CN117624015A - Substituted isatin-melatonin derivative and preparation method and application thereof - Google Patents
Substituted isatin-melatonin derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN117624015A CN117624015A CN202311672405.5A CN202311672405A CN117624015A CN 117624015 A CN117624015 A CN 117624015A CN 202311672405 A CN202311672405 A CN 202311672405A CN 117624015 A CN117624015 A CN 117624015A
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- Prior art keywords
- substituted isatin
- melatonin derivative
- compound
- isatin
- melatonin
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a substituted isatin-melatonin derivative and a preparation method and application thereof. The compound has novel structure and simultaneously has monoamine oxidase-B inhibiting activity and antioxidation effect, the targets are closely related to diseases such as Alzheimer disease, and the mouse memory injury caused by scopolamine can be effectively reversed through the combined action of the two targets, so that the compound can prove that the compound has remarkable treatment effect on the diseases such as Alzheimer disease; in addition, the substituted isatin-melatonin derivative has low biotoxicity, high safety and high medical research and market application value.
Description
Technical Field
The invention belongs to the technical field of biological medicine. More particularly, it relates to a substituted isatin-melatonin derivative and a preparation method and application thereof.
Background
Alzheimer's Disease (AD), also known as Alzheimer's disease, is a chronic progressive degenerative disorder of the central nervous system. With the development of society and the improvement of living standard of people, the world population is gradually aged, so the incidence rate of AD is gradually increased year by year, and the AD has become one of main diseases seriously threatening the life health and quality of life of the aged. The pathogenesis of AD has not been clarified so far, and many influencing factors are involved, such as misfolding and aggregation of β -amyloid, reduced cholinergic levels, inflammation, oxidative stress, hyperphosphorylation of tau protein, mitochondrial damage, abnormal energy metabolism, imbalance of metal ions in the body, and abnormal apoptosis cycle. These factors are interrelated and, in turn, affect each other. Thus, therapeutic effects against a single target are largely undesirable.
In recent years, multi-target drugs become one of the hot spots for research on anti-AD drugs. A number of experiments have shown that MAO-B activity increases gradually with age, especially at higher concentrations around senile plaques in AD patients, and that this increase in activity leads to increased free radicals with neurotoxicity in the brain, increased oxidative stress, and at the same time further accelerated aggregation of Aβ proteins and hyperphosphorylation of tau proteins in the brain, eventually leading to neuronal death by nerve damage, inhibitors of MAO-B have also proved to be of great value in the treatment of AD (Zhang Na. Research progress of monoamine oxidase inhibitors for the treatment of neurodegenerative diseases [ J ]. Medical theory and practice, 2015,28 (13): 1713-1715, 1718.).
Additional studies have shown that oxidative stress plays a very important role in the pathogenesis of AD. Abnormal substance and energy metabolism in brain tissue of AD patients causes free radical accumulation, oxidative damage, and thus apoptosis and neuropathological changes characteristic of AD. A number of experiments have also demonstrated that antioxidants have a protective and delay of progression of AD onset (Chen Mengyuan, zhang Juan, li Chao, etc. potential prevention and treatment of Alzheimer's disease by nitric oxide and natural antioxidants [ J ]. Food and nutrition science 2016,005 (003): P.105-113.DOI: 10.12677/HJFNS.2016.53014.). Therefore, small molecule research with antioxidant effect is also one of the hot spots for anti-AD drug research.
Disclosure of Invention
The invention aims to overcome the defects of single target point and limited treatment effect of the existing anti-AD drugs and provide a substituted isatin-melatonin derivative capable of simultaneously inhibiting MAO-B and resisting oxidation.
The object of the present invention is to provide a process for the preparation of said substituted isatin-melatonin derivatives.
It is another object of the present invention to provide the use of substituted isatin-melatonin derivatives for the preparation of monoamine oxidase-B inhibitors or antioxidants.
Based on the above effects, it is also an object of the present invention to provide the use of the substituted isatin-melatonin derivative for the preparation of a medicament for the treatment of Alzheimer's disease, cerebrovascular dementia, myasthenia gravis, parkinson's disease, huntington's disease or amyotrophic lateral sclerosis.
In addition, the invention also provides a pharmaceutical preparation.
The above object of the present invention is achieved by the following technical scheme:
a substituted isatin-melatonin derivative having the structure of formula (I):
wherein R is mono-or polysubstituted and is independently selected from hydrogen, halogen, C 1～6 One or more of alkoxy groups; r is R 1 Is hydrogen or C 1～6 An alkoxy group.
Preferably R is monosubstituted, selected from hydrogen, halogen, C 1～4 One of the alkoxy groups; r is R 1 Is hydrogen or C 1～4 An alkoxy group.
Preferably, R is a single substituent,one selected from hydrogen, halogen and methoxy; r is R 1 Is hydrogen or methoxy.
More preferably, R is-H, 5-Cl, 5-OCH 3 5-Br or 6-Cl; r is R 1 Is hydrogen or methoxy.
Specifically, the substituted isatin-melatonin derivative has any one of the following structures:
in particular, the substituted isatin-melatonin derivatives also include pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and tautomers thereof.
In addition, the invention also provides a preparation method of the substituted isatin-melatonin derivative, and the synthetic route is as follows:
the method specifically comprises the following steps:
s1, the compound of formula (II)Performing an acylation reaction in an alkaline environment to obtain a compound of formula (III);
s2, carrying out substitution reaction on the compound of the formula (III) obtained in the step S1 and the compound of the formula (IV) under an alkaline condition to obtain a compound of the formula (I);
therein, R, R 1 The definition of (2) is as above.
The preparation method is simple, has low production raw materials, and is very suitable for large-scale industrial production.
In step S1, one or more alkaline reagents selected from triethylamine, anhydrous pyridine and potassium carbonate are added to form the alkaline environment.
Further, in step S1, the solvent for the acylation reaction is one or more of dichloromethane, chloroform, diethyl ether and toluene.
Further, in the step S2, the alkaline condition is formed by adding one or more alkaline reagents of sodium hydroxide, cesium carbonate, potassium carbonate and triethylamine.
Further, in step S2, the solvent for the substitution reaction is one or more of DMF, acetonitrile, tetrahydrofuran, and acetone.
Further, in step S2, the substitution reaction is followed by column chromatography or recrystallization purification.
Experiments prove that the novel structural compound substituted isatin-melatonin derivative has remarkable monoamine oxidase-B inhibition activity and antioxidation effect.
The present invention therefore provides the use of said substituted isatin-melatonin derivatives for the preparation of monoamine oxidase-B inhibitors.
Meanwhile, the invention also provides application of the substituted isatin-melatonin derivative in preparing an antioxidant.
The invention also provides application of the substituted isatin-melatonin derivative in preparing medicines for treating Alzheimer's disease, cerebrovascular dementia, myasthenia gravis, parkinson's disease, huntington's disease or amyotrophic lateral sclerosis.
In addition, the invention also claims a pharmaceutical preparation comprising the substituted isatin-melatonin derivative and pharmaceutically acceptable auxiliary materials.
Further, the dosage form of the pharmaceutical preparation is tablets, pills, capsules, injections, suspending agents or emulsions.
The invention has the following beneficial effects:
the invention provides a substituted isatin-melatonin derivative, which has novel structure, and simultaneously has monoamine oxidase-B inhibiting activity and antioxidation effect, and the targets are closely related to diseases such as Alzheimer's disease, and the combined action of the two targets can effectively reverse the memory damage of mice caused by scopolamine, so that the compound can prove that the compound has remarkable treatment effect on the diseases such as Alzheimer's disease; in addition, the substituted isatin-melatonin derivative has low biotoxicity, high safety and high medical research and market application value.
Drawings
FIG. 1 shows the test compounds IM5 and IM10 vs. H by MTT method in Experimental example 4 2 O 2 Statistical plot of cell viability data of induced damaged SH-SY5Y cells.
FIG. 2 shows the delay time(s) of the test result (A) of the passive avoidance test of the AD model mouse in test example 5; (B) error count data statistics; data are expressed as mean ± standard deviation (n=8), compared to the control group, # p<0.01， * p<0.01， ** p<0.05。
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 Synthesis of Compound 2-bromo-N- [2- (1H-indol-3-yl) -ethyl ] -acetamide (Compound 2 a)
In a 100mL three-necked flask, tryptamine (0.24 g,11.5 mmol), dichloromethane (20 mL), anhydrous potassium carbonate (0.41 g,3.0 mmol) and a dichloromethane solution of bromoacetyl bromide (1.65 mmol of bromoacetyl bromide dissolved in 20mL of dichloromethane) were added dropwise under stirring in an ice bath, after the dropwise addition, the reaction was carried out at room temperature overnight, TLC was followed until the reaction was complete, and dichloromethane was removed by spin evaporation; adding water, dissolving potassium carbonate, extracting water layer with ethyl acetate three times, mixing organic layers, and respectively extracting organic layers with saturated NaHCO 3 The saturated NaCl and water were washed three times (30 mL. Times.3) respectively, and the organic layer was dried over anhydrous sodium sulfate and spunThe dry solvent, crude product was purified by silica gel chromatography using dichloromethane/methanol as eluent to give white solid 2a, yield: 84.3%.
1 H NMR(400MHz,CDCl 3 )δ8.38(s,1H),7.64(d,J＝6.3Hz,1H),7.40(d,J＝6.5Hz,1H),7.25(dd,J＝8.9,3.1Hz,1H),7.18(dd,J＝8.9,3.1Hz,1H),7.06(s,1H),6.67(s,1H),3.84(s,2H),3.64(dd,J＝10.2,5.3Hz,2H),3.03(t,J＝5.4Hz,2H).
EXAMPLE 2 Synthesis of Compound 2b
The difference from example 1 is that the starting material of this example is 5-methoxytryptamine instead of tryptamine, other parameters and the procedure of reference example 1 give compound 2b, yield: 87.6%.
1 H NMR(400MHz,CDCl 3 )δ8.24(s,1H),7.29(d,J＝2.2Hz,1H),7.06(dd,J＝6.9,1.7Hz,2H),6.90(dd,J＝7.0,1.9Hz,1H),6.66(s,1H),3.89(s,3H),3.85(s,2H),3.63(dd,J＝10.2,5.3Hz,2H),3.00(t,J＝5.4Hz,2H).
EXAMPLE 3 Synthesis of substituted isatin-melatonin derivative IM-1
5mL of MeCN and isatin (0.15 g,1.0 mmol) were added to a 25mL round bottom flask, dissolved with stirring, and Cs was added 2 CO 3 (0.49 g,1.5 mmol) was stirred at room temperature for an additional 15min, then KI (0.017 g,0.1 mmol) was added and compound 2a (0.31 g,1.1 mmol) was stirred at room temperature to monitor the progress of the reaction by TLC; after the reaction is finished, the reaction solution is decompressed and dried by spin, water is added and stirred for 2 hours at room temperature, so that the solid is fully precipitated, suction filtration is carried out, the obtained solid is dried, and the isatin-melatonin derivative IM-1 is obtained through silica gel column chromatography separation, and the yield is: 39.8%.
1 H NMR(500MHz,CDCl 3 )δ8.07(s,1H),7.60(d,J＝7.4Hz,1H),7.53(t,J＝7.1Hz,2H),7.34(d,J＝8.1Hz,1H),7.17(dt,J＝20.5,7.6Hz,2H),7.08(t,J＝7.5Hz,1H),6.96(s,1H),6.85(d,J＝8.0Hz,1H),6.00(s,1H),4.29(s,2H),3.63(dd,J＝12.3,6.1Hz,2H),2.98(t,J＝6.5Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ165.62,158.26,150.05,138.60,136.33,133.20,127.05,125.49,124.35,122.33,122.30,119.65,118.39,117.56,112.19,111.39,110.73,44.00,39.74,24.86.ESI-MS m/z:370.12[M+Na] + 。
EXAMPLE 4 Synthesis of substituted isatin-melatonin derivative IM-2
The difference from example 3 is that the starting material of this example is 5-chloroisatin instead of isatin, and other parameters and operations are described in reference to example 3 to give the substituted isatin-melatonin derivative IM-2 in yields: 42.1%.
1 H NMR(400MHz,MeOD)δ7.57(s,2H),7.39(d,J＝17.4Hz,2H),7.11-7.01(m,3H),6.57(s,1H),4.58(s,1H),4.33(d,J＝19.9Hz,2H),3.55(s,2H),2.97(s,2H). 13 C NMR(101MHz,MeOD)δ181.65,167.10,158.55,141.67,136.82,129.90,128.96,128.14,123.92,123.77,122.23,120.95,118.31,117.87,111.66,110.90,110.30,42.19,40.04,24.51.ESI-MS m/z:404.08[M+Na] + 。
EXAMPLE 5 Synthesis of substituted isatin-melatonin derivative IM-3
The difference from example 3 is that the starting material of this example is 6-chloroisatin instead of isatin, and other parameters and operations are described in reference example 3 to give the substituted isatin-melatonin derivative IM-3 in yields: 48.5%.
1 H NMR(400MHz,DMSO-d 6 )δ10.81(s,1H),8.37(s,1H),7.62(d,J＝7.9Hz,1H),7.52(d,J＝7.7Hz,1H),7.34(d,J＝8.0Hz,1H),7.27-7.18(m,2H),7.13(s,1H),7.07(s,1H),6.98(s,1H),4.36(s,2H),3.31-3.40(m,2H),2.82(t,J＝7.1Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ182.11,166.17,158.94,152.27,142.87,136.69,127.57,126.31,123.74,123.18,121.40,118.74,118.61,117.03,111.97,111.87,111.82,43.30,39.75,25.54.ESI-MS m/z:404.08[M+Na] + 。
EXAMPLE 6 Synthesis of substituted isatin-melatonin derivative IM-4
The difference from example 3 is that the starting material of this example is 5-bromoisatin instead of isatin, and other parameters and operations are described in reference example 3 to give the substituted isatin-melatonin derivative IM-4 in yields: 39.7%.
1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),7.67(d,J＝1.6Hz,1H),7.58(dd,J＝6.7,1.7Hz,1H),7.52(d,J＝6.4Hz,1H),7.36(d,J＝6.5Hz,1H),7.21(t,J＝8.0Hz,1H),7.08(t,J＝6.2Hz,1H),6.99(d,J＝1.6Hz,1H),6.68(d,J＝6.7Hz,1H),5.94(s,1H),4.26(d,J＝4.4Hz,2H),3.64(d,J＝5.0Hz,2H),2.99(t,J＝5.2Hz,2H). 13 CNMR(101MHz,CDCl 3 )δ182.08,166.09,158.53,152.72,143.92,136.85,127.75,126.43,123.90,123.50,121.88,118.91,118.48,117.49,111.87,111.37,111.32,43.30,39.89,25.51.ESI-MS m/z:448.04[M+Na] + 。
EXAMPLE 7 Synthesis of substituted isatin-melatonin derivative IM-5
The difference from example 3 is that the starting material of this example is 5-methoxyisatin instead of isatin, and other parameters and operations are described in reference example 3 to give the substituted isatin-melatonin derivative IM-5, yield: 54.1%.
1 H NMR(400MHz,CDCl 3 )δ8.06(s,1H),7.53(d,J＝7.8Hz,1H),7.34(d,J＝8.2Hz,2H),7.19(s,1H),7.13-7.03(m,3H),6.97(s,1H),6.74(d,J＝8.6Hz,1H),5.97(s,1H),4.26(s,2H),3.82(s,3H),3.63(dd,J＝12.4,6.2Hz,3H),2.98(t,J＝6.6Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ189.01,168.21,155.89,150.86,142.11,124.79,122.26,119.64,118.39,117.98,116.14,114.51,111.71,111.36,103.36,102.57,99.99,56.00,44.11,39.69,24.83.ESI-MS m/z:400.13[M+Na] + 。
EXAMPLE 8 Synthesis of substituted isatin-melatonin derivative IM-6
5mL of MeCN and isatin (0.15 g,1.0 mmol) were added to a 25mL round bottom flask, dissolved with stirring, and Cs was added 2 CO 3 (0.49 g,1.5 mmol) was stirred at room temperature for a further 15min, then KI (0.017 g,0.1 mmol) was added and compound 2b (0.37 g,1.2 mmol) was stirred at room temperature to monitor the progress of the reaction by TLC; after the reaction was completed, the reaction solution was dried under reduced pressure, stirred with water at room temperature for 2 hours, extracted with DCM (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to give the substituted isatin-melatonin derivative IM-6, yield: 39.1%.
1 H NMR(400MHz,CDCl 3 )δ7.96(s,1H),7.73(dd,J＝4.6,2.6Hz,2H),7.56(d,J＝1.8Hz,1H),7.23(d,J＝7.0Hz,1H),7.15(dd,J＝6.0,5.5Hz,1H),6.94(dd,J＝5.9,1.8Hz,2H),6.86(dd,J＝4.2,2.2Hz,1H),6.00(s,1H),4.30(s,2H),3.84(s,3H),3.62(dd,J＝10.0,5.2Hz,2H),2.95(t,J＝5.2Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ186.81,167.36,159.40,156.19,153.25,143.65,131.88,127.86,125.43,123.91,118.42,112.53,112.41,111.74,111.58,110.87,100.46,56.14,55.79,43.27,25.54.ESI-MS m/z:400.13[M+Na] + 。
EXAMPLE 9 Synthesis of substituted isatin-melatonin derivative IM-7
The difference from example 8 is that the starting material of this example is 5-chloroisatin instead of isatin, and other parameters and operations are described in reference to example 8 to give the substituted isatin-melatonin derivative IM-7, yield: 42.9%.
1 H NMR(400MHz,DMSO-d 6 )δ10.66(s,1H),8.33(t,J＝4.1Hz,1H),7.67-7.59(m,2H),7.22(d,J＝7.0Hz,1H),7.07(s,1H),6.99(s,1H),6.94(d,J＝6.7Hz,1H),6.74-6.69(m,1H),4.31(s,2H),3.74(s,3H),3.36-3.31(m,2H),2.77(t,J＝5.7Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ182.34,166.06,158.55,153.44,149.39,137.36,131.79,128.04,127.90,124.29,123.92,119.50,112.88,112.48,111.64,111.48,100.44,55.79(2C),43.25,25.44.ESI-MS m/z:434.09[M+Na] + 。
EXAMPLE 10 Synthesis of substituted isatin-melatonin derivative IM-8
The difference from example 8 is that the starting material of this example is 6-chloroisatin instead of isatin, and other parameters and operations are described in reference to example 8 to give the substituted isatin-melatonin derivative IM-8 in yields: 45.7%.
1 H NMR(400MHz,DMSO-d 6 )δ10.65(s,1H),8.36(t,J＝5.4Hz,1H),7.62(d,J＝7.9Hz,1H),7.21(dd,J＝8.3,3.5Hz,3H),7.08(d,J＝1.7Hz,1H),6.99(d,J＝2.0Hz,1H),6.70(dd,J＝8.7,2.3Hz,1H),4.35(s,2H),3.76(d,J＝8.6Hz,3H),3.38-3.33(m,2H),2.77(t,J＝7.4Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ182.25,166.14,159.03,153.45,152.32,142.83,131.81,127.85,126.29,123.83,123.72,117.05,112.51,111.81,111.67,111.52,100.42,60.23,55.79,43.31,25.55.ESI-MS m/z:434.09[M+Na] + 。
EXAMPLE 11 Synthesis of substituted isatin-melatonin derivative IM-9
The difference from example 8 is that the starting material of this example is 5-bromoisatin instead of isatin, and other parameters and operations are described in reference example 8 to give the substituted isatin-melatonin derivative IM-9, yield: 45.1%.
1 H NMR(400MHz,DMSO-d 6 )δ10.67(s,1H),8.34(t,J＝4.1Hz,1H),7.75(d,J＝5.8Hz,2H),7.23(d,J＝7.0Hz,1H),7.08(s,1H),7.00(s,1H),6.89(d,J＝7.1Hz,1H),6.72(d,J＝6.9Hz,1H),4.31(s,2H),3.75(s,3H),3.35(m,2H),2.78(t,J＝5.7Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ182.19,166.04,158.37,153.44,149.76,140.17,131.79,127.90,127.01,123.92,119.87,115.58,113.31,112.48,111.64,111.49,100.44,55.80(2C),43.23,25.44.ESI-MS m/z:478.04[M+Na] + 。
EXAMPLE 12 Synthesis of substituted isatin-melatonin derivative IM-10
The difference from example 8 is that the starting material of this example is 5-methoxyisatin instead of isatin, and other parameters and operations are described in reference to example 8 to give the substituted isatin-melatonin derivative IM-10, yield: 51.4%.
1 H NMR(400MHz,DMSO-d 6 )δ10.67(s,1H),8.35(s,1H),7.38-6.94(m,5H),6.78(d,J＝46.6Hz,2H),4.28(s,2H),3.77(s,6H),2.79(s,2H). 13 C NMR(101MHz,DMSO-d 6 )δ183.72,166.31,158.88,156.25,153.44,144.78,131.80,127.92,124.25,123.92,118.58,112.47,112.17,111.68,111.49,109.49,100.46,56.37,55.80,43.20,25.47.ESI-MS m/z:430.14[M+Na] + 。
Experimental example 1 inhibition of monoamine oxidase-B by substituted isatin-melatonin derivatives
The inhibitory activity of the substituted isatin-melatonin derivatives obtained in examples 3 to 12 on monoamine oxidase-B (MAO-B) was determined by fluorescence photometry. The experimental results are expressed in terms of inhibition rate, with ladostigil as positive control. All tests were performed on a PowerWave XS2 type full wave microplate reader and absorbance was measured at 490 nm. The test concentration of the compound was 40 μm and the inhibition was calculated according to the following formula: inhibition (%) = [1- (sample-sample background)/(blank-blank background) ]x100%. Wherein, the blank set replaced 10 μl of sample solution with 10 μl of PBS (ph=7.6), the blank background set replaced 30 μl of substrate with 30 μl of PBS (ph=7.6), 10 μl of sample solution with 10 μl of PBS (ph=7.6), and the sample background set replaced 30 μl of substrate with 30 μl of PBS (ph=7.6).
(1) Preparing a sample solution:
the samples are respectively weighed and dissolved in dimethyl sulfoxide (DMSO) to prepare 10mM concentration, the samples are preserved in a refrigerator at the low temperature of minus 20 ℃, and the samples are diluted to the required concentration by phosphate buffer solution (0.2 mol/L, pH 7.6) when in use, so that the final concentration of the DMSO is less than or equal to 0.5% (v/v).
(2) Preparation of enzyme stock solution:
monoamine oxidase B was purchased from Sigma; a certain amount of monoamine oxidase B is weighed and diluted with deionized water to a proper activity range.
(3) Preparing a substrate stock solution:
tyramine was purchased from Sigma; a certain amount of tyramine was weighed and prepared into a 2.5mM solution by using a phosphate buffer solution (0.2 mol/L, pH 7.6), and the solution was stored at 4℃under shade.
(4) Preparing a color-developing agent stock solution:
weighing a certain amount of vanillic acid, 4-aminoantipyrine and horseradish peroxidase, preparing a color development solution (1 mM vanillic acid, 0.5mM 4-aminoantipyrine and 4U/mL horseradish peroxidase) by using a phosphate buffer solution (0.2 mol/L, pH 7.6), and performing shading preservation at 4 ℃.
(5) And (3) testing:
in a 96-well plate, 10. Mu.L of an enzyme solution and 10. Mu.L of a sample solution were added, respectively, incubated at 37℃for 20 minutes, 30. Mu.L of a substrate and 10. Mu.L of a color-developing solution were immediately added, and after incubation at 37℃for 60 minutes, absorbance values thereof were measured at λ=490 nm using an enzyme-labeled instrument, and experimental results are shown in Table 1.
TABLE 1 inhibitory Activity of substituted isatin-melatonin derivatives on MAO-B
| Compounds of formula (I) | Inhibition ratio (%) | Compounds of formula (I) | Inhibition ratio (%) |
| IM-1 | 64.9±0.9 | IM-7 | 29.8±0.7 |
| IM-2 | 34.2±1.2 | IM-8 | 30.3±0.9 |
| IM-3 | 35.7±0.9 | IM-9 | 43.7±1.0 |
| IM-4 | 47.8±0.8 | IM-10 | 70.3±1.2 |
| IM-5 | 73.9±0.6 | Ladostigil | 60.2±0.5 |
| IM-6 | 62.7±0.9 |
As can be seen from Table 1, the compounds obtained in the invention all have different degrees of inhibition on MAO-B, wherein the inhibition of the compounds IM-1, IM-5, IM-6 and IM-10 is better, and the inhibition of the compound IM-5 is strongest, reaching 73.9%, and the activity is even stronger than that of a positive control ladostigil. This demonstrates that the substituted isatin-melatonin derivatives obtained according to the invention can be used for the preparation of anti-Alzheimer's disease drugs based on MAO-B inhibition.
In addition, the general structure-effect relationship according to the compound structure and table 1 may be as follows: the aromatic ring of the isatin part is substituted by electron donating groups with higher activity than electron withdrawing groups; and the activity of no substituent group on the indole ring is better.
Experimental example 2 in vitro antioxidant Activity test of substituted isatin-melatonin derivative
The in vitro antioxidant activity of the substituted isatin-melatonin derivatives obtained in examples 3 to 12 was measured by the ORAC method, and the antioxidant capacity of a part of the compounds was evaluated using AAPH as a source of peroxy radicals and sodium Fluorescein (FL) as a fluorescent indicator, and the experimental results were expressed in Trolox equivalent. The method specifically comprises the following steps:
(1) Preparation of Phosphate Buffer (PBS): proper amount of phosphoric acid is measured, and diluted by ultrapure water to obtain 75mM phosphoric acid solution; 8.56g of dipotassium hydrogen phosphate is weighed and dissolved in 500mL of ultrapure water, and the pH value is adjusted to 7.4 by using a phosphoric acid solution, so that 75mM of phosphate buffer solution with the pH value of 7.4 is obtained.
(2) AAPH solution (ready-to-use): AAPH 0.0588g was weighed out precisely, dissolved in 5.42mL of phosphate buffer solution, and the volume was fixed to prepare an AAPH solution having a concentration of 40.0 mM.
(3) Preparation of sodium fluorescein solution: 0.0650g of sodium Fluorescein (FL) was precisely weighed and dissolved in 50mL of high-purity water to prepare a 3.4mM FL solution, which was stored in a refrigerator at 4℃and 2. Mu.L of the solution was dissolved in 50mL of phosphate buffer solution at the time of use to obtain 136nM FL solution.
(4) Preparation of Trolox solution: precisely weighing Trolox 2.50mg, and measuring 1000 mu L of DMSO to dissolve by a pipette to obtain 10mM Trolox solution; the Trolox DMSO solution was precisely aspirated by a pipette and diluted to the test concentration with phosphate buffer.
(5) Preparation of compound solution: an appropriate amount of the compound was accurately weighed by a precision analytical balance, diluted with DMSO to a clear solution at a concentration of 1mM, and diluted with a phosphate buffer to the concentration used when used.
(6) Antioxidant Activity test: respectively sucking 20 mu L of compounds or Trolox with different concentrations, mixing 120 mu L of FL diluent with a black 96-well culture plate, incubating at 37 ℃ for 15min, rapidly adding 60 mu L of AAPH, measuring with a multifunctional enzyme-labeling instrument every 1min, recording fluorescence value, excitation wavelength of 485nm, emission wavelength of 535nm, and recording for 240min. The blank was tested with 20 μl PBS instead of compound. The area between the curve and the coordinates (AUC) was calculated by integral calculation of ORIGIN software, the protection area calculation formula for the sample: net AUC = aucantioxidant-AUC blank, ORAC-FL value calculation: [ (AUC Sample-AUC blank)/(AUC Trolox-AUC blank) ]/[ Trolox concentration/Sample concentration) ], the Sample ORAC value being expressed in Trolox value equivalents.
Table 2 in vitro antioxidant Activity of substituted isatin-melatonin derivatives
As can be seen from Table 2, the compounds obtained in the invention have better antioxidation in vitro, and the substituted isatin-melatonin derivative obtained in the invention can be used for preparing medicines for resisting Alzheimer disease based on the antioxidation.
In addition, some structure-activity relationships can be seen from the compound structure and the data in table 2: wherein, the ORAC value of the compounds IM-10 and IM-5 is up to more than 4.5 under the concentration of 5 mu M, and the oxidation resistance is better, which shows that the activity of the indole ring with methoxy substitution is better than that without methoxy substitution; substituents on the aromatic ring of the isatin moiety have a major effect on activity in the following order: electron donating group substitution > no substituent > electron withdrawing group substitution.
Experimental example 3 toxicity study of substituted isatin-melatonin derivatives on nerve cells
The toxicity of the substituted isatin-melatonin derivatives obtained in examples 3 to 12 on nerve cells (SH-SY 5Y) was determined by MTT method, and the specific steps are as follows:
1. solution preparation
(1) DMEM medium: dissolving the dry powder culture medium in 300mL of ultrapure water by using a 1000mL beaker, flushing the inner surface of the package twice by using 300mL of ultrapure water, combining the solutions, and magnetically stirring to completely dissolve the solution; 3.7g sodium bicarbonate and 2.38g HEPES were added and the mixture was completely dissolved by magnetic stirring; adjusting pH to 7.5 with 10M sodium hydroxide under stirring, sterilizing with 0.22 μm filter membrane in an ultra clean bench, and storing in a refrigerator at 4deg.C; antibiotics (final concentration of penicillin 100U/mL, streptomycin 100. Mu.g/mL) and fetal bovine serum (10%) were added for use.
(2) PBS buffer solution: accurately weighing 8g NaCl and 0.2g KH 2 PO 4 And 2.88g Na 2 HPO 4 ·12H 2 O, dissolving with ultrapure water, fixing the volume to 1L, autoclaving at 120 ℃ for 20min, and preserving in a refrigerator at 4 ℃.
(3) MTT solution: MTT was formulated as 5g/L with PBS, sterilized by filtration through a 0.22. Mu.M filter, and stored in a refrigerator at 4℃in the absence of light.
2. Culture of neural cells SH-SY5Y
Taking nerve cell strain SH-SY5Y, culturing in DMEM medium at 37deg.C under saturated humidity and 5% CO 2 And conventional culture in an incubator with 95% air, and passaging once in 2-3 days.
3. Neurocytotoxicity assays
(1) Taking logarithmic growth phase cells, digesting with 0.25% pancreatin, washing twice with PBS, re-suspending with DMEM medium, counting with a cell counting plate under a microscope and adjusting the cell concentration to 5×10 4 Each of the cells was inoculated into a 96-well cell culture plate at 100. Mu.L/well and cultured for 24 hours to adhere the cells.
(2) Sucking the original culture medium, addingCompound solutions of different concentrations diluted with DMEM medium were prepared in 5 duplicate wells per well at 100 μl. Adding culture medium to replace compound in blank and control group, placing at 37deg.C, 5% CO 2 Culturing in an incubator for 48 hours; culture medium containing 5mg/mL MTT was added to the sample and control groups at 4h before termination of the experiment, 100. Mu.L/well, and incubation was continued for 4h.
(3) Removing the supernatant, adding 100 mu L of DMSO into each well, oscillating to fully dissolve formazan, and measuring absorbance value (OD value) of each well on a full-wavelength microplate reader to obtain 570nm wavelength; cell viability (%) = (OD sample-OD blank)/(OD control-OD blank) ×100% in each sample; cell inhibition (%) =100% to cell survival (%) of each sample, and the concentration is plotted with the inhibition ratio plotted against the concentration, and the concentration with 50% inhibition ratio is the compound IC 50 Values. The results are shown in Table 3.
TABLE 3 toxicity of substituted isatin-melatonin derivatives on nerve cells (SH-SY 5Y)
| Compounds of formula (I) | IC 50 (μM) | Compounds of formula (I) | IC 50 (μM) |
| IM-1 | 197.4±0.5 | IM-6 | 172.5±0.5 |
| IM-2 | 81.6±0.9 | IM-7 | 89.3±0.8 |
| IM-3 | 94.2±0.7 | IM-8 | 105.7±0.3 |
| IM-4 | 116.8±0.4 | IM-9 | 82.2±0.7 |
| IM-5 | 232.9±0.7 | IM-10 | 185.8±0.4 |
As can be seen from Table 3, the substituted isatin-melatonin derivatives obtained according to the present invention have an IC on SH-SY5Y cells 50 Values above 80 μm, showing lower nerve cytotoxicity; IC of compound IM-5 with strongest inhibitory activity on MAO-B 50 The value is 232.9 mu M, and the safety is good.
Experimental example 4 melatonin derivatives IM5 and IM10 vs H 2 O 2 Neuroprotection studies of induced SH-SY5Y cell damage
Determination of the substituted isatin-melatonin derivatives IM5 and IM10 obtained in examples 7, 12 against H by MTT method 2 O 2 The neuroprotection of the induced SH-SY5Y cell damage is as follows:
SH-SY5Y cells were subcultured in 96-well plates with a cell density of 1X 10 per well 4 . After removal of the medium, the compounds IM5 and IM10 (1 and 10 μm) were added at different concentrations and incubated for 3h, melatonin as positive control. Then 10 mu L H is added 2 O 2 (200. Mu.M) incubation was continued for 12h. Cell viability was measured by the MTT method of Experimental example 3 described above, and the results are shown in FIG. 1.
As can be seen from FIG. 1, the substituted isatin-melatonin derivatives IM5 and IM10 of the present invention are directed against H 2 O 2 The induced SH-SY5Y cell injury has better neuroprotection effect and better protective capability than melatonin; wherein after SH-SY5Y cells were treated with 10. Mu.M of compound IM-10, the cell viability was increased to 86.6%.
Experimental example 5 study of the Effect of melatonin derivative IM5 on scopolamine induced dysmnesia mice
The effect of melatonin derivative IM5 obtained in example 7 on scopolamine induced dysmnesia mice was evaluated using a passive avoidance experiment. The method comprises the following specific steps:
(1) AD mouse model establishment
Male SD mice were 60 (3 months old), and all mice were placed in an environment with a temperature of 22-25 ℃, a relative humidity of 50-70% and a light-dark cycle of 12 hours. The 60 male SD mice were randomly divided into 6 groups: a) Control group (normal saline injection, gastric lavage distilled water); b) AD model group (scopolamine 3.0 mg/kg); c) Positive control group (donepezil, 8.0 mg/kg); d) High dose group (IM 5-H8.0 mg/kg); e) Medium dose group (IM 5-M4.0 mg/kg); f) Low dose group (IM 5-L2.0 mg/kg).
(2) Passive avoidance test
In vivo memory enhancement was assessed by a mouse passive avoidance experiment, which included two separate tests (training test and test after 24 hours). The test device consisted of two equally sized compartments (light and dark), separated by a broken-end landing door, illuminated in a light box with a 250lx LED lamp. In the training test, the mice were first placed in the light chamber, free to move for 5 minutes, to become familiar with the surrounding environment. The door was then opened and the mouse quickly entered the dark compartment while the electrostimulator was activated and the animal's foot was shocked (24 v,0.5 ma). Mice were trained repeatedly for 5 minutes. If the mice failed to enter the dark compartment within 180 seconds, they were eliminated for testing.
Mice were perfused with gastric IM5 (2.0, 4.0 and 8.0 mg/kg) or donepezil (8.0 mg/kg) 1 hour prior to each training. After 30 minutes, scopolamine (3.0 mg/kg) was injected intraperitoneally to cause dysmnesia. The test was performed 24 hours after the training test. We put the mice again into the light chamber and open the door. The overall test time was set to 5 minutes. The delay time and the number of errors are recorded during the test time. The delay time (i.e., latency) is the time it takes the mouse to enter the dark compartment, and the number of errors is the number of times the mouse enters the dark compartment within 5 minutes. The results are shown in FIG. 2.
As shown in fig. 2, the latency of scopolamine treated group (model group, 96 sec) was significantly lower than that of control group (242 sec), and the average number of errors was significantly increased within 5 minutes (model group 4.9, control group 1.8), indicating that scopolamine caused memory impairment in mice. After treatment with donepezil and compound IM5 (2.0, 4.0, 8.0 mg/kg) at different concentrations, both latency time and average error number were significantly reversed compared to the model group. Furthermore, compound IM5 prolonged the delay time in a dose dependent manner, reducing the number of errors. Of these, compound IM5 at a dose of 8.0mg/kg had better effects in increasing latency and reducing the number of errors compared to donepezil group.
From the above, the substituted isatin-melatonin derivative has better MAO-B inhibition activity and antioxidation activity, and has smaller toxicity to nerve cells and high safety. Wherein the compound IM5 is opposite to H 2 O 2 The induced SH-SY5Y cell injury has a strong neuroprotective effect; animal experiments show that the high-dose compound IM5 can effectively reverse the memory damage of mice caused by scopolamine. Therefore, the compound provided by the invention is very suitable for preparing the anti-Alzheimer disease medicine.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. A substituted isatin-melatonin derivative, characterized in that the substituted isatin-melatonin derivative has the structure of formula (I):
wherein R is mono-or polysubstituted and is independently selected from hydrogen, halogen, C 1～6 One or more of alkoxy groups; r is R 1 Is hydrogen or C 1～6 An alkoxy group.
2. The substituted isatin-melatonin derivative according to claim 1, characterized in that R is monosubstituted, selected from hydrogen, halogen, C 1～4 One of the alkoxy groups; r is R 1 Is hydrogen or C 1～4 An alkoxy group.
3. The substituted isatin-melatonin derivative according to claim 2, characterized in that R is monosubstituted, selected from one of hydrogen, halogen, methoxy; r is R 1 Is hydrogen or methoxy.
4. The substituted isatin-melatonin derivative of claim 3, wherein the substituted isatin-melatonin derivative has any of the following structures:
5. the substituted isatin-melatonin derivative according to any of claims 1 to 4, characterized in that it also comprises pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and tautomers thereof.
6. The process for the preparation of a substituted isatin-melatonin derivative according to any one of claims 1 to 4, characterized by the following synthetic route:
the method specifically comprises the following steps:
s1, the compound of formula (II)Performing an acylation reaction in an alkaline environment to obtain a compound of formula (III);
s2, carrying out substitution reaction on the compound of the formula (III) obtained in the step S1 and the compound of the formula (IV) under an alkaline condition to obtain a compound of the formula (I);
therein, R, R 1 Is as defined in any one of claims 1 to 3.
7. Use of a substituted isatin-melatonin derivative according to any of claims 1 to 5 for the preparation of monoamine oxidase-B inhibitors.
8. Use of a substituted isatin-melatonin derivative according to any of claims 1 to 5 for the preparation of an antioxidant.
9. Use of a substituted isatin-melatonin derivative according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of alzheimer's disease, cerebrovascular dementia, myasthenia gravis, parkinson's, huntington's disease or amyotrophic lateral sclerosis.
10. A pharmaceutical formulation comprising a substituted isatin-melatonin derivative according to any one of claims 1 to 5 and a pharmaceutically acceptable adjuvant.
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Citations (2)
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|---|---|---|---|---|
| CN1079464A (en) * | 1991-12-18 | 1993-12-15 | 阿斯特拉公司 | Treatment comprises the preparation method of the valuable indolone of illness of cholinergic function reduction and the derivative of indole dione |
| US20200385363A1 (en) * | 2017-06-06 | 2020-12-10 | Adpuerivitam | NMDA Receptor Modulators, Compositions Comprising Same And Use of These Compounds in the Treatment of Diseases Involving the Central Nervous System |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1079464A (en) * | 1991-12-18 | 1993-12-15 | 阿斯特拉公司 | Treatment comprises the preparation method of the valuable indolone of illness of cholinergic function reduction and the derivative of indole dione |
| US20200385363A1 (en) * | 2017-06-06 | 2020-12-10 | Adpuerivitam | NMDA Receptor Modulators, Compositions Comprising Same And Use of These Compounds in the Treatment of Diseases Involving the Central Nervous System |
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