CN114644583A - Indole derivative and preparation method and application thereof - Google Patents

Indole derivative and preparation method and application thereof Download PDF

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CN114644583A
CN114644583A CN202210207255.XA CN202210207255A CN114644583A CN 114644583 A CN114644583 A CN 114644583A CN 202210207255 A CN202210207255 A CN 202210207255A CN 114644583 A CN114644583 A CN 114644583A
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indole
formula
compound
indole derivative
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CN114644583B (en
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山广志
王晓慧
仇小丹
孙忠浩
孙可微
刘伊彤
左利民
赵婷
李怡然
朱志玲
赵学佳
周霞
赵圣楠
姜艺菲
孟庆国
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Institute of Medicinal Biotechnology of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides an indole derivative and a preparation method and application thereof, belonging to the technical field of organic synthesis. The indole derivative provided by the invention has any one of structures shown in formulas I to IV. The indole derivative provided by the invention has good antibacterial activity, can be used for preparing antibacterial drugs, and can be particularly used as a TrpRS inhibitor. When the connecting group between the indole and the aromatic ring in the indole derivative provided by the invention is thiourea, the antibacterial activity of the indole derivative is superior to that of the indole derivative with an amide connecting group. Further, the indole derivative has a better antibacterial activity when the aromatic ring is a benzene ring substituted with an electron-withdrawing group. The results of enzyme activity and affinity experiments show that the indole derivative provided by the invention has an action target of TrpRS, has high affinity for TrpRS, has a value of further clinical development and application, and can be used as a drug lead molecule for further research and development.

Description

Indole derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an indole derivative and a preparation method and application thereof.
Background
In recent years, the pharmaceutical industry has been vigorously developed, and the types of antibiotics have been increasing, but the problem of antibiotic resistance has also become more serious. Infections caused by drug-resistant microorganisms (e.g., methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, and Mycobacterium tuberculosis) have posed a significant threat to global public health. At present, the research and development level of the medicine can not meet the clinical requirement on new antibiotics, and the research and development of new antibiotics is urgently needed.
aminoacyl-tRNA synthetases (aaRSs), also called aminoacyl-tRNA ligases, are widely present in organelles such as archaea, eubacteria, eukaryotic cells, mitochondria and chloroplasts, and can catalyze amino acids and homologous tRNA to be connected through covalent bonds in protein biosynthesis so as to realize accurate translation of genetic information, so that the aaRSs play an important role in protein biosynthesis. Once the aaRSs are inhibited in bacteria, protein biosynthesis is forced to stop, which inevitably leads to a slowing of bacterial growth. aaRSs are ubiquitous in cells, and although their catalytic functions are relatively conserved, the structures of aaRSs of different species are different, and there are large differences between prokaryotes and eukaryotes. The different catalytic site structure of bacteria and human aaRSs makes it possible to design specific aaRSs inhibitors against microorganisms and helps to develop novel antibiotics targeting aaRSs.
Each amino acid has a corresponding aminoacyl-tRNA synthetase. Among them, tryptophan is an important amino acid for protein synthesis and plays an important role in the body, and if Tryptophanyl-tRNA synthetase (TrpRS) is inhibited, protein biosynthesis is forced to be terminated. Therefore, the development of TrpRS targeted inhibitors is of great significance.
Indole ring is an important heterocyclic compound, and has wide pharmacological activity, such as antibiosis, anti-inflammation, antitumor, antivirus, antidepressant, anti-migraine and anti-hypertension. However, the current indole TrpRS inhibitors are of few varieties and are subject to further expansion.
Disclosure of Invention
The invention aims to provide an indole derivative and a preparation method and application thereof. The indole derivative provided by the invention has high antibacterial activity and can be used as a TrpRS inhibitor.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an indole derivative which has any one of structures shown in formulas I to IV:
Figure BDA0003531384530000011
in the formulas I to IV, n is 0 to 3,
in the formula I, R1including-H or benzyloxycarbonyl, R2Including substituted phenyl, six-membered cycloalkyl, five-membered heterocycle or naphthyl;
in the formula II, R3including-H or benzyloxycarbonyl, R4Including substituted phenyl;
in the formula III, R5comprising-H or-CH3；
In the formula IV, R6Including substituted phenyl groups.
Preferably, said R is2Including any of the following structures:
Figure BDA0003531384530000021
preferably, said R is4Any one of the following structures:
Figure BDA0003531384530000022
preferably, said R is6Including any of the following structures:
Figure BDA0003531384530000023
the invention provides a preparation method of the indole derivative in the technical scheme, and the preparation method of the indole derivative with the structure shown in formula I or formula II comprises the following steps:
mixing a first indole compound, a first acyl chloride compound, potassium thiocyanate and a good solvent of indole compounds, and carrying out a first acylation reaction to obtain an indole derivative with a structure shown in formula I or formula II;
the first indole compound has a structure represented by formula V-1 or V-2:
Figure BDA0003531384530000024
n is 0 to 3;
the first acyl chloride compound is R2-COCl or R4-COCl, wherein R2And R in the formula I2Same as R4And R in said formula II4The same;
the preparation method of the indole derivative with the structure shown in the formula III comprises the following steps: mixing a second indole compound, potassium thiocyanate and an alcohol solvent, and carrying out cyclization reaction to obtain an indole derivative with a structure shown in a formula III;
the second indole compound has a structure represented by formula VI:
Figure BDA0003531384530000031
in the formula VI, R5And R in said formula III5The same; n is 0 to 3;
the preparation method of the indole derivative with the structure shown in the formula IV comprises the following steps: a second indole compound, R6-CHO, an alkaline reagent and an alcohol solvent are mixed for substitution reaction to obtain an indole derivative with a structure shown in formula IV;
the R is6-CHO R6And R in said formula IV6The same is true.
Preferably, in the preparation method of the indole derivative having the structure shown in formula I or formula II, the molar ratio of the first indole compound to the first acid chloride compound is 1: 1.0 to 1.5;
the molar ratio of the first indole compound to potassium thiocyanate is 1: 1.0 to 1.5;
the temperature of the first acylation reaction is 50-80 ℃, and the time is 4-8 h.
Preferably, in the preparation method of the indole derivative having the structure shown in formula III, the molar ratio of the second indole compound to potassium thiocyanate is 1: 1.0 to 2.0;
the temperature of the cyclization reaction is 50-90 ℃, and the time is 6-10 h.
Preferably, in the preparation method of the indole derivative with the structure shown in the formula IV, the second indole compound and R6-CHO molar ratio of 1: 1.0 to 1.8;
the temperature of the substitution reaction is 60-90 ℃, and the time is 8-16 h.
Preferably, the preparation method of the second indole compound comprises the following steps:
mixing a compound with a structure shown in a formula VII, an alkaline reagent, a second acyl chloride compound and a soluble compound solvent shown in the formula VII, and carrying out a second acylation reaction to obtain a second indole compound;
Figure BDA0003531384530000032
in the formula VII, n is 0-3;
the second acid chloride compound comprises chloroacetyl chloride or 2-chloropropionyl chloride.
The invention also provides application of the indole derivative in the technical scheme in preparation of antibacterial drugs.
The invention provides an indole derivative which has any one of structures shown in formulas I to IV. The indole derivative provided by the invention has a structure similar to that of an intermediate Trp-AMP with antibacterial activity, has good antibacterial activity, can be used for preparing antibacterial drugs, and can be particularly used as a TrpRS inhibitor. Wherein, when the connecting group between the indole and the aromatic ring is thiourea, the antibacterial activity of the indole derivative is better than that of the indole derivative of the amide connecting group. Further, when the aromatic ring is a benzene ring substituted with an electron-withdrawing group, the antibacterial activity is better. Sensitivity experiment results show that the indole compounds with the structures shown in I-4, I-11, I-12, I-13, I-14, I-16 and I-21 have better antibacterial activity. The results of enzyme activity and affinity experiments show that the indole derivative provided by the invention has an action target of TrpRS, has high affinity for TrpRS, has a value of further clinical development and application, and can be used as a drug lead molecule for further research and development.
The invention provides a preparation method of the indole derivative in the technical scheme. The preparation method provided by the invention is simple to operate, high in yield, wide in raw material source and low in cost, and is suitable for industrial production.
Drawings
FIG. 1 is a reaction scheme of indole compounds having structures shown in formulas I-1 to I-22, formulas II-23 to II-26, and formulas II-29 to II-30;
FIG. 2 is a reaction scheme of indole compounds having the structures shown in formulas I-19, II-27, and II-28;
FIG. 3 is a reaction scheme of indole compounds having the structures shown in formulas III-31 to III-34 and formulas IV-35 to IV-37
FIG. 4 is a graph showing the results of an inhibitory activity test of an indole compound having the structure represented by I-12 on TrpRS;
FIG. 5 is a graph showing the results of an inhibitory activity test of an indole compound having the structure represented by I-13 on TrpRS;
FIG. 6 is a graph showing the result of binding of an indole compound having a structure represented by I-12 to TrpRS based on SPR;
FIG. 7 is a graph showing the result of binding of an indole compound having a structure represented by I-13 to TrpRS based on SPR.
Detailed Description
The invention provides an indole derivative which has any one of structures shown in formulas I to IV:
Figure BDA0003531384530000041
in the invention, in the formula I, n is 0-3, and is more preferably 0, 1 or 2. In the present invention, in the case of the present invention,R1including-H or benzyloxycarbonyl. In the present invention, R2Including substituted phenyl, six-membered cycloalkyl, five-membered heterocycle, or naphthyl, more preferably any one of the following structures:
Figure BDA0003531384530000042
in the invention, when n is 1, R in the formula I1When is-H, R2Preferably including any one of the following structures:
Figure BDA0003531384530000051
in the present invention, when n is 1, R1When it is benzyloxycarbonyl, R2Preferably a
Figure BDA0003531384530000052
In the present invention, when n is 2, R1When is-H, R2Preferably, it is
Figure BDA0003531384530000053
In the present invention, when n is 0, R1When is H, R2Preferably, it is
Figure BDA0003531384530000054
In the invention, in the formula II, n is 0-3, preferably 0, 1 or 2. In the present invention, R3including-H or benzyloxycarbonyl. In the present invention, R4Including substituted phenyl groups, preferably including any one of the following structures:
Figure BDA0003531384530000055
in the present invention, in the formula II, when n is 1, R3When is-H, R4Preferably including any one of the following structures:
Figure BDA0003531384530000061
in the present invention, when n is 1, R3When it is benzyloxycarbonyl, R4Preferably comprises
Figure BDA0003531384530000062
In the present invention, when n is 0, R3When is-H, R4Preferably comprises
Figure BDA0003531384530000063
In the formula III, n is 0-3, preferably 1, 2 or 3. In the present invention, R5comprising-H or-CH3. In the present invention, in the formula III, when n ═ 1 or 3, R5preferably-H. In the present invention, when n is 2, R5preferably-H or-CH3。
In the formula IV, n is 0-3, preferably 1, 2 or 3, and more preferably 2. In the present invention, R6Including substituted phenyl groups, preferably including any one of the following structures:
Figure BDA0003531384530000064
in the present invention, in the formula IV, when n ═ 2, R6Preferably including any one of the following structures:
Figure BDA0003531384530000065
the invention provides a preparation method of the indole derivative in the technical scheme, and the preparation method of the indole derivative with the structure shown in formula I or formula II comprises the following steps:
mixing a first indole compound, a first acyl chloride compound, potassium thiocyanate and a good solvent of the indole compound, and carrying out a first acylation reaction to obtain an indole derivative with a structure shown in formula I or formula II;
the first indole compound has a structure represented by formula V-1 or V-2:
Figure BDA0003531384530000066
in the formulas V-1 and V-2, n is 0-3;
the first acyl chloride compound is R2-COCl or R4-COCl, wherein R2And R in the formula I2Same as R4And R in the formula II4The same;
the preparation method of the indole derivative with the structure shown in the formula III comprises the following steps: mixing a second indole compound, potassium thiocyanate and an alcohol solvent, and carrying out cyclization reaction to obtain an indole derivative with a structure shown in a formula III;
the preparation method of the indole derivative with the structure shown in the formula IV comprises the following steps: a second indole compound, R6-CHO, an alkaline reagent and an alcohol solvent are mixed and subjected to a substitution reaction to obtain an indole derivative with a structure shown in formula IV;
the second indole compound has a structure represented by formula VI:
Figure BDA0003531384530000071
in the formula VI, R is-H or-CH3(ii) a n is 0 to 3;
said R is6-CHO R6And R in said formula IV6The same is true.
In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
In the present invention, the preparation method of the indole derivative having the structure represented by formula I or formula II comprises the following steps: mixing a first indole compound, a first acyl chloride compound, potassium thiocyanate and an indole compound good solvent, and carrying out a first acylation reaction to obtain an indole derivative with a structure shown in formula I or formula II.
In the present invention, the first indole compound has a structure represented by formula V-1 or V-2:
Figure BDA0003531384530000072
in the formulas V-1 and V-2, n is 0-3, and is more preferably 0, 1, 2 or 3. In the present invention, the first indole compound preferably comprises tryptamine (3- (2-aminoethyl) indole), L-tryptophane benzyl ester hydrochloride, 3- (1H-indol-3-yl) propan-1-amine or 1- (1H-indol-2-yl) methylamine.
In the present invention, the first acid chloride compound is R2-COCl or R4-COCl, wherein R2And R in the formula I2Same as R4And R in the formula II4The same is not described herein. In the present invention, the first acid chloride compound preferably includes p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, cyclohexanoyl chloride, m-chlorobenzoyl chloride, 3, 5-dichlorobenzoyl chloride, o-methylbenzoyl chloride, 2,4, 6-trimethylbenzoyl chloride, 3- (chloromethyl) benzoyl chloride, 1-naphthoyl chloride, 2-furoyl chloride, o-fluorobenzoyl chloride, m-fluorobenzoyl chloride, p-fluorobenzoyl chloride, o-chlorobenzoyl chloride, 3-bromobenzoyl chloride, 3- (trifluoromethyl) benzoyl chloride, biphenyl-4-formyl chloride or diphenylcarbamoyl chloride. In the invention, the first acid chloride compound is preferably used in the form of a first acid chloride compound solution, and the concentration of the first acid chloride compound solution is preferably 20-30 mol/L, and more preferably 22-26 mol/L. In the present invention, the solvent in the first acid chloride compound solution preferably includes one or more of dichloromethane, ethyl acetate, anhydrous ethanol and acetonitrile, and more preferably includes dichloromethane, ethyl acetate, anhydrous ethanol or acetonitrile.
In the present invention, the molar ratio of the first indole compound to the first acid chloride compound is preferably 1: 1.0 to 1.5, more preferably 1: 1.2 to 1.3.
In the present invention, the molar ratio of the first indole compound to potassium thiocyanate (KSCN) is preferably 1: 1.0 to 1.5, more preferably 1: 1.2 to 1.3.
In the invention, the indole compound good solvent preferably comprises one or more of acetonitrile, dichloromethane, ethyl acetate and absolute ethyl alcohol, and more preferably acetonitrile and dichloromethane. In the present invention, the volume ratio of acetonitrile to dichloromethane is preferably 1: 0.1 to 1, more preferably 1: 0.2 to 0.5. In a particular embodiment of the invention, the ratio of the amount of substance of the first indole compound to the volume of the soluble indole compound is preferably 1 mol: 13-14L.
In the embodiment of the present invention, the order of mixing is preferably that the first indole compound and potassium thiocyanate are added to the good solvent for indole compound, and the first acid chloride compound solution is added dropwise to the resulting mixture. The dropping speed is not particularly limited in the invention, and the dropping can be carried out dropwise. The mixing method of the present invention is not particularly limited, and the raw materials can be uniformly mixed by a mixing method known to those skilled in the art, such as stirring and mixing. In the present invention, the temperature of the mixing is preferably room temperature.
In the invention, the temperature of the first acylation reaction is preferably 50-80 ℃, more preferably 60-70 ℃, and the time of the first acylation reaction is preferably 4-8 hours, more preferably 5-6 hours. In a specific embodiment of the present invention, the progress of the first acylation reaction is preferably monitored by Thin Layer Chromatography (TLC) using a developing solvent which is preferably an ethyl acetate-petroleum ether mixed solvent, wherein the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 1:2 or 2: 1.
After the first acylation reaction is completed, the invention preferably further comprises the steps of cooling the reaction liquid obtained by the first acylation reaction to room temperature, carrying out solid-liquid separation, concentrating the obtained liquid component, and carrying out silica gel column chromatography separation to obtain the indole derivative with the structure shown in the formula I or the formula II. The cooling method of the present invention is not particularly limited, and a cooling method known to those skilled in the art may be used, specifically, natural cooling. The solid-liquid separation method is not particularly limited, and a solid-liquid separation method known to those skilled in the art, such as filtration, may be employed. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, concentration under reduced pressure. In the present invention, the conditions for the silica gel column chromatography preferably include: the elution mode is preferably gradient elution, the adopted eluent is preferably a large-polarity-small-polarity mixed solvent, the large-polarity solvent in the large-polarity-small-polarity mixed solvent preferably comprises ethyl acetate, methanol or dichloromethane, the small-polarity solvent preferably comprises petroleum ether, n-hexane or carbon tetrachloride, the volume ratio of the large-polarity solvent to the small-polarity solvent is preferably 1: 8-1: 2, and the gradient elution is preferably carried out by using the large-polarity-small-polarity mixed solvent sequentially comprising ethyl acetate and petroleum ether in volume ratio.
In the invention, the preparation method of the indole derivative with the structure shown in the formula III comprises the following steps: and mixing the second indole compound, potassium thiocyanate and an alcohol solvent, and carrying out cyclization reaction to obtain the indole derivative with the structure shown in the formula III.
In the present invention, the second indole compound has the structure shown in formula VI:
Figure BDA0003531384530000081
r in the formula VI5And R in said formula III5The same is true. In the invention, n in the formula VI is 0-3, preferably 1, 2 or 3. In the present invention, the second indole compound preferably has any one of the structures represented by formulas VI-1 to VI-4:
Figure BDA0003531384530000091
Figure BDA0003531384530000092
in the present invention, the process for producing the second indole compound preferably comprises the steps of: and (3) mixing the compound with the structure shown in the formula VII, an alkaline reagent, a second acyl chloride compound and a soluble compound solvent shown in the formula VII, and carrying out a second acylation reaction to obtain a second indole compound.
Figure BDA0003531384530000093
In the formula VII, n is preferably 0-3, and more preferably 0, 1, 2 or 3.
In the present invention, the second acid chloride compound includes chloroacetyl chloride or 2-chloropropionyl chloride. In the present invention, the molar ratio of the compound having the structure represented by formula VII to the second acid chloride compound is preferably 1: 1.0 to 2.0, more preferably 1: 1.5 to 2. In the invention, the second acid chloride compound is preferably used in the form of a second acid chloride compound solution, and the concentration of the second acid chloride compound solution is preferably 20 to 60mol/L, and more preferably 40 to 50 mol/L. In the present invention, the solvent in the second acid chloride compound solution preferably includes one or more of dichloromethane, ethyl acetate and acetonitrile, and more preferably includes dichloromethane, ethyl acetate or acetonitrile.
In the present invention, the alkaline agent preferably includes one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and sodium hydroxide, and more preferably includes potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or sodium hydroxide. In the present invention, the molar ratio of the compound having the structure represented by formula VII to the alkaline agent is preferably 1: 1.0 to 2.0, more preferably 1: 1.5 to 1.8.
In the present invention, the soluble compound solvent of formula VII preferably includes dichloromethane, ethyl acetate and methanol. In the present invention, the amount of the soluble compound of formula VII used is not particularly limited, and the second acylation reaction can be carried out smoothly. In a specific embodiment of the present invention, the ratio of the amount of the substance of the compound having the structure represented by formula VII to the volume of the soluble compound of formula VII solvent is preferably 1 mol: 47-48L.
In an embodiment of the present invention, the mixing is preferably performed by adding the compound having the structure represented by formula VII, potassium thiocyanate and an alkaline reagent to the soluble compound solvent of formula VII, and adding the second acid chloride compound solution dropwise to the resulting mixture. The dropping speed is not particularly limited in the invention, and the dropping can be carried out dropwise. The mixing method of the present invention is not particularly limited, and the raw materials can be uniformly mixed by a mixing method known to those skilled in the art, such as stirring and mixing. In the present invention, the temperature of the mixing is preferably room temperature.
In the invention, the temperature of the second acylation reaction is preferably room temperature, and the time is preferably 12-24 h, and more preferably 15-20 h. In a specific embodiment of the present invention, the progress of the second acylation reaction is preferably monitored by Thin Layer Chromatography (TLC) using a developing solvent preferably a dichloromethane-methanol mixed solvent, wherein the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solvent is preferably 15: 1.
After the second acylation reaction, the method preferably further comprises the steps of mixing the reaction liquid obtained by the second acylation reaction with water, and then sequentially carrying out saturated sodium carbonate washing, saturated salt solution washing and reduced pressure concentration to constant weight to obtain a second indole compound which is directly used for subsequent reactions. In the present invention, the ratio of the amount of the substance of the compound having the structure represented by formula VII to the volume of water is preferably 1 mol: 31 to 32L.
After the second indole compound is obtained, the second indole compound, potassium thiocyanate and an alcohol solvent are mixed for cyclization reaction, and the indole derivative with the structure shown in formula III is obtained.
In the present invention, the molar ratio of the compound having the structure represented by formula VI to potassium thiocyanate is preferably 1: 1.0 to 3.0, more preferably 1: 1.5 to 2.
In the present invention, the alcohol solvent preferably comprises one or more of absolute ethyl alcohol, absolute methyl alcohol and absolute n-butanol, and more preferably comprises absolute ethyl alcohol, absolute methyl alcohol or absolute n-butanol. The dosage of the alcohol solvent is not specially limited, and the cyclization reaction can be ensured to be smoothly carried out. In a particular embodiment of the invention, the ratio of the amount of said second indole compound substance to the volume of alcoholic solvent is preferably 1 mol: 11-12L.
The mixing method of the present invention is not particularly limited, and the raw materials can be uniformly mixed by a mixing method known to those skilled in the art, such as stirring and mixing. In the present invention, the temperature of the mixing is preferably room temperature.
In the invention, the temperature of the cyclization reaction is preferably 50-90 ℃, more preferably 60-90 ℃, and further preferably 70-80 ℃, and the time of the cyclization reaction is preferably 6-10 h, more preferably 7-9 h, and further preferably 8-9 h. In a specific embodiment of the present invention, the progress of the second acylation reaction is preferably monitored by Thin Layer Chromatography (TLC) using a developing solvent which is preferably a dichloromethane-methanol mixed solvent in which the volume ratio of dichloromethane to methanol is preferably 15: 1.
After the cyclization reaction is completed, the invention preferably further comprises the steps of concentrating the reaction liquid obtained by the cyclization reaction, extracting the obtained concentrated liquid, concentrating the obtained organic phase, and then carrying out silica gel column chromatography separation to obtain the indole derivative with the structure shown in the formula III. In the present invention, the manner of concentrating the reaction solution and the organic phase is not particularly limited, and a concentration manner known to those skilled in the art, specifically, concentration under reduced pressure, may be employed. In the present invention, the extraction solvent preferably includes a mixed solvent of water and ethyl acetate, and the volume ratio of the water to the ethyl acetate is 1:1 to 3, and more preferably 1: 2. In the present invention, the conditions for the silica gel column chromatography preferably include: the elution mode is preferably gradient elution, the adopted eluent is preferably a large-polarity-small-polarity mixed solvent, the large-polarity solvent in the large-polarity-small-polarity mixed solvent preferably comprises one or more of ethyl acetate, methanol and dichloromethane, more preferably comprises ethyl acetate, methanol or dichloromethane, the small-polarity solvent preferably comprises one or more of petroleum ether, n-hexane and carbon tetrachloride, more preferably comprises petroleum ether, n-hexane or carbon tetrachloride, and the volume ratio of the large-polarity solvent to the small-polarity solvent is preferably 1: 5-2: 1, and more preferably 1: 3-1: 1.
In the present invention, the preparation method of the indole derivative having the structure shown in formula IV comprises the following steps: a second indole compound, R6-CHO, alkaline reagent and alcohol solvent are mixed for substitution reaction to obtain the indole derivative with the structure shown in formula IV.
The second indole compound has a structure represented by formula VI:
Figure BDA0003531384530000111
in the formula VI, R5And R in said formula III5The same is true. In the invention, n in the formula VI is 0-3, preferably 0, 1, 2 or 3. In the present invention, the second indole compound preferably has the structure represented by the formula VI-2.
In the present invention, said R6-CHO R6And R in said formula IV6The same is not described herein again.
In the present invention, the second indole compound and R6The molar ratio of — CHO is preferably 1: 1.0 to 1.8, more preferably 1: 1.5 to 1.6. In the present invention, said R6-CHO is in particular bromobenzaldehyde, p-methoxybenzaldehyde or m-nitrobenzaldehyde.
In the present invention, the alkaline agent preferably includes one or more of sodium hydroxide, calcium hydroxide and potassium hydroxide, and more preferably includes sodium hydroxide, calcium hydroxide or potassium hydroxide. In the present invention, the alkaline agent is preferably used in the form of an aqueous alkaline agent solution, and the concentration of the aqueous alkaline agent solution is preferably 10 to 40 wt%, and more preferably 25 to 30 wt%. In the present invention, the molar ratio of the amount of the substance of the second indole compound to the basic agent is preferably 1: 0.05 to 0.5, more preferably 1: 0.1 to 0.2.
In the invention, the alcohol solvent preferably comprises one or more of anhydrous methanol, anhydrous n-butanol and anhydrous ethanol, and more preferably comprises anhydrous methanol, anhydrous n-butanol or anhydrous ethanol. The dosage of the alcohol solvent is not particularly limited, and the substitution reaction can be ensured to be smoothly carried out. In a particular embodiment of the invention, the ratio of the amount of said second indole compound substance to the volume of alcoholic solvent is preferably 1 mol: 10L.
In a particular embodiment of the invention, the order of mixing is preferably that of combining the second indole with R6-CHO is added to an alcohol solvent and an alkaline agent is added to the resulting mixture. The mixing method of the present invention is not particularly limited, and the raw materials can be uniformly mixed by a mixing method known to those skilled in the artSpecifically, the mixture is stirred and mixed. In the present invention, the temperature of the mixing is preferably room temperature.
In the invention, the temperature of the substitution reaction is 20-40 ℃, more preferably 30-35 ℃, and the time of the substitution reaction is preferably 8-16 h, more preferably 10-12 h. In a specific embodiment of the present invention, the progress of the substitution reaction is preferably monitored by Thin Layer Chromatography (TLC), the developing solvent used in the thin layer chromatography is preferably ethyl acetate-petroleum ether mixed solvent, and the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether mixed solvent is preferably 3: 1.
After the substitution reaction is completed, the method preferably further comprises the steps of concentrating the reaction liquid obtained by the substitution reaction, extracting the obtained concentrated liquid, concentrating the obtained organic phase, and carrying out silica gel column chromatography separation to obtain the indole derivative with the structure shown in the formula IV. In the present invention, the manner of concentrating the reaction solution and the organic phase is not particularly limited, and a concentration manner known to those skilled in the art may be adopted, specifically, concentration under reduced pressure may be adopted. In the present invention, the extraction solvent preferably includes a mixed solvent of water and ethyl acetate, and the volume ratio of the water to the ethyl acetate is 1:1 to 3, more preferably 1: 2. In the present invention, the conditions for the silica gel column chromatography preferably include: the elution mode is preferably gradient elution, the adopted eluent is preferably a large-polarity-small-polarity mixed solvent, the large-polarity solvent in the large-polarity-small-polarity mixed solvent preferably comprises one or more of ethyl acetate, methanol and dichloromethane, more preferably comprises ethyl acetate, methanol or dichloromethane, the small-polarity solvent preferably comprises one or more of petroleum ether, n-hexane and carbon tetrachloride, more preferably comprises petroleum ether, n-hexane or carbon tetrachloride, and the volume ratio of the large-polarity solvent to the small-polarity solvent is preferably 1: 6-1: 1, more preferably 1: 5-1: 2.
The invention also provides the application of the indole derivative in the technical scheme in the preparation of antibacterial drugs. The indole derivative provided by the invention has high antibacterial activity, can be used for preparing antibacterial drugs, and especially can be used as a TrpRS inhibitor.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The reaction routes for preparing indole compounds of examples 1 to 31 are shown in FIGS. 1 to 3, wherein FIG. 1 is a reaction route diagram of an indole compound having a structure represented by formulae I-1 to I-22, formulae II-23 to II-26, and formulae II-29 to II-30, FIG. 2 is a reaction route diagram of an indole compound having a structure represented by formulae I-19, formulae II-27, and II-28, and FIG. 3 is a reaction route diagram of an indole compound having formulae III-31 to III-34 and formulae IV-35 to IV-37.
Example 1
Synthesis of indole derivative I-1
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL of paranitrobenzoyl chloride (668.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-1(526.6mg, orange-yellow solid, yield 47.7%). m.p.157.3-157.5 ℃.1H NMR(600MHz,CDCl3)δ10.53(s,1H),8.98(s,1H),8.40-8.27(m,2H),8.05(d,J＝25.4Hz,1H),7.99-7.90(m,2H),7.68(d,J＝7.9Hz,1H),7.39(d,J＝8.1Hz,1H),7.24-7.18(m,1H),7.17-7.10(m,2H),4.05(td,J＝6.9,5.4Hz,2H),3.21(t,J＝6.9Hz,2H).HR-MS:calcd for C18H16N4O3S[M+H]+369.1016,found 369.0993。
Example 2
Synthesis of indole derivative I-2
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL p-chlorobenzoyl chloride (630.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-2(500.3mg, pale yellow solid, yield 46.7%). m.p.143.9-144.6 ℃.1H NMR(600MHz,CDCl3)δ10.66(s,1H),8.93(s,1H),8.08(s,1H),7.76-7.70(m,2H),7.68(d,J＝7.9Hz,1H),7.51-7.43(m,2H),7.38(d,J＝8.1Hz,1H),7.24-7.17(m,1H),7.17-7.09(m,2H),4.04(td,J＝7.0,5.6Hz,2H),3.19(t,J＝6.9Hz,2H).HR-MS:calcd for C18H17ON3ClS[M+H]+358.07754,found 358.07809。
Example 3
Synthesis of indole derivative I-3
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL cyclohexanecarbonyl chloride (527.8mg, 3.6mmol, 1.2eq) of CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-3(500.2mg, pale yellow solid, yield 50.7%). m.p.134.8-135.6 ℃.1H NMR(600MHz,CDCl3)δ10.56(s,1H),8.37(s,1H),8.03(s,1H),7.65(d,J＝7.9Hz,1H),7.37(d,J＝8.1Hz,1H),7.25-7.18(m,1H),7.18-7.03(m,2H),3.97(td,J＝7.0,5.5Hz,2H),3.14(t,J＝7.0Hz,2H),1.86(d,J＝12.1Hz,2H),1.84-1.72(m,2H),1.69(d,J＝11.4Hz,1H),1.41(ddd,J＝24.5,12.3,3.0Hz,2H),1.34-1.13(m,3H).HR-MS:calcd for C18H22ON3S[M+H]+328.14781,found 328.14810。
Example 4
Synthesis of indole derivative I-4
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL m-chlorobenzoyl chloride (630.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-4(566.2mg, white solid, yield 52.9%). m.p.145.1-146.5 ℃.1H NMR(600MHz,CDCl3)δ10.61(s,1H),8.90(s,1H),8.06(s,1H),7.80(d,J＝1.6Hz,1H),7.68(d,J＝7.9Hz,1H),7.64(d,J＝7.8Hz,1H),7.58(d,J＝7.5Hz,1H),7.43(t,J＝7.9Hz,1H),7.38(d,J＝8.1Hz,1H),7.22(t,J＝7.5Hz,1H),7.13(dd,J＝24.9,17.7Hz,2H),4.04(dd,J＝13.0,6.1Hz,2H),3.20(t,J＝6.9Hz,2H).HR-MS:calcd for C18H17ON3ClS[M+H]+358.07754,found 358.07758。
Example 5
Synthesis of indole derivatives I-5 and II-15
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL of 3, 5-dichlorobenzoyl chloride (754.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure, subjected to silica gel column chromatography, and gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) was carried out to give indole derivative I-5(580.36mg, pale yellow solid, yield 49.5%) and indole derivative II-15(250.6mg, pale yellow solid, yield 49.5%)Yellow solid, yield 26.2%). Indole derivative I-5: m.p.170.5-170.9 ℃.1H NMR(600MHz,CDCl3)δ10.49(s,1H),8.86(s,1H),8.06(s,1H),7.66(t,J＝8.2Hz,1H),7.58(d,J＝1.6Hz,1H),7.38(d,J＝8.1Hz,1H),7.24–7.18(m,1H),7.14(t,J＝7.3Hz,2H),4.04(dd,J＝12.2,5.4Hz,2H),3.19(t,J＝6.7Hz,2H).HR-MS:calcd for C18H16ON3Cl2S[M+H]+392.03856, found 392.03857. Indole derivatives II-15: m.p.148.8-149.5 ℃.1H NMR(600MHz,CDCl3)δ8.12(s,1H),7.63(d,J＝7.9Hz,1H),7.50(d,J＝1.8Hz,2H),7.43(t,J＝1.8Hz,1H),7.38(t,J＝11.8Hz,1H),7.23(dd,J＝11.2,3.9Hz,1H),7.15(t,J＝7.2Hz,1H),7.06(d,J＝2.1Hz,1H),6.17(s,1H),3.77(dd,J＝12.6,6.5Hz,2H),3.09(t,J＝6.6Hz,2H).HR-MS:calcd for C17H15ON2Cl2[M+H]+333.05560,found 333.05566。
Example 6
Synthesis of indole derivative I-6
A100 mL round bottom flask was charged with 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added, and 10mL o-methylbenzoyl chloride (556.5mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and reaction solution were heated under reflux for 10min, and tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (1/2 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-6(580.7mg, white solid, yield 57.4%). m.p.189.6-190.5 ℃.1H NMR(600MHz,CDCl3)δ10.65(s,1H),8.67(s,1H),8.05(s,1H),7.69(d,J＝7.9Hz,1H),7.46-7.35(m,3H),7.22(t,J＝7.6Hz,1H),7.19-7.06(m,2H),4.04(dd,J＝12.5,6.9Hz,2H),3.21(t,J＝7.0Hz,2H),2.45(s,3H).HR-MS:calcd for C17H15ON2Cl2[M+H]+338.13216,found 338.13220.
Example 7
Synthesis of indole derivative I-7
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL of 2,4, 6-trimethylbenzoyl chloride (548.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (1/2 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-7(542.2mg, white solid, yield 49.5%). m.p.180.9-181.9 ℃.1H NMR(600MHz,CDCl3)δ10.63(s,1H),8.52(s,1H),8.06(s,1H),7.69(d,J＝7.8Hz,1H),7.37(d,J＝8.1Hz,1H),7.21(t,J＝7.5Hz,1H),7.18-7.08(m,2H),6.85(s,2H),4.03(dt,J＝7.0,3.8Hz,2H),3.21(t,J＝6.9Hz,2H),2.27(d,J＝9.1Hz,9H).HR-MS:calcd for C17H15ON2Cl2[M+H]+366.16346,found 366.16351。
Example 8
Synthesis of indole derivative I-8
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL3- (chloromethyl) benzoyl chloride (680.5mg, 3.6mmol, 1.2eq) of CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-8(567.2mg, white solid, yield 51.0%). m.p.149.3-150.9 ℃.1H NMR(600MHz,CDCl3)δ10.68(s,1H),8.94(s,1H),8.06(s,1H),7.82(s,1H),7.73(d,J＝7.8Hz,1H),7.67(t,J＝13.4Hz,1H),7.63(d,J＝7.7Hz,1H),7.50(t,J＝7.7Hz,1H),7.38(d,J＝8.1Hz,1H),7.23-7.18(m,1H),7.13(dt,J＝30.8,16.1Hz,2H),4.62(s,2H),4.05(td,J＝6.9,5.5Hz,2H),3.20(t,J＝7.0Hz,2H).HR-MS:calcd for C17H15ON2Cl2[M+H]+372.09319,found 372.09332.
Example 9
Synthesis of indole derivative I-9
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL 1-naphthoyl chloride (686.3mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and reaction solution were heated under reflux for 10min, and tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (1/2 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-9(589.3mg, white solid, yield 52.6%). m.p.182.9-183.6 ℃.1H NMR(600MHz,CDCl3)δ10.76(s,1H),8.95(s,1H),8.22(d,J＝8.2Hz,1H),8.08(s,1H),8.02(d,J＝7.9Hz,1H),7.90(d,J＝7.9Hz,1H),7.72(s,2H),7.59(dd,J＝14.5,7.7Hz,2H),7.50(t,J＝7.6Hz,1H),7.39(d,J＝8.1Hz,1H),7.21(dd,J＝19.7,9.5Hz,2H),7.16(t,J＝7.4Hz,1H),4.09(d,J＝4.8Hz,2H),3.25(s,2H).HR-MS:calcd for C22H20ON3S[M+H]+374.13216,found 374.13272.
Example 10
Synthesis of indole derivative I-10
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL 2-naphthoyl chloride (680.5mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-10(603.6mg, pale yellow solid, yield 53.9%). m.p.166.2～166.6℃。1H NMR(600MHz,CDCl3)δ10.80(s,1H),9.12(s,1H),8.32(s,1H),8.08(s,1H),7.93(dd,J＝17.5,9.8Hz,2H),7.89(d,J＝8.1Hz,1H),7.80(d,J＝8.5Hz,1H),7.70(d,J＝7.8Hz,1H),7.63(t,J＝7.4Hz,1H),7.59(t,J＝7.4Hz,1H),7.39(d,J＝8.1Hz,1H),7.22(t,J＝7.5Hz,1H),7.16(dd,J＝15.3,7.8Hz,2H),4.08(dd,J＝12.4,6.6Hz,2H),3.22(t,J＝6.9Hz,2H).HR-MS:calcd for C22H20ON3S[M+H]+374.13216,found 374.13269.
Example 11
Synthesis of indole derivative I-11
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL 2-furanbenzoyl chloride (527.4mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether ═ 2:1, v/v) monitored the progress of the reaction, and 6.0h the disappearance of starting material stopped the reaction. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-11(546.5mg, white solid, yield 58.2%). m.p.147.0-147.5 ℃.1H NMR(600MHz,CDCl3)δ10.54(s,1H),8.81(s,1H),8.05(s,1H),7.76-7.65(m,2H),7.63(d,J＝3.7Hz,1H),7.38(d,J＝8.1Hz,1H),7.21(t,J＝7.5Hz,1H),7.15-7.11(m,2H),4.03(dd,J＝12.4,6.8Hz,2H),3.18(t,J＝7.0Hz,2H).HR-MS:calcd for C16H16O2N3S[M+H]+314.09577,found 314.09656.
Example 12
Synthesis of indole derivative I-12
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL o-fluorobenzoyl chloride (480.7mg, 3.6mmol, 1.2eq) of CH was added dropwise at room temperature2Cl2The solution and reaction solution were heated under reflux for 10min, and tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether: 1/2, v/v) monitored the progress of the reaction, and 6.0h the starting material disappeared and was stoppedStopping the reaction. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-12(530.9mg, yellow solid, yield 51.9%). m.p.300.4-300.5 ℃.1H NMR(600MHz,CDCl3)δ10.70(s,1H),9.62(d,J＝13.0Hz,1H),9.14(s,1H),7.95(dd,J＝17.1,9.3Hz,1H),7.65(t,J＝13.8Hz,1H),7.62-7.52(m,1H),7.38(t,J＝13.0Hz,1H),7.30(t,J＝7.5Hz,1H),7.23-7.13(m,3H),7.10(d,J＝7.3Hz,1H),4.03(dd,J＝12.3,6.6Hz,2H),3.28-3.08(m,2H).HR-MS:calcd for C18H17ON3FS[M+H]+342.10709,found 342.10818。
Example 13
Synthesis of indole derivative I-13
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added, and 10mL m-fluorobenzoyl chloride (480.7mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-13(516.6mg of a yellow solid, yield 50.5%). m.p.130.7-132.0 ℃.1H NMR(600MHz,CDCl3)δ10.64(s,1H),9.01(s,1H),8.11(s,1H),7.74-7.61(m,1H),7.58-7.48(m,2H),7.42(ddd,J＝33.8,10.5,4.0Hz,2H),7.30-7.17(m,2H),4.16-3.96(m,2H),3.29-3.07(m,2H).HR-MS:calcd for C18H17ON3FS[M+H]+342.10709,found 342.10788。
Example 14
Synthesis of indole derivative I-14
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL p-fluorobenzoyl chloride (570.8mg, 3.6mmol, 1.2eq) of CH was added dropwise at room temperature2Cl2The solution is prepared by mixing a solvent and a solvent,after the reaction mixture was refluxed for 10min, tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (1/2 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-14(648.8mg, pale yellow solid, yield 63.4%). m.p.125.3-126.2 ℃.1H NMR(600MHz,CDCl3)δ10.69(s,1H),9.11(s,1H),8.20(s,1H),7.76–7.58(m,3H),7.32(d,J＝8.1Hz,1H),7.21–7.15(m,1H),7.11(dt,J＝21.7,7.3Hz,1H),7.04(ddd,J＝11.5,4.3,2.6Hz,3H),3.99(dd,J＝12.4,7.0Hz,2H),3.14(t,J＝7.0Hz,2H).HR-MS:calcd for C18H17ON3FS[M+H]+342.10709,found 342.10651。
Example 15
Synthesis of indole derivative I-15
A100 mL round bottom flask was charged with 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added, and 10mL o-chlorobenzoyl chloride (630.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-15(638.4mg, yellow solid, yield 59.6%). m.p.226.5-226.5 ℃.1H NMR(600MHz,CDCl3)δ10.52(s,1H),9.05(s,1H),8.07(s,1H),7.69(d,J＝7.8Hz,1H),7.62(d,J＝7.7Hz,1H),7.46(s,2H),7.38(d,J＝7.8Hz,2H),7.22(t,J＝7.5Hz,1H),7.20–7.11(m,2H),4.05(dd,J＝12.2,5.4Hz,2H),3.21(t,J＝6.7Hz,2H).HR-MS:calcdfor C18H17ON3ClS[M+H]+358.07754,found 358.07715。
Example 16
Synthesis of indole derivative I-16
To a 100mL round bottom flask40mL of acetonitrile was added, KSCN (349.8mg, 3.6mmol, 1.2eq) was added, and 10mL of 3-bromobenzoyl chloride (790.1mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (1/2 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-16(594.4mg, yellow solid, yield 51.2%). m.p.147.0-147.5 ℃.1H NMR(600MHz,CDCl3)δ10.62(s,1H),8.96(s,1H),8.08(s,1H),7.96(t,J＝1.7Hz,1H),7.76–7.65(m,3H),7.41–7.34(m,2H),7.22(t,J＝7.6Hz,1H),7.19–7.11(m,2H),4.04(dd,J＝12.3,6.9Hz,2H),3.20(t,J＝6.9Hz,2H).HR-MS:calcd for C18H17ON3BrS[M+H]+402.02702,found 402.02612。
Example 17
Synthesis of indole derivatives I-17 and II-25
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL3- (trifluoromethyl) benzoyl chloride (750.8mg, 3.6mmol, 1.2eq) of CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-17(545.3mg, yellow solid, yield 48.2%) and indole derivative II-25(215.7mg, dark yellow solid, yield 22.6%). Indole derivative I-17: m.p.171.7-173.8 ℃.1H NMR(600MHz,CDCl3)δ10.63(s,1H),9.07(s,1H),8.09(s,2H),7.96(d,J＝7.9Hz,1H),7.86(d,J＝7.8Hz,1H),7.67(t,J＝8.6Hz,1H),7.64(t,J＝7.8Hz,1H),7.39(d,J＝8.1Hz,1H),7.24–7.19(m,1H),7.18–7.12(m,2H),4.05(td,J＝6.9,5.5Hz,2H),3.20(t,J＝6.9Hz,2H).HR-MS:calcd for C19H17ON3F3S[M+H]+392.10389, found 392.10364. Indole derivatives II-25: m.p.113.5-113.7 ℃.1H NMR(600MHz,CDCl3)δ8.20(s,1H),7.92(s,1H),7.82(d,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.63(d,J＝7.9Hz,1H),7.54–7.45(m,1H),7.38(d,J＝8.1Hz,1H),7.21(t,J＝7.5Hz,1H),7.12(t,J＝7.5Hz,1H),7.06(t,J＝5.6Hz,1H),6.33(s,1H),3.84–3.73(m,2H),3.10(t,J＝6.7Hz,2H).HR-MS:calcd for C18H16ON2F3[M+H]+333.12092,found 333.12073。
Example 18
Synthesis of indole derivatives I-18 and II-26
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added, and 10mL of biphenyl-4-carbonyl chloride (780.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and reaction solution were heated under reflux for 10min, and tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-18(641.8mg as a pale yellow solid, yield 53.6%) and indole derivative II-26(209.5mg as a yellow solid, yield 20.5%). Indole derivatives I-18: m.p.183.1-183.8 ℃.1H NMR(600MHz,CDCl3)δ10.70(s,1H),8.89(d,J＝46.8Hz,1H),7.99(s,1H),7.84–7.74(m,2H),7.71–7.59(m,3H),7.59–7.51(m,2H),7.44–7.37(m,2H),7.37–7.25(m,2H),7.17–7.12(m,1H),7.12–7.01(m,2H),3.99(td,J＝7.0,5.5Hz,2H),3.14(t,J＝7.0Hz,2H).HR-MS:calcd for C24H22ON3S[M+H]+400.14781, found 400.14719. Indole derivatives II-26: m.p.185.2-187.6 ℃.1H NMR(600MHz,CDCl3)δ8.10(s,1H),7.80–7.73(m,2H),7.70(d,J＝7.9Hz,1H),7.68–7.54(m,4H),7.51–7.45(m,2H),7.45–7.37(m,2H),7.28–7.23(m,1H),7.21–7.15(m,1H),7.12(t,J＝6.1Hz,1H),6.27(s,1H),3.86(dd,J＝12.5,6.6Hz,2H),3.16(t,J＝6.6Hz,2H).HR-MS:calcdfor C23H21ON2[M+H]+341.16484,found 341.16470。
Example 19
Synthesis of indole derivatives I-19 and II-27
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL of paranitrobenzoyl chloride (668.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then L-tryptophan benzyl ester hydrochloride (992.4mg, 3.0mmol, 1.0eq) was added. TLC (1/2 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-19(663.7mg of an orange-yellow solid, yield 44.1%) and indole derivative II-27(287.5mg of a yellow solid, yield 21.6%). Indole derivative I-19: m.p.74.4-84.8 ℃.1HNMR(600MHz,CDCl3)δ10.92(d,J＝7.0Hz,1H),9.01(s,1H),8.38-8.25(m,2H),8.01(s,1H),7.94(dd,J＝8.8,2.1Hz,2H),7.58(d,J＝7.9Hz,1H),7.36(dd,J＝31.5,27.3Hz,4H),7.16(t,J＝7.6Hz,1H),7.06(q,J＝6.9Hz,1H),6.93(d,J＝2.1Hz,1H),5.39(dd,J＝12.8,5.8Hz,1H),5.22-5.09(m,2H),3.59(dd,J＝14.9,5.7Hz,1H),3.48(dd,J＝14.9,5.7Hz,1H).HR-MS:calcd for C26H23O5N4S[M+H]+503.13837, found 503.13846. Indole derivatives II-27: m.p.144.4-144.6 ℃.1H NMR(600MHz,CDCl3)δ8.22-8.11(m,2H),8.09(s,1H),7.73(dd,J＝15.4,8.6Hz,2H),7.53-7.43(m,1H),7.41-7.27(m,5H),7.20-7.12(m,1H),7.07-6.99(m,1H),6.81-6.59(m,2H),5.30-4.92(m,3H),3.55-3.31(m,2H).HR-MS:calcd for C25H22N5O3[M+H]+444.15540,found444.15637。
Example 20
Synthesis of indole derivative I-20
To a 100mL round bottom flask was added 40mL acetonitrile, addKSCN (93.3mg, 0.96mmol, 1.2eq) was added dropwise to 10mL of m-chlorobenzoyl chloride (168.0mg, 0.96mmol, 1.2eq) in CH at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then 3- (1H-indol-3-yl) propan-1-amine (139.4mg, 0.8mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-20(149.0mg, yellow solid, yield 50.2%). m.p.82.4-86.0 ℃.1HNMR(600MHz,CDCl3)δ10.70(s,1H),9.05(s,1H),8.16–7.96(m,1H),7.85(s,1H),7.64(t,J＝12.9Hz,2H),7.62–7.55(m,1H),7.48–7.41(m,1H),7.38(d,J＝8.1Hz,1H),7.25–7.19(m,1H),7.16(t,J＝7.3Hz,1H),7.09(d,J＝19.9Hz,1H),3.80(dd,J＝12.7,7.0Hz,2H),2.93(t,J＝7.4Hz,2H),2.19(p,J＝7.2Hz,2H).HR-MS:calcd for C19H19ON3ClS[M+H]+372.09319,found 372.09256。
Example 21
Synthesis of indole derivatives I-21 and II-29
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (233.2mg, 2.4mmol, 1.2eq) and 10mL p-chlorobenzoyl chloride (210.0mg, 2.4mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and reaction solution were heated under reflux for 10min, and 1- (1H-indol-2-yl) methylamine (292.4mg, 2.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative I-21(511.5mg, white solid, yield 49.7%) and indole derivative II-29(145.4mg, pale pink solid, yield 25.6%). Indole derivatives I-21: m.p. 178.9-179.6 ℃.1H NMR(600MHz,CDCl3)δ11.08(s,1H),9.07(d,J＝19.9Hz,2H),7.75(dd,J＝7.0,1.5Hz,2H),7.57(d,J＝7.8Hz,1H),7.48(dd,J＝7.1,1.5Hz,2H),7.35(d,J＝8.1Hz,1H),7.18(t,J＝7.6Hz,1H),7.09(t,J＝7.5Hz,1H),6.47(s,1H),5.07(d,J＝5.7Hz,2H).HR-MS:calcd for C17H15ON3ClS[M+H]+344.06189, found 344.06116. Indole derivatives II-29: m.p.174.9-179.5 ℃.1H NMR(600MHz,CDCl3)δ9.02(s,1H),7.70(dd,J＝5.5,2.9Hz,2H),7.55(d,J＝7.8Hz,1H),7.40(dd,J＝5.6,2.9Hz,2H),7.33(d,J＝8.0Hz,1H),7.16(t,J＝7.6Hz,1H),7.08(t,J＝7.4Hz,1H),6.69(s,1H),6.38(s,1H),4.69(d,J＝5.5Hz,2H).HR-MS:calcd for C16H14ON2Cl[M+H]+285.07892,found 285.07870。
Example 22
Synthesis of indole derivatives I-22 and II-30
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (233.2mg, 2.4mmol, 1.2eq) and 10mL m-chlorobenzoyl chloride (210.0mg, 2.4mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and reaction solution were heated under reflux for 10min, and 1- (1H-indol-2-yl) methylamine (292.4mg, 2.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative I-22(547.5mg, white solid, yield 53.2%) and indole derivative II-30(205.4mg, white solid, yield 24.1%). Indole derivative I-22: m.p.163.3-164.0 ℃.1H NMR(600MHz,CDCl3)δ11.05(s,1H),9.08(s,2H),7.82(s,1H),7.68(d,J＝7.8Hz,1H),7.59(dd,J＝14.1,4.9Hz,2H),7.45(dd,J＝14.5,6.5Hz,1H),7.36(d,J＝8.2Hz,1H),7.18(t,J＝7.6Hz,1H),7.09(t,J＝7.5Hz,1H),6.48(s,1H),5.07(d,J＝6.0Hz,2H).HR-MS:calcd for C17H15ON3ClS[M+H]+344.06189, found 344.06131. Indole derivatives II-30: m.p.157.6-162.6 ℃.1H NMR(600MHz,CDCl3)δ8.98(s,1H),7.77(t,J＝1.7Hz,1H),7.62(d,J＝7.8Hz,1H),7.57–7.51(m,1H),7.47(dd,J＝7.9,0.9Hz,1H),7.39–7.29(m,2H),7.20–7.12(m,1H),7.08(t,J＝7.4Hz,1H),6.73(s,1H),6.37(d,J＝0.9Hz,1H),4.68(d,J＝6.0Hz,2H).HR-MS:calcd for C16H14ON2Cl[M+H]+285.07892,found 285.07880。
Example 23
Synthesis of indole derivative II-24
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL of dibenzoylchloride (838.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then tryptamine (480.7mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 2/1, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative II-24(556.6mg, light brown solid, yield 52.2%). m.p.79.9-80.1 ℃.1H NMR(600MHz,CDCl3)δ8.91(s,1H),7.48(dd,J＝24.5,8.1Hz,1H),7.23(d,J＝8.1Hz,1H),7.17(t,J＝7.7Hz,4H),7.08(dq,J＝14.9,7.5Hz,7H),7.01(t,J＝7.4Hz,1H),6.64(s,1H),4.68(t,J＝5.5Hz,1H),3.54(dd,J＝12.6,6.3Hz,2H),2.90(t,J＝6.8Hz,2H).HR-MS:calcd for C23H22N3O[M+H]+356.17574,found 356.17627。
Example 24
Synthesis of indole derivative II-28
To a 100mL round bottom flask was added 40mL acetonitrile, KSCN (349.8mg, 3.6mmol, 1.2eq) was added and 10mL of 3, 5-dichlorobenzoyl chloride (754.0mg, 3.6mmol, 1.2eq) in CH was added dropwise at room temperature2Cl2The solution and the reaction mixture were refluxed for 10min, and then L-tryptophan benzyl ester hydrochloride (992.4mg, 3.0mmol, 1.0eq) was added. TLC (ethyl acetate/petroleum ether) 1/2, v/v) monitored the progress of the reaction and stopped the reaction after 6.0h of disappearance of starting material. The reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography with gradient elution (ethyl acetate/petroleum ether volume ratios 1:8, 1:6, 1:4, 1:2, 1:1, and 2:1, respectively) to give indole derivative II-28(579.3mg, white solid, yield 41.1％)。m.p.156.5～157.2℃。1H NMR(600MHz,CDCl3)δ7.99(s,1H),7.50(dd,J＝22.0,4.8Hz,2H),7.44(s,1H),7.40-7.34(m,3H),7.33(dd,J＝11.0,8.5Hz,2H),7.26(s,1H),7.24-7.18(m,1H),7.15-7.07(m,1H),6.70(s,1H),6.55(d,J＝7.5Hz,1H),5.20(d,J＝12.1Hz,1H),5.18-5.06(m,2H),3.43(ddd,J＝25.0,14.7,5.0Hz,2H).HR-MS:calcd for C25H21N2O3Cl2[M+H]+467.09237,found 467.09331。
Example 25
Synthesis of indole derivatives III-31
To a 100mL round bottom flask was added 30mL of dichloromethane and 1- (1H-indol-2-yl) methylamine (409.3mg, 2.8mmol, 1.0eq), K was added2CO3(580.5mg, 4.2mmol, 1.5eq) and then 10mL of chloroacetyl chloride (632.5mg, 5.6mmol, 2.0eq) in CH are added dropwise2Cl2Solution, and reacting at room temperature. TLC (dichloromethane/methanol) 15/1, v/v) monitored the progress of the reaction, and 16.0h the starting material disappeared to stop the reaction. The reaction solution was slowly poured into 20mL of water, and the organic phase was washed with saturated sodium carbonate and brine solution in this order, and concentrated under reduced pressure to give Compound VII-1(511.7mg, pink solid, yield 82.3%) which was used directly in the subsequent reaction.
Into a 100mL reaction flask were charged 30mL of anhydrous ethanol and Compound VII-1(511.7mg, 2.3mmol, 1.0eq), followed by KSCN (335.3mg, 3.45mmol, 1.5eq), and the reaction mixture was heated under reflux at 70 ℃. TLC (15/1 in dichloromethane/methanol, v/v) monitored the progress of the reaction for 8 h. The reaction mixture was concentrated under reduced pressure, extracted with an appropriate amount of ethyl acetate and water, the organic phases were combined, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:6, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative III-31 (418.3mg, pale pink solid, yield 70.2%). m.p.208.0-217.3 ℃.1HNMR(600MHz,CDCl3)δ9.18(s,1H),7.49(d,J＝7.8Hz,1H),7.25(d,J＝8.0Hz,1H),7.10(t,J＝7.5Hz,1H),7.00(t,J＝7.4Hz,1H),6.48(s,1H),5.01(s,2H),3.84(s,2H).HR-MS:calcd for C12H12ON3S[M+H]+246.06956,found 246.06950。
Example 26
Synthesis of indole derivatives III-32
To a 100mL round bottom flask was added 30mL of dichloromethane and tryptamine (480.7mg, 3.0mmol, 1.0eq), K was added2CO3(621.9mg, 4.5mmol, 1.5eq) and then 10mL of chloroacetyl chloride (677.6mg, 6.0mmol, 2.0eq) in CH are added dropwise2Cl2Solution, and reacting at room temperature. TLC (dichloromethane/methanol) 15/1, v/v) monitored the progress of the reaction, and 16.0h the starting material disappeared to stop the reaction. The reaction solution was slowly poured into 20mL of water, and the organic phase was washed successively with saturated sodium carbonate and a saline solution, and concentrated under reduced pressure to give compound VII-2(613.3mg, pale yellow solid, yield 86.6%) which was used directly in the subsequent reaction.
Into a 100mL reaction flask were charged 30mL of anhydrous ethanol and Compound VII-2(613.3mg, 2.6mmol, 1.0eq), followed by KSCN (379.0mg, 3.9mmol, 1.5eq), and the reaction mixture was heated under reflux at 70 ℃. TLC (dichloromethane/methanol-15/1, v/v) monitored the progress of the reaction and was complete for 8 h. The reaction mixture was concentrated under reduced pressure, extracted with an appropriate amount of ethyl acetate and water, the organic phases were combined, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:8, 1:6, 1:4, 1:2, 1:1 and 2:1, respectively) to give indole derivative III-32 (594.6mg, white solid, yield 76.5%). m.p.112.9-114.1 ℃.1HNMR(600MHz,CDCl3)δ8.23(d,J＝46.2Hz,1H),7.59–7.50(m,1H),7.32(dd,J＝7.7,4.0Hz,1H),7.18(dd,J＝11.4,7.2Hz,1H),7.09(dd,J＝11.5,7.1Hz,1H),6.99(s,1H),6.29(s,1H),3.60–3.50(m,2H),3.39(d,J＝4.3Hz,2H),3.00–2.89(m,2H).HR-MS:calcd for C13H14ON3S[M+H]+260.08521,found 260.08505。
Example 27
Synthesis of indole derivatives III-33
To a 100mL round bottom flask was added 30mL of dichloromethane and tryptamine (480.7mg, 3.0mmol, 1.0eq), K was added2CO3(621.9mg, 4.5mmol, 1.5eq), and then 10mL of 2-chloroacetyl chloride (761.7mg, 6.0mmol, 2.0eq) in CH was added dropwise2Cl2Solution, and reacting at room temperature. TLC (dichloromethane/methanol 15/1, v/v) monitored the reactionAnd (4) in the process, the raw material disappears within 16.0h, and the reaction is stopped. The reaction solution was slowly poured into 20mL of water, and the organic phase was washed successively with saturated sodium carbonate and a saline solution, and concentrated under reduced pressure to give compound VII-3(624.2mg, pale yellow solid, yield 83.2%) which was used directly in the subsequent reaction.
To a 100mL reaction flask were added 30mL of anhydrous ethanol and Compound VII-3(624.2mg, 2.5mmol, 1.0eq), followed by addition of KSCN (364.4mg, 3.75mmol, 1.5eq), and the reaction mixture was heated under reflux at 70 ℃. TLC (15/1 in dichloromethane/methanol, v/v) monitored the progress of the reaction for 8 h. The reaction mixture was concentrated under reduced pressure, extracted with an appropriate amount of ethyl acetate and water, the organic phases were combined, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:5, 1:3, 1:1 and 2:1, respectively) to give indole derivative III-33 (449.1mg, dark yellow solid, yield 73.1%). m.p.101.3-103.1 ℃.1H NMR(600MHz,CDCl3)δ8.04(s,1H),7.53(t,J＝10.8Hz,1H),7.30(t,J＝11.1Hz,1H),7.18–7.12(m,1H),7.06(dt,J＝14.3,3.6Hz,1H),7.01(d,J＝1.9Hz,1H),5.87(s,1H),3.67(q,J＝7.1Hz,1H),3.63–3.53(m,2H),3.01–2.91(m,2H),1.54(d,J＝7.1Hz,3H).HR-MS:calcd for C14H16ON3S[M+H]+274.10086,found 274.10074。
Example 28
Synthesis of indole derivatives III-34
To a 100mL round bottom flask was added 30mL of dichloromethane and 3- (1H-indol-3-yl) propan-1-amine (110.6mg, 0.63mmol, 1.0eq), K was added2CO3(130.6mg, 0.945mmol, 1.5eq), and then 10mL of chloroacetyl chloride (142.3mg, 1.26mmol, 2.0eq) in CH was added dropwise2Cl2Solution, and reacting at room temperature. TLC (dichloromethane/methanol) 15/1, v/v) monitored the progress of the reaction, and 16.0h the starting material disappeared to stop the reaction. The reaction was slowly poured into 20mL of water, and the organic phase was washed with saturated sodium carbonate and aqueous sodium chloride solution in this order, and concentrated under reduced pressure to give compound VII-4(131.9mg, pale yellow solid, yield 83.7%) which was used directly in the subsequent reaction.
30mL of absolute ethanol and the compound VII-4(131.9mg, 0.53mmol, 1.0eq) were added to a 100mL reaction flask, followed by addition of KSCN (223.0mg, 2.295mmol, 1.5eq), and the reaction mixture was heated under reflux at 70 ℃. TLC (15/1 in dichloromethane/methanol, v/v) monitored the progress of the reaction for 8 h. The reaction mixture was concentrated under reduced pressure, extracted with an appropriate amount of ethyl acetate and water, the organic phases were combined, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:5, 1:3, 1:1 and 2:1, respectively) to give indole derivative III-34 (112.2mg, brown oily liquid, yield 77.5%).1H NMR(600MHz,CDCl3)δ7.97(s,1H),7.51(d,J＝7.6Hz,1H),7.29(d,J＝7.8Hz,1H),7.13(t,J＝7.1Hz,1H),7.05(t,J＝7.1Hz,1H),6.94(s,1H),5.89(s,1H),3.34(d,J＝27.7Hz,2H),3.30(d,J＝5.8Hz,2H),2.77(t,J＝6.2Hz,2H),1.94–1.87(m,2H).HR-MS:calcd for C14H16ON3S[M+H]+274.10086,found 274.10074。
Example 29
Synthesis of indole derivative IV-35
To a 20mL round-bottom flask, 5mL of methanol was added, compound VII-2(129.5mg, 0.5mmol, 1.0eq) and m-bromobenzaldehyde (138.8mg, 0.75mmol, 1.5eq) were added, and 2.5mL of a 25% aqueous solution of sodium hydroxide was added and reacted at room temperature. TLC (ethyl acetate/petroleum ether) 3/1, v/v) monitored the progress of the reaction and stopped the reaction after 12.0h of disappearance of starting material. The reaction solution was concentrated under reduced pressure, extracted with an appropriate amount of ethyl acetate and water, the organic phases were combined, subjected to silica gel column chromatography, and gradient elution (ethyl acetate/petroleum ether volume ratios were 1:6, 1:5, and 1:3, respectively) was employed to obtain indole derivative IV-35(79.1mg, yellow solid, yield 37.2%). m.p.201.3-202.4 ℃.1H NMR(600MHz,CDCl3)δ8.05(s,1H),7.99(s,1H),7.81(d,J＝7.8Hz,1H),7.61(d,J＝9.7Hz,2H),7.52(t,J＝8.5Hz,1H),7.35(ddd,J＝24.8,17.0,7.8Hz,3H),7.20(t,J＝7.2Hz,1H),7.15(t,J＝7.2Hz,1H),7.11(d,J＝1.7Hz,1H),4.19(dd,J＝27.4,19.4Hz,2H),3.25–3.13(m,2H).HR-MS:calcd for C20H17ON3BrS[M+H]+426.02702,found 426.02597。
Example 30
Synthesis of indole derivative IV-36
To a 20mL round bottom flask was added 5mL of methanol and Compound VII-2(129.5mg, 0.5mmol, 1.0eq) and p-methoxybenzaldehyde (102.1mg, 0.75mmol, 1.5eq) were reacted at room temperature with 2.5mL of 25% aqueous sodium hydroxide solution. TLC (3/1 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 12.0h of disappearance of starting material. The reaction solution was concentrated under reduced pressure, extracted with an appropriate amount of ethyl acetate and water, the organic phases were combined, subjected to silica gel column chromatography, and gradient elution (ethyl acetate/petroleum ether volume ratios were 1:6, 1:5, and 1:3, respectively) was employed to obtain indole derivative IV-36(58.3mg, pale yellow solid, yield 30.9%). m.p.196.5-197.2 ℃.1H NMR(600MHz,CDCl3)δ7.98(s,1H),7.92(s,1H),7.83(d,J＝7.8Hz,1H),7.68(s,1H),7.42(dd,J＝12.4,8.1Hz,2H),7.36(d,J＝8.3Hz,1H),7.21–7.18(m,1H),7.17–7.14(m,1H),7.12(s,1H),6.98(d,J＝8.8Hz,2H),4.23–4.16(m,2H),3.86(d,J＝5.5Hz,3H),3.21–3.15(m,2H).HR-MS:calcd forC21H20O2N3S[M+H]+378.12707,found 378.12662。
Example 31
Synthesis of indole derivative IV-37
To a 20mL round-bottom flask, 5mL of methanol was added, compound VII-2(129.5mg, 0.5mmol, 1.0eq) and m-nitrobenzaldehyde (113.3mg, 0.75mmol, 1.5eq) were added, and 2.5mL of a 25% aqueous solution of sodium hydroxide was added and reacted at room temperature. TLC (3/1 in ethyl acetate/petroleum ether, v/v) monitored the progress of the reaction and stopped the reaction after 12.0h of disappearance of starting material. The reaction mixture was concentrated under reduced pressure, extracted with an appropriate amount of ethyl acetate and water, the organic phases were combined, and subjected to silica gel column chromatography using gradient elution (ethyl acetate/petroleum ether volume ratios were 1:6, 1:5, and 1:3, respectively) to give indole derivative IV-37(61.4mg, yellow solid, yield 31.3%). m.p.177.4-181.5 ℃.1H NMR(600MHz,DMSO)δ10.85(s,1H),10.07(s,1H),8.41(s,1H),8.26(t,J＝13.5Hz,1H),8.02(d,J＝7.6Hz,1H),7.81(dd,J＝18.4,10.4Hz,2H),7.65(d,J＝7.7Hz,1H),7.34(d,J＝8.0Hz,1H),7.20(s,1H),7.07(t,J＝7.2Hz,1H),7.00(t,J＝7.1Hz,1H),4.03(dd,J＝23.6,15.8Hz,2H),3.09–2.98(m,2H).HR-MS:calcd for C20H17N4O3S[M+H]+393.10159,found 393.10098。
Test example 1
Antibacterial Activity test of indole derivatives prepared in examples 1 to 31
(1) Sensitivity test
Detection of minimum inhibitory concentration MIC indole derivatives were tested for antibacterial activity against staphylococcus aureus saurus atcc29213 and MRSA181223 by broth microdilution method in Clinical and Laboratories Institute (CLSI) guidelines, with vancomycin as a positive control. Selecting several colonies from blood agar cultured for 18-24 h, and directly preparing the colonies into bacterial suspension by MHB. The turbidity of the calibrated bacterial suspension is 0.5 McLeod unit turbidity standard which is about (1-2) multiplied by 108Colony Forming Units (CFU)/ml. Then, it was diluted to 5X 10 with MHB5CFU/ml. Adding the diluted bacterium solution into a sterile 96-well plate, wherein the first well is 200 mu L, and the rest are 100 mu L/well, adding 4 mu L of medicine stock solution (64 mu g/mL) into the first well, uniformly mixing, and then carrying out dilution by times so that the medicine concentration is 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 and 0.03125 mu g/mL in sequence. And culturing the detection plate at 37 ℃ for 20-24 h, and reading the MIC of the drug to be detected to pathogenic bacteria. The drug concentration of the first hole in which no bacteria can grow is MIC, and if the hole jumping occurs, the drug concentration in which bacteria can not grow is MIC. Wherein the drug stock solutions are DMSO solutions of the indole derivatives and the positive control drugs prepared in examples 1 to 31, respectively.
(2) TrpRS enzyme Activity assay
Enzyme activity assays were performed in pure white opaque flat-bottomed 96-well plates using Kinase-GloPlus luminescence Kinase (Promega, Wis., USA). To a 96-well plate, 50. mu.L of a test drug at a concentration of 200. mu. mol/L, Bacillus stearothermophilus TrpRS, and MgCl dissolved in Tris (pH8.0) buffer were added2And DTT mix, 2-fold diluted. Then 25. mu.L of a mixture of L-tryptophan and ATP was added. The system finally contained 1. mu.M of TrpRS, 16. mu.MATP, 40mM Tris (pH8.0), 8mM MgCl20.8mM DTT, 1mM L-tryptophan and 0-25 μ M of the indole derivatives prepared in examples 1-31 and a positive control drug. Incubating the mixture at 37 deg.C for 90min, adding equal volume of Kinase-Glo reagent into each well, and mixing well. After standing at room temperature for 60min, the luminescence value was measured on a SYNERGYH1 microplate reader. The inhibition rate of each drug to be tested is calculated according to the following formula:
Figure BDA0003531384530000241
IC of the Compound50Determined by GraphpadPrism5 software.
(3) Affinity assay
Surface Plasmon Resonance (SPR) binding assay was performed on a Biacore T200 apparatus (GEHealthcare) by covalently immobilizing the Bacillus stearothermophilus TrpRS protein on a CM5 chip using a 2-fold dilution method, and using 5% DMSO in PBS-P+The buffer solution is respectively prepared into drug samples to be tested with the concentrations of 250 mu M, 125 mu M, 62.5 mu M, 31.25 mu M, 15.6 mu M, 7.8 mu M and 3.9 mu M, vancomycin is used as a positive control, and the obtained data is analyzed by T200 evaluation software to calculate the equilibrium dissociation constant K of the drug to be testedDThe value is obtained.
The test results are shown in Table 1 and FIGS. 4 to 7, in which FIG. 4 is a graph showing the results of the test of the inhibitory activity against TrpRS by the indole compound having the structure shown in I-12, FIG. 5 is a graph showing the results of the test of the inhibitory activity against TrpRS by the indole compound having the structure shown in I-13, FIG. 6 is a graph showing the results of the test of the binding against TrpRS by the indole compound having the structure shown in I-12 based on SPR, and FIG. 7 is a graph showing the results of the binding against TrpRS by the indole compound having the structure shown in I-13 based on SPR.
TABLE 1 results of activity test relating to indole derivatives prepared in examples 1 to 31
Figure BDA0003531384530000242
Figure BDA0003531384530000251
Figure BDA0003531384530000261
Note: NT means not tested.
Pharmacological experimental data shown in table 1 and fig. 4 to 7 indicate that, in the indole derivative provided by the invention, when the connecting group between the indole and the aromatic ring is thiourea, the antibacterial activity of the indole derivative is superior to that of the indole derivative with the amide connecting group. Further, when the aromatic ring is a benzene ring substituted with an electron-withdrawing group, the antibacterial activity is better. Sensitivity experiment results show that the indole compounds with the structures shown in I-4, I-11, I-12, I-13, I-14, I-16 and I-21 have better antibacterial activity. The results of enzyme activity and affinity experiments show that the indole derivative provided by the invention has an action target of TrpRS, has high affinity for TrpRS, has a value of further clinical development and application, and can be used as a drug lead molecule for further research and development.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. An indole derivative having any one of the structures represented by formulae I to IV:
Figure FDA0003531384520000011
in the formulas I to IV, n is 0 to 3,
in the formula I, R1including-H or benzyloxycarbonyl, R2Including substituted phenyl, six-membered cycloalkyl, five-membered heterocycle or naphthyl;
in the formula II, R3including-H or benzyloxycarbonyl, R4Including substituted phenyl groups;
in the formula III, R5comprising-H or-CH3；
In the formula IV, R6Including substituted phenyl。
2. The indole derivative of claim 1, wherein R is2Including any of the following structures:
Figure FDA0003531384520000012
3. the indole derivative of claim 1, wherein R is4Any one of the following structures:
Figure FDA0003531384520000013
4. the indole derivative of claim 1, wherein R is6Including any of the following structures:
Figure FDA0003531384520000021
5. the process for producing an indole derivative according to any one of claims 1 to 4, wherein the process for producing an indole derivative having a structure represented by formula I or formula II comprises the steps of:
mixing a first indole compound, a first acyl chloride compound, potassium thiocyanate and a good solvent of indole compounds, and carrying out a first acylation reaction to obtain an indole derivative with a structure shown in formula I or formula II;
the first indole compound has a structure represented by formula V-1 or V-2:
Figure FDA0003531384520000022
in the formulas V-1 and V-2, n is 0-3;
the first acyl chloride compound is R2-COCl or R4-COCl, wherein R2And R in the formula I2Same as R4And R in the formula II4The same;
the preparation method of the indole derivative with the structure shown in the formula III comprises the following steps: mixing a second indole compound, potassium thiocyanate and an alcohol solvent, and carrying out cyclization reaction to obtain an indole derivative with a structure shown in a formula III;
the second indole compound has a structure represented by formula VI:
Figure FDA0003531384520000023
r in the formula VI5And R in said formula III5The same; n is 0 to 3;
the preparation method of the indole derivative with the structure shown in the formula IV comprises the following steps: a second indole compound, R6-CHO, an alkaline reagent and an alcohol solvent are mixed for substitution reaction to obtain an indole derivative with a structure shown in formula IV;
said R is6-CHO R6And R in said formula IV6The same is true.
6. The process according to claim 5, wherein the indole derivative having the structure represented by formula I or formula II is produced in a molar ratio of the first indole compound to the first acid chloride compound of 1: 1.0 to 1.5;
the molar ratio of the first indole compound to potassium thiocyanate is 1: 1.0 to 1.5;
the temperature of the first acylation reaction is 50-80 ℃, and the time is 4-8 h.
7. The process according to claim 5, wherein the indole derivative having the structure represented by formula III is produced in a molar ratio of the second indole compound to potassium thiocyanate of 1: 1.0 to 2.0;
the temperature of the cyclization reaction is 50-90 ℃, and the time is 6-10 h.
8. The process of claim 5, wherein in the process for preparing an indole derivative having the structure of formula IV, the second indole compound is reacted with R6-CHO molar ratio of 1: 1.0 to 1.8;
the temperature of the substitution reaction is 60-90 ℃, and the time is 8-16 h.
9. The process of claim 5, 7 or 8, wherein the second indole compound is prepared by a process comprising the steps of:
mixing a compound with a structure shown in a formula VII, an alkaline reagent, a second acyl chloride compound and a soluble compound solvent shown in the formula VII, and carrying out a second acylation reaction to obtain a second indole compound;
Figure FDA0003531384520000031
in the formula VII, n is 0-3;
the second acid chloride compound comprises chloroacetyl chloride or 2-chloropropionyl chloride.
10. Use of the indole derivative according to any one of claims 1 to 4 for the preparation of an antibacterial agent.
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MATTHEW D. STEPHENS等: "Potentiation of Francisella resistance to conventional antibiotics through small molecule adjuvants", 《MED. CHEM. COMMUN.》, vol. 7, no. 1, pages 128 - 131 *

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