CN111362930A - 1, 2, 4-oxadiazole-pyridine compound and application thereof - Google Patents

1, 2, 4-oxadiazole-pyridine compound and application thereof Download PDF

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CN111362930A
CN111362930A CN202010295587.9A CN202010295587A CN111362930A CN 111362930 A CN111362930 A CN 111362930A CN 202010295587 A CN202010295587 A CN 202010295587A CN 111362930 A CN111362930 A CN 111362930A
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thiophene
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CN111362930B (en
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李增
王敏
武明飞
韩健飞
刘彤彤
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Abstract

The invention discloses a 1, 2, 4-oxadiazole-pyridine compound and application thereof, wherein the structural formula of the 1, 2, 4-oxadiazole-pyridine compound is shown as a formula (A):
Figure DEST_PATH_IMAGE002
r in the formula (A)1Is 4-trifluoromethoxy, 4-ethylbenzene, 4-trifluoromethylbenzene, 4-isopropylbenzene; r2Is 4-nitrobenzene, 4-methoxybenzene, 4-tert-butylbenzene, 2-thiophene, 2-methoxycarbonyl-3-thiophene, 2-trifluoromethoxybenzene, N-acetaminophenyl, 5-chloro-2-thiophene, 4-trifluoromethoxybenzene, 3-chloro-4-fluorobenzene, 4-The 1, 2, 4-oxadiazole-pyridine compound has a good inhibition effect on the kinase GSK-3 β, and can well inhibit the release of NO, so that the compound has the potential to be developed into an effective GSK-3 β inhibitor and an anti-inflammatory drug and become a drug for treating Alzheimer's disease.

Description

1, 2, 4-oxadiazole-pyridine compound and application thereof
Technical Field
The invention belongs to the technical field of pharmacotherapeutics and pharmaceutical chemistry, and particularly relates to a 1, 2, 4-oxadiazole-pyridine compound and application thereof.
Background
Alzheimer's Disease (AD) is an age-related chronic neurodegenerative disease characterized clinically by progressive memory loss and speech impairment. In recent years, the prevalence has increased year by year with the aging of the global population. By 2050, AD is expected to reach 1.3 billion worldwide. However, few clinical drugs are currently used for treating AD, and they can only improve symptoms and delay disease progression. Therefore, the development of new effective anti-AD drugs is urgently required.
Although the pathogenesis of AD has been studied for decades, the exact etiology is unclear, the characteristic features of AD are extracellular amyloid peptide (a β) deposition and intracellular formation of neurofibrillary tangles (NFT) other features include inflammatory mediators, Reactive Oxygen Species (ROS), inflammation and loss of synaptic connectivity GSK-3 β plays a key and central role in the pathogenesis of AD GSK-3 β was originally identified for its role in glycogen metabolism, a proline-directed serine/threonine kinase, widely present in neuronal cells, one of the major players in tau phosphorylation, tau is a microtubule-associated protein with its role in stabilizing microtubules and promoting microtubule assembly, when GSK-3 β hyperphosphorylates tau abnormally, it makes tau unable to bind microtubules, destabilizes microtubules, and dissociated tau accumulate and aggregate in neurons, leading to neurofibrillary tangle formation and neuronal death, studies of automated high-throughput fluorescence imaging systems indicate that increased activity of GSK-353, and increased activity of BACE-related drugs may lead to a decrease in neuronal pro-secretory AD β and thus a significant inhibition of neuronal pro-amyloid receptor activity in the neuronal models of GSK-3 receptor- β -3, which may lead to a decrease in neuronal death, a neuronal apoptosis, a pathogenesis, a decrease, a pathogenesis-related drug, a β -3, a potent inhibitory effect, a decrease in neuronal activation, and a decrease in neuronal activation, a β -3, probably a β -3, a β -.
In recent years, there is increasing evidence that neuroinflammation plays an important role in the pathogenesis of AD, microglia are the main cells that produce inflammatory factors in the brain, Nitric Oxide (NO), tumor necrosis factor (TNF- α) and interleukin 1 β (IL-1 β) can directly induce neuronal apoptosis or enhance local inflammatory response.
Disclosure of Invention
The invention aims to make up the defects of the prior art and provides a 1, 2, 4-oxadiazole-pyridine compound and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
a1, 2, 4-oxadiazole-pyridine compound has a structural formula shown as a formula (A):
Figure BDA0002452067700000021
wherein R is1Is 4-trifluoromethoxy, 4-ethylbenzene, 4-trifluoromethylbenzene, 4-isopropylbenzene; r2Is any one of 4-nitrobenzene, 4-methoxybenzene, 4-tert-butylbenzene, 2-thiophene, 2-methoxycarbonyl-3-thiophene, 2-trifluoromethoxybenzene, N-acetaminophenyl, 5-chloro-2-thiophene, 4-trifluoromethoxybenzene, 3-chloro-4-fluorobenzene, 4-fluorobenzene and 4-bromobenzene.
The preparation route of the 1, 2, 4-oxadiazole-pyridine compound is as follows:
Figure BDA0002452067700000022
the preparation routes are mainly intended to illustrate the invention, but not to limit it.
(1) The main synthesis steps of the compound 4 comprise: firstly, 2-chloro-4-cyanopyridine and various anilines are subjected to nucleophilic substitution reaction, and a crude product is purified by column chromatography to obtain a compound 1, wherein the compound 1 and hydroxylamine hydrochloride are reacted at K2CO3Reacting under the action to generate a compound 2, then reacting the intermediate 2 with 4-nitrobenzoyl chloride to obtain a compound 3, and reducing the compound 3 to obtain an intermediate 4;
(2) and (3) reacting the intermediate 4 with various benzene sulfonyl chlorides in pyridine (room temperature), and performing column chromatography purification to obtain the compounds 5a-5 q. Wherein R1 is 4-trifluoromethoxy, 4-ethylbenzene, 4-trifluoromethylbenzene, 4-isopropylbenzene; r2 is one of 4-nitrobenzene, 4-methoxybenzene, 4-tert-butylbenzene, 2-thiophene, 2-methoxycarbonyl-3-thiophene, 2-trifluoromethoxybenzene, N-acetaminophenyl, 5-chloro-2-thiophene, 4-trifluoromethoxybenzene, 3-chloro-4-fluorobenzene, 4-fluorobenzene and 4-bromobenzene.
The invention also aims to provide application of the 1, 2, 4-oxadiazole-pyridine compound in inhibiting GSK-3 β and anti-inflammatory drugs and application in treating Alzheimer's disease.
Furthermore, the application medicine is any one of injection, tablets, pills, capsules, suspending agents or emulsion.
The invention has the advantages that:
1. the 1, 2, 4-oxadiazole-pyridine compounds have a good inhibition effect on the kinase GSK-3 β, and show that the compounds have the potential to be developed into effective GSK-3 β inhibitors.
2. The 1, 2, 4-oxadiazole-pyridine compounds can well inhibit the release of NO by measuring in BV2 cells induced by LPS, and the compounds can be used as anti-inflammatory drugs.
3. The compound provided by the invention has the potential to be developed into a medicament for treating the Alzheimer disease.
Detailed Description
The technical scheme of the invention is further explained by combining the specific examples as follows:
example 1
Compound 5a synthesis:
Figure BDA0002452067700000031
compound 4(207mg,0.5mmol) was dissolved in 20mL pyridine and stirred on a magnetic stirrer, followed by addition of 4-nitrobenzoyl chloride (557mg,1.5mmol) and stirring at room temperature for 3 hours. The progress of the reaction was checked by TLC. After the reaction, dilute hydrochloric acid aqueous solution was added, and the mixture was placed on ice to precipitate a solid. Suction filtration is carried out, and the solid is dried. Dissolving the crude product in ethyl acetate, adding a proper amount of silica gel, and performing vacuum rotary evaporation to remove the ethyl acetate. Silica gel column chromatography with dichloromethane: purification with methanol (300:1) afforded compound 5a as a pale yellow solid in 68% yield.1H NMR(400MHz,DMSO)TM11.32(s,1H),9.64(s,1H),8.44–8.38(m,2H),8.34(d,J＝5.3Hz,1H),8.16–8.04(m,4H),7.89-7.79(m,2H),7.52(s,1H),7.40(d,J＝8.8Hz,2H),7.36–7.23(m,3H)；13C NMR(101MHz,DMSO)TM175.29,167.02,156.19,150.06,148.58,144.48,141.86,141.77,140.48,134.53,129.58,128.28,124.86,124.01,121.58,121.48,119.49,119.10,118.95,118.54,111.35,108.71；MS(ESI):m/z 599.1[M+H]+。
The chemical formula of compound 5a is as follows:
Figure BDA0002452067700000041
example 2:
synthesis of compound 5 b: the procedure is as in example one, except that the R2 group is replaced with 4-methoxybenzene to give a white solid in 46% yield.1H NMR(400MHz,DMSO)TM10.92(s,1H),9.65(s,1H),8.34(d,J＝5.3Hz,1H),8.05(d,J＝8.8Hz,2H),7.86–7.77(m,4H),7.53(s,1H),7.37(d,J＝8.8Hz,2H),7.33-7.25(m,3H),7.13–7.05(m,2H),3.79(s,3H)；13C NMR(101MHz,DMSO)δ175.43,166.99,162.75,156.19,148.56,142.77,140.50,134.59,130.70,129.42,128.97,121.58,119.10,118.67,117.70,114.60,111.36,108.73,55.65；MS(ESI):m/z 584.1[M+H]+。
Compound 5b has the formula:
Figure BDA0002452067700000042
example 3:
synthesis of compound 5 c:
the procedure is as in example one, except that the R2 group is replaced by 4-tert-butylbenzene to give a white solid in 67% yield.1H NMR(400MHz,DMSO)TM11.05(s,1H),9.65(s,1H),8.35(d,J＝5.3Hz,1H),8.06(d,J＝8.7Hz,2H),7.82(ddd,J＝8.6,6.0,2.6Hz,4H),7.61(d,J＝8.5Hz,2H),7.53(s,1H),7.40(d,J＝8.8Hz,2H),7.30(dd,J＝15.0,7.1Hz,3H),1.25(s,9H)；13C NMR(101MHz,MeOD)δ175.42,167.00,156.37,156.20,148.59,142.69,140.50,136.52,134.58,129.51,126.56,126.37,121.59,119.10,118.52,117.71,111.36,108.71,34.88,30.64；MS(ESI):m/z610.2[M+H]+。
Compound 5c has the formula:
Figure BDA0002452067700000051
example 4:
synthesis of compound 5 d:
the procedure is as in example one, except that the R2 group is replaced with 2-trifluoromethoxybenzene to give a white solid in 51% yield.1H NMR(400MHz,DMSO)TM11.30(s,1H),9.64(s,1H),8.34(d,J＝5.2Hz,1H),8.12–8.03(m,3H),7.85–7.77(m,3H),7.57(dd,J＝20.4,12.6Hz,3H),7.38–7.34(m,2H),7.33–7.26(m,3H).13C NMR(101MHz,DMSO)TM175.39,167.01,156.20,148.57,145.09,142.19,141.76,140.51,135.88,134.58,131.13,131.10,129.42,127.63,121.58,121.12,119.10,118.64,117.91,111.37,108.73.MS(ESI):m/z 638.1[M+H]+。
Compound 5d has the formula:
Figure BDA0002452067700000061
example 5:
synthesis of compound 5 e:
the procedure is as in example one, except that the R2 group is replaced with 3-trifluoromethylbenzene to give a white solid in 58% yield.1H NMR(400MHz,DMSO)TM11.19(s,1H),9.65(s,1H),8.35(d,J＝5.3Hz,1H),8.15(d,J＝7.9Hz,2H),8.07(t,J＝7.7Hz,3H),7.89–7.79(m,3H),7.53(s,1H),7.44–7.39(m,2H),7.34–7.25(m,3H).13C NMR(101MHz,DMSO)TM175.31,167.02,156.20,148.60,141.91,140.49,140.28,134.54,131.26,130.71,130.20,129.57,123.15,121.59,119.49,119.10,118.55,111.35,108.74.MS(ESI):m/z622.0[M+H]+。
Compound 5e has the formula:
Figure BDA0002452067700000062
example 6:
synthesis of compound 5 f:
the procedure is as in example one, except that the R2 group is replaced by 3-acetamidophenyl, giving a white solid in 49% yield.1H NMR(400MHz,DMSO)TM10.94(s,1H),10.33(s,1H),9.64(s,1H),8.34(d,J＝5.3Hz,1H),8.04(d,J＝8.8Hz,2H),7.86–7.78(m,4H),7.74(d,J＝9.0Hz,2H),7.53(s,1H),7.37(d,J＝8.8Hz,2H),7.33–7.26(m,3H),2.05(s,3H)；13C NMR(101MHz,DMSO)TM175.43,169.05,166.99,156.20,148.57,143.51,142.72,141.77,140.51,134.59,132.53,129.41,128.05,121.58,121.50,119.10,118.96,118.75,118.70,117.73,111.36,108.74,24.08；MS(ESI):m/z 611.1[M+H]+。
The chemical formula of compound 5f is as follows:
Figure BDA0002452067700000071
example 7:
synthesis of 5g of Compound:
the procedure is as in example one, except that the R2 group is replaced by 4-trifluoromethoxybenzene to giveWhite solid, yield 53%.1H NMR(400MHz,DMSO)TM11.17(s,1H),9.64(s,1H),8.34(d,J＝5.3Hz,1H),8.10–7.98(m,4H),7.86–7.80(m,2H),7.59(d,J＝8.2Hz,2H),7.53(s,1H),7.43–7.37(m,2H),7.33–7.25(m,3H).13C NMR(101MHz,DMSO)TM175.34,167.02,156.20,151.34,148.57,142.17,141.76,140.49,138.05,134.55,129.53,129.36,121.60,121.56,121.49,121.03,119.13,119.10,118.95,118.46,118.26,111.35,108.72.MS(ESI):m/z 638.1[M+H]+。
Compound 5g has the formula:
Figure BDA0002452067700000072
example 8:
synthesis of compound 5 h:
the procedure is as in example one, except that the R2 group is replaced with 3-chloro-4-fluorobenzene to give a white solid in 46% yield.1H NMR(400MHz,DMSO)TM11.14(s,1H),9.64(s,1H),8.34(d,J＝5.3Hz,1H),8.11–8.04(m,3H),7.89–7.80(m,3H),7.65(t,J＝8.9Hz,1H),7.53(s,1H),7.40(d,J＝8.8Hz,2H),7.33–7.25(m,3H).13C NMR(101MHz,DMSO)TM175.32,167.02,161.13,158.60,156.19,148.56,141.93,141.75,140.49,136.61,136.58,134.54,129.55,129.29,128.23,128.14,121.55,121.48,121.14,120.95,119.37,119.09,118.49,118.46,118.26,111.34,108.72.MS(ESI):m/z 606.0[M+H]+。
Compound 5h has the formula:
Figure BDA0002452067700000081
example 9:
synthesis of compound 5 i:
the procedure is as in example one, except that the R2 group is replaced with 3-chloro-4-fluorobenzene to give a white solid in 49% yield. 1H NMR (400MHz, DMSO)TM11.07(s,1H),9.64(s,1H),8.35(d,J＝5.3Hz,1H),8.06(d,J＝8.8Hz,2H),7.96–7.91(m,2H),7.86–7.80(m,2H),7.53(s,1H),7.47–7.35(m,4H),7.33–7.26(m,3H).13C NMR(101MHz,DMSO)TM175.36,167.01,165.79,163.28,156.20,148.57,142.34,141.76,140.49,135.52,135.49,134.57,129.85,129.76,129.49,121.57,121.48,119.10,119.07,118.13,116.85,116.63,111.36,108.72.RMS(ESI):m/z 572.1[M+H]+。
The chemical formula of compound 5i is as follows:
Figure BDA0002452067700000082
example 10:
synthesis of compound 5 j:
the procedure is as in example one, except that the R2 group is replaced with 3-chloro-4-fluorobenzene to give a white solid in 54% yield.1H NMR(400MHz,DMSO)TM11.12(s,1H),9.64(s,1H),8.34(d,J＝5.3Hz,1H),8.06(d,J＝8.8Hz,2H),7.86–7.75(m,6H),7.53(s,1H),7.38(d,J＝8.7Hz,2H),7.34–7.24(m,3H).13CNMR(101MHz,DMSO)TM175.34,167.01,156.19,148.56,142.20,141.75,140.49,138.40,134.55,132.61,129.50,128.65,127.31,121.56,119.16,119.10,118.23,111.35,108.72.MS(ESI):m/z 633.0[M+H]+。
The chemical formula of compound 5j is as follows:
Figure BDA0002452067700000091
example 11:
synthesis of compound 5 k:
the procedure is as in example one, except that the R2 group is replaced by 2-thiophene to give a white solid in 43% yield.1HNMR(400MHz,DMSO)TM11.19(s,1H),9.65(s,1H),8.35(d,J＝5.2Hz,1H),8.12–8.07(m,2H),7.96(dd,J＝5.0,1.4Hz,1H),7.86–7.80(m,2H),7.71(dt,J＝5.6,2.8Hz,1H),7.54(s,1H),7.46–7.41(m,2H),7.34–7.26(m,3H),7.16(dd,J＝5.0,3.8Hz,1H)；13C NMR(101MHz,DMSO)TM175.39,167.02,156.20,148.57,142.26,140.51,139.50,134.58,134.05,133.08,129.45,127.80,121.58,119.14,119.10,118.24,111.36,108.75；MS(ESI):m/z 560.1[M+H]+。
Compound 5k has the formula:
Figure BDA0002452067700000092
example 12:
synthesis of Compound 5 l:
the procedure is as in example one, except that the R2 group is replaced with 2-methoxycarbonyl-3-thiophene, giving a white solid in 47% yield.1H NMR(400MHz,DMSO)TM10.97(s,1H),9.63(d,J＝9.9Hz,1H),8.33(dd,J＝10.3,7.0Hz,1H),8.08–7.99(m,3H),7.85–7.80(m,2H),7.59–7.51(m,2H),7.40–7.35(m,2H),7.34–7.25(m,3H),3.89(s,3H)；13C NMR(101MHz,DMSO)TM175.41,167.01,159.65,156.20,148.57,142.27,141.80,140.51,134.59,133.02,132.34,130.60,129.43,121.57,121.49,119.10,118.96,118.59,117.85,111.37,108.73,53.21；MS(ESI):m/z 618.1[M+H]+。
The chemical formula of compound 5l is as follows:
Figure BDA0002452067700000101
example 13:
synthesis of compound 5 m:
the procedure is as in example one, except that the R2 group is replaced with 5-chloro-2-thiophene, giving a white solid in 52% yield. 1H NMR (400MHz, DMSO)TM11.31(s,1H),9.65(s,1H),8.35(d,J＝5.2Hz,1H),8.15–8.08(m,2H),7.87–7.80(m,2H),7.61(d,J＝4.1Hz,1H),7.54(s,1H),7.47–7.41(m,2H),7.33(dd,J＝5.3,1.4Hz,1H),7.26(dd,J＝16.2,6.3Hz,3H)；13C NMR(101MHz,DMSO)TM175.34,167.04,156.20,148.57,141.80,140.50,137.72,135.89,134.56,133.04,129.54,128.15,121.57,119.46,119.10,118.63,111.35,108.75；MS(ESI):m/z 595.0[M+H]+。
The chemical formula of compound 5m is as follows:
Figure BDA0002452067700000111
example 14:
synthesis of compound 5 n:
the same procedure as in example one, except that the R1 group was 4-ethylbenzene and the R2 group was 4-tert-butylbenzene. A white solid was obtained in 58% yield.1H NMR(400MHz,DMSO)TM11.04(s,1H),9.31(s,1H),8.29(d,J＝5.3Hz,1H),8.05(d,J＝8.8Hz,2H),7.84–7.76(m,2H),7.60(dd,J＝8.6,1.7Hz,4H),7.48(s,1H),7.40(d,J＝8.8Hz,2H),7.23(dd,J＝5.3,1.3Hz,1H),7.11(d,J＝8.5Hz,2H),2.57–2.52(m,2H),1.24(s,9H),1.15(t,J＝7.6Hz,3H)；13C NMR(101MHz,DMSO)TM175.34,167.12,156.72,156.35,148.65,142.65,138.80,136.52,136.40,134.32,129.48,127.82,126.56,126.34,118.65,118.51,117.73,110.47,108.06,34.86,30.62,27.54,15.79；MS(ESI):m/z 554.3[M+H]+。
The chemical formula of compound 5n is as follows:
Figure BDA0002452067700000112
example 15:
synthesis of compound 5 o:
the procedure is as in example one except that the R1 group is 4-trifluoromethylbenzene and the R2 group is 4-tert-butylbenzene. A white solid was obtained with a yield of 61%.1H NMR(400MHz,DMSO)TM11.05(s,1H),9.86(s,1H),8.39(d,J＝5.3Hz,1H),8.05(d,J＝8.8Hz,2H),7.93(d,J＝8.6Hz,2H),7.85–7.78(m,2H),7.65–7.55(m,5H),7.43–7.34(m,3H),1.24(s,9H)；13C NMR(101MHz,DMSO)TM175.43,166.91,156.36,155.93,148.60,144.78,142.70,136.53,134.72,129.48,126.56,126.34,125.91,125.88,118.51,117.68,117.44,111.99,109.23,34.86,30.62；MS(ESI):m/z 554.3[M+H]+。
Compound 5o has the formula:
Figure BDA0002452067700000121
example 16:
synthesis of compound 5 p:
the procedure is as in example one except that the R1 radical is 4-isopropylbenzene and the R2 radical is 4-tert-butylbenzene. A white solid was obtained in 63% yield.1H NMR(400MHz,DMSO)TM11.05(s,1H),9.34(s,1H),8.29(d,J＝5.3Hz,1H),8.05(d,J＝8.8Hz,2H),7.81(d,J＝8.6Hz,2H),7.64–7.56(m,4H),7.49(s,1H),7.40(d,J＝8.8Hz,2H),7.24(dd,J＝5.3,1.3Hz,1H),7.15(d,J＝8.6Hz,2H),2.82(dt,J＝13.7,6.9Hz,1H),1.24(s,9H),1.18(d,J＝6.9Hz,6H)；13C NMR(101MHz,DMSO)TM175.35,167.10,156.65,156.35,148.52,142.66,141.20,138.76,136.52,134.39,129.48,126.55,126.34,118.75,118.52,117.72,110.48,108.10,34.86,32.76,30.63,24.01；MS(ESI):m/z 568.2[M+H]+。
The chemical formula of compound 5p is as follows:
Figure BDA0002452067700000122
GSK-3 β inhibitory experiments and results:
1) preparation of compound solution: test compounds were prepared at 100. mu.M concentration (solvent: DMSO), stored at-20 ℃ at low temperature, and diluted to the desired concentration with the desired cell culture medium at the time of use.
2) Inhibition assay for GSK-3 β
Using ADP-Glo assay kit (Promega Corporation, Auburn, VIC) in white polystyrene 96-well plates (Sigma Aldrich, Castle Hill, NSW, Australia) for screening at 1. mu.M Compound concentration, 1. mu.L of a 10. mu.M solution of the compound (5% DMSO) was added to the kinase reaction mixture prepared from 3. mu.L of standard assay buffer (167 mM HEPES-NaOH, pH 7.5, 10mM MgCl. sub.2,10mM MnCl2) And (4) forming. 10 μ M sodium orthovanadate and 3.33mM DTT), 1.5 μ L kinase dilution buffer (50 mM HEPES-NaOH at pH 7.5, 0.25mg/mL PEG)20,000And 1mM DTT) containing 80ng of GSK-3 β protein kinase, 2.5. mu.L of 50mM HEPES containing 0.24. mu.g of RBERIRStide substrate, and finally, 2mu.L ATP (19.5. mu.M) and 1. mu.L test compound, giving a total assay volume of 10. mu.L. The kinase reaction is as follows: (1) after addition of ATP, a kinase reaction was carried out at 37 ℃ for 40 minutes; (2) ATP was depleted with ADP-Glo reagent for 40 min at room temperature; (3) the ADP-ATP conversion step was performed in a dark room for 1 hour by kinase detection reagents. Finally, use
Figure BDA0002452067700000132
Luminescence was quantified by a multi-label microplate reader (PerkinElmer, Beacons field, Buckinghamshire, UK) with an integration time of 1 second per well, positive and negative controls were performed in 5% DMSO, respectively, in the presence and absence of GSK-3 β kinase.
The results are expressed as the inhibition of GSK-3 β, as shown in Table 1:
Figure BDA0002452067700000131
Figure BDA0002452067700000141
the results discuss that all synthesized compounds have certain inhibition effect on GSK-3 β, wherein the inhibition rate of 5d, 5l and 5o kinases reaches more than 50%, and the compounds are proved to have certain inhibition effect on GSK-3 β and have the potential of developing into medicines for treating GSK-3 β related diseases.
3) Inhibition of NO Release
BV2 cells were cultured in modified MEM media additionally supplemented with 10% fetal calf serum, 1% non-essential amino acids, 1% glutathione and penicillin 100U/mL, streptomycin 100U/mL BV2 cells at 6 × 10 per well 6 36104The cells were inoculated in 48-well plates and humidified at 37 deg.C in an incubator (containing 5% CO)2) And culturing for 24 h. The old medium was discarded. Then pre-treated with pre-prepared drug-containing media of different concentrations for 1 hour and incubated with LPS at a concentration of 1. mu.g/ml for 24 hours. 50 μ L of the supernatant was pipetted into 96 wellsThe percentage of inhibition of NO by the compounds was calculated using the following formula (FL-FC)/(FL-F0) × 100% where FL is the absorbance of the LPS-only treated group, FC is the absorbance of the test compound and LPS co-treated group, F0 is the absorbance of the normal group.
IC50Defined as the concentration of compound that inhibited 50% NO, the results are expressed as the mean ± SD of three experiments, as shown in table 2:
Figure BDA0002452067700000142
Figure BDA0002452067700000151
discussion of the results: as can be seen from Table 2, all the compounds showed good inhibitory action on NO release, and all the compounds showed superior inhibitory activity to the positive drug resveratrol. Of these, Compound 5c showed the best inhibitory Activity (IC)500.72 μ M). The compound can inhibit the release of inflammatory factors NO to some extent.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (5)

1. A1, 2, 4-oxadiazole-pyridine compound is characterized in that the structural formula is shown as a formula (A):
Figure FDA0002452067690000011
wherein R is1Is 4-trifluoromethoxy, 4-ethylbenzene, 4-trifluoromethylbenzene, 4-isopropylbenzene; r2Is 4-nitrobenzene, 4Any one of-methoxybenzene, 4-tert-butylbenzene, 2-thiophene, 2-methoxycarbonyl-3-thiophene, 2-trifluoromethoxybenzene, N-acetamidobenzene, 5-chloro-2-thiophene, 4-trifluoromethoxybenzene, 3-chloro-4-fluorobenzene, 4-fluorobenzene and 4-bromobenzene.
2. Use of a 1, 2, 4-oxadiazole-pyridine compound according to claim 1 for inhibiting GSK-3 β kinase.
3. Use of the 1, 2, 4-oxadiazole-pyridine compound of claim 1 for the preparation of an anti-neuritis agent.
4. Use according to claim 2 or 3, wherein the 1, 2, 4-oxadiazole-pyridine compound is used for the manufacture of a medicament for the treatment of Alzheimer's disease.
5. The use according to claim 2 or 3, wherein the medicament for use is any one of an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
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