibacterial activity of the methyl chloride extract of Miia constitutions, isolated triproperant acids, and unsaturated acids derivatives [ J ] Pharm.P., 2010, 48, 166-169 ] reported that ursolic acid was used as a matrix, acetyl and methyl ester derivatives 1a and 1b were synthesized, and the results of the bioactivity test showed that compounds 1a and 1b had superior inhibitory activity against Streptococcus pneumoniae.
In 2015, dwivedi et al [ Dwivedi, g.r., maurya, a., yadav, d.k., khan, f., darokar, m.p., srivastava, s.k.drug resistance reversal pore patent of uric acid derivatives against crude acid and multidrug resistance [. J ]. Chem Boil Drug des, 2015, 86, 272-283 ] reported the synthesis of 6 semisynthetic ursolic acid derivatives, the results of the bioactivity tests showed that while all of the ursolic acid derivatives were sensitive to semisynthetic nalidixic acid by themselves and resistant to nalidixic acid, the strains of Escherichia coli were not significantly bioactive, when used in combination with nalidixic acid, were able to greatly reduce the MIC of nalidixic acid-sensitive and resistant strains of nalidixic acid compared to nalidixic acid (minimum inhibitory concentration of Escherichia coli strains (MIC).
In 2014, do Nasciento et al [ do Nasciento, P.G.G., lemos, T.L.G., bizerra, A.M.C., arriaga, A.M.C., ferreira, D.A., santiago, G.M.P., braz Filho, R.C., costa, J.G.M.Antibacteral and antioxidant activity of Ursolic acid and derivitives, molles, 2014, 19, 1317-1327 ] reported the synthesis of C-3 modified Ursolic acid, and kanamycin, and bioactivity test results showed that 3 β -formyloxy Ursolic acid at a concentration of 64 μ g/mL was used in combination with kanamycin to reduce the Minimum Inhibitory Concentration (MIC) against E.coli from 128 μ g/mL to 8 μ g/mL
In 2015, gu et al [ Gu, w., hao, y, zhang, g., wang, s.f., miao, t.t., zhang, k.p. synthesis, in vitro antimicrobial and cytoxic activities of new bacterial microorganisms of urslic acid, bioorg.med.chem.lett.,2015, 25, 554-557 ] reported that a series of novel ursolic acid carbazole derivatives were synthesized and evaluated for antibacterial activity against 4 bacteria and 3 fungi, and biological test results showed that compounds 3a,3b,4a,4b and 5a-5f exhibited good antibacterial activity against at least one bacteria, with the lowest inhibitory concentration (MIC) ranging from: 3.9-15.6 mu g/mL.
Disclosure of Invention
The invention provides a 3 beta-acetoxy ursolic acid-28-piperazine compound containing an isopropanolamine substructure or a stereoisomer thereof, or a salt or a solvate thereof.
Another object of the present invention is to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt or solvate thereof, and a preparation method thereof.
It is still another object of the present invention to provide a composition comprising the above compound or a stereoisomer thereof, or a salt or solvate thereof.
It is also an object of the present invention to provide the above-mentioned compounds or stereoisomers thereof, or salts or solvates thereof, or uses of the composition.
Another object of the present invention is to provide a method for controlling agricultural pests using the above-mentioned compound or a stereoisomer thereof, or a salt or solvate thereof, or the composition.
In order to realize the purpose, the invention adopts the following technical scheme:
3 beta-acetoxy ursolic acid-28-piperazine compound containing isopropanolamine substructure, or stereoisomer thereof, or salt thereof or solvate thereof, wherein the compound has a structure shown as a general formula (I):
wherein
R 1 And R 2 Each independently is selected from one or more of hydrogen, deuterium, halogen, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl; or R 1 And R 2 Connecting to form an optionally substituted 5-10 membered ring or a ring containing heteroatoms, wherein the heteroatoms are one or more of N, O and S;
R 3 selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl,Alkoxy, cycloalkyl, alkanoyloxy, OH, -NH 2 One or more of, -SH;
R 1 and R 2 Each independently selected from hydrogen, deuterium, halogen, optionally substituted or unsubstituted C 1-6 Alkyl, optionally substituted or unsubstituted C 2-6 Alkenyl, optionally substituted or unsubstituted C 2-6 Alkynyl, optionally substituted or unsubstituted C 1-6 Alkoxy, optionally substituted or unsubstituted C 5-10 Cycloalkyl, optionally substituted or unsubstituted C 5-10 Aryl, optionally substituted or unsubstituted C 5-10 A heteroaryl group; or R 1 And R 2 Are connected to form an optionally substituted 5-to 10-membered ring or a heteroatom-containing ring;
preferably, R 1 And R 2 Each independently selected from hydrogen, methyl, ethyl, propyl, vinyl, propenyl, allyl, phenyl chlorophenyl group, dichlorophenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, tolyl group, benzylidene group, tolylidene group,
when R is 1 And R 2 When the two groups are connected to form a ring, the following groups are used:
preferably, R 3 Selected from hydrogen, deuterium, methyl, ethyl, vinyl, propenyl, allyl, methacryloxy, ethylacyloxy, OH, -NH 2 -SH, or a combination thereof.
Most preferably, the compound or stereoisomer thereof, or salt or solvate thereof is selected from the following specific compounds:
the invention also provides an intermediate compound for preparing the 3 beta-acetoxy ursolic acid-28-piperazine compound containing the isopropanolamine substructure or a stereoisomer thereof, or a salt thereof or a solvate thereof, which is characterized by comprising the following components in percentage by weight:
the invention also provides a preparation method of the isopropanolamine substructure 3 beta-acetoxy ursolic acid-28-piperazine compound or a stereoisomer thereof, or a salt thereof or a solvate thereof, which is characterized by comprising the following steps:
wherein R is 1 、R 2 And R 3 As described above.
The invention also provides a composition containing the compound or the stereoisomer or the salt or the solvate thereof, and an agriculturally acceptable auxiliary agent or bactericide, pesticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), dusts (DP), wettable Powders (WP), granules (GR), aqueous Solutions (AS), suspension Concentrates (SC), ultra low volume sprays (ULV), soluble Powders (SP), microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
The compound or the stereoisomer thereof, or the salt or the solvate thereof, or the composition can be used for controlling agricultural pests, preferably bacterial or fungal diseases of plants; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogen, sclerotinia rot of colza, wheat scab pathogen, potato late blight pathogen and blueberry root rot.
The invention also provides a method for preventing and controlling agricultural pests, which enables the compound or the stereoisomer thereof, the salt thereof or the solvate thereof, or the composition to act on the pests or the living environment thereof; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogen, sclerotinia rot of colza, wheat fusarium graminearum, potato late blight and blueberry root rot.
The present invention also provides a method for protecting a plant from an agricultural pest comprising a method step wherein a plant is contacted with the compound or stereoisomer thereof, or salt or solvate thereof, or the composition.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C 1-10 Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C 1-6 Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
"alkenyl" is intended to include both straight and branched chain hydrocarbons having one or more carbon-carbon double bonds at any stable point in the chain. E.g. "C 2-6 Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
An "alkynyl" group is a hydrocarbon that includes both straight and branched chain structures and has one or more carbon-carbon triple bonds that occur at any stable point in the chain. E.g. "C 2-6 Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C = C, C = N, or N = N). When referring to substitution, especially polysubstitution, it is meant that the various substituents are substituted at various positions on the indicated group, e.g. dichlorophenyl means 1, 2-dichlorophenyl, 1, 3-dichlorophenyl and 1, 4-dichlorophenyl.
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from a reaction mixture with which it is formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O) 2 H or an S (O) H group.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.
The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl; even though halo in haloalkyl is specified as fluoro, chloro, bromo, iodo, the same refers to substituted alkyl having one or more fluoro, chloro, bromo, iodo substituents.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, preferably 1,2 or 3 heteroatoms selected from O, S and N in the heteroatom-containing ring. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with = O (oxygen), as valency permits.
Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, isoindolinyl, tetrahydroquinolinyl, and the like.
The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (inner salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps employed in the preparation process, and are therefore included within the scope of the invention.
Preferably, C 1 -C 10 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and isomers thereof; c 1 -C 10 Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomers thereof; c 2 -C 5 Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl, and isomers thereof.
When reference is made to substituents being alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino as specified, one to three of the above substituents are meant. Such as methylphenyl refers to phenyl substituted with one to three methyl groups.
By adopting the technical scheme, a series of 3 beta-acetoxyl ursolic acid-28-piperazine compounds containing isopropanolamine substructure are synthesized based on ursolic acid compounds, and the compounds are found to have good inhibition effect on pathogenic bacteria, have good inhibition effect on pathogenic bacteria such as rice bacterial blight (Xoo), citrus canker (Xanthomonas axonopodis pv. Citri, xac) and the like, and provide important scientific basis for research and development of new pesticides.
Examples
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.
Example 1: preparation of intermediate 3 beta-acetoxy ursolic acid
Adding ursolic acid (21.9 mmol) into 20mL of anhydrous pyridine dissolved with DMAP (2.6 mmol) and acetic anhydride (87.6 mmol), reacting at normal temperature for 12h, stopping reaction, desolventizing, adding 50mL of water, adjusting pH to 2-3 with dilute hydrochloric acid, and filtering to obtain white solid with yield of 94.4%. The nuclear magnetic data are: 1 H NMR(400MHz，CDCl 3 )δ5.22(t，J＝3.2Hz，1H，12-CH＝C)，4.55-4.43(m，1H，3-CHOOCCH 3 )，2.17(d，J＝11.2Hz，1H，18-H)，2.04(s，3H，2′-CH 3 COO)，2.01-1.80(m，4H，11-H+2-H)，1.76-1.58(m，6H，16-H+9-H+22-H+20-H)，1.56-1.42(m，4H，6a-H+1-H+19-H)，1.37-1.24(m，5H，6b-H+21-H+7-H)，1.10-1.02(m，2H，15-H)，1.06(s，3H，27-CH 3 )，0.94(d，J＝8.2Hz，3H，30-CH 3 )，0.93(s，3H，23-CH 3 )，0.86(s，3H，25-CH 3 )，0.85(d，J＝7.5Hz，3H，29-CH 3 )，0.84(s，3H，26-CH 3 )，0.81(s，1H，5-H)，0.76(s，3H，24-CH 3 )； 13 C NMR(101MHz，CDCl 3 )δ184.4，171.4，138.3，126.0，81.3，55.6，52.8，48.3，47.8，42.2，39.8，39.3，39.1，38.6，38.0，37.2，37.0，33.1，30.9，28.4，28.3，24.3，23.9，23.8，23.6，21.7，21.5，18.5，17.4，17.3，17.0，15.9.
example 2: preparation of intermediate 3 beta-acetoxy ursolic acid-28-acyl chloride
Slowly dripping oxalyl chloride (41.2 mmol) into 30mL dichloromethane solution dissolved with 3 beta-acetoxy ursolic acid (20.6 mmol), reacting at normal temperature for 4h, stopping reaction, and desolventizing the system for later use;
example 3: preparation of intermediate 3 beta-acetoxy ursolic acid-28-piperazine
Dissolving the obtained 3 beta-acetoxy ursolic acid-28-acyl chloride in 20mL of dichloromethane, slowly dropwise adding the mixture into 20mL of dichloromethane in which anhydrous piperazine (61.8 mmol) and triethylamine (41.2 mmol) are dissolved under an ice bath condition, reacting for 8 hours at 0 ℃, stopping the reaction, extracting with 50mL of dichloromethane, washing with water, drying, desolventizing, and carrying out column chromatography to obtain a white solid with the yield of 86.6%. The nuclear magnetic data are: 1 H NMR(400MHz，CDCl 3 )δ5.21(s，1H，12-CH＝C)，4.48(dd，J＝8.9，7.1Hz，1H，3-CHOOCCH 3 )，3.57(s，4H，1′-NCH 2 )，2.82(s，4H，2′-NCH 2 )，2.12(d，J＝13.2Hz，1H，18-H)，2.04(s，3H，4′-CH 3 COO)，1.91(d，J＝7.2Hz，2H，11-H)，1.78-1.57(m，8H，2-H+16-H+9-H+22-H+20-H)，1.56-1.42(m，4H，6a-H+1-H+19-H)，1.42-1.22(m，5H，6b-H+21-H+7-H)，1.11-1.00(m，2H，15-H)，1.06(s，3H，27-CH 3 )，0.93(d，J＝4.9Hz，3H，30-CH 3 )，0.93(s，3H，23-CH 3 )，0.88(s，3H，25-CH 3 )，0.87(d，J＝7.5Hz，3H，29-CH 3 )，0.84(s，3H，26-CH 3 )，0.80(s，1H，5-H)，0.75(s，3H，24-CH 3 )； 13 C NMR(101MHz，CDCl 3 )δ175.6，171.4，139.0，125.4，81.3，60.7，55.7，53.8，48.8，47.9，47.1，46.5，42.5，39.8，39.7，39.1，38.6，38.0，37.2，34.6，33.3，30.9，28.6，28.4，23.9，23.6，21.7，21.6，18.5，17.8，17.3，17.1，15.8.
example 4: preparation of intermediate 4- (oxyethylene-2-ylmethyl) -1- (3 beta-acetoxy ursolic acid) -piperazine
Adding 3 beta-acetoxy ursolic acid-28-piperazine (14.4 mmol) into potassium carbonate (14.4 mm)ol) and epoxy bromopropane (17.3 mmol) in 25ml of DMF, reacting at normal temperature for 12h, stopping the reaction, extracting with ethyl acetate, washing with saturated ammonium chloride, drying, desolventizing, and performing column chromatography to obtain a white solid with the yield of 62.6%. The nuclear magnetic data are: 1 H NMR(400MHz，CDCl 3 )δ5.21(s，1H，12-CH＝C)，4.49(dd，J＝8.8，7.2Hz，1H，3-CHOOCCH 3 )，3.64(s，4H，1′-NCH 2 )，3.15-3.05(m，1H，4′-OCH)，2.83-2.75(m，2H，3′-N 2 CHCH)，2.61-2.40(m，5H，2′-NCH 2 +5′a-CH 2 O)，2.26-2.18(m，1H，5′b-CH 2 O)，2.12(d，J＝12.2Hz，1H，18-H)，2.04(s，3H，7′-CH 3 COO)，1.91(d，J＝7.6Hz，2H，11-H)，1.81-1.57(m，8H，2-H+16-H+9-H+22-H+20-H)，1.55-1.42(m，4H，6a-H+1-H+19-H)，1.42-1.22(m，5H，6b-H+21-H+7-H)，1.11-1.00(m，2H，15-H)，1.06(s，3H，27-CH 3 )，0.94(d，J＝5.6Hz，3H，30-CH 3 )，0.93(s，3H，23-CH 3 )，0.88(s，3H，25-CH 3 )，0.87(d，J＝7.5Hz，3H，29-CH 3 )，0.84(s，3H，26-CH 3 )，0.81(s，1H，5-H)，0.74(s，3H，24-CH 3 )； 13 C NMR(101MHz，CDCl 3 )δ175.7，171.4，139.1，125.5，81.3，61.3，55.7，54.1，50.6，48.8，47.9，45.7，45.1，42.5，39.8，39.1，38.6，38.0，37.3，34.6，33.4，30.9，28.6，28.4，23.9，23.6，21.7，21.6，18.5，17.8，17.3，17.1，15.8.
example 5:1- (1-methylpiperazino) -3- (3 beta-acetoxy ursolic acid-28-piperazinyl) -2-hydroxy propanol
Adding 4- (ethylene oxide-2-ylmethyl) -1- (3 beta-acetoxy ursolic acid) -piperazine (0.5 mmol) into 5mL of isopropanol solution dissolved with potassium carbonate (0.5 mmol) and N-methylpiperazine (0.6 mmol), reacting at 60 ℃ for 24h, stopping the reaction, extracting with 30mL of dichloromethane, washing with water, drying, desolventizing, and carrying out column chromatography to obtain a white solid with the yield of 87.1%.
The structure, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized 3 beta-acetoxy ursolic acid-28-piperazine compound containing an isopropanolamine substructure are shown in table 1, and the physicochemical properties are shown in table 2.
Nuclear magnetic resonance hydrogen and carbon spectra data for the compounds of table 1
TABLE 2 physicochemical Properties of the subject Compounds
Pharmacological example 1:
EC 50 (mean effective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to compounds, and is also an important parameter for setting the concentration of the compounds when researching the action mechanism of target compounds. In the concentration gradient experiment, proper 5 concentrations are set by a double dilution method, the inhibition rate of the medicament on plant pathogenic bacteria and the medicament concentration are converted into paired numerical values, a toxicity curve is obtained through SPSS software regression analysis, and EC is calculated 50 。
Testing the effective medium concentration EC of target compound on plant pathogenic bacteria by adopting turbidity method 50 The test subjects were rice bacterial blight (Xoo) and citrus canker (Xac). DMSO was dissolved in the medium as a blank control. Putting rice bacterial blight bacteria (bacterial blight pathogenic bacteria in M210 solid culture medium) into NB culture medium, and performing shake culture in constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for use; the citrus canker pathogen (on M210 solid medium) was placed in NB medium and shake-cultured in a constant temperature shaker at 28 ℃ and 180rpm until logarithmic phase for use. 5mL of toxic NB-containing liquid medium prepared with different concentrations (e.g., 100, 50, 25, 12.5, 6.25. Mu.g/mL) of the drug (compound) was added to the test tube, 40. Mu.L of NB liquid medium containing the phytophthora parasitica was added, and the mixture was shaken in a constant temperature shaker at 180rpm at 28-30 ℃ for 36h and 48h for bacterial blight of rice and citrus canker of citrus. The OD was measured on a spectrophotometer using the bacterial solutions of the respective concentrations 595 Value, and additionally determining the OD of the corresponding concentration of the sterilized NB-containing liquid medium 595 The value is obtained.
Corrected OD value = OD value of bacteria-containing medium-OD value of sterile medium
Inhibition ratio% = [ (corrected control culture medium liquid OD value-corrected toxin-containing culture medium OD value)/corrected control culture medium liquid OD value ] × 100
The examples of the present invention are given to illustrate the technical means of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.
TABLE 3 EC of 3 β -acetoxyursolic acid-28-piperazines containing isopropanolamine substructure against phytopathogenic bacteria 50
"NT" means not tested
As can be seen from Table 3, the target compounds showed good inhibitory activity against plant pathogenic bacteria such as rice bacterial blight and citrus canker in the in vitro test. Compounds 6-7, 10-13 and 15-26 showed excellent inhibitory activity against Xanthomonas oryzae (Xanthomonas oryzae pv. Oryzae, xoo) with EC thereof 50 0.37-7.97 mu g/mL; at the same time, the compound also shows excellent inhibitory activity on Xanthomonas (Xanthomonas axonopodis pv. Citri, xac), and the EC thereof 50 1.03-10.9 mug/mL; can be used for preparing pesticide for resisting plant pathogenic bacteria.
Claims (8)
1. A3 beta-acetoxy ursolic acid-28-piperazine compound containing an isopropanolamine substructure is characterized in that the compound has a structure shown as a general formula (I):
wherein R is 1 And R 2 Each independently selected from hydrogenMethyl, ethyl, propyl; or when R is 1 And R 2 When the two groups are connected to form a ring, the following groups are used:
R 3 selected from hydrogen, methacryloxy, ethylacetoxy, OH.
2. 3 β -acetoxyursolic acid-28-piperazine based compound containing isopropanolamine substructure according to claim 1, characterized by being selected from the following compounds:
3. an intermediate compound for preparing the 3 beta-acetoxy ursolic acid-28-piperazine compound containing an isopropanolamine substructure as defined in claim 1, which is characterized by the following:
4. the method for preparing 3 β -acetoxyursolic acid-28-piperazine compounds with isopropanolamine substructure as claimed in claim 1, which comprises the following steps:
wherein R is 1 、R 2 As claimed in claim 1.
5. A composition characterized by comprising a compound of claim 1 or 2, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; the formulation of the composition is selected from missible oil, powder, granules, aqueous solution, suspending agent, ultra-low volume spraying agent, microcapsule, smoke agent and aqueous emulsion.
6. Use of the compound of claim 1 or 2 or the composition of claim 5 for controlling agricultural pests, such as bacterial blight of rice and citrus canker.
7. A method for controlling agricultural pests is characterized in that: allowing the compound of claim 1 or 2 or the composition of claim 5 to act on the pest or its living environment; the agricultural diseases and pests are rice bacterial leaf blight and citrus canker.
8. A method for protecting a plant from an agricultural pest comprising the method step wherein the plant is contacted with a compound of claim 1 or 2 or a composition of claim 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911058407.9A CN110776548B (en) | 2019-10-31 | 2019-10-31 | Acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911058407.9A CN110776548B (en) | 2019-10-31 | 2019-10-31 | Acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110776548A CN110776548A (en) | 2020-02-11 |
| CN110776548B true CN110776548B (en) | 2022-10-18 |
Family
ID=69388500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911058407.9A Active CN110776548B (en) | 2019-10-31 | 2019-10-31 | Acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110776548B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114605489B (en) * | 2022-03-22 | 2023-08-08 | 贵州大学 | 18 beta-glycyrrhetinic acid amide compound containing isopropanolamine structure and preparation method and application thereof |
| CN114920793B (en) * | 2022-06-01 | 2023-08-08 | 贵州大学 | Estrone compound containing isopropanolamine substructure, preparation method, composition and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0548798A1 (en) * | 1991-12-18 | 1993-06-30 | Sanwa Kagaku Kenkyusho Co., Ltd. | Antiviral agent |
| CN102675405A (en) * | 2012-05-24 | 2012-09-19 | 贵州大学 | Piperazinoamide ursolate compounds, and preparation method and application thereof |
| CN107033212A (en) * | 2017-05-16 | 2017-08-11 | 烟台大学 | A kind of ursolic acid derivative with anti-inflammatory activity and its production and use |
-
2019
- 2019-10-31 CN CN201911058407.9A patent/CN110776548B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0548798A1 (en) * | 1991-12-18 | 1993-06-30 | Sanwa Kagaku Kenkyusho Co., Ltd. | Antiviral agent |
| CN102675405A (en) * | 2012-05-24 | 2012-09-19 | 贵州大学 | Piperazinoamide ursolate compounds, and preparation method and application thereof |
| CN107033212A (en) * | 2017-05-16 | 2017-08-11 | 烟台大学 | A kind of ursolic acid derivative with anti-inflammatory activity and its production and use |
Non-Patent Citations (1)
| Title |
|---|
| Design, synthesis and in vitro evaluation of novel ursolic acid derivatives as potential anticancer agents;Shi-Xian Hua 等;《European Journal of Medicinal Chemistry》;20150323;第95卷;第436页Scheme 1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110776548A (en) | 2020-02-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109627206B (en) | Preparation method and application of carbazolyl isopropanolamine derivatives with chiral centers | |
| CN110713512B (en) | Isopropanolamine substructure-containing glycyrrhetinic acid piperazine compounds and preparation method and application thereof | |
| CN111454260B (en) | 1,2,3,4-tetrahydro-beta-carboline compounds containing isopropanolamine substructure as well as preparation method and application thereof | |
| CN109627205B (en) | Preparation method and application of carbazolyl isopropanolamine derivatives | |
| CN109535145B (en) | 1,3,4-oxa (thia) diazolyl imidazole compound and preparation method and application thereof | |
| CN111548320B (en) | 1,3,4-oxadiazole hydrazide compounds and preparation method and application thereof | |
| CN110776548B (en) | Acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure as well as preparation method and application thereof | |
| CN112592335A (en) | Carbazole isopropanol diamine compound containing 1, 2, 3-triazole and preparation method and application thereof | |
| CN112608307A (en) | Heterocyclic ring substituted 1,3, 4-oxadiazole hydrazide compounds, and preparation method and application thereof | |
| CN109942567B (en) | 1,3,4-oxa (thia) diazolyl imidazole compound and preparation method and application thereof | |
| CN110642916B (en) | Ursolic acid ester compounds containing tertiary amine structure and preparation method and application thereof | |
| CN113278020B (en) | Pityriacitrin alkaloid derivative containing acylthiourea structure and preparation method and application thereof | |
| CN111285814B (en) | Quinazolinone compound containing hydrazone structural unit or stereoisomer thereof, or salt or solvate thereof | |
| CN114751885B (en) | Coumarin compound containing isopropanolamine structure and preparation method and application thereof | |
| CN114605489B (en) | 18 beta-glycyrrhetinic acid amide compound containing isopropanolamine structure and preparation method and application thereof | |
| CN115260046B (en) | Rosin acid ester compound and preparation method and application thereof | |
| CN113461634A (en) | Thiazole hydrazide compounds and preparation method and application thereof | |
| CN113563281B (en) | Benzophenone compound containing 1,3, 4-thiadiazole thioether structure and application thereof | |
| CN111393359A (en) | Pyridine salt-containing N- (cinnamoyl) -N' - (substituted) propyl hydrazide compound and preparation method and application thereof | |
| CN112592321A (en) | 1, 2, 3-triazole hydrazide or amide compounds and preparation method and application thereof | |
| CN115536543B (en) | Triclosan compound containing isopropanolamine structure and preparation method and application thereof | |
| CN112624962B (en) | Carbazolyl isopropanolamine derivatives with double chiral centers and preparation method and application thereof | |
| CN113999222B (en) | Adamantyl oxadiazole-containing compound and preparation method and application thereof | |
| CN114920793A (en) | Estrone compound containing isopropanolamine substructure, preparation method, composition and application | |
| CN115521306B (en) | 1,2,3, 4-tetrahydro-beta-carboline derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |