CN103288817A - Schiff base ramification based on 1,3,4-thiadiazole and 1,3,4-oxadiazole as well as preparation method and application thereof - Google Patents

Abstract

A kind of Schiff base derivative based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, its preparation method is: use acetone as solvent, PEG-400 as catalyst, in the presence of acid-binding agent Next, a series of preparations based on 1, Schiff base derivatives of 3,4-thiadiazole and 1,3,4-oxadiazole. The advantages of the present invention are: the structure is confirmed by infrared spectrum, hydrogen nuclear magnetic resonance spectrum and elemental analysis, etc., and the inhibitory activity of human breast cancer cells, liver cancer cells and lung cancer cells is tested, and the results show that: the derivative has an effect on human breast cancer cells MCF -7. Human liver cancer cell SMMC-7721 and human lung cancer cell A549 have good inhibitory effects and have potential application prospects.

Description

A Schiff base derivative based on 1,3,4-thiadiazole and 1,3,4-oxadiazole and its preparation method and application

technical field

The invention relates to the technical field of medicine, in particular to a Schiff base derivative based on 1,3,4-thiadiazole and 1,3,4-oxadiazole and its preparation method and application. the

Background technique

1,3,4-thiadiazole and 1,3,4-oxadiazole and their derivatives have various biological activities such as anticancer, antibacterial, antifungal, antiviral, antispasmodic, etc., and are basic pharmacophore. See: Literature 1) Singh H. Indian J Chem, 1982, 21B: 480; Literature 2) Yu Jianxin, Liu Fangming. Chemical Journal of Chinese Universities, 1999,8(8):123; Literature 3) Omar AME, Aboulwafa OM. Heterocycle Chem, 1986, 23:1339; Document 4) Invidiata FP, Grimaudo S, Giammanco P, et al. Farmaco, 1991, 46:1489; Document 5) Holla BS, Poojary KN, Kallaraya B, et al. Farmaco, 1996, 51: 793; Literature 6) Todoulou OG, Popadaki VA, Filippatos EC, et al. J Med Chem, 1994, 29, 127, especially the "carbon nitrogen sulfur" structure energy of 1,3,4-thiadiazole derivatives As the active center, it chelates certain metal ions in organisms and has good tissue cell permeability, which has aroused widespread interest and in-depth research on this type of compound by scholars at home and abroad, and has become a new research topic for azole compounds. hotspot. the

Studies have shown that the "SCH ₂ " group is a functional group that has biocompatibility and can maintain the free rotation of the molecule. The introduction of this group in the drug molecule is conducive to the drug entering the organism and combining with the receptor at a suitable position. Therefore, The SCH ₂ group is an important functional group usually introduced in drug design, see: Document 7) Jian-Feng Tang, Xian-Hai Lv, Xiao-Liang Wang, et al. Bioorg Med Chem, 2012, 20, 4226;

Dedicated 8) Hu Zhiqiang, Yang Yaxun, Zhang Gongsheng, et al. Organic Chemistry, 2007,27(3):419.

In the prior art in this field, Song Baoan et al. in 2005, see: Literature 9) Song Baoan, Chen Caijun, Yang Song, etc. Acta Chemica Sinica 2005,63(18):1720; Literature 10) Chen Jiang, Xu Ruiqing, Song Baoan etc. Organic Chemistry. 2006,26(10):1418, reported that gallic acid with anticancer activity was used as a lead compound, and a plurality of 2-substituted phenyl-(3,4,5-trimethoxybenzene base)-1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives, by testing the anti-proliferation activity of these compounds on prostate cancer cell PC3 and gastric cancer cell BGC-823, the results showed that: Some of the compounds showed good growth inhibitory ability on human prostate cancer cells and gastric cancer cells, realizing the superposition of biological activities of different active groups. the

In 2008 Zheng Kaibo et al., see: Literature 11) Zheng Kaibo, He Jun, Zhang Jie. West China Pharmaceutical Journal, 2008, 23(5): 528, based on the pharmacological activity of amide compounds and -1,3,4-thiadiazole, to A series of N ₁ -acetylamino-(1,3,4-thiadiazol-2-yl)-5-Fu derivatives were synthesized using 5-fluorouracil (5-Fu), a commonly used antineoplastic drug. The anti-proliferation activity of these compounds on lung cancer cell A549 and liver cancer cell Bel-7402. The results showed that some compounds showed better anti-proliferation ability on the two cancer cells.

In 2008, Hu Guoqiang et al., see: Document 12) Hu Guoqiang, Mu Xiaokui, Wang Xin, etc. Acta Pharmaceutica Sinica, 2008, 43(11):1112, designed and synthesized a series of cyprofluoroquinolone thiadiazole Schiff base derivatives, through The anticancer activity of these compounds on human liver cancer cell SMMC-7721, human leukemia cell line HL60 and murine leukemia cell line L1210 was determined. The results showed that most of the compounds showed positive inhibitory activity against the three tumor cell lines, and the IC ₅₀ values of some compounds reached or lower than the order of micromolar concentration, which provided a new way for searching for anti-tumor fluoroquinolone lead compounds with new structures.

In 2011, Zou Xiajuan et al., see: Literature 13) Zou Xiajuan, Li Ying, Liu Zhenming, etc. Organic Chemistry, 2011, 31(11):1923, designed and synthesized the series N ₁ -(5-substituent-1,3,4- Thiadiazol-2-yl)-N ₃ -substituted phenyl-urea compounds, and their antitumor activity was determined. The results showed that some compounds were effective against tumor-bearing growth of Lewis lung cancer mice and against human leukemia cells HL-60 , human gastric cancer cell BGC-823, human liver cancer cell Bel-7402 and human nasopharyngeal cancer cell KB have good inhibitory activity.

Based on this idea, given that Schiff base compounds containing 1,3,4-thiadiazole have antitumor activity, see: Literature 14) Hu G Q, Mu XK, Wang X, et al. Acta Pharm Sinica, 2008 , 43, 1112, and the heterocycles are connected by the electron-donating element S, which is beneficial to enhance the affinity between the receptor and the ligand, and can have an important impact on the biological activity. Therefore, through a certain reaction form, the synthesis series is based on 1 , Schiff base derivatives of 3,4-thiadiazole and 1,3,4-oxadiazole, and then use the CCK-8 method to determine the anti-proliferation activity of these compounds on tumor cells, in order to realize the pharmacophore Synergistic and superposition of biological activity. the

Contents of the invention

The purpose of the present invention is to solve the problem that there are few types of anticancer drugs and the lack of preparation technology, and provide a Schiff base derivative based on 1,3,4-thiadiazole and 1,3,4-oxadiazole and The preparation method thereof, the compound has good anticancer activity, and is a class of good potential anticancer drugs. the

Technical scheme of the present invention:

A Schiff base derivative based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, characterized in that said derivative has the following chemical structural formula:

In the structural formula: R is a C1-6 alkyl group, a C3-8 cycloalkyl group or a C5-14 aromatic ring group, wherein the aromatic ring group can be replaced by 1-3 hydroxyl groups, nitro groups, halogen atoms, cyano groups, C1-6 alkoxy or C1-6 alkyl group is substituted, it can also be one or two groups in C1-6 alkyl, C1-6 alkylsulfonyl and C1-6 alkylcarbonyl Substituted by a substituted amino group, the halogen atom is a fluorine, chlorine, bromine or iodine atom.

A method for preparing Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, characterized in that: acetone is used as a solvent and PEG-400 is used as a catalyst. Prepared by condensation reaction of 2-mercapto-5-(2-hydroxyphenylmethyleneamino)-1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives in the presence of an acid-binding agent , the specific method is: 2-mercapto-5-(2-hydroxyphenylmethyleneamino)-1,3,4 thiadiazole, 1,3,4-oxadiazole derivatives, PEG-400 catalyst, Acetone solvent and acid-binding agent are mixed and stirred evenly, reflux reaction, the reaction time is 2-5h; after cooling, the solvent is distilled off, and a solid is precipitated; recrystallized with DMF-water, the target product can be obtained. the

The 1,3,4-oxadiazole derivatives are 2-chloromethyl-5-phenyl-1,3,4-oxadiazole, 2-chloromethyl-5-p-fluorophenyl-1 ,3,4-oxadiazole, 2-chloromethyl-5-o-bromophenyl-1,3,4-oxadiazole, 2-chloromethyl-5-p-methoxyphenyl-1,3, 4-oxadiazole, 2-chloromethyl-5-m-nitrophenyl-1,3,4-oxadiazole or 2-chloromethyl-5-p-nitrophenyl-1,3,4- Oxadiazole, the molar ratio of 2-mercapto-5-(2-hydroxyphenylmethyleneamino)-1,3,4 thiadiazole to 1,3,4-oxadiazole derivatives is 1-1.2: 1. The molar ratio of PEG-400 to 1,3,4-oxadiazole derivatives is 1-2:4, and the ratio of acetone solvent to 1,3,4-oxadiazole derivatives is 1 mmol : 10-15mL. the

The acid-binding agent is potassium carbonate, triethylamine, potassium hydroxide or sodium hydroxide, and the mol ratio of the acid-binding agent to 2-chloromethyl-5-substituted-1,3,4-oxadiazole is 0.6- 2:1. the

The synthetic route of this preparation method is shown as follows:

An application of the Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole for the preparation of anti-tumor pharmaceutical compositions, especially for the preparation of anti-liver cancer , gastric cancer, lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, pancreatic cancer, rectal cancer, lymphatic cancer, esophageal cancer, oral cavity cancer, nasopharyngeal cancer or skin cancer.

The beneficial effects of the present invention are: According to the theory and method of new drug design, the present invention has prepared a series of Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole for the first time, and obtained by infrared The structure was confirmed by spectrum, H NMR spectrum and elemental analysis, and the proliferation inhibitory activity of the derivative on human breast cancer cell MCF-7, human liver cancer cell SMMC-7721 and human lung cancer cell A549 was tested by CCK-8 method. The results show that the derivative has good inhibitory effect on tumor cell proliferation and has potential application prospects. the

【Detailed ways】

Example 1:

A method for preparing Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, using acetone as a solvent, PEG-400 as a catalyst, and in the presence of an acid-binding agent, Condensation of 2-mercapto-5-(2-hydroxyphenylmethyleneamino)-1,3,4-thiadiazole with 2-chloromethyl-5-phenyl-1,3,4-oxadiazole Reaction preparation, concrete method is:

In a 100mL round bottom flask, add 1.42g (6mmol) 2-mercapto-5-(2-hydroxyphenylmethyleneamino)-1,3,4-thiadiazole, 1.17g (6mmol) 2-chloromethyl Base-5-phenyl-1,3,4-oxadiazole, 0.55g (4mmol) anhydrous potassium carbonate, 1mmol PEG-400 and 60 mL acetone, stirred and refluxed for 2h; after cooling, distilled off the solvent and precipitated a solid ; Recrystallized with DMF-water to obtain light yellow solid target 2-(5-phenyl-1,3,4-oxadiazole-2-methylthio)-5-(2-hydroxyphenylmethyleneamino )-1,3,4-thiadiazole 1.22g, yield 51.5%, melting point 191.8-193.7°C. The obtained product is designated as a.

Example 2:

A method for preparing Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, the preparation conditions, method and conditions are basically the same as in Example 1, except that: The raw material is 2-chloromethyl-5-p-fluorophenyl-1,3,4-oxadiazole, and the target product is 2-(5-p-fluorophenyl-1,3,4-oxadiazole- 2-methylthio)-5-(2-hydroxyphenylmethyleneamino)-1,3,4-thiadiazole. The obtained product is designated as b.

Example 3:

A method for preparing Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, the preparation conditions, method and conditions are basically the same as in Example 1, except that: The raw material is 2-chloromethyl-5-o-bromophenyl-1,3,4-oxadiazole, and the target product is 2-(5-o-bromophenyl-1,3,4-oxadiazole- 2-methylthio)-5-(2-hydroxyphenylmethyleneamino)-1,3,4-thiadiazole. The obtained product is designated as c.

Example 4:

A method for preparing Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, the preparation conditions, method and conditions are basically the same as in Example 1, except that: The raw material is 2-chloromethyl-5-p-methoxyphenyl-1,3,4-oxadiazole, and the target product is 2-(5-p-methoxyphenyl-1,3,4-oxadiazole Azole-2-methylthio)-5-(2-hydroxyphenylmethyleneamino)-1,3,4-thiadiazole. The obtained product is designated as d.

Embodiment 5:

A method for preparing Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, the preparation conditions, method and conditions are basically the same as in Example 1, except that: The raw material is 2-chloromethyl-5-m-nitrophenyl-1,3,4-oxadiazole, and the target product is 2-(5-m-nitrophenyl-1,3,4-oxadiazole Azole-2-methylthio)-5-(2-hydroxyphenylmethyleneamino)-1,3,4-thiadiazole. The obtained product is designated as e.

Embodiment 6:

A method for preparing Schiff base derivatives based on 1,3,4-thiadiazole and 1,3,4-oxadiazole, the preparation conditions, method and conditions are basically the same as in Example 1, except that: The raw material is 2-chloromethyl-5-p-nitrophenyl-1,3,4-oxadiazole, and the target product is 2-(5-p-nitrophenyl-1,3,4-oxadiazole Azole-2-methylthio. The obtained product is designated as f.

The in vitro screening test of the anti-tumor biological activity prepared: the sample was dissolved in DMSO, the concentration of the test compound was 5×10 ^-5 mol/L, and the drug was treated for 48 hours. -7. Proliferation inhibition rate of human liver cancer cell SMMC-7721 and human lung cancer cell A549.

Test results:

1) The physical data of the product are shown in Table 1:

Table 1 compound physical form recrystallization solvent Melting point/℃ Yield % a yellow powder DMF-water 191.8～193.7 51.5 b yellow powder DMF-water 183.5～185.6 44.0 c yellow powder DMF-water 210.1～212.0 40.2 d yellow powder DMF-water 159.7～161.5 53.7 e yellow powder DMF-water 224.6～226.5 41.9 f yellow powder DMF-water 184.8～186.9 49.2

2) The elemental analysis value (calculated value) of the product is shown in Table 2:

Table 2

3) The infrared spectrum (IR) data of the product are shown in Table: 3:

table 3 compound IR(cm ^-1 ) a 3455(OH),1620(C=N),1450(C=C),1273(COC),1068(CS) b 3454(OH), 1624(C=N), 1496(C=C), 1235(COC), 1085(CS) c 3455(OH),1620(C=N),1450(C=C),1273(COC),1068(CS) d 3444(OH), 1617(C=N), 1502(C=C), 1263(COC), 1084(CS) e 3416(OH),1618(C=N),1527(C=C),1348(COC),1152(CS) f 3413(OH),1618(C=N),1517(C=C),1186(COC),1087(CS)

4) The ¹ HNMR data of the product are shown in Table 4:

Table 4

5) The proliferation inhibition rate of the product is shown in Table 5:

table 5

 The test results show that the anticancer drug has a good inhibitory effect on tumor cell proliferation and has potential application prospects.

The above content is only a representative embodiment of the present invention, and does not limit the present invention in any form. All simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention still belong to the technical solution of the present invention In the range. the

Claims (5)

1. Shiff base derivative based on 1,3,4-thiadiazoles and 1,3,4-oxadiazole, it is characterized in that: described derivative has the following chemical structure formula:

In the structural formula: R is the aromatic group of C1-6 alkyl, C3-8 cycloalkyl or C5-14; wherein aromatic group is by being replaced by the group of 1-3 hydroxyl, nitro, halogen atom, cyano group, C1-6 alkoxyl group or C1-6 alkyl; also can be the amino that is replaced by one or two group in C1-6 alkyl, C1-6 alkyl sulphonyl and the C1-6 alkyl-carbonyl and replace, described halogen atom is fluorine, chlorine, bromine or iodine atom.

2. one kind according to claim 1 based on 1,3,4-thiadiazoles and 1,3, the preparation method of the Shiff base derivative of 4-oxadiazole, it is characterized in that: be solvent with acetone, PEG-400 is catalyzer, in the presence of acid binding agent, by 2-sulfydryl-5-(2-hydroxy phenyl methylene amino)-1,3,4-thiadiazoles and 1,3,4-oxadiazole analog derivative carries out the condensation reaction preparation, concrete grammar is: with 2-sulfydryl-5-(2-hydroxy phenyl methylene amino)-1,3,4 thiadiazoles, 1,3,4-oxadiazole analog derivative, the PEG-400 catalyzer, acetone solvent and acid binding agent mix and stir, back flow reaction, and the reaction times is 2-5h; After the cooling, steam solvent, separate out solid; With DMF-water recrystallization, can make target compound.

3. described based on 1,3,4-thiadiazoles and 1 according to claim 2, the preparation method of the Shiff base derivative of 3,4-oxadiazole is characterized in that: described 1,3,4-oxadiazole analog derivative is 2-chloromethyl-5-phenyl-1,3, the 4-oxadiazole, 2-chloromethyl-5-fluorophenyl-1,3,4-oxadiazole, 2-chloromethyl-5-o-bromophenyl-1,3, the 4-oxadiazole, 2-chloromethyl-5-p-methoxyphenyl-1,3,4-oxadiazole, 2-chloromethyl-5-m-nitro base-1,3,4-oxadiazole or 2-chloromethyl-5-p-nitrophenyl-1,3,4-oxadiazole, 2-sulfydryl-5-(2-hydroxy phenyl methylene amino)-1,3, the mol ratio of 4 thiadiazoles and 1,3,4-oxadiazole analog derivative is 1-1.2:1, PEG-400 and 1, the mol ratio of 3,4-oxadiazole analog derivative is 1-2:4, acetone solvent and 1, the amount ratio of 3,4-oxadiazole analog derivative is 1 mmole: 10-15mL.

4. described based on 1 according to claim 2,3,4-thiadiazoles and 1,3, the preparation method of the Shiff base derivative of 4-oxadiazole is characterized in that: described acid binding agent is salt of wormwood, triethylamine, potassium hydroxide or sodium hydroxide, and acid binding agent and 2-chloromethyl-5-replaces-1, the mol ratio of 3,4-oxadiazole is 0.6-2:1.

5. one kind according to claim 1 based on 1,3,4-thiadiazoles and 1,3, the application of the Shiff base derivative of 4-oxadiazole, it is characterized in that: for the preparation of antitumor medicine composition, especially for the pharmaceutical composition of the anti-liver cancer of preparation, cancer of the stomach, lung cancer, mammary cancer, prostate cancer, ovarian cancer, cervical cancer, carcinoma of the pancreas, the rectum cancer, lymphatic cancer, esophagus cancer, oral carcinoma, nasopharyngeal carcinoma or skin carcinoma.