A 1,3,4-oxadiazole derivative containing a biphenyl unit, and a preparation method and application thereof

Abstract

The application discloses a 1,3,4-oxadiazole derivative containing a biphenyl unit and a preparation method and application thereof, a structural formula of the derivative is shown as formula I, and the preparation method is that an oxadiazole molecule containing a phenoxy (sulfone) methyl is subjected to a substitution reaction with 2-bromo-4'-phenyl phenylethanone in a solvent containing potassium carbonate to obtain a target compound. The 1,3,4-oxadiazole derivative containing the biphenyl unit has obvious inhibiting effects on human pancreatic cancer cells (PANC-1) and human hepatoma cells (HepG2), and can be used as a potential new type of antitumor candidate drug molecule.

Description

Technical Field

[0001] This invention relates to a compound, and more particularly to a 1,3,4-oxadiazole derivative containing a biphenyl unit, its preparation method, and its application. Background Technology

[0002] Malignant tumors pose a serious threat to human health. Statistics show that my country has 4.57 million new cancer patients and 3 million cancer deaths annually, accounting for 23.7% and 30% of global cancer cases, respectively. Meanwhile, the incidence and mortality rates of malignant tumors in my country are showing an upward trend year by year. Currently, drugs are the main treatment for cancer, but traditional chemotherapy drugs often have drawbacks such as significant toxic side effects and easy development of drug resistance, severely limiting the clinical application of anti-tumor drugs. Therefore, the development of new and highly effective anti-tumor drugs is urgently needed. Summary of the Invention

[0003] Objectives of the Invention: The first objective of this invention is to provide a 1,3,4-oxadiazole derivative containing a biphenyl unit with antitumor activity; the second objective of this invention is to provide a method for preparing the 1,3,4-oxadiazole derivative containing a biphenyl unit; and the third objective of this invention is to provide applications of the 1,3,4-oxadiazole derivative containing a biphenyl unit.

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

[0005]

[0006] Wherein, R is a monosubstituted, disubstituted, or trisubstituted group, the monosubstituted group being methyl, methoxy, or halogen; the disubstituted group being a disubstituted methyl or disubstituted halogen; the trisubstituted group being a trisubstituted halogen; and Z is an oxygen or sulfone group.

[0007] Preferably, the position of the disubstituent is a di-meta substitution or an 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; Z is an oxygen or sulfone fragment.

[0009] Preferably, the compound has the following structural formula:

[0010]

[0011]

[0012] The method for preparing the 1,3,4-oxadiazole derivative containing a biphenyl unit according to the present invention includes the following steps: 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 synthetic route is as follows:

[0013] The synthesis 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 application of the 1,3,4-oxadiazole derivative containing a biphenyl unit described in this invention in the preparation of antitumor cell drugs.

[0019] The tumor cells are human pancreatic cancer cells (PANC-1) or human liver cancer 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 unit 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 novel anti-tumor drug candidate molecule; (2) The preparation method is novel and efficient, easy to operate, and the raw materials are readily available. Attached Figure Description

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

[0022] Figure 2 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 1;

[0023] Figure 3 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 1;

[0024] Figure 4 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 2;

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

[0026] Figure 6 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 3;

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

[0028] Figure 8 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 4;

[0029] Figure 9 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 4;

[0030] Figure 10 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 5;

[0031] Figure 11 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 5;

[0032] Figure 12 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 6;

[0033] Figure 13 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 6;

[0034] Figure 14 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 7;

[0035] Figure 15 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 7;

[0036] Figure 16 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 8;

[0037] Figure 17 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 8;

[0038] Figure 18 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 9;

[0039] Figure 19 High-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 9;

[0040] Figure 20The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 10;

[0041] Figure 21 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 10;

[0042] Figure 22 The 1H NMR spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 11;

[0043] Figure 23 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 11;

[0044] Figure 24 The proton NMR spectrum of the 1,3,4-oxadiazole derivative containing a biphenyl unit prepared in Example 12;

[0045] Figure 25 The high-resolution mass spectrum of the 1,3,4-oxadiazole derivative containing biphenyl units prepared in Example 12 is shown. Detailed Implementation

[0046] The technical solution of the present invention will be further described below with reference to the embodiments.

[0047] Example 1

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

[0049]

[0050] The synthetic route for 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-oxadiazol-2-thiol (429 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for about 5 h. After the reaction was completed by TLC (petroleum ether:ethyl acetate volume ratio = 4:1), potassium carbonate was removed by filtration, and the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to give the target product L1 as a yellow solid.

[0053] The target compound L1 is a yellow solid with a yield of 58%; mp1 10℃; 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] + calcd for C 25 H 22 N2O3S:431.1424,found:431.1426( Figure 3 ).

[0054] Example 2

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

[0056]

[0057] The synthetic route for 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-oxadiazol-2-thiol (403 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain the target product L2 as a yellow solid.

[0060] The target compound L2 was a yellow solid with a yield of 60%; mp 146℃. 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] + calcd for C 24 H 20 N2O3S:417.1267,found:417.1264( Figure 5 ).

[0061] Example 3

[0062] The present invention relates to a 1,3,4-oxadiazol derivative containing a biphenyl unit, R = 3-methoxy. Its chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-(((3-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and its English name is 1-((1,1'-biphenyl-4-yl)-2-((5-((3-methoxyphenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, with the following structural formula;

[0063]

[0064] The synthetic route for 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-oxadiazol-2-thiol (432 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for about 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to give the target product L3 as a yellow solid.

[0067] The target compound L3 was a yellow solid with a yield of 57%; mp 126℃; 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] + calcd for C 24 H 20 N2O4S:433.1217,found:433.1215( Figure 7 ).

[0068] Example 4

[0069] The present invention relates to a 1,3,4-oxadiazol derivative containing a biphenyl unit, where R = 3-chloro. Its chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-(((3-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and its English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((3-chlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, with the following structural formula;

[0070]

[0071] The synthetic route for 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-oxadiazol-2-thiol (441 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain the target product L4 as a yellow solid.

[0074] The target compound L4 is a yellow solid with a yield of 55%; mp 115℃; 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] + calcd for C 23 H 17 ClN2O3S:437.0721,found:437.0722( Figure 9 ).

[0075] Example 5

[0076] The present invention relates to a 1,3,4-oxadiazol derivative containing a biphenyl unit, R = 3,5-dichloro. Its 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, and its 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, with the following structural formula;

[0077]

[0078] The synthetic route for 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-oxadiazol-2-thiol (503 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate volume ratio = 5:1) to give the white solid target product L5.

[0081] The target compound L5 was a white solid with a yield of 53%; mp 153℃; 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)( Figure 10 ); HRMS(ESI)m / z[M+H] + calcdfor C 23 H 16 Cl2N2O3S:471.0332,found:471.0336( Figure 11 ).

[0082] Example 6

[0083] The present invention relates to a 1,3,4-oxadiazol derivative containing a biphenyl unit, R = 6-methyl. Its chemical name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((o-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and its English name is 1-((1,1'-biphenyl)-4-yl)-2-((5-((o-tolyloxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, with the following structural formula;

[0084]

[0085] The synthetic route for 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-oxadiazol-2-thiol (403 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for about 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to give the target product L6 as a yellow solid.

[0088] The target compound L6 was a yellow solid with a yield of 53%; mp 140℃; 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)( Figure 12 ); HRMS(ESI)m / z[M+H] + calcd for C 24 H 20N2O3S:417.1267,found:417.1264( Figure 13 ).

[0089] Example 7

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

[0091]

[0092] The synthetic route for 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-oxadiazol-2-thiol (432 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain the target product L7 as a yellow solid.

[0095] The target compound L7 was a yellow solid with a yield of 52%; mp 132℃; 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)( Figure 14); HRMS(ESI)m / z[M+H] + calcd for C 24 H 20 N2O4S:433.1217,found:433.1215( Figure 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 the chemical name 1-((1,1'-biphenyl)-4-yl)-2-((5-(((2,4,6-trichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the English name 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4,6-trichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, with the following structural formula;

[0098]

[0099] The synthetic route for 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-oxadiazol-2-thiol (566 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain the target product L8 as a yellow solid.

[0102] The target compound L8 was a yellow solid with a yield of 52%; mp 170℃; 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)( Figure 16 ); HRMS(ESI)m / z[M+H] + calcd for C 23 H 15 Cl3N2O3S:504.9942,found:504.9946( Figure 17 ).

[0103] Example 9

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

[0105]

[0106] The synthetic route for 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-oxadiazol-2-thiol (441 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain the white solid target product L9.

[0109] The target compound L9 was a white solid with a yield of 54%; mp 146℃. 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)( Figure 18 ); HRMS(ESI)m / z[M+H] + calcd for C 23 H 17 ClN2O3S:437.0721,found:437.0724( Figure 19 ).

[0110] Example 10

[0111] The 1,3,4-oxadiazol derivative containing a biphenyl unit of the present invention, R = 2,4-dichloro, has the chemical name 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, and the English name 1-((1,1'-biphenyl)-4-yl)-2-((5-((2,4-dichlorophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio)ethan-1-one, with the following structural formula;

[0112]

[0113] The synthetic route for 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-oxadiazol-2-thiol (503 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain the target product L10 as a yellow solid.

[0116] The target compound L10 was a yellow solid with a yield of 59%; mp 145℃; 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)( Figure 20 ); HRMS(ESI)m / z[M+H] + calcd for C 23 H 16 Cl2N2O3S:471.0332,found:471.0333( Figure 21 ).

[0117] Example 11

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

[0119]

[0120] The synthetic route for 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-oxadiazol-2-thiol (441 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for approximately 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to obtain the target product L11 as a yellow solid.

[0123] The target compound L11 is a yellow solid with a yield of 58%; mp 184℃; 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)( Figure 22 ); HRMS(ESI)m / z[M+H] + calcd for C 23 H 17 ClN2O3S:437.0721,found:437.0724( Figure 23 ).

[0124] Example 12

[0125] The 1,3,4-oxadiazol derivative containing a biphenyl unit of the present invention, R = 4-chloro, has the chemical name 1-((1,1'-biphenyl)-4-yl)-2-((5-((((4-chlorophenyl)sulfonyl)methyl)-1,3,4-oxadiazol-2-yl)thio)et han-1-one, and the English name 1-((1,1'-biphenyl)-4-yl)-2-((5-((((4-chlorophenyl)sulfonyl)methyl)-1,3,4-oxadiazol-2-yl)thio)et han-1-one, with the following structural formula;

[0126]

[0127] The synthetic route for 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-oxadiazol-2-thiol (528 mg, synthesized according to Arabian Journal of Chemistry, 2024, 17:105455) were added to acetonitrile (35 mL) and the mixture was heated to reflux at 85 °C for about 5 h. The reaction was monitored by TLC (petroleum ether:ethyl acetate volume ratio = 4:1) until completion. After removing potassium carbonate by filtration, the product was separated by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1) to give the white solid target product L12.

[0130] The target compound L12 was a white solid with a yield of 52%; mp12 ℃; 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)( Figure 24 ); HRMS(ESI)m / z[M+H]+calcd for C 23 H 17 ClN2O4S2:485.0391,found:485.0389( Figure 25 ).

[0131] Application performance testing

[0132] In vitro antitumor activity assay: The inhibitory effect of the synthesized target compound at a concentration of 100 μmol / L on human pancreatic cancer cells (PANC-1) and human liver cancer cells (HepG2) was determined using the CCK 8 assay. Cells were seeded at a density of 7000 cells per well in 96-well plates, with 100 μL of complete culture medium added to each well. The edges of the 96-well plates were filled with PBS and incubated at 37°C in 90% humidity and 5% CO2 for 24 h until the cells covered the bottom of the 96-well plates. The drugs synthesized in Examples 1-12 were diluted to 100 μmol / L with DMEM medium containing 10% serum. 5-Fluorouracil was used as a positive control. Three replicates were set up, with 100 μL of diluent added to each well, and incubated for 48 h. The culture medium was then replaced with 100 μL of DMEM containing 10 μL of CCK 8 dye, and incubated for 2 h. The absorbance at 450 nm was measured using a microplate reader. The cell inhibition rate was calculated based on the measured absorbance. The inhibition rate was calculated using the formula: (OD of negative control group - OD of drug-treated group) / (OD of negative control group - OD of blank group) * 100%. The test results are shown in Table 1.

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

[0134] Compound numbering 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] Table 1 shows that the inhibitory effect of the target molecules on human pancreatic cancer cells (PANC-1) at a concentration of 100 μmol / L was generally better than that on human liver cancer cells (HepG2). Specifically, target molecules L5 and L6 achieved inhibition rates of 79.1% and 84.4% against human pancreatic cancer cells (PANC-1), respectively, which were superior to the control drug 5-fluorouracil (78.8%). Meanwhile, compound L3 showed strong inhibitory activity against liver cancer cells (HepG2), with an inhibition rate of 56.1%. These activity data fully demonstrate that the 1,3,4-oxadiazole derivatives containing biphenyl units have significant inhibitory activity against human pancreatic cancer cells and human liver cancer cells, and can be developed as candidate molecules for novel antitumor drugs.

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 monosubstituted, disubstituted, or trisubstituted group, the monosubstituted group being methyl, methoxy, or halogen; the disubstituted group being a disubstituted methyl or a disubstituted halogen, wherein the disubstituted halogen is not 3,5-dichloro; the trisubstituted group being a trisubstituted halogen; and Z being an oxygen or sulfone group.

2. The 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 1, characterized in that, The position of the disubstituent is either meta-substitution or ortho- and para-substitution.

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

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: , , , , , , , , , or .

5. A method for preparing a 1,3,4-oxadiazole derivative containing a biphenyl unit as described in any one of claims 1 to 4, characterized in that, Includes the following steps: Compound 1 and compound 2 undergo a substitution reaction in a solvent to give the 1,3,4-oxadiazole derivative I containing a biphenyl unit. The synthetic route is as follows: The synthesis route is as follows: 。 6. The method for preparing the 1,3,4-oxadiazole derivative containing a biphenyl unit according to claim 5, characterized in that, The temperature for the substitution reaction is 80~90℃.

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

9. The use of a 1,3,4-oxadiazole derivative containing a biphenyl unit as described in any one of claims 1 to 4 in the preparation of an antitumor cell drug.

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

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