CN109053584B - Preparation and application of 1, 2-diaryl benzimidazole derivatives - Google Patents

Preparation and application of 1, 2-diaryl benzimidazole derivatives Download PDF

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CN109053584B
CN109053584B CN201811083566.XA CN201811083566A CN109053584B CN 109053584 B CN109053584 B CN 109053584B CN 201811083566 A CN201811083566 A CN 201811083566A CN 109053584 B CN109053584 B CN 109053584B
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CN109053584A (en
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朱海亮
杨蓉
夏林颖
张雅亮
王保忠
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Nanjing University
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Abstract

The invention discloses a preparation method of a novel microtubule inhibitor 1, 2-diaryl benzimidazole derivative and application thereof in the aspect of tumor resistance. Has a structure shown in formula I:

Description

Preparation and application of 1, 2-diaryl benzimidazole derivatives
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method, activity evaluation and anti-tumor application of 1, 2-diaryl benzimidazole derivatives.
Background
Tumors are diseases which seriously threaten human health at present, the lethality rate is high, and the malignant cell proliferation is the main characteristic of the tumors. The aim of resisting tumor can be achieved by inhibiting the malignant cell proliferation, the cell proliferation depends on the regulation and control of the spindle body on the cell division in the cell division period, and the formation of the spindle body is closely related to the microtubules, so the aim of resisting tumor is achieved by inhibiting the malignant cell proliferation by inhibiting the formation of the microtubules. Microtubule inhibitors can be divided into two broad categories depending on the target of action: the first are microtubule stabilizing agents, such as paclitaxel; the second class is microtubule destabilizing agents such as colchicine, vincristine, CA-4, and the like. CA-4 is one of the most active compounds in the currently known tubulin inhibitors, has simple structure, high efficiency and low toxicity, but has poor water solubility, low bioavailability and poor structural stability, and can be easily isomerized into a trans-structure with no pharmacological activity and relative stability from a cis-stilbene active structure after administration. The maintenance of the cis configuration of two benzene rings in the CA-4 structure is the primary condition for maintaining the activity, so that researchers do a lot of work to modify the structure of the CA-4 structure, and the invention further modifies the structure of the CA-4 based on the basic skeleton of the CA-4 and the previous research.
Imidazole is a five-membered aromatic heterocyclic compound containing two meta-position nitrogen atoms in a molecular structure, an unshared electron pair of the 1-position nitrogen atom in the imidazole ring participates in cyclic conjugation, and the electron density of the nitrogen atom is reduced, so that hydrogen on the nitrogen atom is easy to leave in a hydrogen ion form, and a substitution reaction is easy to occur. Imidazole is used as a medicinal raw material for preparing antifungal agents, hypoglycemic therapeutic agents, artificial blood plasma, trichomonad therapeutic agents, bronchial asthma therapeutic agents, anti-rash agents and the like, and is one of the main raw materials of imidazole antifungal agents, diclosimidazole, econazole, ketoconazole and clotrimazole. In addition, the compound is used as a pesticide raw material, a synergist of a boric acid preparation, an insecticide, a bactericide and the like. In recent years, imidazole rings are increasingly applied to the field of medicine, and the research on imidazole compounds has become one of the hot spots of the research on drug design and synthesis at present.
Therefore, the invention takes the colchicine action site as a target spot, carries out modification based on a CA-4 basic skeleton, introduces a rigid structure of a benzimidazole ring to replace a homoeopathic double bond, retains two benzene rings in the CA-4 structure, designs and synthesizes a series of 1, 2-diaryl benzimidazole derivatives, and researches the potential value of the derivatives in the aspect of tumor resistance.
Disclosure of Invention
The purpose of the invention is as follows:
1. provided are 1, 2-diarylbenzimidazole derivatives having microtubule-inhibiting activity.
2. Provides a simple and efficient method for synthesizing the compound of the object 1.
3. Provides the application of the compound in the object 1 in the aspect of tumor resistance.
The technical scheme is as follows: the 1, 2-diaryl benzimidazole derivative has a structure shown in a formula I:
Figure BSA0000170808820000021
wherein: r1Selected from: -H, -Br, -OH, -OCH3；R2Selected from: -H, -Br, -CH3、-OH、-OCH3；R3Selected from: -H, -F, -Cl, -Br, -CH3、-OH、-OCH3、-NO2、-SCH3；R4Selected from: -H, -OCH3；R5Selected from: -H, -OCH3、-OH；R6Selected from: -H, -OCH3；R7Selected from: -H, -OCH3、-OH。
The invention relates to a 1, 2-diaryl benzimidazole derivative, which is prepared by the following steps:
Figure BSA0000170808820000022
step i: o-fluoronitrobenzene (10mmol) and mono-or poly-substituted aniline (12mmol) were added to water (20mL) and reacted under reflux for 6h with stirring. The reaction was cooled to room temperature and NaHCO was used3(about 1.7g), extracting with ethyl acetate (3X 100mL), combining ethyl acetate extracts, washing with water, drying over anhydrous sodium sulfate, vacuum evaporating to obtain crude product of the corresponding compound of general formula (2a-2t), and purifying with silica gel column chromatography (eluent system: petroleum ether/ethyl acetate) to obtain the corresponding compound of general formula (2a-2 t).
Step ii: a mixed solution of tetrahydrofuran (100mL) containing a compound corresponding to the general formula (2a-2k) (20.0mmol) and absolute ethanol (50mL) was added dropwise to a solution of sodium dithionite (320mmol) in water (125mL) under ice-bath conditions, and the mixed solution was stirred at room temperature for 1 hour and reacted with saturated NaHCO3Basified with aqueous solution, concentrated, the aqueous layer extracted with ethyl acetate (3X 100mL), the ethyl acetate extracts combined and washed with saturated NaHCO3Washing with water solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude product of compound represented by general formula (3a-3t), and purifying with silica gel column chromatography (eluent system: petroleum ether/ethyl acetate) to obtain compound represented by general formula (3a-3 t).
Step iii: dissolving a compound (10mmol) corresponding to the general formula (3a-3t) in an absolute ethyl alcohol solution (20mL), adding benzaldehyde (10mmol), stirring and refluxing for 1h, filtering to obtain a solid crude product of a compound corresponding to the general formula (4a-4x), and recrystallizing in an ethanol system to obtain the compound corresponding to the general formula (4a-4 x).
The 1, 2-diaryl benzimidazole derivative has obvious inhibition effect on malignant proliferation of human cervical carcinoma cells (HeLa), human liver cancer cells (HepG2), human lung cancer cells (A549) and human breast cancer cells (MCF-7), wherein the anti-tumor effect of the compound 4x is equivalent to that of Colchicine. Therefore, the 1, 2-diaryl benzimidazole derivatives have the potential of being developed into antitumor drugs.
Detailed Description
The first embodiment is as follows:
preparation of 1-phenyl-2- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4a)
Figure BSA0000170808820000031
O-fluoronitrobenzene (1.41g, 10mmol) and 3, 4, 5-trimethoxyaniline (1.692g, 12mmol) were added to water (20mL) and reacted under reflux for 6h with stirring. The reaction was cooled to room temperature and NaHCO was used3(about 1.7g) and extracted with ethyl acetate (3X 100mL), the combined ethyl acetate extracts were washed with water, dried over anhydrous sodium sulfate, evaporated to dryness in vacuo to give crude compound 2a, which was purified by silica gel column chromatography (eluent system: petroleum ether/ethyl acetate) to give compound 2a as an orange powder. A mixed solution of tetrahydrofuran (100mL) containing Compound 2a (6.37g, 20.0mmol) and absolute ethanol (50mL) was added dropwise to a solution of sodium dithionite (55.7g, 320mmol) in water (125mL) under ice-bath conditions, and the mixed solution was stirred at room temperature for 1h and reacted with saturated NaHCO3Basified with aqueous solution, concentrated, the aqueous layer extracted with ethyl acetate (3X 100mL), the ethyl acetate extracts combined and washed with saturated NaHCO3Washing with water solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain crude compound 3a, and purifying with silica gel column chromatography (eluent system: petroleum ether/ethyl acetate) to obtain compound 3a as brown powder. Dissolving the compound 3a (10mmol) in an absolute ethyl alcohol solution (20mL), adding benzaldehyde (10mmol), stirring and refluxing for 1h, filtering to obtain a solid crude product of the compound 4a, and recrystallizing in an ethanol system to obtain the compound 4 a. A yellow powder was obtained, yield: 78.4%, m.p.165-167 ℃.1H NMR(600MHz，DMSO-d6)δ7.81(d，J＝8.0Hz，1H)，7.67-7.53(m，3H)，7.50-7.45(m，2H)，7.35-7.23(m，2H)，7.16(d，J＝8.0Hz，1H)，6.84(s，2H)，3.68(s，3H)，3.57(s，6H).
Example two:
preparation of 2-methoxy-5- (2- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenol (4b)
Figure BSA0000170808820000032
The preparation method refers to the first embodiment. White powder was obtained, yield: 65.6 percent and m.p.194-196 ℃.1H NMR(600MHz，DMSO-d6)δ7.83(s，1H)，7.26(d，J＝12.9Hz，1H)，7.09(d，J＝10.5Hz，1H)，6.73(t，J＝15.4Hz，1H)，6.51-6.44(m，2H)，6.37(d，J＝5.5Hz，2H)，6.29-6.22(m，2H)，3.83(s，3H)，3.71-3.64(m，6H)，3.53(s，3H).
Example three:
preparation of 1- (4-methoxyphenyl) -2- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4c)
Figure BSA0000170808820000041
The preparation method refers to the first embodiment. White powder was obtained, yield: 77.5%, m.p.171-173 ℃.1H NMR(600MHz，DMSO-d6)δ7.02(d，J＝18.6Hz，1H)，6.83(t，J＝12.0Hz，1H)，6.71-6.67(m，3H)，6.52(s，1H)，6.28(m，2H)，6.17(s，2H)，3.91(s，3H)，3.83(s，3H)，3.75(s，3H)，3.67(s，3H).
Example four:
preparation of 3- (2- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenol (4d)
Figure BSA0000170808820000042
The preparation method refers to the first embodiment. So as to obtain the white powder,yield: 71.3 percent and m.p.163-165 ℃.1H NMR(600MHz，DMSO-d6)δ8.07-7.87(m，2H)，7.31(dd，J＝28.5，7.9Hz，3H)，7.19(t，J＝7.1Hz，1H)，7.01-6.96(m，1H)，6.72-6.48(m，2H)，6.24(s，2H)，3.72-3.67(m，6H)，3.62-3.57(m，3H).
Example five:
preparation of 2-phenyl-1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4e)
Figure BSA0000170808820000043
The preparation method refers to the first embodiment. White powder was obtained, yield: 81.6%, m.p.171-173 ℃.1H NMR(600MHz，DMSO-d6)δ7.04-6.99(m，1H)，6.97(s，1H)，6.84-6.77(m，1H)，6.72(dd，J＝7.9，1.2Hz，1H)，6.54(td，J＝7.6，1.3Hz，1H)，6.05(s，2H)，4.72(s，2H)，3.65(s，6H)，3.56(s，3H).
Example six:
preparation of 2-methoxy-5- (1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazol-2-yl) phenol (4f)
Figure BSA0000170808820000051
The preparation method refers to the first embodiment. White powder was obtained, yield: 67.5%, m.p.191-193 ℃.1H NMR(600MHz，DMSO-d6)δ7.92(s，1H)，7.83(s，1H)，7.47(t，J＝5.4Hz，1H)，6.92-6.78(m，2H)，6.54(t，J＝13.9Hz，1H)，6.47(s，1H)，6.42(d，J＝7.5Hz，1H)，6.32-6.28(m，2H)，3.82(s，3H)，3.73(s，3H)，3.62(s，3H)，3.57(s，3H).
Example seven:
preparation of 2- (4-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4g)
Figure BSA0000170808820000052
The preparation method refers to the first embodiment. White powder was obtained, yield: 71.7 percent and m.p.178-180 ℃.1H NMR(600MHz，DMSO-d6)δ7.07(dd，J＝55.9，13.9Hz，5H)，6.79-6.67(m，3H)，6.61(t，J＝7.0Hz，1H)，6.29(s，1H)，3.84(s，3H)，3.69(s，3H)，3.63(s，3H)，3.57(s，3H).
Example eight:
preparation of 3- (1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazol-2-yl) phenol (4H)
Figure BSA0000170808820000053
The preparation method refers to the first embodiment. White powder was obtained, yield: 80.3 percent and m.p.172-174 ℃.1H NMR(600MHz，DMSO-d6)δ9.62(s，1H)，7.78-7.73(m，1H)，7.33-7.25(m，2H)，7.17(t，J＝7.9Hz，1H)，7.10-7.06(m，1H)，6.96(d，J＝7.9Hz，1H)，6.83-6.77(m，1H)，6.75(s，2H)，3.75(s，3H)，3.69(s，6H).
Example nine:
preparation of 2- (4-bromophenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4i)
Figure BSA0000170808820000061
The preparation method refers to the first embodiment. White powder was obtained, yield: 72.5%, m.p.176-177 ℃.1H NMR(600MHz，DMSO-d6)δ7.41(d，J＝8.5Hz，2H)，7.22-6.95(m，5H)，6.73(s，1H)，6.62(t，J＝6.6Hz，1H)，6.28(s，1H)，3.84(s，3H)，3.69(s，3H)，3.60(s，3H).
Example ten:
preparation of 2- (3-bromophenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4j)
Figure BSA0000170808820000062
The preparation method refers to the first embodiment. White powder was obtained, yield: 85.7 percent and m.p.176-178 ℃.1H NMR(600MHz，DMSO-d6)δ7.86(d，J＝7.7Hz，1H)，7.76(d，J＝7.9Hz，1H)，7.62(t，J＝8.0Hz，1H)，7.49(d，J＝8.3Hz，1H)，7.44-7.36(m，4H)，6.87(s，2H)，3.71(s，3H)，3.66(d，J＝5.0Hz，6H).
Example eleven:
preparation of 2- (2-bromophenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4k)
Figure BSA0000170808820000063
The preparation method refers to the first embodiment. White powder was obtained, yield: 86.2%, m.p.177-179 ℃.1H NMR(600MHz，DMSO-d6)δ7.43-7.19(m，5H)，7.13(q，J＝7.5Hz，1H)，7.10(d，J＝7.7Hz，1H)，7.02-6.96(m，1H)，6.58(d，J＝33.5Hz，1H)，6.25(d，J＝12.7Hz，1H)，3.70(s，3H)，3.59(t，J＝8.6Hz，6H).
Example twelve:
preparation of 3- (3-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4l)
Figure BSA0000170808820000071
The preparation method refers to the first embodiment. White powder was obtained, yield: 72.1%, m.p.179-181 ℃.1H NMR(600MHz，DMSO-d6)δ7.15(s，1H)，7.05(dd，J＝28.4，20.4Hz，4H)，6.75-6.67(m，2H)，6.65-6.56(m，2H)，6.30(s，1H)，3.84(s，3H)，3.70(s，3H)，3.62(d，J＝21.6Hz，6H).
Example thirteen:
preparation of 2- (2-methoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4m)
Figure BSA0000170808820000072
The preparation method refers to the first embodiment. White powder was obtained, yield: 70.4%, m.p.175-177 ℃.1H NMR(600MHz，DMSO-d6)δ7.71-7.65(m，1H)，7.15(t，J＝7.5Hz，1H)，7.08(t，J＝7.5Hz，1H)，6.93(t，J＝15.4Hz，3H)，6.70(s，1H)，6.64(t，J＝7.5Hz，1H)，6.55(s，1H)，6.42(d，J＝7.1Hz，1H)，4.00-3.87(m，6H)，3.85(s，3H)，3.69(d，J＝4.9Hz，3H).
Example fourteen:
preparation of 2- (1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazol-2-yl) phenol (4n)
Figure BSA0000170808820000081
The preparation method refers to the first embodiment. White powder was obtained, yield: 69.8 percent and m.p.164-166 ℃.1H NMR(600MHz，DMSO-d6)δ9.49(s，1H)，9.16(s，1H)，7.02(dd，J＝37.6，18.9Hz，4H)，6.70(d，J＝23.3Hz，1H)，6.61(t，J＝7.3Hz，1H)，6.54(d，J＝8.7Hz，2H)，6.27(s，1H)，3.83(s，3H)，3.68(s，3H)，3.56(s，3H).
Example fifteen:
preparation of 2- (p-tolyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4o)
Figure BSA0000170808820000082
The preparation method refers to the first embodiment. White powder was obtained, yield: 77.4 percent and m.p.184-186 ℃.1H NMR(600MHz，DMSO-d6)δ6.99(ddd，J＝34.9，21.5，7.7Hz，8H)，6.61(d，J＝50.8Hz，3H)，6.22(s，2H)，3.82(d，J＝15.1Hz，3H)，3.69(s，3H)，3.58(s，3H).
Example sixteen:
preparation of 2- (m-tolyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4 p).
Figure BSA0000170808820000083
The preparation method refers to the first embodiment. White powder was obtained, yield: 76.4%, m.p.167-169 ℃.1H NMR(600MHz，DMSO-d6)δ8.04(s，1H)，7.82(d，J＝13.9Hz，1H)，7.72-7.66(m，2H)，7.57(t，J＝12.5Hz，2H)，7.42-7.31(m，2H)，7.19(d，J＝7.5Hz，2H)，7.12(s，3H)，3.68(s，6H)，3.59(s，3H).
Example seventeen:
preparation of 2- (4- (methylthio) phenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4 q).
Figure BSA0000170808820000091
The preparation method refers to the first embodiment. White powder was obtained, yield: 81.4%, m.p.187-189 ℃.1H NMR(600MHz，DMSO-d6)δ7.95(s，1H)，7.40-7.34(m，2H)，7.15(d，J＝8.4Hz，3H)，7.04(dd，J＝16.1，9.6Hz，4H)，6.73(s，1H)，6.62(t，J＝7.2Hz，1H)，6.30(s，1H)，3.84(s，3H)，3.70(d，J＝9.2Hz，3H)，3.59(s，3H).
Example eighteen:
preparation of 3- (4-nitrophenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4 r).
Figure BSA0000170808820000092
The preparation method refers to the first embodiment. White powder was obtained, yield: 83.6 percent and m.p.170-172 ℃.1H NMR(600MHz，DMSO-d6)δ8.07(d，J＝8.8Hz，2H)，7.40(d，J＝4.7Hz，2H)，6.67(dd，J＝78.2，37.9Hz，5H)，6.03(s，1H)，3.80(d，J＝9.4Hz，3H)，3.68(d，J＝7.3Hz，3H)，3.61(d，J＝4.4Hz，3H).
Example nineteenth:
preparation of 2- (4-fluorophenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4 s).
Figure BSA0000170808820000093
The preparation method refers to the first embodiment. White powder was obtained, yield: 75.6 percent and m.p.167-169 ℃.1H NMR(600MHz，DMSO-d6)δ7.23(dd，J＝7.9，5.6Hz，2H)，7.12-6.92(m，5H)，6.69(s，1H)，6.59(t，J＝7.0Hz，1H)，6.28(s，1H)，3.82(s，3H)，3.68(s，3H)，3.58(s，3H).
Example twenty:
preparation of 2- (4-chlorophenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4 t).
Figure BSA0000170808820000101
The preparation method refers to the first embodiment. White powder was obtained, yield: 73.3 percent and m.p.173-175 ℃.1H NMR(600MHz，DMSO-d6)δ7.26(dd，J＝23.9，8.6Hz，4H)，7.01(t，J＝41.4Hz，3H)，6.71(s，1H)，6.61(t，J＝6.7Hz，1H)，6.28(s，1H)，3.83(s，3H)，3.69(s，3H)，3.60(s，3H).
Example twenty one:
preparation of 4- (1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazol-2-yl) benzene-1, 3-diol (4u)
Figure BSA0000170808820000102
The preparation method refers to the first embodiment. White powder was obtained, yield: 73.9 percent and m.p.183-185 ℃.1H NMR(600MHz，DMSO-d6)δ7.61(s，2H)，7.44(d，J＝10.5Hz，1H)，7.32(d，J＝10.5Hz，1H)，7.15-7.09(m，3H)，6.85(t，J＝15.2Hz，2H)，6.78(d，J＝5.9Hz，1H)，6.71(s，1H)，3.75(s，3H)，3.62(s，3H)，3.47(s，3H).
Example twenty two:
preparation of 4- (1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazol-2-yl) benzene-1, 2-diol (4 v).
Figure BSA0000170808820000103
The preparation method refers to the first embodiment. White powder was obtained, yield: 81.9% and m.p.189-191 ℃.1H NMR(600MHz，DMSO-d6)δ7.31(d，J＝10.5Hz，2H)，7.21(d，J＝7.5Hz，1H)，7.13(s，1H)，7.02-6.85(m，3H)，6.71(s，1H)，6.62(d，J＝8.6Hz，1H)，6.57(t，J＝12.5Hz，2H)，3.62(s，6H)，3.57(s，3H).
Example twenty three:
preparation of 2- (2, 4-dimethoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4 w).
Figure BSA0000170808820000111
The preparation method refers to the first embodiment. White powder was obtained, yield: 68.1 percent and m.p.191-193 ℃.1H NMR(600MHz，DMSO-d6)δ7.01(d，J＝25.1Hz，2H)，6.90(s，1H)，6.74(s，1H)，6.60(s，1H)，6.48(d，J＝2.3Hz，1H)，6.35-6.27(m，2H)，6.21(dd，J＝8.6，2.3Hz，1H)，3.97-3.91(m，3H)，3.83(d，J＝15.8Hz，3H)，3.70(s，3H)，3.61(d，J＝24.2Hz，6H).
Example twenty-four:
preparation of 2- (3, 4-dimethoxyphenyl) -1- (3, 4, 5-trimethoxyphenyl) -1H-benzo [ d ] imidazole (4 x).
Figure BSA0000170808820000112
The preparation method refers to the first embodiment. White powder was obtained, yield: 67.9%, m.p.190-192 ℃.1H NMR(600MHz，DMSO-d6)δ7.36(d，J＝6.5Hz，1H)，7.22(d，J＝26.3Hz，1H)，7.05(dd，J＝44.0，11.5Hz，2H)，6.74-6.61(m，3H)，6.33(dd，J＝8.3，1.9Hz，2H)，3.84(d，J＝6.5Hz，3H)，3.70(s，3H)，3.67(s，3H)，3.61(d，J＝3.2Hz，6H).
Example twenty-five:
the compounds of the above examples were tested for antitumor activity.
MTT [3- (4, 5) -dimethyl-2-thiazole- (2, 5) -phenyl bromide tetrazolium blue is adopted]The method is used for determining the drug concentration (IC) of the 1, 2-diaryl benzimidazole derivative when the inhibition rate of the 1, 2-diaryl benzimidazole derivative on human cervical cancer cells (HeLa), human liver cancer cells (HepG2), human lung cancer cells (A549) and human breast cancer cells (MCF-7) reaches 50 percent50)。
Selecting four kinds of cells, culturing to form a plate, digesting, counting, and making into a concentration of 0.5-1.0 × 105Mixing the cell suspension/mL, adding into 96-well culture plate (100 μ L/well), setting blank group and negative control group at 37 deg.C, and adding 5% CO2Culturing for 12h in an incubator; preparing a compound to be detected and a positive control drug by using 2% culture solution to reach a required concentration gradient, and adding 100 mu L of corresponding drug-containing culture solution into each hole; after administration 96-well plates were placed at 37 ℃ in 5% CO2Culturing for 48h in an incubator; to a 96-well plate, MTT (5mg/mL) was added at 5. mu.L/well, incubation was continued for 4 hours, the supernatant was removed, DMSO was added at 150. mu.L/well, shaking was performed until formazan crystals were completely dissolved, optical density (OD value) of each well was measured at a wavelength of 570nm with an automatic microplate reader, and IC was calculated using GraphPad Prism 5 as software50The value is obtained. The results are shown in Table 1 below:
table 1: IC of 1, 2-diaryl benzimidazole derivative on tumor cells50Value of
Figure BSA0000170808820000121
The 1, 2-diaryl benzimidazole derivative has obvious inhibition effect on malignant proliferation of human cervical cancer cells (HeLa), human liver cancer cells (HepG2), human lung cancer cells (A549) and human breast cancer cells (MCF-7), wherein the tumor inhibition effect of the compound 4x is equivalent to that of Colchicine. Therefore, the 1, 2-diaryl benzimidazole derivatives have the potential of being developed into antitumor drugs.

Claims (4)

1. A1, 2-diaryl benzimidazole derivative is characterized by having a structure shown in a general formula III:
Figure FSB0000196980840000011
wherein: r1Selected from: -H, -Br, -OH, -OCH3；R2Selected from: -H, -Br, -CH3、-OH、-OCH3；R3Selected from: -H, -F, -Cl, -Br, -CH3、-OH、-OCH3、-NO2、-SCH3；R4is-H; r5、R6、R7Are all-OCH3。
2. The preparation method of the 1, 2-diaryl benzimidazole derivative according to claim 1, which is characterized by comprising the following steps:
Figure FSB0000196980840000012
(1) a process for the preparation of corresponding compounds of the general formula (I): adding o-fluoronitrobenzene and mono-substituted or multi-substituted aniline into water, stirring, carrying out reflux reaction for 6 hours, cooling the reaction liquid to room temperature, and using NaHCO3Neutralizing, and extracting with ethyl acetate to obtain a compound corresponding to the general formula (I);
(2) a process for the preparation of corresponding compounds of the general formula (II): dripping a mixed solution of tetrahydrofuran and absolute ethyl alcohol containing a compound corresponding to the general formula (I) into an aqueous solution of sodium hydrosulfite under the ice-bath condition, stirring the mixed reaction solution at room temperature for reaction for 1h, and reacting with saturated NaHCO3Alkalizing the aqueous solution, concentrating, and extracting with ethyl acetate to obtain a compound corresponding to the general formula (II);
(3) a process for the preparation of corresponding compounds of the general formula (III): dissolving the compound corresponding to the general formula (II) in an absolute ethyl alcohol solution, adding benzaldehyde, stirring and refluxing for 1h, and filtering to obtain the compound corresponding to the general formula (III).
3. The use of a class of 1, 2-diarylbenzimidazole derivatives according to claim 1 in the preparation of anti-tumor drugs.
4. An antitumor tubulin inhibitory drug comprising the 1, 2-diarylbenzimidazole derivative of claim 1 and a pharmaceutically acceptable carrier.
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