CN111285860A - Indole derivatives containing disulfanyl heterocyclic structure or stereoisomer thereof, or salt or solvate thereof - Google Patents

Indole derivatives containing disulfanyl heterocyclic structure or stereoisomer thereof, or salt or solvate thereof Download PDF

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CN111285860A
CN111285860A CN202010220141.XA CN202010220141A CN111285860A CN 111285860 A CN111285860 A CN 111285860A CN 202010220141 A CN202010220141 A CN 202010220141A CN 111285860 A CN111285860 A CN 111285860A
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CN111285860B (en
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欧阳贵平
王贞超
胡伟男
漆亚云
李文
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • A01N43/82—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 five-membered rings with three ring hetero atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention relates to a preparation method and application of indole derivatives containing disulfanyl heterocyclic structures. The compound has a structure shown as a general formula (I):

Description

Indole derivatives containing disulfanyl heterocyclic structure or stereoisomer thereof, or salt or solvate thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method and application of indole derivatives containing disulfanyl heterocyclic structures.
Background
The plant bacterial disease is one of the most destructive plant diseases in the world, even causes crop failure in severe conditions, and causes great harm to crops and economic crops in China. Among them, bacterial diseases such as Xanthomonas oryzae pv. oryzae, Xoo, Xanthomonas oryzae (Xanthomonas oryzae) and the like cause losses of hundreds of millions of dollars to agriculture each year. The existing commercial antibacterial agents (such as bismerthiazol, thiabendazole, fluazinam and the like) not only have the problems of poor prevention effect, high toxicity, serious environmental pollution and the like, but also increase the drug resistance of pathogens, and urgently need to discover active compounds of high-efficiency anti-plant disease bacteria, so that a new green pesticide with main intellectual property rights is created on the basis, and a candidate drug is provided for the prevention and control of the bacterial diseases of crops.
Indole is reported in the literature to be a class of alkaloids which are commonly found in nature, because the indole or indole derivatives have good biological activity due to the specific chemical structure, such as: antibacterial, antiviral, antiinflammatory, antioxidant, and anticancer effects. The 1,2,4-triazole and the 1,3,4-oxadiazole diazole are key intermediates in pesticide and medicine, and are widely applied due to the biological activities of insecticide, bacteriostasis, antivirus, antioxidation and the like. Disulfide derivatives have been attracting attention because of their excellent biological activities in many respects, such as antibacterial, antifungal, antitumor, central exciting activities, etc., such as disulfide Pyritinol (Pyritinol).
In order to search for high-efficiency bactericidal active compounds, indole, 1,3,4-oxadiazole and 1,2,4-triazole compounds are taken as the basis, a disulfide bond with bioactivity is introduced into the system, a series of 3- (5-disulfanyl-4H-1, 2, 4-triazole) -1H-indole derivatives and 3- (5-disulfanyl-1, 3, 4-oxadiazole) -1H-indole derivatives are synthesized, the bioactivity of the derivatives is investigated, and important scientific bases are provided for the research and development of new pesticides.
The study of the biological activity of indole derivatives has progressed as follows:
in 2006,13 3-substituted indole derivatives were designed and synthesized from indoles as raw materials by Al-Hiari [ Al-Hiari, Y.M.; Qaisi, A.M.; El-Abadelah, M.M.; Voelter, W.Synthesis and antibacterial activity of sodium substitated 3- (aryl) -and 3- (heteroaryl) indoles [ J ]. Monatsheft f ü r Chemie/Chemical Monthly.2006,137(2),243-248], and others, and bacteriostatic activity tests of Escherichia coli, Staphylococcus aureus, Candida albicans and Aspergillus were performed in vitro.
2011, Ravi [ Ravi, j.; shah, Neha r.modi.; manth j. patel.; patel, laxmanbhaij.; bhuprasin f. chauhan; 10 indole derivatives were synthesized from Madhabhai M.Patel.design, synthesis and invitro antibiotics and antisense activities of the same novel spiro [ azetidine-2,3 '-indole ] -2,4 (1' h) -dione [ J ]. Med.chem, Res.2011,20(5), 587-. The biological activity results show that: the bromine-substituted indole derivative has good inhibition activity on bacteria like the compound 7c, the nitro-containing compound has obvious inhibition activity on fungi like the compound 7h, and the MIC mean value is 6.25 mu g/mL.
2013, Deokar [ Deokar, h.; chaskar, j.; chaskar, A. Synthesis and Activity Evaluation of Novel oxydiazino/Thiadiazino-indium and oxydiazole/Thiadiazole Derivatives of 2-Oxo-2H-benzopyran [ J].J.Heterocyclic.Chem.2014,51(3),719-725]And the like, designs and synthesizes a series of indole compounds containing oxadiazole structures, and adopts a culture medium dilution method to test the biological activity of staphylococcus aureus active salmonella typhi and escherichia coli in vitro. The results show that the compound 3b has better inhibiting effect on three bacteria and MIC (minimal inhibitory concentration)50The values are 50, 50L, 50. mu.g/mL and control respectivelyThe drug griseofulvin (50. mu.g/mL) was equivalent.
The study of the biological activity of 1,3,4-oxadiazole compounds has progressed as follows:
2016, Wang et al [ Wang, P.Y.; zhou, l.; zhou, j.; wu, z.b.; xue, w.; song, b.a.; yang, S.; synthesis and antibiotic activity of pyridine-substituted 2,5-substituted-1,3, 4-oxodiazole thioether/sulfoxide derivatives [ J].Bioorg.Med.Chem.Lett.,2016,26,1214-1217.]A series of 1,3,4-oxadiazole thioether (sulfoxide and sulfone) derivatives are reported, and biological activity test results show that the compounds I-8, I-10 and I-10 have EC (environmental impact resistance) on rice bacterial blight (Xanthomonas oryzae pv. Oryzae), tobacco bacterial wilt (Ralstonia solanacearum) and citrus canker (Xanthomonas axonopodis pv. citri)50The value is 0.54 mu g/mL-12.14 mu g/mL, which is better than that of the control medicament bismerthiazol (EC)50The value is 92.61 mug/mL), SAR analysis results show that the biological activity of the target compound is improved along with the increase of an alkane chain, and the biological activity of the thioether derivative is better than that of the sulfoxide/sulfone derivative.
2017, Li et al [ Li, P.; tian, p.y.; chen, y.z.; song, x.p.; xue, w.; jin, l.h.; hu, d.y.; yang, S.; song, B.A. novel bioshiether derivatives relating a 1,3, 4-oxomolar entity design, synthesis, antibiotic and neuronal activities [ J].Pest Manag.Sci.2018,74,844–852.]A series of 1,3, 4-oxadiazole-containing dithioether derivatives were reported and tested for biological activity. Wherein the compound 4f has the best activity against rice bacterial blight, rice bacterial streak germ and citrus canker germ, and the EC thereof is50The values are respectively 4.82 mu g/mL,11.15 mu g/mL and 16.57 mu g/mL, which are superior to the control medicaments of the thiabendazole and the thiacumidine. Meanwhile, the compound 4f has the best activity against caenorhabditis elegans within 48h, and LC thereof50The value is 2.89 mu g/mL, which is superior to the control agents ethoprophos and fosthiazate. The analysis of structure-activity relationship shows that the activity of the 5-position phenyl ring thioether is better than that of benzyl thioether, and the activity of the 4-Cl substituent group on the phenyl ring is better than that of 4-F; when the 5-position group is fixed, the activity of the sulfydryl-connected small group is better than that of the large group.
2016, Zhao et al [ Zhao, j.j.; wang, x.f.; li, b.l.; zhang, r.l.; li and B.；Liu,Y.M.；Li,C.W.；Liu,J.B.；Chen,B.Q.Synthesis and in vitro antiproliferative evaluationof novel nonsymmetrical disulfides bearing 1,3,4-oxadiazole moiety[J].Bioorg.Med.Chem.Lett.,2016,26,4414-4416.]A series of asymmetric novel 1,3,4-oxadiazole derivatives containing disulfide bonds are reported, and biological activity test results show that the compounds have different inhibition effects on different cancer cells, wherein the compound 7J has the best inhibition activity on human liver cancer cells (SMMC-7721), and the IC of the compound is IC50The value was 3.40. mu.M, and the inhibitory activity of Compound 7a against human cervical cancer cells (Hela) was the best, its IC50The value is 3.40 μ M, the inhibitory activity of compound 7g to human lung adenocarcinoma cell line (A549) is best, and IC thereof50The value was 6.26. mu.M.
The research on the biological activity of the 1,2,4-triazole compound progresses as follows:
in 2008, triazole compound 5- [2- (substituted sulfamoyl) -4, 5-dimethoxy-benzyl ] -4-aryl-thiazole-3-thione was synthesized and tested for its bacteriostatic activity in vitro by I.R. Ezabadi [ Camuitsis C, Geronikaki A, Ciric A, et al. Sulfonamide-1,2,4-thiadiazole derivatives as antibacterial and antibacterial agents, synthesis, biological evaluation, lipophilicity, and formatting students. The result shows that the minimum inhibitory concentration MIC of the compound to Escherichia coli is 100 mug/mL and is better than that of a control drug chloramphenicol (MIC is 250 mug/m L).
In 2010,1, 2, 4-triazoles containing pyridine were designed and synthesized by Saadeh [ Saadeh H A, Mosleh I M, Al-Bakri A G, et Al, chem InformimAbstract: Synthesis and antibacterial Activity of New 1,2, 4-Triazol-3-thiolmetronidazoledrovaries [ J ] Chemform, 2010,141(4):471-478 ]. And the synthesized compound is tested for the antibacterial activity against gram-positive bacteria, gram-negative bacteria and fungi, and the compound 3d is found to have a minimum inhibitory concentration MIC (MIC) of 17.10 mu g/mL against Clostridium (Cl. sponogenes) and show a better inhibitory effect than a reference substance Metronidazole (MIC) of 42.9 mu g/mL.
In 2012, Wang et al [ Wang Q P, Zhang J Q, Damu G L V, et al synthesis and biological activity of novel polypeptides as novel polypeptides and anti-fungal agents [ J ]. Science chinese Chemistry,2012,55(10): 2134:. 2153 ] designed and synthesized a series of compounds containing a bis 1,2,4-triazole heterocyclic structure, in which compound 9b had better inhibitory activity against gram-positive bacteria, gram-negative bacteria and fungi, had MIC of 1 μ G/mL for escherichia coli, 2 μ G/mL for staphylococcus aureus and had minimal MIC of 2 μ G/mL for candida albicans, and had more than 2 times the effect on chloramphenicol and norfloxacin.
Disclosure of Invention
The invention provides an indole derivative containing a disulfanyl heterocyclic structure 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 a further object of the present invention to provide the above compounds or stereoisomers thereof, or salts or solvates thereof, or the use of said compositions.
Another object of the present invention is to provide a method for controlling agricultural pests using the above 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:
indole derivatives containing a disulfanyl heterocyclic structure or stereoisomers thereof, or salts or solvates thereof, wherein the compounds have a structure shown as general formula (I):
Figure BDA0002425785200000051
wherein,
x is NH or O atom;
r is selected from any substituted or unsubstituted alkyl, any substituted or unsubstituted cycloalkyl and any substituted or unsubstituted aryl.
Preferably, R is selected from C1-C6Alkyl, optionally substituted or unsubstituted cycloalkyl, substituted or unsubstituted C6-C15One or more of aryl, wherein the aryl and benzyl groups may be substituted by one or more C1-C6Alkyl radical, C1-C6Alkoxy, amino, hydroxy, halogen, nitro or trifluoromethyl.
More preferably, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, substituted or unsubstituted phenyl, wherein said aryl and benzyl groups may be substituted by one or more C1-C6Alkyl radical, C1-C6Alkoxy, amino, hydroxy, halogen, nitro or trifluoromethyl.
The indole derivative containing the disulfanyl heterocyclic structure or a stereoisomer thereof, or a salt or a solvate thereof is selected from the following compounds:
Figure BDA0002425785200000061
the invention also provides an intermediate compound for preparing the indole derivative containing the disulfanyl heterocyclic structure or the stereoisomer thereof, or the salt or the solvate thereof, which is shown as follows:
Figure BDA0002425785200000062
the invention also provides a preparation method of the indole derivative containing the disulfanyl heterocyclic structure or the stereoisomer thereof, or the salt or the solvate thereof, which comprises the following steps:
Figure BDA0002425785200000071
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 and diseases are rice bacterial blight, cucumber bacterial blight, konjak bacterial blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt, sclerotinia rot of colza, wheat scab, potato late blight and blueberry root rot.
The invention also provides a method for preventing and treating agricultural diseases and insect pests. Allowing said compound or a stereoisomer thereof, or a salt or solvate thereof, or said composition to act on the noxious substances or their living environments; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial blight, tobacco bacterial wilt, cucumber bacterial blight, konjak bacterial blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt, sclerotinia sclerotiorum, wheat fusarium graminearum, potato late blight and blueberry root rot.
The invention also provides a method for protecting a plant from an agricultural pest comprising the step of contacting the plant with the compound or a stereoisomer thereof, or a 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. "C1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C1-6Alkyl "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. And, when reference is made to hexyl, heptyl, octyl, all isomers thereof are included in addition to n-hexyl, n-heptyl, n-octyl.
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 the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O)2H or 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 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 (internal 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 in the preparation process, and are therefore included within the scope of the present invention.
Preferably, C1-C10Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; c1-C10Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomers thereof; c2-C5Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl, and isomers thereof. Similarly, C1-C5Alkyl refers to methyl, ethyl, propyl, butyl, pentyl and isomers thereof; c1-C5Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentoxy and isomers thereof;
when substituents are mentioned, such as 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, 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, the indole derivative containing a disulfanyl heterocyclic structure is synthesized on the basis of indole, 1,3,4-oxadiazole and 1,2,4-triazole structures, and the compound is found to have a good inhibition effect on pathogenic bacteria, has a good inhibition effect on pathogenic bacteria [ such as Xanthomonas oryzae pv. oryzae, Xoo ] and Ralstonia solanacearum (R. solanacearum), and the like, and provides an important scientific basis for research and development of new pesticides.
Detailed Description
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: synthesis of 3- (5-disulfanyl-4H-1, 2, 4-triazole) -1H-indole derivative
(1) Preparation of 1H-indole-3-formylhydrazine
To a 250mL round bottom flask were added 10.0g (57.08mmol) of methyl 1H-indole-3-carboxylate followed by 180mL of 80% hydrazine hydrate. Then heating to 80 ℃ for reflux, TLC shows that the reaction of the disappearance of the raw material point is finished, cooling to room temperature, precipitating white solid, performing suction filtration, and drying to obtain 8.9g of white solid with the yield of 89.1%.
(2) Preparation of 2- (1H-indole-3-carbonyl) hydrazine thiocarboxamide
180ml of water and 10.0g (57.08mmol) of 1H-indole-3-formylhydrazine are placed in a round-bottomed flask, 7.0g (69.95mmol) of concentrated hydrochloric acid and 11.1g of KSCN (114.16mmol) are added dropwise, the mixture is stirred under reflux, and TLC shows the end of the disappearance of the starting material. The solid was precipitated by cooling, washed with water and dried to give 12.6g of a light brown powder with a yield of 93.9%.
(3) Preparation of 5- (1H-indol-3-yl) -4H-1,2, 4-triazole-3-thiol
A mixture of 10.0g (42.68mmol)2- (1H-indole-3-carbonyl) hydrazine thiocarboxamide and 120ml 4% aqueous KOH is heated at reflux. TLC showed the end of the reaction when starting material disappeared, then the mixture was cooled to room temperature and filtered. The filtrate was neutralized with concentrated hydrochloric acid to PH 3-4. Filtered and dried to collect the resulting white solid 8.25g, 89.37% yield.
(4) Preparation of 4-methoxyphenyl sulfenyl chloride
0.30g (2.22mmol) of sulfonyl chloride was added dropwise to a solution of 0.30g (2.14mmol) of 4-methoxythiophenol in 15mL of dichloromethane at 0 ℃ in ice bath, and the reaction mixture was stirred at the same temperature for 1 hour and then concentrated in vacuo to give 4-methoxyphenylsulfenyl chloride as a red liquid which was used immediately in the next step. Other sulfenyl chloride intermediate compounds are synthesized by adopting corresponding raw materials according to the step (4).
(5) Preparation of 3- (5- (4-methoxyphenyl) disulfanyl-4H-1, 2, 4-triazole) -1H-indole
5mL of the freshly prepared 4-methoxyphenylsulfenyl ether solution in 5mL of anhydrous ether was added dropwise to a solution of 0.40g (1.85mmol) of 5- (1H-indol-3-yl) -4H-1,2, 4-triazole-3-thiol in 5mL of anhydrous ether. The reaction mixture was stirred at room temperature and the reaction was followed by TLC after the reaction was complete. The product was filtered, washed with anhydrous ether, and purified by column chromatography (dichloromethane: methanol 60: 1) to obtain 0.4g of a refined off-white crystal in a yield of 61.0%, and other target compounds were synthesized using the corresponding starting materials or substituents according to step (5).
Example 2: synthesis of 3- (5-disulfanyl-1, 3, 4-oxadiazole) -1H-indole derivatives
(1) Preparation of 5- (1H-indol-3-yl) -4H-1,3, 4-oxadiazole-2-thiol
10.0g (57.08mmol) of 1H-indole-3-formylhydrazine, 5.0g (891mmol) of potassium hydroxide and 180mL of absolute ethyl alcohol are respectively added into a 250mL three-neck round-bottom flask, the mixture is stirred until the solid is dissolved, then 7.0g (91.95mmol) of carbon disulfide is slowly dripped until the solution is yellow and turbid rapidly, the temperature is raised to reflux after the dripping is finished, and the reaction is tracked by TLC. And after the reaction is finished, cooling, decompressing and removing a reaction solvent to obtain a yellow solid, dissolving the yellow solid with a proper amount of water to obtain a solid, acidifying the solid with dilute hydrochloric acid, adjusting the pH to 4-5, precipitating a white solid, standing, performing suction filtration, and drying to obtain 8.0g of the white solid, wherein the yield is 66.9%.
(2) Preparation of 3- (5- (4-methoxyphenyl) disulfanyl-1, 3, 4-oxadiazole) -1H-indole
5mL of the freshly prepared 4-methoxyphenylsulfenyl ether solution in anhydrous ether was added dropwise to a solution of 0.40g (1.84mmol) of 5- (1H-indol-3-yl) -1,3, 4-oxadiazole-2-thiol in 5mL of anhydrous ether. The reaction mixture was stirred at room temperature and the reaction was followed by TLC after the reaction was complete. The product was filtered, washed with dehydrated ether, and recrystallized from ethyl acetate to give 0.3g of refined pale yellow crystals, in 45.8% yield, and other target compounds were synthesized using the corresponding starting materials or substituents according to step (2).
Synthetic moieties3- (5-disulfanyl-4H-1, 2, 4-triazole) -1H-indole derivativesAnd3- (5-disulfanyl-) 1,3, 4-oxadiazole) -1H-indole derivativesThe structure, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of (a) are shown in Table 1, and the physicochemical properties are shown in Table 2.
TABLE 1 NMR hydrogen and carbon spectra data for some of the compounds
Figure BDA0002425785200000111
Figure BDA0002425785200000121
Figure BDA0002425785200000131
Figure BDA0002425785200000141
Figure BDA0002425785200000151
Table 2 physicochemical properties of the target compounds
Figure BDA0002425785200000152
Figure BDA0002425785200000161
Pharmacological example 1:
the inhibition rate of the target compound on plant pathogenic bacteria is tested by a turbidity method, and the test objects are rice bacterial blight (Xoo), tobacco bacterial wilt (Rs) and citrus canker pathogen (Xac). DMSO was dissolved in the medium as a blank control. Placing rice bacterial leaf blight bacteria (in M210 solid culture medium) in NB culture medium, and shake culturing in constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for use; placing ralstonia solanacearum (on M210 solid culture medium) into NB culture medium, and performing shake culture in a constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for later 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 culture medium prepared into different concentrations (e.g., 100, 50. mu.g/mL) of the medicament (compound) is added into a test tube, 40. mu.L of NB liquid culture medium containing plant-borne bacteria is respectively added, shaking is carried out in a constant-temperature shaking table at 28-30 ℃ and 180rpm, and the bacterial blight of rice is cultured for 36h, and the bacterial wilt of tobacco and citrus canker are cultured for 48 h. The OD was measured on a spectrophotometer using the bacterial solutions of the respective concentrations595Value, and additionally determining the OD of the corresponding concentration of the sterilized NB-containing liquid medium595The value is obtained.
Corrected OD value-bacteria-containing medium OD value-sterile medium OD value
Percent inhibition ratio [ (corrected contrast culture medium bacterial liquid OD value-corrected toxin-containing culture medium OD value)
OD value of the control medium bacterial liquid after correction is multiplied by 100
The examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and some experimental results of the target compounds are shown in table 3.
TABLE 3 inhibitory Activity of a class of indole derivatives containing a disulfanyl heterocycle Structure against plant pathogenic bacteria
Figure BDA0002425785200000171
"NT" means not tested
As can be seen from Table 3, the target compounds showed good inhibitory activity against plant pathogenic bacteria (e.g., rice bacterial blight, tobacco bacterial wilt and citrus canker pathogen) in the in vitro test. Wherein, the inhibitory activity of the compounds 1-3, 1-6, 1-8, 2-1-2-3 and 2-8 on the rice bacterial blight at the concentration of 100 mu g/mL is 68.24, 75.67, 78.72, 71.35, 77.86, 80.05 and 66.77 respectively, and the inhibitory activity of the compounds 1-3, 1-6, 2-1-2-3 and 2-8 on the rice bacterial blight at the concentration of 50 mu g/mL is 70.31, 66.10, 72.93, 67.87, 73.12, 81.43, 76.64 and 68.54%; the inhibition rates of the compounds 1-1, 1-2, 1-4, 1-6, 1-8-1-11, 2-1, 2-8 and 2-12 on ralstonia solanacearum at the concentration of 100 mu g/mL are 82.89, 80.04, 87.82, 70.16, 68.49, 82.09, 77.13, 73.80, 84.66, 82.73 and 107.87 respectively, and the inhibition activities of the compounds 1-1, 1-2, 1-8, 1-9, 2-2 and 2-12 on ralstonia solanacearum at the concentration of 50 mu g/mL are 84.75, 81.71, 83.52, 65.88, 88.78 and 107.62 respectively; the inhibition rate of the compound 1-1 to the citrus canker pathogenic bacteria at the concentration of 100 mu g/mL is 66.28%, and the inhibition activities of the compound 1-1 and the compound 1-2 to the citrus canker pathogenic bacteria at the concentration of 50 mu g/mL are 68.05 and 67.68% respectively. Can be used for preparing pesticide for resisting plant pathogenic bacteria.
Pharmacological example 2:
testing the inhibition rate of the target compound on human tumor cells by adopting an MTT method, wherein A549 (lung cancer cells, Kunming cell bank of Chinese academy of sciences) is cultured to logarithmic growth phase by using an RPMI-1640 culture medium; PC-3 (prostate cancer cells, Kunming cell bank of Chinese academy of sciences) is cultured by using a DMEM culture medium until a logarithmic growth phase, then inoculated into a 96-well plate, provided with a blank control hole and a negative control hole, placed in a carbon dioxide incubator for overnight adherence, added with 20 muL of liquid medicine with the concentration of 10 muM, added with 20 muL of DMSO in the negative control group, added with no substance in the blank control group, then placed in the incubator, incubated for 48h, added with MTT (5mg/mL) solution in a dark place, reacted in the incubator for 4h, then taken out, discarded supernatant, added with DMSO, shaken on a shaking table for 10 min (150r/min), and the absorbance (OD) value of the cell is measured on an enzyme labeling instrument. The inhibition rate was calculated as 1- (administration group OD value mean-blank OD value mean)/(negative group OD value mean-blank OD value mean) 100%.
TABLE 4 inhibition of human tumor cells by a class of dithioalkyl-heterocycle containing indole derivatives
Figure BDA0002425785200000181

Claims (8)

1. Indole derivatives containing a disulfanyl heterocyclic structure or stereoisomers thereof, or salts or solvates thereof, characterized in that: the compound has a structure shown as a general formula (I):
Figure FDA0002425785190000011
wherein,
x is NH or O atom;
r is selected from any substituted or unsubstituted alkyl, any substituted or unsubstituted cycloalkyl and any substituted or unsubstituted aryl.
2. The dithioalkyl-heterocycle structure-containing indole derivative or a stereoisomer thereof, or a salt thereof or a solvate thereof according to claim 1, wherein: preferably, R is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C6-C15Aryl and benzyl, wherein the aryl and benzyl groups may be substituted by one or more C1-C6Alkyl radical, C1-C6Alkoxy, amino, hydroxy, halogen, nitro or trifluoromethyl.
3. The dithioalkyl-heterocycle structure-containing indole derivative or a stereoisomer thereof, or a salt thereof or a solvate thereof according to claim 2, wherein: more preferably, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butylAlkyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or benzyl, wherein the aryl and benzyl groups may be substituted by one or more C1-C6Alkyl radical, C1-C6Alkoxy, amino, hydroxy, halogen, nitro or trifluoromethyl.
4. An intermediate compound for preparing the dithioalkyl hetero ring structure-containing indole derivative or a stereoisomer thereof, or a salt or a solvate thereof according to claim 1, wherein: the intermediate compound has the following structural formula:
Figure FDA0002425785190000021
wherein X is NH or an O atom.
5. A process for the preparation of a dithioalkyl-heterocycle structure-containing indole derivative or a stereoisomer thereof, or a salt or solvate thereof, as claimed in any one of claims 1 to 4, which comprises the steps of:
Figure FDA0002425785190000022
6. a composition comprising a compound according to any one of claims 1 to 4 or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide.
7. Use of a compound according to any one of claims 1 to 4 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 7, for controlling an agricultural pest.
8. Use according to claim 7, characterized in that: preferably, the agricultural pest is a bacterial or fungal disease of a plant; 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 gray mold, pepper wilt, rape sclerotinia rot, wheat scab, potato late blight and blueberry root rot.
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