CN110078717B - Bis-benzofuran-benzimidazole salt compound with anti-tumor activity and preparation method thereof - Google Patents
Bis-benzofuran-benzimidazole salt compound with anti-tumor activity and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 7
- -1 dibenzofuran compound Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
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- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 3
- 208000032839 leukemia Diseases 0.000 abstract description 3
- 201000007270 liver cancer Diseases 0.000 abstract description 3
- 208000014018 liver neoplasm Diseases 0.000 abstract description 3
- 201000005202 lung cancer Diseases 0.000 abstract description 3
- 208000020816 lung neoplasm Diseases 0.000 abstract description 3
- TXCDCPKCNAJMEE-UHFFFAOYSA-N Dibenzofuran Natural products C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract 2
- 238000000338 in vitro Methods 0.000 abstract 1
- 229910052697 platinum Inorganic materials 0.000 abstract 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 230000004614 tumor growth Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 7
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000001472 cytotoxic effect Effects 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000005918 in vitro anti-tumor Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- SUDMKGNNRMLBMF-UHFFFAOYSA-N prop-2-enyl methanesulfonate Chemical compound CS(=O)(=O)OCC=C SUDMKGNNRMLBMF-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LDZYRENCLPUXAX-UHFFFAOYSA-N 2-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1 LDZYRENCLPUXAX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- ZZBWQLJDYOBEKI-UHFFFAOYSA-N 1-(1-benzofuran-2-yl)prop-2-en-1-ol Chemical compound C1=CC=C2OC(C(C=C)O)=CC2=C1 ZZBWQLJDYOBEKI-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KZIBQYUFIVUOHY-UHFFFAOYSA-N bis(2-methylpropyl)alumane toluene Chemical compound Cc1ccccc1.[H][Al](CC(C)C)CC(C)C KZIBQYUFIVUOHY-UHFFFAOYSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
- C07D405/14—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 three or more hetero rings
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Abstract
The invention belongs to the technical field of medicines, and relates to a dibenzofuran-benzimidazole salt compound with a novel structure and remarkable anti-tumor activity and a preparation method thereof. The invention carries out active molecule design based on a dibenzofuran compound and a benzimidazole compound with good activity, the synthesis method is efficient and simple, the dibenzofuran-benzimidazole salt compound with the structure shown in the formula I has obvious in-vitro tumor growth inhibition activity on 5 human cancer cells (leukemia, liver cancer, lung cancer, breast cancer and colon cancer cells), the inhibition activity is superior to that of an anticancer drug cis-platinum (DDP), and the dibenzofuran-benzimidazole salt compound has potential of being an antitumor drug.
Description
One, the technical field
The invention relates to a novel bis-benzofuran-benzimidazole salt compound, a preparation method thereof and application of the compound in the aspect of tumor resistance.
Second, background Art
Tumors become a common disease seriously threatening human health, are listed as one of five absolute diseases in the world, are one of the main causes of human death, and cause over 700 million deaths each year. Chemotherapy, i.e., drug therapy, plays an important role in the treatment of malignant tumors and has a rapid rate of development. However, many chemotherapy drugs used in clinical practice have poor selectivity and can cause toxic and side effects on normal human cells. Therefore, the search for highly active, non-toxic or low-toxic anticancer compounds remains an important topic for new drug research.
The natural product and the related research thereof are the source of medicine research innovation and are the most important way for developing new medicines. Among natural products, benzofuran and benzimidazole derivatives are heterocyclic compounds with a wide range of biological activities, and exist in synthetic drug molecules as important physiologically active pharmacophores. The dibenzofuran compound with two benzofuran pharmacophores has a novel structure and obvious activity, and has a good application prospect and a good research value. The bis-benzofuran-benzimidazole salt compound and the preparation method thereof related to the patent are not reported in documents so far.
Third, the invention
The invention discloses a series of bis-benzofuran-benzimidazole salt compounds with a structural general formula (I) and a preparation method thereof, which take salicylaldehyde and 1, 3-dichloroacetone as raw materials to prepare a target compound through six steps of condensation, Witting reaction, reduction, methanesulfonic acid esterification, benzimidazole grafting and salifying. The compound has obvious cytotoxic activity through in vitro anti-tumor activity cytotoxicity test results.
The invention provides a bis-benzofuran-benzimidazole salt compound which is represented by the following structural general formula (I):
R1artibenzoylmethyl, 4-phenylbenzoylmethyl, 4-methoxybenzoylmethyl, 4-bromobenzoylmethyl, 2-naphthoylmethyl
R2＝H，CH3
The preparation method of the compound with the structural general formula (I) provided by the invention is shown as follows, and the method comprises the following steps:
A. the method comprises the steps of taking salicylaldehyde and 1, 3-dichloroacetone as raw materials, synthesizing bis (benzofuran-2-yl) methyl ketone in an acetone solvent under the condition of potassium carbonate, dissolving the salicylaldehyde in the acetone, adding potassium carbonate, adding 1, 3-dichloroacetone according to the molar ratio of 2.1/1/3.1 to 1 of salicylaldehyde/1, 3-dichloroacetone/potassium carbonate and 3mL/g of the salicylaldehyde, reacting for 2 hours, pouring a reaction liquid into 50mL of water, separating out solids, filtering, washing a filter cake with water, and recrystallizing ethanol to obtain the bis (benzofuran-2-yl) methyl ketone.
B. Bis (benzofuran-2-yl) methyl ketone and methyl triphenyl phosphine ethyl ester are used as raw materials, 3-bis (benzofuran-2-yl) methyl acrylate is synthesized by Witting reaction in a toluene solvent, wherein bis (benzofuran-2-yl) methyl ketone is dissolved in toluene, methyl triphenyl phosphine ethyl ester is added, the molar ratio of the used bis (benzofuran-2-yl) methyl ketone to the used methyl triphenyl phosphine ethyl ester is 1/1.5, the used toluene amount is 15mL/g bis (benzofuran-2-yl) methyl ketone, after 12 hours of reaction, the solvent is removed under reduced pressure, and the 3, 3-bis (benzofuran-2-yl) methyl acrylate is obtained by silica gel column chromatography.
C. 3, 3-bis (benzofuran-2-yl) prop-2-ene-1-ol is synthesized by taking 3, 3-bis (benzofuran-2-yl) methyl acrylate as a raw material and carrying out DIBAL-H reduction in anhydrous dichloromethane: dissolving 3, 3-bis (benzofuran-2-yl) methyl acrylate in anhydrous dichloromethane, cooling to-78 deg.C, slowly adding 1M DIBAL-H toluene solution in the molar ratio of 3, 3-bis (benzofuran-2-yl) methyl acrylate/DIBAL-H ═ 1/2.2, anhydrous dichloromethane in the amount of 20mL/g3, 3-bis (benzofuran-2-yl) methyl acrylate, reacting for 1.5 hr, adding saturated ammonium chloride (10mL), quenching, returning to room temperature, extracting with dichloromethane (50mL) for three times, and extracting the organic phase with anhydrous NaSO4Drying, filtering, concentrating the solvent under reduced pressure, and performing silica gel column chromatography to obtain 3, 3-bis (benzofuran-2-yl) prop-2-ene-1-ol.
D. Synthesizing 3, 3-bis (benzofuran-2-yl) prop-2-ene-1-ol and methanesulfonyl chloride serving as raw materials in anhydrous dichloromethane solvent under the condition of triethylamine, and synthesizing 1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzene in acetonitrile solvent together with benzimidazole or 2-methylbenzimidazoleAnd (3) a benzimidazole: dissolving 3, 3-bis (benzofuran-2-yl) prop-2-ene-1-ol in anhydrous dichloromethane, cooling to 0 ℃, adding triethylamine and methanesulfonyl chloride, wherein the molar ratio of the triethylamine to the methanesulfonyl chloride is 3, 3-bis (benzofuran-2-yl) prop-2-ene-1-ol to the triethylamine to the methanesulfonyl chloride is 1/1.5/1.2, the molar ratio of the dichloromethane is 40-60 mL/g3, the 3-bis (benzofuran-2-yl) prop-2-ene-1-ol to the dichloromethane, reacting at room temperature for 2 hours, adding dichloromethane to dilute (30mL/g substrate), washing with water and saturated saline water respectively, and washing an organic phase with anhydrous NaSO4Drying, filtering, and concentrating the solvent under reduced pressure to obtain 3, 3-bis (benzofuran-2-yl) allyl methanesulfonate; dissolving 3, 3-bis (benzofuran-2-yl) allyl methanesulfonate in acetonitrile, adding benzimidazole or 2-methylbenzimidazole, wherein the molar ratio of the amount of the added benzimidazole to the amount of the benzimidazole or 2-methylbenzimidazole is 1/3, the amount of the acetonitrile is 20-30 mL/g of 3, 3-bis (benzofuran-2-yl) allyl methanesulfonate, heating and refluxing for 12 hours, removing the solvent under reduced pressure, and performing silica gel column chromatography to obtain a compound 1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzimidazole.
E. Synthesizing 1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole salt or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzimidazole salt in an acetone solvent by using 1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzimidazole and halogenated alkane as raw materials: dissolving 1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzimidazole in acetone, adding halogenated alkane while stirring, wherein the molar ratio of the amount of the halogenated alkane is 1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzimidazole/halogenated alkane is 1/1.2, and the amount of the acetone is 8-10 mL/g1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzimidazole is refluxed for 24-48 hours, cooled to room temperature, precipitated solid is separated out, filtered, washed with diethyl ether for multiple times and dried, and the 1- (3, 3-bis (benzofuran-2-yl) allyl) -benzimidazole salt or 1- (3, 3-bis (benzofuran-2-yl) allyl) -2-methylbenzimidazole salt is prepared.
Description of the drawings
FIG. 1 shows a general structural formula of a bis-benzofuran-benzimidazole salt compound according to the present invention.
FIG. 2 is a process for preparing bis-benzofuran-benzimidazole salt compounds provided by the present invention.
Fifth, detailed description of the invention
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the embodiments described herein are only for the purpose of illustrating the present invention and are not intended to limit the present invention.
Example 11- (3, 3-bis (benzofuran-2-yl) allyl) -3- (phenacyl) benzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 81%.
1H-NMR(400MHz,DMSO-d6)δ:9.95(1H,s),8.17(2H,d,J＝7.2Hz),8.15 (1H,s),8.09(1H,dd,J＝2.0,6.0Hz),7.81(2H,t,J＝8.0Hz),7.73-7.67(6H,m), 7.60(1H,d,J＝8.0Hz),7.50(1H,s),7.46(1H,t,J＝7.2Hz),7.40(1H,d,J＝7.2 Hz),7.36(1H,d,J＝7.6Hz),7.28(1H,t,J＝7.2Hz),7.18(1H,s),6.90(1H,t,J＝ 6.8Hz),6.53(2H,s),5.91(2H,d,J＝6.4Hz).
13C-NMR(100MHz,DMSO-d6)δ:191.73,154.88,154.69,152.74,149.92, 144.15,135.07,134.26,132.62,131.22,129.54,128.95,128.66,128.23,127.36, 127.27,126.18,126.11,125.48,125.30,124.03,123.94,122.33,114.68,114.16, 112.05,111.56,110.08,107.72,53.88,46.62.
Example 21- (3, 3-bis (benzofuran-2-yl) allyl) -3- (4-phenylbenzoylmethyl) benzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 96%.
1H-NMR(400MHz,DMSO-d6)δ:10.01(1H,s),8.26(2H,d,J＝8.4Hz), 8.19-8.17(1H,m),8.11-8.08(1H,m),7.99(2H,d,J＝8.4Hz),7.84-7.82(3H,m), 7.75-7.73(3H,m),7.69(1H,d,J＝8.0Hz),7.60(1H,d,J＝8.0Hz),7.55(2H,t,J＝ 7.2Hz),7.51(1H,s),7.47(2H,t,J＝7.2Hz),7.40(1H,d,J＝7.6Hz),7.36(1H,d,J ＝8.0Hz),7.28(1H,t,J＝7.6Hz),7.18(1H,s),6.91(1H,t,J＝6.8Hz),6.58(2H,s), 5.91(2H,d,J＝6.8Hz).
13C-NMR(100MHz,DMSO-d6)δ:191.29,154.90,154.70,152.74,149.92, 146.26,144.16,139.04,133.06,132.63,131.22,129.74,129.67,129.21,128.66, 128.24,127.60,127.58,127.37,127.28,126.18,126.12,125.48,125.30,124.04, 123.94,122.34,122.31,114.70,114.16,112.07,111.57,110.11,107.73,53.92,46.65.
Example 31- (3, 3-bis (benzofuran-2-yl) allyl) -3- (4-methoxybenzoylmethyl) benzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 72%.
1H-NMR(400MHz,DMSO-d6)δ:9.96(1H,s),8.16-8.12(3H,m),8.09(1H,dd, J＝2.0,6.0Hz),7.82(1H,d,J＝7.6Hz),7.74-7.71(3H,m),7.69(1H,d,J＝8.0Hz), 7.60(1H,d,J＝8.4Hz),7.50(1H,s),7.46(1H,t,J＝8.0Hz),7.39(1H,d,J＝7.6 Hz),7.36(1H,d,J＝7.6Hz),7.28(1H,t,J＝7.6Hz),7.21(1H,s),7.19(2H,d,J＝ 4.4Hz),6.90(1H,t,J＝6.8Hz),6.47(2H,s),5.89(2H,d,J＝6.8Hz),3.91(3H,s).
13C-NMR(100MHz,DMSO-d6)δ:189.93,164.69,154.88,154.69,152.74, 149.92,144.18,132.63,131.42,131.20,128.66,128.23,127.33,127.23,127.08, 126.18,126.10,125.47,125.30,124.03,123.93,122.33,114.81,114.64,114.14, 112.05,111.56,110.08,107.71,56.31,53.47,46.60.
Example 41- (3, 3-bis (benzofuran-2-yl) allyl) -3- (4-bromobenzoylmethyl) benzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 80%.
1H-NMR(400MHz,DMSO-d6)δ:9.91(1H,s),8.15(1H,dd,J＝3.2,7.2Hz), 8.09(3H,d,J＝8.0Hz),7.91(2H,d,J＝8.4Hz),7.82(1H,d,J＝7.6Hz),7.76-7.67 (4H,m),7.59(1H,d,J＝8.4Hz),7.49(1H,s),7.46(1H,t,J＝8.0Hz),7.39(1H,d,J ＝7.2Hz),7.36(1H,d,J＝7.2Hz),7.28(1H,t,J＝7.6Hz),7.18(1H,s),6.89(1H,t, J＝6.8Hz),6.49(2H,s),5.88(2H,d,J＝6.8Hz).
13C-NMR(100MHz,DMSO-d6)δ:191.11,154.88,154.68,152.72,149.91, 144.12,133.31,132.62,132.59,131.21,130.90,129.19,128.66,128.23,127.37, 127.29,126.18,126.10,125.48,125.28,124.03,123.94,122.32,114.68,114.17, 112.04,111.55,110.07,107.72,53.83,46.62.
Example 51- (3, 3-bis (benzofuran-2-yl) allyl) -3- (2-naphthoylmethyl) benzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 46%.
1H-NMR(300MHz,DMSO-d6)δ:9.92(1H,s),8.96(1H,s),8.27-8.10(6H,m), 7.83-7.74(7H,m),7.59(1H,d,J＝7.5Hz),7.49-7.44(2H,m),7.38(2H,s),7.29(1H, d,J＝6.9Hz),7.18(1H,s),6.91(1H,s),6.60(2H,s),5.89(2H,s).
13C-NMR(75MHz,DMSO-d6)δ:191.11,154.37,154.18,152.22,149.42,143.71, 135.55,132.15,132.01,131.03,130.75,129.70,129.37,128.70,128.15,127.87, 127.72,127.40,126.90,126.80,125.70,125.62,124.99,124.76,123.54,123.31, 121.83,114.14,113.68,111.54,111.05,109.57,107.24,53.30,46.11.
Example 61- (3, 3-bis (benzofuran-2-yl) allyl) -3- (phenacyl) -2-methylbenzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 82%.
1H-NMR(300MHz,DMSO-d6)δ:8.22(2H,d,J＝7.5Hz),8.10-8.07(1H,m), 7.98-7.95(1H,m),7.85-7.75(3H,m),7.71-7.63(5H,m),7.56(2H,d,J＝9.3Hz), 7.48(1H,t,J＝7.2Hz),7.41(1H,d,J＝7.5Hz),7.35(1H,t,J＝6.3Hz),7.27(1H,t, J＝7.5Hz),7.15(1H,s),6.78(1H,t,J＝6.3Hz),6.57(2H,s),5.89(2H,d,J＝6.3 Hz),2.95(3H,s).
13C-NMR(75MHz,DMSO-d6)δ:191.13,154.40,154.13,153.42,152.26, 149.42,134.64,133.70,131.57,130.62,128.91,128.81,127.77,126.33,125.58, 124.17,123.53,121.82,121.75,113.36,112.89,111.57,111.00,109.66,106.92, 52.14,44.91,10.85.
Example 71- (3, 3-bis (benzofuran-2-yl) allyl) -3- (4-phenylbenzoylmethyl) -2-methylbenzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 92%.
1H-NMR(300MHz,DMSO-d6)δ:8.30(2H,d,J＝8.1Hz),8.12-8.09(1H,m), 8.01-7.96(3H,m),7.84-7.81(3H,m),7.77(1H,d,J＝8.4Hz),7.69-7.63(3H,m), 7.58-7.53(4H,m),7.50-7.46(2H,m),7.41(1H,d,J＝7.5Hz),7.36(1H,t,J＝6.3 Hz),7.27(1H,t,J＝7.5Hz),7.15(1H,s),6.79(1H,t,J＝6.0Hz),6.60(2H,s),5.90 (2H,d,J＝6.0Hz),2.96(3H,s).
13C-NMR(75MHz,DMSO-d6)δ:190.66,154.41,154.13,153.42,152.26, 149.43,145.88,138.59,132.51,131.59,130.63,129.57,129.17,128.71,128.19, 127.77,127.09,127.00,126.34,125.59,124.17,123.54,123.41,121.83,121.76, 113.35,112.90,111.58,111.00,109.67,106.93,52.12,44.90,10.86.
Example 81- (3, 3-bis (benzofuran-2-yl) allyl) -3- (4-methoxybenzoylmethyl) -2-methylbenzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 78%.
1H-NMR(300MHz,DMSO-d6)δ:8.19(2H,d,J＝8.7Hz),8.08-8.05(1H,m), 7.97-7.94(1H,m),7.83(1H,d,J＝7.5Hz),7.77(1H,d,J＝8.1Hz),7.68-7.62(3H, m),7.56(2H,d,J＝10.2Hz),7.48(1H,t,J＝7.2Hz),7.40(1H,d,J＝7.5Hz),7.35 (1H,t,J＝6.0Hz),7.28(1H,d,J＝7.5Hz),7.24-7.19(2H,m),7.14(1H,s),6.77 (1H,t,J＝6.3Hz),6.50(2H,s),5.88(2H,d,J＝6.0Hz),3.92(3H,s),2.93(3H,s).
13C-NMR(75MHz,DMSO-d6)δ:189.28,164.30,154.40,154.12,153.39, 152.25,149.41,131.59,131.27,130.60,128.18,127.76,126.55,126.30,125.58, 124.15,123.52,123.40,121.82,121.75,114.20,113.28,112.88,111.57,111.00, 109.66,106.92,55.84,51.70,10.84.
Example 91- (3, 3-bis (benzofuran-2-yl) allyl) -3- (4-bromobenzoylmethyl) -2-methylbenzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 88%.
1H-NMR(300MHz,DMSO-d6)δ:8.13(2H,d,J＝8.4Hz),8.09-8.06(1H,m), 7.97-7.94(1H,m),7.91(2H,d,J＝8.4Hz),7.83(1H,d,J＝7.5Hz),7.76(1H,d,J＝ 8.4Hz),7.68-7.62(3H,m),7.55(2H,d,J＝10.8Hz),7.48(1H,t,J＝7.2Hz),7.40 (1H,d,J＝7.5Hz),7.35(1H,t,J＝8.1Hz),7.27(1H,t,J＝7.5Hz),7.14(1H,s), 6.77(1H,t,J＝6.3Hz),6.53(2H,s),5.88(2H,d,J＝6.0Hz),2.94(3H,s).
13C-NMR(75MHz,DMSO-d6)δ:190.51,154.39,154.12,153.42,152.25, 149.42,132.76,131.95,131.53,130.75,130.61,128.78,127.76,126.35,126.30, 125.58,124.16,123.52,123.39,121.81,121.75,113.38,112.89,111.56,110.98, 109.64,106.92,52.10,44.90,10.85.
Example 101- (3, 3-bis (benzofuran-2-yl) allyl) -3- (2-naphthoylmethyl) -2-methylbenzimidazole bromide salt
The preparation process comprises the following steps: see preparation A, B, C, D, E, supra, for details.
White amorphous powder, yield 76%.
1H-NMR(400MHz,DMSO-d6)δ:9.10(1H,s),8.26(1H,d,J＝7.6Hz), 8.14-8.12(3H,m),8.09(1H,d,J＝8.0Hz),7.98(1H,d,J＝7.2Hz),7.84(1H,d,J＝ 7.6Hz),7.79-7.72(3H,m),7.69-7.64(3H,m),7.57(2H,d,J＝8.4Hz),7.48(1H,d, J＝7.2Hz),7.42-7.33(2H,m),7.27(1H,t,J＝7.6Hz),7.16(1H,s),6.81(1H,t,J＝ 6.0Hz),6.72(2H,s),5.91(2H,d,J＝6.0Hz),2.99(3H,s).
13C-NMR(100MHz,DMSO-d6)δ:191.58,154.92,154.64,153.97,152.78, 149.94,136.11,132.49,132.13,132.09,131.53,131.16,130.23,129,89,129,03, 128.70,128.37,128.29,127.86,126.86,126.84,126.11,124.68,124.04,123.92, 122.34,122.27,113.89,113.42,112.10,111.52,110.19,107.44,52.70,45.45,11.43.
Results of experiments on antitumor cytotoxic activity of the compounds 1 to 10 of examples:
example Compounds 1-10 Using the MTS method, 5 cell lines of leukemia, liver, lung, breast and colon cancer were screened for anti-tumor cytotoxic activity, half-inhibitory amount (IC)50Value, μ M) was compared with cisplatin (DDP), which is a commercially available anticancer drug, in the following table.
The data show that the compounds have good in-vitro anti-tumor cytotoxic activity for breast cancer cell lines, and the compounds 3, 5, 6, 7, 8 and 10 have very good in-vitro anti-tumor cytotoxic activity for 5 cell lines of leukemia, liver cancer, lung cancer, breast cancer and colon cancer, and the activity of the compounds is superior to that of a commercialized anti-tumor medicament, namely cisplatin (DDP).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (2)
1. A bis-benzofuran-benzimidazole salt compound is characterized by having the following structural general formula (I):
general structural formula (I): r1Artibenzoylmethyl, 4-phenylbenzoylmethyl, 4-methoxyPhenacyl, 4-bromobenzoyl methyl, 2-naphthoyl methyl; r2＝H，CH3。
2. Use of the bis-benzofuran-benzimidazole salt compound as defined in claim 1 in the preparation of an anti-tumor medicament.
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| CN103408537A (en) * | 2012-11-19 | 2013-11-27 | 云南大学 | 5-substituted dihydrobenzofuran-imidazolium salt compound and preparation method thereof |
| CN108299401A (en) * | 2018-04-26 | 2018-07-20 | 红河学院 | A kind of 3- benzyls substituted cumarin-imidazole salt compound and preparation method thereof |
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| CN103408537A (en) * | 2012-11-19 | 2013-11-27 | 云南大学 | 5-substituted dihydrobenzofuran-imidazolium salt compound and preparation method thereof |
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| 杂合体在抗真菌、抗结核和抗肿瘤领域的研究进展;解小兵 等;《国外医药抗生素分册》;20180131;第39卷(第1期);第28-42页 * |
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