CN109053701B - Arctigenin compound, preparation method and application - Google Patents
Arctigenin compound, preparation method and application Download PDFInfo
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Abstract
The invention discloses an arctigenin-based compound and a preparation method and application thereof. The compound of the invention is obtained by taking arctigenin as a mother nucleus and substituted 1,2, 3-triazole as a chemical modification unit, and has good toxoplasma gondii resistance activity.
Description
Technical Field
The invention relates to an arctigenin compound and a preparation method and application thereof.
Background
Toxoplasma gondii (Toxoplasma gondii) is an opportunistic pathogenic parasite that is obligately parasitic on the nucleated cells of warm-blooded animals and can infect most mammals including humans and birds. The entire life history of toxoplasma includes five stages, tachyzoite, cysts, schizonts, gametophytes and oocysts, with tachyzoites (tachyzoites) being the major pathogenic stage. Toxoplasma disease (Toxoplasma) caused by Toxoplasma infection is distributed worldwide, and about one third of the population in the world is in chronic Toxoplasma infection, which mainly damages the physiological functions of host eyes, brain, heart, liver and other organs and also causes malformation of fetus in pregnancy. Toxoplasmosis usually has no obvious clinical symptoms, is recessive infection, has long latency, wide spread range and large degree of harm, and seriously affects the safety of human beings, farm animals and food.
Currently, drugs for treating toxoplasmosis are mainly pyrimethamine (pyrimethamine), sulfadiazine (sulfadiazine), spiramycin (spiramycin), atovaquone (atovaquone), etc. Clinical studies show that pyrimethamine and sulfadiazine when administered together exhibit significant anti-insect effects, but the combination of both drugs can cause serious adverse effects (such as allergy, myelosuppression, intolerance, etc.), and also increase the risk of liver and kidney complications. The use of atovaquone, although successful to some extent, has had limited anti-insect efficacy. Spiramycin acts as a macrolide antibacterial agent, which has only been shown to prolong survival of infected rodents at high doses. Administration of these drugs early in pregnancy may cause fetal abnormalities, and thus none are suitable for pregnant women. Therefore, the development of low-toxicity, highly effective anti-Toxoplasma gondii drugs is urgently required.
Burdock (Arctium lappa L.) is a biennial herb of the genus Arctium of the family Compositae, and its mature fruit, Arctii (Fructus Arctii), has been used as a traditional herb in China for thousands of years. Arctiin (arctinin) and Arctigenin (Arctigenin) are the main active ingredients of arctium fruit. Wherein arctigenin has pharmacological activities of anti-inflammatory, antivirus, anti-Alzheimer disease and anti-tumor.
Non-patent document 1 ("protective effect of arctiin on toxoplasma gondii heat shock protein 70 induced toxoplasma gondii infected mouse acute liver injury", chenozan et al, extensive university medical science report, vol.38, No. 4, p.270-273, 12 months 2015), non-patent document 2 ("research progress on pharmacological activity of arctiin", fanxiaoqing et al, shanghai medical journal, vol.51, No. 4, 2017), non-patent document 3 ("research progress on liver protective effect of active ingredients in arctium", zhangming month et al, washingi medical journal, vol.32, No. 6, p.661, 663, 2017) respectively disclose that arctiin has protective effect on toxoplasma gondii protein 70(t.g. hsp70) induced toxoplasma gondii infected mouse acute liver injury, and can significantly reduce expression of alanine Aminotransferase (ALT) and glutamic aminotransferase (AST (IL-1 β), tumor necrosis factor (TNF- α), platelet activating factor (paah) mRNA in mouse serum.
CN101284823A, CN102342929A and WO2013023145A1 respectively disclose the application of esterification, etherification and alkylation derivatives of arctigenin in the aspects of improving organism tolerance, anti-inflammation, anti-endotoxin, anti-tumor, skin whitening and the like, CN103467417A discloses that arctigenin carboxamide derivatives can be used for treating diseases related to β -amyloid peptide formation, CN105732598A discloses the application of arctigenin ether derivatives in the preparation of medicines for preventing and treating neurodegenerative diseases, and CN105616400A discloses the application of arctigenin carbamate derivatives in the preparation of medicines for treating Alzheimer disease.
However, there is no report that arctigenin or its derivative has anti-toxoplasma activity in the prior art.
Disclosure of Invention
An object of the present invention is to provide arctigenin-based compounds having anti-toxoplasma activity. It is a further object of the present invention to provide the above compounds, which have low toxicity and high efficacy.
Another object of the present invention is to provide a process for preparing the above compound, which is simple and stable.
It is a further object of the present invention to provide the use of the above compounds for the preparation of a medicament having anti-Toxoplasma gondii activity.
In one aspect, the present invention provides an arctigenin-based compound having a structure represented by formula (I):
in the formula (I), R1～R5The same or different, are respectively and independently selected from hydrogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio; r6Selected from a single bond, C1-6 alkylene or C2-C6 heteroalkylene; r has the structure shown in formula (II):
in the formula (II), R7Selected from a single bond, C1-6 alkylene or C2-C6 heteroalkylene; r8～R12The same or different, are respectively and independently selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio.
The compound according to the invention, preferably R1～R5The same or different, are independently selected from hydrogen or C1-C3 alkyl; r6Selected from a single bond or C1-C3 alkylene; r7Selected from a single bond or C1-C3 alkylene; r8～R12The same or different, are respectively and independently selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy.
The compound according to the invention, preferably R1～R5The same or different, are each independently selected from hydrogen, methyl or ethyl; r6Selected from a single bond, methylene or ethylene; r7Selected from a single bond, methylene or ethylene; r8～R12The same or different, are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy.
According to the compounds of the present invention, preferably, R is selected from one of the following groups:
according to the compounds of the present invention, preferably, R is selected from one of the following groups:
the compound according to the present invention, preferably the compound of formula (I), is selected from one of the following compounds:
in another aspect, the present invention provides a process for the preparation of the above compound, comprising the steps of:
(1) reacting a compound shown in a formula (III) with a compound shown in a formula (IV) to form an intermediate product A;
in the formula (III), R1～R5The same or different, are respectively and independently selected from hydrogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio; in the formula (IV), R6Selected from single bonds, C1-6 alkylene or C2-C6 heteroalkylene, X represents halogen and ≡ represents alkynyl;
(2) reacting the intermediate product A with a compound shown as a formula (V) to obtain a compound shown as a formula (I);
in the formula (V), R7Selected from a single bond, C1-6 alkylene or C2-C6 heteroalkylene; r8～R12The same or different, are respectively and independently selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio; n is a radical of3Represents an azide group.
According to the preparation method provided by the invention, preferably, in the step (1), the compound shown in the formula (III) and the compound shown in the formula (IV) in a molar ratio of 1: 1-3 react in an acetone solvent by using potassium carbonate as a catalyst to form an intermediate product A; in the step (2), the intermediate product A and the compound shown in the formula (V) in a molar ratio of 1: 1-3 react in a mixed solvent of butanol and water by taking copper sulfate and sodium ascorbate as catalysts to obtain the compound shown in the formula (I).
The preparation method according to the invention preferably comprises the following specific steps:
(1) adding a compound shown as a formula (III), a compound shown as a formula (IV) and potassium carbonate in a molar ratio of 1: 1-3: 1-4, and an acetone solvent into a reaction container, and reacting for 5-20 hours at a temperature of 40-80 ℃ in a stirring state; pouring the reaction product into ice water, extracting for 2-5 times by using ethyl acetate, and then washing the extract for 2-5 times by using a saturated saline solution; drying the organic layer by anhydrous sodium sulfate, filtering, decompressing, concentrating and carrying out column chromatography to obtain an intermediate product A;
(2) mixing a mixed solvent of butanol and water in a volume ratio of 1-10: 1, an intermediate product A in a molar ratio of 1: 1-3: 0.05-0.2: 0.1-0.4, a compound shown in a formula (V), and copper sulfate pentahydrate CuSO4·5H2Adding O and sodium ascorbate VC-Na into a reaction container, and reacting for 12-48 h at the temperature of 20-60 ℃ in a stirring state; and pouring the reaction product into ice water, extracting for 2-5 times by using ethyl acetate, washing an organic layer for 2-5 times by using a saturated saline solution, drying by using anhydrous sodium sulfate, carrying out suction filtration, carrying out reduced pressure concentration and carrying out column chromatography to obtain the compound shown in the formula (I).
In a further aspect, the invention also provides the use of a compound as described above in the manufacture of a medicament having anti-toxoplasma activity.
According to the invention, the arctigenin is modified by adopting a specific group, so that a compound with good toxoplasma gondii resistance activity can be obtained. The hydroxyl of the arctigenin is modified by the substituted 1,2, 3-triazole, so that the stability of the synthesis process of the compound is improved, and the activity of the compound against toxoplasma gondii is improved.
Drawings
FIG. 1 shows the effect of compounds D1-D12 on host cell survival. P <0.05 compared to the spiramycin group. The control group is a control group, Ar is an arctigenin experimental group, and Spy represents a spiramycin experimental group.
FIG. 2 shows the effect of Compound D4 and a control compound on Toxoplasma gondii-infected host cells.
Wherein, fig. 2a is HeLa host cell, fig. 2b is toxoplasma gondii-infected cell, fig. 2c is toxoplasma gondii-infected cell treated by compound D4, fig. 2D is toxoplasma gondii-infected cell treated by spiramycin, and fig. 2e is toxoplasma gondii-infected cell treated by arctigenin.
Figure 3 shows the effect of compound D4 and the control compound on the number of mouse abdominal worms. Control represents a Control group, Ar represents an arctigenin experimental group, Sp represents an spiramycin experimental group, and D4 represents a compound D4 experimental group.
Detailed Description
The present invention will be further described with reference to the following specific examples, but the scope of the present invention is not limited thereto.
The inventors of the present application have surprisingly found that arctigenin compounds modified with a specific group have good anti-toxoplasma activity in the course of intensive research on arctigenin derivatives, thereby completing the present invention.
< interpretation of terms >
In the present invention, Cm-Cn represents a group having m to n carbon atoms; for example, the C1-C20 alkyl group represents an alkyl group having 1 to 20 carbon atoms.
In the present invention, "single bond" means that two atoms or groups are directly bonded with a covalent bond having a valence of 1. "alkyl" means a group derived from a straight or branched chain aliphatic hydrocarbon having one point of attachment. "heteroalkyl" means an alkyl group having at least one heteroatom with one point of attachment. "alkylene" means a group derived from a straight or branched aliphatic hydrocarbon having two points of attachment. "Heteroalkylene" means an alkylene group having at least one heteroatom with two points of attachment. "hetero" in the foregoing terms means that one or more carbon atoms have been replaced by a different atom.
Unless otherwise specified, all groups may be substituted or unsubstituted. According to some embodiments of the invention, the substituent is selected from halogen, alkyl or alkoxy.
In the present invention, the "Click Chemistry Reaction" refers to a chemical Reaction between a compound having an alkynyl group and a compound having an azido group in the presence of a catalyst to form a1, 2, 3-triazole linker by the Reaction between the alkynyl group and the azido group.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
< Compound >
The compound based on arctigenin of the invention represents a substance, the mother nucleus of which is arctigenin, and the hydroxyl group of the benzene ring of the compound is chemically modified by a chemical synthesis method, and the compound can also be chemically modified at a substitutable position of the benzene ring. The arctigenin-based compound of the present invention has a structure represented by formula (I):
the hydroxyl of the arctigenin is modified by the substituted 1,2, 3-triazole, so that the stability of the synthesis process of the compound is improved, and the activity of the compound against toxoplasma gondii is improved.
In the present invention, R1～R5The same or different, are respectively and independently selected from hydrogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio. Preferably, R1～R5Each independently selected from hydrogen, C1-C3 alkyl, C2-C5 heteroalkyl, C5-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio; more preferably, R1～R5Each independently selected from hydrogen or C1-C3 alkyl.
In the present invention, the C1-C6 alkyl group may include, but is not limited to, a straight chain alkyl group or a branched chain alkyl group; preferably C1-C3 alkyl, more preferably C1-C3 straight chain alkyl. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl and the like. Further, the C1-C6 alkyl group of the present invention may include a substituted alkyl group or an unsubstituted alkyl group. The substituents in the substituted alkyl groups may contain heteroatoms such as O, S, N or halogen. Halogens of the present invention include, but are not limited to, fluorine, chlorine, bromine, iodine.
In the present invention, the C2-C6 heteroalkyl group may include, but is not limited to, a straight or branched heteroalkyl group; preferably C2-C5 heteroalkyl, more preferably C2-C3 heteroalkyl. The heteroalkyl group in the present invention refers to a group formed by substituting a carbon atom on an alkyl chain with another heteroatom. The above heteroatom includes O, S or N, preferably O or S. Specific examples of C2-C6 heteroalkyl groups of the present invention include, but are not limited to, -CH2-O-CH3、-CH2-O-CH2CH3、-CH2-O-CH(CH3)CH3、-CH2-S-CH3、-CH2-S-CH2CH3、-CH2-S-CH(CH3)CH3。
In the present invention, the C3-C6 cycloalkyl group may include a substituted cycloalkyl group and an unsubstituted cycloalkyl group; preferably C5-C6 cycloalkyl, more preferably C5 cycloalkyl. Specific examples of C3-C6 cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-methylcyclopentyl, 3-methylcyclohexyl, and 3-ethylcyclohexyl, with cyclopentyl and cyclohexyl being preferred.
In the present invention, the C1-C6 alkoxy group may include, but is not limited to, a linear alkoxy group or a branched alkoxy group; preferably C1-C3 alkoxy, more preferably C1-C3 straight chain alkoxy. Examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexoxy, and the like.
In the present invention, C1-C6 alkylthio may include, but is not limited to, straight or branched alkylthio; preferably C1-C3 alkylthio, more preferably C1-C3 straight chain alkylthio. Examples of C1-C6 alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, hexylthio, and the like.
According to one embodiment of the invention, R1～R5Each independently selected from hydrogen, methyl or ethyl.
In the present invention, R6Selected from a single bond, C1-6 alkylene or C2-C6 heteroalkylene. Preferably, R6Selected from a single bond, C1-3 alkylene or C2-C5 heteroalkyl; more preferably R6Selected from a single bond or C1-3 alkylene.
In the present invention, a single bond means that two atoms or groups are directly bonded with a covalent bond of 1 valence therebetween.
In the present invention, the C1-6 alkylene group may include, but is not limited to, a straight chain alkylene group or a branched chain alkylene group; preferably a C1-C3 alkylene group, more preferably a C1-C3 straight chain alkylene group. Examples of C1-C6 alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, t-butylene, n-pentylene, isopentylene, neopentylene, hexylene, and the like. Further, the C1-C6 alkylene group of the present invention may include a substituted alkylene group or an unsubstituted alkylene group. The substituents in the substituted alkylene group may contain heteroatoms such as O, S, N or halogen. Halogens of the present invention include, but are not limited to, fluorine, chlorine, bromine, iodine.
In the present invention, the C2-C6 heteroalkylene group may include, but is not limited to, a linear heteroalkylene group or a branched heteroalkylene group; preferably C2-C5 heteroalkylene, more preferably C2-C3 heteroalkylene. Heteroalkylidene in the present invention refers to a group formed by substituting a carbon atom on an alkylene chain with another heteroatom. The above heteroatom includes O, S or N, preferably O or S. Specific examples of C2-C6 heteroalkylenes of the invention include, but are not limited to, -CH2-O-CH2-、-CH2-O-CH2CH2-、-CH2-O-CH(CH3)CH2-、-CH2-S-CH2-、-CH2-S-CH2CH2-、-CH2-S-CH(CH3)CH2-。
According to one embodiment of the invention, R6Selected from single bonds, methylene or ethylene.
In the present invention, R has a structure represented by formula (II):
in the formula (II), R7Selected from a single bond, C1-6 alkylene or C2-C6 heteroalkylene. Preferably, R7Selected from a single bond, C1-C3 alkylene or C2-C5 heteroalkylene; more preferably, R7Selected from single bonds or C1-C3 alkylene. The "alkylene" and "heteroalkylene" groups mentioned herein are those substituents whose scope is defined above and which are not further described herein.
According to one embodiment of the invention, R7Selected from single bonds, methylene or ethylene.
In the formula (II), R8～R12The same or different, are respectively and independently selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio. Preferably, R8～R12Each independently selected from hydrogen, halogen, C1-C3 alkyl, C2-C5 heteroalkyl, C5-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio; more preferably, R8～R12Each independently selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy. The substituents of "halogen", "alkyl", "heteroalkyl", "cycloalkyl" and "alkylthio" mentioned herein are mentioned above and are not repeated herein.
According to one embodiment of the invention, R8～R12Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy.
Examples of R groups include, but are not limited to, the following:
to further enhance the anti-toxoplasma activity of the compounds of the invention, R is selected from one of the following groups:
according to one embodiment of the invention, R is selected from one of the following groups:
the compound has a high selectivity index SI, low cytotoxicity and high toxoplasma resisting activity, and in view of the medication safety, R is the following group:
the compounds of the invention may be selected from one of the following compounds:
the compound has simple synthesis process and good process stability.
< preparation method >
The preparation method of the compound of the invention comprises the following steps: (1) a step of synthesizing an intermediate product A; (2) the intermediate product A reacts with azide compound to synthesize the compound of the invention.
In step (1) of the present invention, a compound represented by formula (III) is reacted with a compound represented by formula (IV) to form intermediate product a.
In the formula (III), R1～R5The same or different, are respectively and independently selected from hydrogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio. In the formula (IV), R6Selected from single bondsC1-6 alkylene or C2-C6 heteroalkylene, X represents halogen and ≡ represents alkynyl.
In the formula (III), R1～R5Can be independently selected from hydrogen, C1-C3 alkyl, C2-C5 heteroalkyl, C5-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio; more preferably, R1～R5Each independently selected from hydrogen or C1-C3 alkyl.
In formula (III), the C1-C6 alkyl group can include, but is not limited to, a straight chain alkyl or branched chain alkyl; preferably C1-C3 alkyl, more preferably C1-C3 straight chain alkyl. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl and the like. Further, the C1-C6 alkyl group of the present invention may include a substituted alkyl group or an unsubstituted alkyl group. The substituents in the substituted alkyl groups may contain heteroatoms such as O, S, N or halogen. Halogens of the present invention include, but are not limited to, fluorine, chlorine, bromine, iodine. C2-C6 heteroalkyl can include, but is not limited to, straight or branched chain heteroalkyl; preferably C2-C5 heteroalkyl, more preferably C2-C3 heteroalkyl. The heteroalkyl group in the present invention refers to a group formed by substituting a carbon atom on an alkyl chain with another heteroatom. The above heteroatom includes O, S or N, preferably O or S. Specific examples of C2-C6 heteroalkyl groups of the present invention include, but are not limited to, -CH2-O-CH3、-CH2-O-CH2CH3、-CH2-O-CH(CH3)CH3、-CH2-S-CH3、-CH2-S-CH2CH3、-CH2-S-CH(CH3)CH3. C3-C6 cycloalkyl can include substituted cycloalkyl and unsubstituted cycloalkyl; preferably C5-C6 cycloalkyl, more preferably C5 cycloalkyl. Specific examples of C3-C6 cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-methylcyclopentyl, 3-methylcyclohexyl, and 3-ethylcyclohexyl, with cyclopentyl and cyclohexyl being preferred. C1-C6 alkoxy can include, but is not limited to, straight or branched chain alkoxy; preferably C1-C3 alkoxy, more preferably C1-C3 straight chain alkoxy. Examples of C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy,N-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexoxy, and the like. C1-C6 alkylthio can include, but is not limited to, straight or branched alkylthio; preferably C1-C3 alkylthio, more preferably C1-C3 straight chain alkylthio. Examples of C1-C6 alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, hexylthio, and the like. According to one embodiment of the invention, R1～R5Each independently selected from hydrogen, methyl or ethyl.
In the formula (IV), R6May be selected from a single bond, C1-3 alkylene or C2-C5 heteroalkyl; more preferably R6Selected from a single bond or C1-3 alkylene.
In formula (IV), a single bond means a direct bond between two atoms or groups with a covalent bond of 1 valence. C1-6 alkylene can include, but is not limited to, straight or branched chain alkylene; preferably a C1-C3 alkylene group, more preferably a C1-C3 straight chain alkylene group. Examples of C1-C6 alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, t-butylene, n-pentylene, isopentylene, neopentylene, hexylene, and the like. Further, the C1-C6 alkylene group of the present invention may include a substituted alkylene group or an unsubstituted alkylene group. The substituents in the substituted alkylene group may contain heteroatoms such as O, S, N or halogen. Halogens of the present invention include, but are not limited to, fluorine, chlorine, bromine, iodine. C2-C6 heteroalkylene groups can include, but are not limited to, linear heteroalkylene groups or branched heteroalkylene groups; preferably C2-C5 heteroalkylene, more preferably C2-C3 heteroalkylene. Heteroalkylidene in the present invention refers to a group formed by substituting a carbon atom on an alkylene chain with another heteroatom. The above heteroatom includes O, S or N, preferably O or S. Specific examples of C2-C6 heteroalkylenes of the invention include, but are not limited to, -CH2-O-CH2-、-CH2-O-CH2CH2-、-CH2-O-CH(CH3)CH2-、-CH2-S-CH2-、-CH2-S-CH2CH2-、-CH2-S-CH(CH3)CH2-. According to one embodiment of the invention, R6Selected from single bonds, methylene or ethylene.
The compound shown in the formula (III) is a compound in which the benzene ring of the arctigenin is substituted or unsubstituted. When R is1～R5When both are hydrogen, it represents arctigenin; when R is1～R5And other substituents represent chemically modified arctigenin. The substituents may be attached to the phenyl ring using synthetic methods well known in the art and will not be described further herein.
The compound represented by the formula (IV) is a haloalkynyl compound, which has a substituent X at one end thereof and is capable of undergoing a condensation reaction with a hydroxyl group of the compound represented by the formula (III), and has an alkynyl group at the other end thereof and is capable of undergoing a click chemistry reaction with an azido group of the compound represented by the formula (V). When R is6A single bond, for example, a halogenated acetylene such as 2-bromo-1-acetylene; when R is6When it is methylene, it represents halopropyne such as 3-bromo-1-propyne, etc.; when R is6And when the substituent is other, other types of halogenated acetylene compounds are shown. These haloalkynes can be obtained by synthetic methods known in the art and will not be described further herein.
In the step (1), the molar ratio of the compound represented by the formula (III) to the compound represented by the formula (IV) may be 1:1 to 3, preferably 1:1 to 2, and more preferably 1: 1.2. The reaction may be carried out in an acetone solvent. The reaction is carried out in the presence of a basic catalyst, examples of which include, but are not limited to, potassium carbonate K2CO3And the like. The molar ratio of the compound represented by the formula (III) to the basic catalyst is 1: 1-4, preferably 1: 1.5-3, and preferably 1: 2.
According to one embodiment of the invention, the compound shown in the formula (III), the compound shown in the formula (IV), potassium carbonate and acetone are added into a reaction vessel and reacted for 5-20h at the temperature of 40-80 ℃ in a stirring state; pouring the reaction product into ice water, extracting for 2-5 times by using ethyl acetate, and then washing the extract for 2-5 times by using a saturated saline solution; drying the organic layer by anhydrous sodium sulfate, filtering, decompressing, concentrating and column chromatography to obtain an intermediate product A. The compound represented by formula (III) may be arctigenin or the like. The compound represented by the formula (IV) may be 3-bromo-1-propyne or the like. In a reaction vessel, reacting the compound shown in the formula (III) and the compound shown in the formula (IV) under the catalysis of potassium carbonate, wherein the reaction time can be 5-20h, and is preferably 8-15 h. And pouring the obtained reaction product into ice water, and extracting with ethyl acetate for 2-5 times, preferably 2-3 times. The obtained extract is washed with a saturated saline solution 2 to 5 times, preferably 2 to 3 times. And drying the washed organic layer by anhydrous sodium sulfate, carrying out suction filtration, carrying out reduced pressure concentration and column chromatography to obtain an intermediate product A. Drying, suction filtration, concentration under reduced pressure and column chromatography conditions may be those well known in the art and will not be described herein.
In step (2) of the present invention, the intermediate product a is reacted with a compound represented by formula (V) to obtain a compound represented by formula (I);
in the formula (V), R7Selected from a single bond, C1-6 alkylene or C2-C6 heteroalkylene; r8～R12The same or different, are respectively and independently selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio; n is a radical of3Represents an azide group. The "alkylene" and "heteroalkylene" groups mentioned herein are those substituents whose scope is defined above and which are not further described herein. According to one embodiment of the invention, R7Selected from single bonds, methylene or ethylene.
In the formula (V), R8～R12The same or different, are respectively and independently selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy or C1-C6 alkylthio. Preferably, R8～R12Each independently selected from hydrogen, halogen, C1-C3 alkyl, C2-C5 heteroalkyl, C5-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 alkylthio; more preferably, R8～R12Each independently selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy. As used herein, "halogen", "alkyl", and,"heteroalkyl," "cycloalkyl," "alkylthio," and the range of substituents encompassed therein are mentioned above and are not further described herein. According to one embodiment of the invention, R8～R12Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy.
In step (2) of the present invention, the alkynyl group of intermediate product a undergoes a click chemistry reaction with the azido group of the compound represented by formula (V), thereby forming an R group of formula (I) from the chemical structure of the compound represented by formula (V) except the azido group.
Examples of R groups include, but are not limited to, the following:
in certain embodiments, the R group is selected from one of the following groups:
according to one embodiment of the invention, the R group is selected from one of the following groups:
examples of the compound represented by the formula (V) include, but are not limited to, the compounds listed in Table 1.
TABLE 1
In the step (2), a mixed solvent of butanol and water can be used for the reaction, and the volume ratio of the butanol to the water in the mixed solvent is 1-10: 1, preferably 1-5: 1. The molar ratio of the intermediate product A to the compound represented by the formula (V) may be 1:1 to 3, preferably 1:1 to 2, and more preferably 1: 1.5. The intermediate product A and a compound shown as a formula (V) are subjected to click chemistry reaction in the presence of a catalystThe reagent may be any substance known in the art capable of catalyzing the click chemistry of azido and alkynyl groups, including but not limited to CuSO, copper sulfate pentahydrate4·5H2O and sodium ascorbate VC-Na. When copper sulfate pentahydrate CuSO is adopted4·5H2When O and sodium ascorbate VC-Na are used as catalysts, the intermediate product A and copper sulfate pentahydrate CuSO4·5H2The molar ratio of O to sodium ascorbate VC-Na can be 1: 0.05-0.2: 0.1-0.4, preferably 1: 0.08-0.15: 0.15-0.3, and more preferably 1:0.1: 0.2.
According to one embodiment of the present invention, the step (2) is: mixing a mixed solvent of butanol and water in a volume ratio of 1-10: 1, an intermediate product A in a molar ratio of 1: 1-3: 0.05-0.2: 0.1-0.4, a compound shown in a formula (V), and copper sulfate pentahydrate CuSO4·5H2Adding O and sodium ascorbate VC-Na into a reaction container, and reacting for 12-48 h at the temperature of 20-60 ℃ in a stirring state; and pouring the reaction product into ice water, extracting for 2-5 times by using ethyl acetate, washing an organic layer for 2-5 times by using a saturated saline solution, drying by using anhydrous sodium sulfate, carrying out suction filtration, carrying out reduced pressure concentration and carrying out column chromatography to obtain the compound shown in the formula (I). In a reaction vessel, the intermediate product A and the compound shown as the formula (V) are added in copper sulfate pentahydrate CuSO4·5H2Reacting O and sodium ascorbate VC-Na under catalysis, wherein the reaction temperature can be 20-60 ℃, and preferably 30-50 ℃; the reaction time can be 12-48 h, preferably 15-30 h. And pouring the obtained reaction product into ice water in a stirring state, and extracting for 2-5 times by using ethyl acetate, preferably extracting for 2-3 times. The obtained extract is washed with a saturated saline solution 2 to 5 times, preferably 2 to 3 times. Drying the obtained organic layer by anhydrous sodium sulfate, filtering, decompressing, concentrating and carrying out column chromatography to obtain the compound shown in the formula (I). Drying, suction filtration, concentration under reduced pressure and column chromatography conditions may be those well known in the art and will not be described herein.
< application >
The compounds of the present invention have anti-toxoplasma activity and the present invention thus provides the use of the compounds in the manufacture of a medicament having anti-toxoplasma activity. The compounds of the invention are useful in the clinical treatment of toxoplasma. The compound of the invention is mixed with conventional pharmaceutical excipients to obtain the preparation.
< test methods >
IR was measured using FT-IR 1730 Fourier transform infrared spectrometer (Shimadzu, Japan).
1H NMR and13c NMR was measured by Bruker AV-300(Bruker, Switzerland) NMR spectrometer using deuterated chloroform CDCl3As a solvent.
Mass spectra were determined using a 1100-HPLC mass spectrometer (Agilent, USA).
High resolution mass spectra were determined using a MALDI-TOF/TOF mass spectrometer (Bruker Daltonik, Germany).
The starting materials used in the following embodiments are known compounds, are commercially available, or may be synthesized by methods known in the art.
Example 1
Arctigenin (100.44mg, 0.27mmol), 3-bromo-1-propyne (38.54mg, 0.324mmol), and potassium carbonate (74.52mg, 0.54mmol) were sequentially added to a 25mL round-bottomed flask, followed by addition of 15mL of acetone solvent. The reaction materials are slowly heated to 60 ℃ and stirred for reaction for 10 hours at the temperature. The reaction product was poured into ice water and extracted 3 times with ethyl acetate (15 mL each time). The extract was washed 3 times with saturated brine. Drying the organic layer by anhydrous sodium sulfate, filtering, decompressing, concentrating and carrying out column chromatography to obtain an intermediate product A. Intermediate a was yellow and intermediate Ad was obtained in 90% yield.
A mixed solvent of n-butanol and water (volume ratio of n-butanol to water: 1) was added to a 25mL round-bottomed flask, and then intermediate A (0.2mmol), azide compound V1(1- (azidomethyl) benzene) (0.3mmol), and copper sulfate pentahydrate CuSO were added in this order4·5H2O (0.02mmol) and sodium ascorbate VC-Na (0.04 mmol). The reaction materials are heated to 38 ℃ and reacted for 24h under stirring. The reaction product was poured into ice water under stirring and extracted 3 times with ethyl acetate (15 mL each time). Washing the organic layer with saturated NaCl water solution for 3 times, drying with anhydrous sodium sulfate, vacuum filtering, concentrating under reduced pressure, and performing column chromatography to obtain compound D1,the yield was 42%.
The method is repeated for 8 times, so that the same intermediate product A and the same compound D1 are obtained, the yield of the intermediate product A is 88-93%, and the yield of the compound D1 is 40-46%. This shows that the preparation method of the invention has good process stability.
D1 structural identification data are as follows:
1H NMR(300MHz，CDCl3): δ 7.54(s, 1H, triazolone-H), 7.38-7.33(m, 3H, Ar-H), 7.24(s, 2H, Ar-H), 6.95(d, J ═ 8.1Hz, 1H, Ar-H), 6.75(d, J ═ 8.1Hz, 1H, Ar-H), 6.69(d, J ═ 1.6Hz, 1H, Ar-H), 6.63(d, J ═ 8.0Hz, 1H, Ar-H), 6.56-6.51(m, 1H, Ar-H), 6.49(s, 1H, Ar-H), 5.49(s, 2H, -CH), -CH2-)，5.23(s，2H，-CH2-)，4.11(dd，J＝9.0，6.8Hz，1H，12-H)，3.89(s，1H，12-H)，3.85(s，3H，-OCH3)，3.82(s,3H,-OCH3)，3.78(s，3H，-OCH3)，2.93(t，J＝5.1Hz，2H，-CH2-)，2.55(ddd，J＝24.9，13.7，5.1Hz，4H,-CH2-，8-H，9-H)。
13C NMR(75MHz，CDCl3)：δ178.67，149.71，149.03，147.88，146.53，144.62，134.41，131.36，130.39，129.12，128.80，128.15，122.84，121.43，120.57，114.28，112.76，111.84，111.38，71.24，63.30，55.92，55.88，55.84，54.22，46.52，41.11，38.16，34.54。
ESI-HRMS(m/z)：C31H33N3NaO6[M+Na]+: calculated value 566.2267; found 566.2264.
The melting point is 146-147 ℃.
Examples 2 to 12
The azide compounds V1 were replaced with azide compounds V2 to V12, respectively, and the remaining conditions were the same as in example 1, thereby obtaining compounds D2 to D12 (see the summary of the invention). Compounds D2-D12 differed from compound D1 only in the R group, as detailed in Table 2.
TABLE 2
EXAMPLE 1 Effect of test Compounds on the number of viable cells
Trypan blue staining experiments were performed to investigate the inhibitory effects of the compounds D1-D12 of examples 1-12 on Toxoplasma gondii. To reduce the toxicity of the compounds on the host cells (HeLa), the compounds were selected for experimental studies at a concentration of 100. mu. mol/L, which had no effect on the morphological observation of the cells. As is clear from FIG. 1, the compounds D1 to D12 had higher activity, and particularly the compounds D4, D7 and D11 had higher anti-Toxoplasma gondii activity.
EXAMPLE 2 Effect of test Compounds on the number of viable cells
The compounds D1-D12 of examples 1-12 were tested for cytotoxicity against host cells (HeLa) and in vitro antiprotozoal activity using the MTT colorimetric method (T.gondii RH). On the basis of preliminary detection that the administration concentration of different compounds is 100 mu M/L, the compound solution of each compound with the concentration of 1-500 mu M/L has no harm to host cells and has good killing performance to toxoplasma gondii, the experiment tests the cytotoxicity and the anti-toxoplasma gondii activity of the compound solution of each compound with the concentration of 100 mu M/L. From three independent experimental data, the IC of the compound on Toxoplasma gondii-infected HeLa cells was calculated50Value, TD of Compound on HeLa cells50Value and Selectivity Index (SI) of the compound. The results of the relevant tests are recorded in table 3.
TABLE 3
In Table 3, IC50The median inhibitory concentration is indicated and is used to measure the inhibitory effect of the drug on Toxoplasma tachyzoites. TD50The median toxic dose is expressed and is used to measure cytotoxicity to the host cell. SI represents a selectivity index, therapeutic index or therapeutic index, in accordance with TD50/IC50And (4) calculating. When TD is used50When the ratio is more than or equal to 500.00, SI is 500/IC50(ii) a When IC50Greater than or equal to 500.00, SI ═ TD50/500. As is clear from Table 1, all of the compounds D1 to D12 had anti-Toxoplasma gondii activity, and the selectivity of D2, D4, D7 and D11 was better.
EXAMPLE 3 Effect of Compound D4 and control Compounds on Toxoplasma gondii-infected host cells
As shown in FIG. 2, the growth state of Toxoplasma gondii-infected host cells was significantly changed. The cells infected by the toxoplasma are shrunk, cracked and dead, and the number of the cells is obviously reduced compared with that of the normal HeLa cells. The cell state of the Toxoplasma gondii-infected cell group treated by spiramycin is better than that of the Toxoplasma gondii-infected cell group, the cell activity is slightly recovered, the cell shrinkage degree is reduced, and the number of dead cells is reduced. The cell state in the arctigenin experimental group is obviously better than that in the spiramycin group. The cell state of the compound D4 test group was substantially recovered, and the cell growth state was not different from that of normal cells.
Experimental example 4-Effect of Compound D4 and control Compounds on the number of mouse Abdominal parasites
In vivo anti-Toxoplasma gondii experiments were performed in mice and evaluated by counting the number of Toxoplasma gondii in the abdominal cavity of each group of mice. Compound D4 was selected for further studies of anti-toxoplasma activity in vivo. The medicine is continuously administrated for 4 days by establishing an acute toxoplasma infection animal model. As shown in fig. 3, D4 and arctigenin were able to significantly reduce the number of toxoplasma tachyzoites compared to the control group, the effect was better than that of spiramycin at the same dose, and the compound D4 was more effective. The inhibition rate of compound D4 reached 75.13% due to arctigenin. When tachyzoites were counted under an optical microscope, tachyzoites in the abdominal cavity of mice treated with compound D4 were found to have wrinkles or malformations.
The present invention is not limited to the above-described embodiments, and any variations, modifications, and substitutions which may occur to those skilled in the art may be made without departing from the spirit of the invention.
Claims (8)
1. An arctigenin-based compound, characterized in that it has a structure represented by formula (I):
in the formula (I), R1～R5The same or different, are each independently selected from hydrogen, methyl or ethyl; r6Selected from a single bond, methylene or ethylene; r has the structure shown in formula (II):
in the formula (II), R7Selected from a single bond, methylene or ethylene; r8～R12The same or different, are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy.
2. The compound of claim 1, wherein R is selected from one of the following groups:
3. a compound according to any one of claims 1 to 2, wherein R is selected from one of the following groups:
4. the compound of claim 1, wherein the compound of formula (I) is selected from one of the following compounds:
5. a process for the preparation of a compound according to claim 1, comprising the steps of:
(1) reacting a compound shown in a formula (III) with a compound shown in a formula (IV) to form an intermediate product A;
in the formula (III), R1～R5The same or different, are each independently selected from hydrogen, methyl or ethyl; in the formula (IV), R6Selected from the group consisting of a single bond, methylene or ethylene, X represents halogen and ≡ represents alkynyl;
(2) reacting the intermediate product A with a compound shown as a formula (V) to obtain a compound shown as a formula (I);
in the formula (V), R7Selected from a single bond, methylene or ethylene; r8～R12The same or different, are respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy; n is a radical of3Represents an azide group.
6. The method of claim 5, wherein:
in the step (1), a compound shown as a formula (III) and a compound shown as a formula (IV) in a molar ratio of 1: 1-3 react in an acetone solvent by using potassium carbonate as a catalyst to form an intermediate product A;
in the step (2), the intermediate product A and the compound shown in the formula (V) in a molar ratio of 1: 1-3 react in a mixed solvent of butanol and water by taking copper sulfate and sodium ascorbate VC-Na as catalysts to obtain the compound shown in the formula (I).
7. The preparation method according to claim 6, comprising the following specific steps:
(1) adding a compound shown as a formula (III), a compound shown as a formula (IV) and potassium carbonate in a molar ratio of 1: 1-3: 1-4, and an acetone solvent into a reaction container, and reacting for 5-20 hours at a temperature of 40-80 ℃ in a stirring state; pouring the reaction product into ice water, extracting for 2-5 times by using ethyl acetate, and then washing the extract for 2-5 times by using a saturated saline solution; drying the organic layer by anhydrous sodium sulfate, filtering, decompressing, concentrating and carrying out column chromatography to obtain an intermediate product A;
(2) mixing a mixed solvent of butanol and water in a volume ratio of 1-10: 1, an intermediate product A in a molar ratio of 1: 1-3: 0.05-0.2: 0.1-0.4, a compound shown in a formula (V), and copper sulfate pentahydrate CuSO4·5H2Adding O and sodium ascorbate VC-Na into a reaction container, and reacting for 12-48 h at the temperature of 20-60 ℃ in a stirring state; and pouring the reaction product into ice water, extracting for 2-5 times by using ethyl acetate, washing an organic layer for 2-5 times by using a saturated saline solution, drying by using anhydrous sodium sulfate, carrying out suction filtration, carrying out reduced pressure concentration and carrying out column chromatography to obtain the compound shown in the formula (I).
8. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament having activity against Toxoplasma gondii.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284823A (en) * | 2007-04-13 | 2008-10-15 | 烟台靶点药物研究有限公司 | Arctigenin pro-drug, preparation method and use thereof |
| WO2010108187A2 (en) * | 2009-03-20 | 2010-09-23 | Brandeis University | Compounds and methods for treating mammalian gastrointestinal microbial infections |
| WO2013023145A1 (en) * | 2011-08-10 | 2013-02-14 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
| CN105541765A (en) * | 2016-02-03 | 2016-05-04 | 辽宁中医药大学 | Arctigenin amino-acid ester derivatives, and preparation method and application thereof |
| CN105616400A (en) * | 2014-11-05 | 2016-06-01 | 中国科学院上海药物研究所 | Use of arctigenin carbamate derivatives in preparation of drug for treating Alzheimer disease |
| CN107951877A (en) * | 2016-08-08 | 2018-04-24 | 吉林农业大学 | Arctigenin isoleucine ester hydrochloride |
-
2018
- 2018-08-03 CN CN201810878074.3A patent/CN109053701B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284823A (en) * | 2007-04-13 | 2008-10-15 | 烟台靶点药物研究有限公司 | Arctigenin pro-drug, preparation method and use thereof |
| WO2010108187A2 (en) * | 2009-03-20 | 2010-09-23 | Brandeis University | Compounds and methods for treating mammalian gastrointestinal microbial infections |
| WO2013023145A1 (en) * | 2011-08-10 | 2013-02-14 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
| CN105616400A (en) * | 2014-11-05 | 2016-06-01 | 中国科学院上海药物研究所 | Use of arctigenin carbamate derivatives in preparation of drug for treating Alzheimer disease |
| CN105541765A (en) * | 2016-02-03 | 2016-05-04 | 辽宁中医药大学 | Arctigenin amino-acid ester derivatives, and preparation method and application thereof |
| CN107951877A (en) * | 2016-08-08 | 2018-04-24 | 吉林农业大学 | Arctigenin isoleucine ester hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| Synthesis and anthelmintic activity of arctigenin derivatives against Dactylogyrus intermedius in goldfish;Yang Hu，等;《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》;20170801;第27卷(第15期);第3314页图2化合物4a * |
| 牛蒡苷对弓形虫热休克蛋白70诱导弓形虫感染小鼠急性肝损伤的保护作用;程小艳，等;《延边大学医学学报》;20151226;第38卷(第4期);270-273 * |
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