1, 3, 4-oxadiazole derivative containing biphenyl unit as well as preparation method and application of 1, 3, 4-oxadiazole derivative

Abstract

The invention discloses a 1, 3, 4-oxadiazole derivative containing a biphenyl unit and a preparation method and application thereof.The structural formula of the derivative is shown in the formula I. The preparation method of the derivative comprises the step that oxadiazole molecules containing phenoxy (sulfone) methyl and 2-bromo-4 '-phenyl acetophenone are subjected to a substitution reaction in a solvent containing potassium carbonate, and a target compound is obtained. The 1, 3, 4-oxadiazole derivative containing the biphenyl unit has an obvious inhibition effect on human pancreatic cancer cells (PANC-1) and human liver cancer cells (HepG2), and can be used as a potential novel anti-tumor candidate drug molecule. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound, in particular to a 1,3,4-oxadiazole derivative containing a biphenyl unit and a preparation method and application thereof. Background Art

[0002] Malignant tumors pose a serious threat to human health. According to statistics, there are 4.57 million new cancer patients and 3 million deaths in my country each year, accounting for 23.7% and 30% of global cancer patients respectively. At the same time, the incidence and mortality of malignant tumors in my country are also increasing year by year. At present, drugs are the main treatment for tumors, but traditional chemotherapy drugs are often accompanied by drawbacks such as large toxic side effects and easy drug resistance during use, which seriously limits the clinical application of anti-tumor drugs. Therefore, it is urgent to develop new and efficient anti-tumor drugs. Summary of the invention

[0003] Purpose of the invention: The first purpose of the present invention is to provide a 1,3,4-oxadiazole derivative containing a biphenyl unit having anti-tumor activity; the second purpose of the present invention is to provide a method for preparing the 1,3,4-oxadiazole derivative containing a biphenyl unit; the third purpose of the present invention is to provide the application of the 1,3,4-oxadiazole derivative containing a biphenyl unit.

[0004] Technical solution: The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention has a structural formula as shown in Formula I:

[0005]

[0006] Wherein, R is a mono-, di- or tri-substituent, the mono-substituent is methyl, methoxy or halogen; the di-substituent is di-substituted methyl or di-substituted halogen; the tri-substituent is tri-substituted halogen; and Z is oxygen or a sulfone fragment.

[0007] Preferably, the positions of the disubstituted groups are di-meta-substitution or di-ortho- and para-substitution.

[0008] Preferably, R is 3,5-dimethyl, 4-methyl, 3-methoxy, 3-chloro, 3,5-dichloro, 6-methyl, 4-methoxy, 2,4,6-trichloro, 4-chloro, 2,4-dichloro or 2-chloro; and Z is oxygen or a sulfone fragment.

[0009] Preferably, the structural formula of the compound is as follows:

[0010]

[0011]

[0012] The method for preparing the biphenyl-unit-containing 1,3,4-oxadiazole derivative of the present invention comprises the following steps: Compound 1 and Compound 2 undergo a substitution reaction in a solvent to obtain the biphenyl-unit-containing 1,3,4-oxadiazole derivative I. The synthesis route is as follows:

[0013] The synthetic route is as follows:

[0014]

[0015] Preferably, the temperature of the substitution reaction is 80-90°C.

[0016] Preferably, the solvent is acetonitrile.

[0017] Preferably, the solvent also includes potassium carbonate.

[0018] The invention discloses an application of the 1,3,4-oxadiazole derivative containing biphenyl units in the preparation of anti-tumor cell drugs.

[0019] The tumor cells are human pancreatic cancer cells (PANC-1) or human hepatoma cells (HepG2).

[0020] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The 1,3,4-oxadiazole derivative containing biphenyl units has a significant inhibitory effect on human pancreatic cancer cells (PANC-1) and human liver cancer cells (HepG2), and can be used as a potential new anti-tumor candidate drug molecule; (2) The preparation method has a novel and efficient reaction, simple operation, and readily available raw materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the synthetic route diagram of the present invention;

[0022] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 1;

[0023] Figure 3 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 1;

[0024] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 2;

[0025] Figure 5 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 2;

[0026] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 3;

[0027] Figure 7 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 3;

[0028] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 4;

[0029] Fig. 9 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 4;

[0030] Fig.10 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 5;

[0031] Fig.11 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 5;

[0032] Fig.12 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 6;

[0033] Fig.13 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 6;

[0034] Fig.14 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 7;

[0035] Fig.15 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 7;

[0036] Fig.16 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 8;

[0037] Fig.17 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 8;

[0038] Fig.18 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 9;

[0039] Fig.19 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 9;

[0040] Fig. 20This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 10;

[0041] Fig.21 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 10;

[0042] Fig. 22 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 11;

[0043] Fig.23 This is a high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 11;

[0044] Fig.24 This is the hydrogen nuclear magnetic resonance spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 12;

[0045] Fig.25 This is the high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 12. DETAILED DESCRIPTION

[0046] The technical solution of the present invention is further described below in conjunction with embodiments.

[0047] Example 1

[0048] The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention, R = 3,5-dimethyl, has a chemical name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3,5-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, an English name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3,5-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and has the following structural formula:

[0049]

[0050] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3,5-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0051]

[0052] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((3,5-dimethylphenoxy)methyl)-1,3,4-oxadiazole-2-thiol (429 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, potassium carbonate was removed by suction filtration, and the target product L1 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0053] The target compound L1 is a yellow solid with a yield of 58%; mp 110°C; 1 H NMR (400MHz, CDCl3) δ8.16–8.07(m,2H),7.79–7.71(m,2H),7.70–7.62(m,2H),7.55–7.47(m,2H),7. 47–7.41(m,1H),6.69(s,1H),6.65(s,2H),5.24–5.18(m,2H),5.01–4.95(m,2H),2.35–2.28(m,6H)( Figure 2 ); HRMS (ESI) m / z [M+H] + Calculate for C 25 H 22 N2O3S:431.1424,found:431.1426( Figure 3 ).

[0054] Example 2

[0055] The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention, R = 4-methyl, the chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((p-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, the English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((p-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the structural formula is as follows:

[0056]

[0057] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((p-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0058]

[0059] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((p-tolyloxy)methyl)-1,3,4-oxadiazole-2-thiol (403 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L2 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0060] The target compound L2 is a yellow solid with a yield of 60%; mp 146°C; 1 H NMR (400MHz, CDCl3) δ8.15–8.10(m,2H),7.78–7.73(m,2H),7.69–7.64(m,2H),7.54–7.48(m,2H) ,7.48–7.42(m,1H),7.16–7.10(m,2H),6.95–6.90(m,2H),5.22(s,2H),4.99(s,2H),2.32(s,3H)( Figure 4 ); HRMS (ESI) m / z [M+H] + Calculate for C 24 H 20 N2O3S:417.1267,found:417.1264( Figure 5 ).

[0061] Example 3

[0062] The 1,3,4-oxadiazole derivative containing biphenyl units of the present invention, R = 3-methoxy. The chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((3-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, the English name is 1-((1,1'-biphenyl-4-yl)-2-((5-((3-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the structural formula is as follows:

[0063]

[0064] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0065]

[0066] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((3-methoxyphenoxy)methyl)-1,3,4-oxadiazole-2-thiol (432 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L3 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0067] The target compound L3 is a yellow solid with a yield of 57%; mp 126°C; 1 H NMR (400MHz, CDCl3) δ8.14–8.10(m,2H),7.78–7.73(m,2H),7.69–7.64(m,2H),7.54–7.48(m,2H),7 .48–7.42(m,1H),7.23(t,J=8.1Hz,1H),6.64–6.58(m,3H),5.23(s,2H),4.99(s,2H),3.81(s,3H)( Figure 6 ); HRMS (ESI) m / z [M+H] + Calculate for C 24 H 20 N2O4S:433.1217,found:433.1215( Figure 7 ).

[0068] Example 4

[0069] The 1,3,4-oxadiazole derivative containing biphenyl units of the present invention, R = 3-chloro, has a chemical name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, an English name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and has the following structural formula:

[0070]

[0071] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0072]

[0073] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((3-chlorophenoxy)methyl)-1,3,4-oxadiazole-2-thiol (441 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L4 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0074] The target compound L4 is a yellow solid with a yield of 55%; mp 115°C; 1 H NMR (400MHz, CDCl3) δ8.14–8.10(m,2H),7.78–7.73(m,2H),7.68–7.64(m,2H),7.54–7.48(m,2H),7.48–7.4 2(m,1H),7.28–7.23(m,1H),7.06–7.02(m,2H),6.92(ddd,J=8.4,2.4,1.0Hz,1H),5.24(s,2H),5.00(s,2H)( Figure 8 ); HRMS (ESI) m / z [M+H] + Calculate for C 23 H 17 ClN2O3S:437.0721,found:437.0722( Fig. 9 ).

[0075] Example 5

[0076] The 1,3,4-oxadiazole derivative containing biphenyl units of the present invention, R = 3,5-dichloro. The chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((3,5-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, the English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((3,5-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the structural formula is as follows:

[0077]

[0078] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((3,5-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0079]

[0080] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((3,5-dichlorophenoxy)methyl)-1,3,4-oxadiazole-2-thiol (503 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L5 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a white solid.

[0081] The target compound L5 is a white solid with a yield of 53%; mp 153°C; 1 H NMR (400MHz, CDCl3) δ8.12(d,J=8.0Hz,2H),7.76(d,J=8.0Hz,2H),7.66(d,J=7.5Hz,2 H),7.48(dt,J=25.4,7.4Hz,3H),7.05(s,1H),6.94(s,2H),5.22(s,2H),5.00(s,2H)( Fig.10 ); HRMS (ESI) m / z [M+H] + calcdfor C 23 H 16 Cl2N2O3S:471.0332,found:471.0336( Fig.11 ).

[0082] Example 6

[0083] The 1,3,4-oxadiazole derivative containing biphenyl units of the present invention, R = 6-methyl, has a chemical name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((o-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, an English name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((o-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and has the following structural formula:

[0084]

[0085] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((o-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0086]

[0087] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((o-tolyloxy)methyl)-1,3,4-oxadiazole-2-thiol (403 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L6 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0088] The target compound L6 is a yellow solid with a yield of 53%; mp 140°C; 1 H NMR (400MHz, CDCl3) δ8.15–8.11(m,2H),7.78–7.74(m,2H),7.69–7.64(m,2H),7.55–7.48(m,2H),7 .48–7.42(m,1H),7.22–7.16(m,2H),6.96(t,J=7.6Hz,2H),5.26(s,2H),5.00(s,2H),2.27(s,3H)( Fig.12 ); HRMS (ESI) m / z [M+H] + Calculate for C 24 H 20N2O3S:417.1267,found:417.1264( Fig.13 ).

[0089] Example 7

[0090] The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention, R=4-methoxy, has a chemical name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((4-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, an English name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((4-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and has the following structural formula:

[0091]

[0092] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((4-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0093]

[0094] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((4-methoxyphenoxy)methyl)-1,3,4-oxadiazole-2-thiol (432 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L7 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0095] The target compound L7 is a yellow solid with a yield of 52%; mp 132°C; 1 H NMR (400MHz, CDCl3) δ8.13–8.08(m,2H),7.77–7.72(m,2H),7.68–7.63(m,2H),7.50(dd,J=8.3,6.5Hz ,2H),7.47–7.41(m,1H),6.99–6.93(m,2H),6.89–6.83(m,2H),5.19(s,2H),4.98(s,2H),3.78(s,3H)( Fig.14); HRMS (ESI) m / z [M+H] + Calculate for C 24 H 20 N2O4S:433.1217,found:433.1215( Fig.15 ).

[0096] Example 8

[0097] The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention, R=2,4,6-trichloro, has a chemical name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4,6-trichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)etha n-1-one, an English name of 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4,6-trichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)etha n-1-one, and has the following structural formula:

[0098]

[0099] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4,6-trichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0100]

[0101] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((2,4,6-trichlorophenoxy)methyl)-1,3,4-oxadiazole-2-thiol (566 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L8 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0102] The target compound L8 is a yellow solid with a yield of 52%; mp 170°C; 1H NMR (400MHz, CDCl3) δ8.13(d,J=8.2Hz,2H),7.76(d,J=8.2Hz,2H),7.67(dd,J=8.2,1.4Hz, 2H),7.51(dd,J=8.1,6.7Hz,2H),7.48–7.42(m,1H),7.35(s,2H),5.23(s,2H),5.02(s,2H)( Fig.16 ); HRMS (ESI) m / z [M+H] + Calculate for C 23 H 15 Cl3N2O3S:504.9942,found:504.9946( Fig.17 ).

[0103] Example 9

[0104] The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention, R = 4-chloro, the chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((4-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, the English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((4-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the structural formula is as follows:

[0105]

[0106] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((4-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0107]

[0108] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((4-chlorophenoxy)methyl)-1,3,4-oxadiazole-2-thiol (441 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L9 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a white solid.

[0109] The target compound L9 is a white solid with a yield of 54%; mp 146°C; 1 H NMR (400MHz, CDCl3) δ8.14–8.09(m,2H),7.78–7.73(m,2H),7.69–7.63(m,2H),7.55–7.48(m,2H),7 .48–7.42(m,1H),7.29(d,J=2.2Hz,1H),7.27(s,1H),6.99–6.94(m,2H),5.22(s,2H),4.99(s,2H)( Fig.18 ); HRMS (ESI) m / z [M+H] + Calculate for C 23 H 17 ClN2O3S:437.0721,found:437.0724( Fig.19 ).

[0110] Example 10

[0111] The 1,3,4-oxadiazole derivative containing biphenyl units of the present invention, R = 2,4-dichloro, the chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, the English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the structural formula is as follows:

[0112]

[0113] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0114]

[0115] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((2,4-dichlorophenoxy)methyl)-1,3,4-oxadiazole-2-thiol (503 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L10 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0116] The target compound L10 is a yellow solid with a yield of 59%; mp 145°C; 1 H NMR (400MHz, CDCl3) δ8.14–8.09(m,2H),7.78–7.73(m,2H),7.69–7.63(m,2H),7.54–7.48(m,2H),7.48–7.42 (m,1H),7.41(d,J=2.5Hz,1H),7.22(dd,J=8.8,2.5Hz,1H),7.06(d,J=8.8Hz,1H),5.30(s,2H),4.99(s,2H)( Fig. 20 ); HRMS (ESI) m / z [M+H] + Calculate for C 23 H 16 Cl2N2O3S:471.0332,found:471.0333( Fig.21 ).

[0117] Embodiment 11

[0118] The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention, R = 2-chloro, the chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((2-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, the English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((2-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the structural formula is as follows:

[0119]

[0120] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-((2-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0121]

[0122] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-((2-chlorophenoxy)methyl)-1,3,4-oxadiazole-2-thiol (441 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L11 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a yellow solid.

[0123] The target compound L11 is a yellow solid with a yield of 58%; mp 184°C; 1 H NMR (400MHz, CDCl3) δ8.12(d,J=8.0Hz,2H),7.76(d,J=8.3Hz,2H),7.66(d,J=7.5Hz,2H),7.51(t,J=7.5Hz,2H),7 .43(dd,J=17.6,7.7Hz,2H),7.25(t,J=7.7Hz,1H),7.11(s,1H),7.01(t,J=7.7Hz,1H),5.32(s,2H),5.00(s,2H)( Fig. 22 ); HRMS (ESI) m / z [M+H] + Calculate for C 23 H 17 ClN2O3S:437.0721,found:437.0724( Fig.23 ).

[0124] Example 12

[0125] The 1,3,4-oxadiazole derivative containing a biphenyl unit of the present invention, R = 4-chloro, the chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-(((4-chlorophenyl)sulfonyl)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one, the English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-(((4-chlorophenyl)sulfonyl)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one, and the structural formula is as follows:

[0126]

[0127] The synthetic route of 1-((1,1'-biphenyl)-4-yl)-2-((5-(((4-chlorophenyl)sulfonyl)methyl)-1,3,4-oxadiazol-2-yl)thio)ethane-1-one is as follows:

[0128]

[0129] 2-Bromo-4'-phenylacetophenone (500 mg), potassium carbonate (753 mg) and 5-(((4-chlorophenyl)sulfonyl)methyl)-1,3,4-oxadiazole-2-thiol (528 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and heated under reflux at 85°C for about 5 h. After the reaction was completed, TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) was used to monitor the reaction. Potassium carbonate was removed by suction filtration, and the target product L12 was obtained by silica gel column chromatography (eluent: petroleum ether: ethyl acetate volume ratio = 5:1) to obtain a white solid.

[0130] The target compound L12 is a white solid with a yield of 52%; mp 122°C; 1 H NMR (400MHz, CDCl3) δ8.11(d,J=8.1Hz,2H),7.77(dd,J=11.9,8.2Hz,4H),7.66(d,J=7.6Hz,2 H),7.58(d,J=8.2Hz,2H),7.51(t,J=7.4Hz,2H),7.48–7.40(m,1H),4.97(s,2H),4.66(s,2H)( Fig.24 ); HRMS(ESI)m / z[M+H]+calcd for C 23 H 17 ClN2O4S2:485.0391,found:485.0389( Fig.25 ).

[0131] Application performance testing

[0132] In vitro anti-tumor activity test method: The inhibitory effect of the synthesized target compound on human pancreatic cancer cells (PANC-1) and human liver cancer cells (HepG2) at a concentration of 100 μmol / L was determined by the CCK 8 method. The cells were inoculated in a 96-well plate at a density of 7000 cells per well, 100 μL of complete medium was added to each well, the edge of the 96-well plate was filled with PBS, and placed in a 37°C incubator with 90% humidity and 5% CO2 for 24 hours until the cells covered the bottom of the 96-well plate. The drugs synthesized in Examples 1 to 12 were diluted to 100 μmol / L with DMEM medium containing 10% serum, 5-fluorouracil was used as a positive control, three replicate wells were set, 100 μL of diluent was added to each well, and incubated for 48 hours. The culture medium was replaced with 100 μL DMEM containing 10 μL CCK 8 dye and incubated for 2 hours. The absorbance at 450 nm was measured using an enzyme reader. The cell inhibition rate was calculated based on the measured absorbance. The inhibition rate was calculated as follows: (OD of negative control group - OD of drug administration group) / (OD of negative control group - OD of blank group)*100%. The test results are shown in Table 1.

[0133] Table 1 Inhibitory effects of compounds L1-L12 on tumor cells at a concentration of 100 μmol / L

[0134] Compound No. PANC-1(%) HepG2(%) L1 63.2±1.7 45.1±3.1 L2 67.4±2.0 / L3 67.5±1.8 56.1±1.5 L4 47.2±1.8 48.7±2.5 L5 79.1±1.7 / L6 84.4±2.2 33.8±2.5 L7 67.3±1.2 44.6±1.9 L8 75.1±1.6 / L9 58.8±0.8 8.5±1.3 L10 47.6±2.9 / L11 16.1±1.8 6.3±1.3 L12 57.9±1.2 14.0±1.2 5-Fluorouracil 78.8±1.2 61.1±2.3

[0135] Note: “ / ” indicates no activity.

[0136] As shown in Table 1, the inhibitory effect of the target molecule on human pancreatic cancer cells (PANC-1) at a concentration of 100 μmol / L is generally better than its inhibitory effect on human liver cancer cells (HepG2). Among them, the inhibitory rates of target molecules L5 and L6 on human pancreatic cancer cells (PANC-1) reached 79.1% and 84.4%, respectively, and the inhibitory effect was better than the control agent 5-fluorouracil (78.8%). At the same time, compound L3 showed strong inhibitory activity on liver cancer cells (HepG2), and its inhibitory effect reached 56.1%. The above activity data fully demonstrate that 1,3,4-oxadiazole derivatives containing biphenyl units have significant inhibitory activity on human pancreatic cancer cells and human liver cancer cells, and can be developed as new anti-tumor drug candidate molecules.

Claims

1. A 1,3,4-oxadiazole derivative containing a biphenyl unit, characterized in that: The structural formula is shown in Formula I: Wherein, R is a mono-, di- or tri-substituent, the mono-substituent is methyl, methoxy or halogen; the di-substituent is di-substituted methyl or di-substituted halogen; the tri-substituent is tri-substituted halogen; and Z is oxygen or a sulfone fragment.

2. The 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 1, characterized in that: The positions of the disubstituted groups are di-meta-substitution or di-ortho- and para-substitution.

3. The 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 1, characterized in that: The R is 3,5-dimethyl, 4-methyl, 3-methoxy, 3-chloro, 3,5-dichloro, 6-methyl, 4-methoxy, 2,4,6-trichloro, 4-chloro, 2,4-dichloro or 2-chloro; and Z is oxygen or a sulfone fragment.

4. The 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 1, characterized in that: The structural formula of the compound is as follows:

5. A method for preparing a 1,3,4-oxadiazole derivative containing a biphenyl unit according to any one of claims 1 to 4, characterized in that: The following steps are involved: Compound 1 and compound 2 undergo a substitution reaction in a solvent to obtain the 1,3,4-oxadiazole derivative I containing a biphenyl unit. The synthesis route is as follows: The synthetic route is as follows:

6. The method for preparing a 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 5, characterized in that: The temperature of the substitution reaction is 80-90°C.

7. The method for preparing a 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 5, characterized in that: The solvent is acetonitrile.

8. The method for preparing a 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 5, characterized in that: The solvent also includes potassium carbonate.

9. Use of the 1,3,4-oxadiazole derivative containing biphenyl units according to any one of claims 1 to 4 in the preparation of anti-tumor cell drugs.

10. The use according to claim 9, characterized in that: The tumor cells are human pancreatic cancer cells or human liver cancer cells.

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