Use of 2-aminothiazole derivative in preparation of Anti-aging drug

Abstract

Disclosed in the present invention is a use of a 2-aminothiazole derivative in the preparation of an anti-aging drug. The 2-aminothiazole derivative can effectively alleviate microglial cell aging in vitro, reduce accumulation of senescence-associated β-galactosidase in aged cells, decrease secretion of a senescence-associated secretory phenotype, and ameliorate apoptosis and oxidative stress damage in the aged cells. In a mouse in vivo experiment, compounds A1-A10 can significantly improve aging-induced cognitive dysfunction and impairment of long-term and short-term learning and memory abilities, reduce transcriptional expression levels of pro-inflammatory factors in the brain, and alleviate neuroinflammation. In summary, the present inventors propose that 2-aminothiazole derivatives have good anti-aging efficacy and possess great application potential in anti-aging.

Description

Application of 2-aminothiazole derivatives in the preparation of anti-aging drugs Technical Field

[0001] This invention belongs to the field of pharmaceuticals and relates to the application of 2-aminothiazole derivatives in the preparation of anti-aging drugs. Background Technology

[0002] Aging is a natural phenomenon that accompanies the increase of age, manifested as the accumulation of damage and functional decline at the cellular and even systemic levels, ultimately leading to death. Aging is the leading risk factor for the development of age-related diseases. Currently, 12 recognized biomarkers of aging have been identified, including cellular senescence, genomic instability, telomere wear, epigenetic alterations, loss of protein homeostasis, dystrophic nutrient sensing, mitochondrial dysfunction, stem cell depletion, altered intercellular communication, chronic inflammation, gut microbiota dysbiosis, and autophagy dysfunction. The emergence of these biomarkers has broadened our understanding of the fundamental mechanisms of aging and may become potential targets for aging intervention.

[0003] Aging has always been a significant issue affecting the health and development of human society as a whole, and research on drugs to delay aging has become a hot topic and a key focus in the life sciences. Over the past few decades of anti-aging research, several drugs with potential anti-aging effects have been discovered, including metformin, rapamycin, spermidine, and senolytics (drugs that eliminate senescent cells). However, currently only a few of these drugs have entered clinical trials, and progress is slow. Therefore, there is an urgent need to develop novel and effective small-molecule anti-aging drugs. The discovery of highly effective anti-aging drugs remains a major scientific problem that urgently needs to be solved.

[0004] CN 115322208 B discloses a class of 2-aminothiazole derivatives and their application in the preparation of drugs for treating dementia symptoms. However, the anti-aging efficacy of these compounds has not yet been disclosed. Summary of the Invention

[0005] The purpose of this invention is to address the above-mentioned shortcomings of the prior art by providing the application of 2-aminothiazole derivatives in the preparation of anti-aging drugs.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] The application of 2-aminothiazole derivatives represented by formula (I) in the preparation of anti-aging drugs.

[0008] Wherein, Z is H or a C1-C3 alkyl group;

[0009] R 1 R 3 and R 4 It is H or halogen;

[0010] R 2 -N(H)-C(O)-R, substituted or unsubstituted 5 R 5 Selected from C6~C 10 Aryl or C2~C 10 Heteroaryl; the substituent is selected from H, halogen, -CN, -NO2, -OH, -COOH, -NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -N(H)-C(O)-C1-C3 alkyl or C1-C6 alkylamino.

[0011] As a preferred embodiment of the present invention, Z is H, R 1 R 3 and R 4 For H, R 2 -N(H)-C(O)-R, substituted or unsubstituted 5 R 5 Selected from C6~C 10 Aryl or C2~C 10 Heteroaryl; the substituent is selected from H, halogen, -CN, -NO2, -OH, -COOH, -NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -N(H)-C(O)-C1-C3 alkyl or C1-C6 alkylamino.

[0012] As a further preferred embodiment of the present invention, R 2 -N(H)-C(O)-R, substituted or unsubstituted 5 R 5 The substituent is selected from benzene, pyridine, pyrazine, thiophene, pyrazole, thiazole, pyrimidine, naphthalene, furan, pyrrole, indene, quinoline, or indole; the substituent is selected from H, halogen, -CN, -NO2, -OH, -COOH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -N(H)-C(O)-C1-C4 alkyl, or C1-C4 alkylamino.

[0013] As a further preferred embodiment of the present invention, Z is H, and R is... 1 R 3 and R 4 For H, the R mentioned 5 It is selected from pyridine, 5-cyanopyridine, 5-fluoropyridine, 5-chloropyridine, 5-methoxypyridine, 5-methylpyridine, 3,5-dichloropyridine, 5-methoxypyrazine, 3-chloro-5-methylpyridine, and phenyl.

[0014] In some embodiments of the present invention, the 2-aminothiazole derivatives are selected from any one of the following:

[0015] As a further preferred embodiment of the present invention, the 2-aminothiazole derivative is used in the preparation of drugs to improve age-related cognitive impairment and short- and long-term learning and memory impairment, and to alleviate neuroinflammation.

[0016] As a further preferred embodiment of the present invention, the 2-aminothiazole derivative is used in the preparation of drugs that alleviate microglial senescence, reduce the accumulation of senescence-related β-galactosidase in senescent cells, reduce the secretion of senescence-related secretory phenotypes, and improve apoptosis and oxidative stress loss in senescent cells. Beneficial effects:

[0017] This invention provides the application of the 2-aminothiazole derivatives shown in formula (I) in the preparation of anti-aging drugs. Experiments have demonstrated that the representative compounds A1-A10 of the 2-aminothiazole derivatives of this invention can effectively alleviate microglial senescence in vitro, reduce the accumulation of senescence-related β-galactosidase in senescent cells, reduce the secretion of senescence-related secretory phenotypes, and improve apoptosis and oxidative stress loss in senescent cells. In in vivo experiments in mice, compounds A1-A10 can significantly improve age-related cognitive impairment and short- and long-term learning and memory impairment, reduce the transcriptional expression level of pro-inflammatory factors in the brain, and alleviate neuroinflammation. Attached Figure Description

[0018] Figure 1. Changes in β-galactosidase in senescent cells after intervention with compounds A1-A10. A. β-galactosidase staining assay to detect the β-galactosidase content in senescent HMC3 cells after intervention with compounds A1-A10. B. Quantitative graph of β-galactosidase content in senescent HMC3 cells after intervention with compounds A1-A10, detected by β-galactosidase staining assay. Statistical data are expressed as mean ± standard deviation (n=4). *P<0.05 indicates a significant difference compared to the control group, and #P<0.05 indicates a significant difference compared to the model group.

[0019] Figure 2. Effects of compound A1-A10 intervention on senescence-associated secretory phenotype (SASP) secretion in senescent cells. A. qPCR detection of Il1β secretion in senescent HMC3 cells after compound A1-A10 intervention. B. qPCR detection of Mcp1 secretion in senescent HMC3 cells after compound A1-A10 intervention. Statistical data are expressed as mean ± standard deviation (n=4). *P<0.05 indicates significant difference compared to the control group, and #P<0.05 indicates significant difference compared to the model group.

[0020] Figure 3. Protective effect of compounds A1-A10 against etoposide-induced HMC3 cell damage. A. MTT assay was used to detect cell viability of senescent HMC3 cells treated with compound A1-A10 for 24 h. B. Flow cytometry was used to detect the apoptosis rate of senescent HMC3 cells treated with compound A1-A10 for 24 h. Statistical data are expressed as mean ± standard deviation (n=4). * P<0.05 indicates a significant difference compared to the control group. # P<0.05 indicates a significant difference compared to the model group.

[0021] Figure 4. Alleviating effect of compounds A1-A10 on oxidative stress damage in senescent cells. A. Live-cell imaging detection of reactive oxygen species (ROS) changes in a senescent HMC3 cell model treated with compounds A1-A10 for 24 h. B. Quantitative graph of ROS changes in a senescent HMC3 cell model treated with compounds A1-A10 for 24 h using live-cell imaging. Statistical data are expressed as mean ± standard deviation (n=4). * P<0.05 indicates a significant difference compared to the control group. # P<0.05 indicates a significant difference compared to the model group.

[0022] Figure 5. The alleviating effect of compounds A1-A10 on cognitive abilities in aging mice. The AY maze test was used to examine the effect of compound A1-A10 intervention on short-term memory cognitive abilities in aging mice. B. The novel object recognition test was used to examine the effect of compound A1-A10 intervention on environmental perception memory abilities in aging mice. Statistical data are expressed as mean ± standard deviation (n = 10). * P<0.05 indicates a significant difference compared to the control group. # P<0.05 indicates a significant difference compared to the model group.

[0023] Figure 6. The alleviating effect of compounds A1-A10 on long-term learning, memory, and cognitive abilities in aging mice. A. Water maze test to assess the latency of aging mice to reach the platform during the test phase after intervention with compounds A1-A10. B. Water maze test to assess the swimming route of aging mice to reach the platform during the test phase after intervention with compounds A1-A10. Statistical data are expressed as mean ± standard deviation (n = 10). * P<0.05 indicates a significant difference compared to the control group. # P<0.05 indicates a significant difference compared to the model group.

[0024] Figure 7. The alleviating effect of compound A1-A10 intervention on neuroinflammation in the brain of aging mice. A. Effect of compound A1-A10 intervention on the level of pro-inflammatory factor Il1β in the brain of aging mice by qPCR. B. Effect of compound A1-A10 intervention on the level of pro-inflammatory factor Tnf in the brain of aging mice by qPCR. Statistical data are expressed as mean ± standard deviation (n = 6). * P<0.05 indicates a significant difference compared to the control group. # P<0.05 indicates a significant difference compared to the model group. Detailed Implementation

[0025] The structures of compounds A1-A10 are shown below, and the preparation methods are described in Example 202110510040.0.

[0026] Example 1.

[0027] Studies have reported that senescence-associated β-galactosidase (SA-β-Gal) accumulates and increases in cells during cellular senescence. This study investigated the effects of compounds A1-A10 on senescence-associated β-galactosidase in senescent cells using cellular β-galactosidase staining.

[0028] HMC3 cells in the logarithmic growth phase were seeded into 6-well plates at a seeding density of 2 x 10⁻⁶ cells per well. 6 Once the cells reached 80% confluence, they were induced with 1 μM etoposide. After 12 hours of induction, the medium was replaced with complete medium, and 50 μM of compounds A1-A10 were added for intervention. The control group received a corresponding volume of solvent. Forty-eight hours after administration, the cell senescence β-galactosidase staining kit (Beyotime, C0602) was used for detection, and staining was performed according to the instructions. The cell culture medium was aspirated, and the cells were washed once with PBS. 1 mL of β-galactosidase staining fixative was added, and the cells were fixed at room temperature for 15 minutes. The fixative was aspirated, and the cells were washed three times with PBS for 3 minutes each time. 1 mL of staining working solution (10 μL staining solution A, 10 μL staining solution B, 930 μL staining solution C, and 50 μL X-Gal solution) was added to each well, and the cells were incubated overnight at 37°C. After incubation, the staining results were observed under a regular optical microscope.

[0029] As shown in Figures 1A and 1B, the β-galactosidase staining experiment of cell senescence showed that the intervention of compound A1-A10 could significantly reduce the accumulation of intracellular β-galactosidase.

[0030] Example 2.

[0031] Studies have reported an increase in senescence-associated secretory phenotype (SASP) secretion during cellular senescence. This study used real-time quantitative PCR to detect the effect of compound A1-A10 intervention on SASP secretion in senescent cells.

[0032] HMC3 cells in the logarithmic growth phase were seeded into 12-well plates at a seeding density of 4 x 10⁻⁶ cells per well. 5 Once cell confluence reached 80%, cells were induced with 1 μM etoposide. After 12 hours of induction, the medium was replaced with complete medium, and 50 μM of compound A1-A10 was added for intervention for 48 hours. The control group received a corresponding volume of solvent. Adherent cell samples were washed with PBS, and 500 μL of RNA isolater Total RNA Extraction Reagent was added for collection. Cells were then incubated on ice for 10 min for lysis. RNA was extracted from the treated cell samples using chloroform and isopropanol according to the reagent instructions. After washing with 75% ethanol, the RNA precipitate was dissolved in DEPC water. RNA concentration and purity were detected using Nanodrop, and RNA concentration was homogenized among different samples. RNA reverse transcription and amplification were performed using the RT SuperMix for qPCR and Taq Pro Universal SYBR qPCR Master Mix according to the manufacturer's instructions. Both reverse transcription and quantitative real-time PCR were performed using a Bio-Rad real-time PCR instrument. Primers were designed and their specificity validated using the NCBI website, and were adjusted according to the internal control using 2... -△△Ct The relative expression level of the target gene is calculated using this method.

[0033] ① Reverse transcription: Prepare a 20 μL mixture in an RNase-free centrifuge tube, including template RNA (1 μg), 4×g DNA wiper Mix (4 μL), and RNase-free water (to a final volume of 16 μL). Incubate at 42°C for 2 min, then add 4 μL of 5×g DNA wiper mix. III qRT SuperMix, mix thoroughly by blowing, incubate at 37°C for 15 min, then incubate at 85°C for 5 s.

[0034] ② Quantitative real-time PCR reaction:

[0035] The fluorescence quantitative reaction system (20 μL) was prepared as shown in the table below.

[0036] Perform the qPCR reaction according to the following procedure.

[0037] ③ Results were obtained using the cell's own GAPDH as an internal reference, with 2 -△△CtThe method calculates the relative expression level of the target gene in cells.

[0038] As shown in Figures 2A and 2B, qPCR results indicate that intervention with compound A1-A10 significantly reduced the secretion of pro-inflammatory factors Il1β and Mcp1 by senescent cells.

[0039] Example 3

[0040] 3.1 MTT assay to detect the effect of compound A1-A10 on etoposide-induced senescence-induced damage to HMC3 cell viability

[0041] HMC3 cells in the logarithmic growth phase were seeded into 96-well plates, with 5 × 10⁶ cells per well. 3 Cells were cultured in 6 replicates per experimental group, with 100 μL of cells per well. Once cell confluence reached 80%, cells were induced with 1 μM etoposide. After 12 hours of induction, the medium was replaced with complete medium, and 50 μM of compound A1-A10 was added for intervention. The control group received the same volume of solvent. After 48 hours of treatment, the medium was aspirated, and complete medium containing 0.5 mg / mL MTT was added. The 96-well plate was incubated at 37°C for 4 hours. The medium was then removed, and 150 μL of DMSO was added to each well. The plate was shaken at 37°C to dissolve any crystals. After the 96-well plate cooled to room temperature, the absorbance at 490 nm was measured using an automated microplate reader to calculate cell viability.

[0042] 3.2. Annexin V FITC / PI double staining method to detect the effect of compounds A1-A10 on etoposide-induced senescence-induced apoptosis in HMC3 cells.

[0043] HMC3 cells in logarithmic growth phase were seeded into 6-well plates, with 3 replicates per experimental group, and cultured overnight. The next day, when cell adhesion was observed under a microscope, cells were induced with 1 μM etoposide. After 12 hours of induction, the medium was replaced with complete medium, and 50 μM of compound A1-A10 was added for intervention. The control group received the same volume of solvent. After 48 hours of treatment, the adherent cells were digested and collected, washed once with pre-cooled PBS, and centrifuged, discarding the supernatant. The cells were gently resuspended in 500 μL of Annexin V-FITC binding buffer, and 5 μL of Annexin V-FITC and 10 μL of propidium iodide staining solution were added and gently mixed. The cells were incubated at room temperature in the dark for 10-20 min, and the apoptosis rate was calculated using flow cytometry.

[0044] In this embodiment, an etoposide-induced senescent HMC3 cell model was treated with compound A1-A10 for 24 h to investigate the effects of compound A1-A10 on senescent cell damage and apoptosis. As shown in Figure 3A, compared with the model group, compound A1-A10 significantly increased the cell viability of senescent cells, as measured by the MTT assay.

[0045] The effect of compound A1-A10 treatment on apoptosis was then examined by flow cytometry. As shown in Figure 3B, compound A1-A10 significantly reduced the apoptosis rate compared with the senescence-damaged model group.

[0046] Example 4. Live-cell imaging to detect the effect of compound A1-A10 on intracellular ROS in senescent cells

[0047] HMC3 cells in the logarithmic growth phase were seeded into 6-well plates at a seeding density of 2 x 10⁻⁶ cells per well. 6 Once cell confluence reached 80%, cells were induced with 1 μM etoposide. After 12 hours of induction, the medium was replaced with complete medium, and 50 μM of compound A1-A10 was added for intervention. The control group received a corresponding volume of solvent. Forty-eight hours after drug administration, reactive oxygen species (ROS) were detected using a reactive oxygen species (ROS) detection kit (Beyotime, S0033), following the manufacturer's instructions. DCFH-DA was diluted 1:1000 with serum-free culture medium to a final concentration of 10 μM. The cell culture medium was removed, and 1 mL of diluted DCFH-DA was added to each well. The 6-well plate was incubated at 37°C for 20 minutes. Cells were washed three times with serum-free cell culture medium to thoroughly remove any DCFH-DA that had not entered the cells. Intracellular ROS levels were observed using a live-cell imaging system with an excitation wavelength of 488 nm and an emission wavelength of 525 nm.

[0048] Studies have shown that during the cellular senescence process, intracellular oxidative stress levels increase and reactive oxygen species (ROS) release increases, as shown in Figures 4A and 4B. Live cell imaging results indicate that after etoposide-induced senescence of HMC3 cells, the level of ROS in the cytoplasm increases, and after intervention with compounds A1-A10, the production of ROS is significantly reduced.

[0049] Example 5.

[0050] 5.1 Intervention with compound A1-A10 in aging mice

[0051] Twenty-two-month-old c57BL6J mice were selected as an aging animal model, and eight-week-old c57bL6J mice were selected as a normal control group. Each group consisted of ten mice, half male and half female. Ten compounds were dissolved in a composite solution (dimethyl sulfoxide: polyethylene glycol 200: Tween-20: physiological saline, 500:4000:500:5000). The compounds were administered via gavage at a dose of 20 mg / kg, once daily, according to the mice's body weight. After two months of treatment, behavioral tests were performed to examine the effects of compounds A1-A10 on cognitive and memory function in aging mice.

[0052] 5.2 Effects of Y-maze test on the short-term memory of compound A1-A10 administration in aging mice

[0053] The Y-maze consists of three arms of equal length, allowing mice to move freely within them. Each arm forms a 120° angle and is open at the top for video recording. All three inner arms and the bottom are painted black. A mouse is placed at the end of any arm of the Y-maze and allowed to explore freely for 8 minutes. The camera system records the animal's exploration behavior during these 8 minutes, recording the following indicators: ① Total number of arm entries: The total number of times the mouse enters an arm is recorded, defined as all four of the mouse's feet entering the arm. ② Number of correct arm entries in sequence: The number of times the mouse consecutively enters all three arms of the Y-maze. The score for spontaneous arm entry in sequence is calculated as (Number of correct arm entries in sequence / Total number of arm entries) x 100%. These indicators are used to evaluate the mouse's memory and cognitive abilities.

[0054] 5.3. Effects of administration of novel object recognition and detection compound A1-A10 on environmental perception and memory in aging mice

[0055] Before the formal experiment, mice were placed in a square open space and allowed to move freely for 10 minutes to adapt to the new environment, ensuring data stability. At the start of the experiment, a cylinder was placed in each of two adjacent corners of the open space, and the mice were then placed back in the center. Using a camera system, the time spent by the mice exploring the cylinders was recorded over 5 minutes. Touching the object or approaching it within approximately 2-3 cm was considered exploration. After exploration, one hour later, one of the cylinders in the open space was replaced with a cuboid (a new object), and the time spent exploring the new and old objects was recorded separately. The ratio of the time spent exploring the new object to the total exploration time was calculated for data analysis.

[0056] Compound A1-A10 was orally administered to 22-month-old naturally aging mice. The short-term memory cognitive ability of the mice was assessed using a Y-maze test, and their environmental perception and memory abilities were assessed using a novel object recognition test. As shown in Figure 5A, the Y-maze results indicated that compound A1-A10 improved the short-term memory cognitive ability of aging mice. As shown in Figure 5B, the novel object recognition test results indicated that compound A1-A10 improved the environmental perception and memory abilities of aging mice.

[0057] Example 6. Effects of water maze test on the long-term learning, memory, and cognitive abilities of aging mice after administration of compounds A1-A10.

[0058] The water maze system mainly consists of a black circular pool, a white aqueous solution dyed with titanium dioxide powder, a circular hidden platform 1 cm underwater, and a video analysis system. The experimental maze is divided into four quadrants. We systematically changed the platform's position within each quadrant daily, designating the quadrant containing the platform as the third quadrant. The day before the formal experiment, mice were placed in the pool to swim and acclimatize. The water maze testing period lasted six days, including five consecutive days of hidden platform training and a sixth day of exploration. During the hidden platform training, mice were given 90 seconds to swim and locate the target platform four times. Each mouse entered the pool from the position opposite the platform in the first quadrant. Timing started from the moment the mouse entered the pool, and the video analysis system automatically recorded the time it took for the mouse to successfully climb onto the platform. If a mouse could not reach the platform within 90 seconds, it was manually guided to the target location and allowed to stay on the platform for 30 seconds, using markers around the pool to locate its position. On the sixth day, the exploration experiment was conducted, using video tracking technology to record and analyze parameters such as latency, path length, swimming speed, time spent in the target quadrant, and movement trajectory. After each water maze experiment, the mice were dried with a dry towel to improve their adaptability to the experiment.

[0059] As shown in Figure 6A, intervention with compounds A1-A10 significantly shortened the latency for AD mice to reach the platform during the water maze test. Furthermore, as shown in Figure 6B, intervention with compounds A1-A10 significantly shortened the path to the platform, indicating that compounds A1-A10 can significantly improve the cognitive abilities and long-term learning and memory abilities of AD mice.

[0060] Example 7.

[0061] Neuroinflammation is a core pathological feature of neurodegenerative diseases. Senescence-associated secretory phenotypes (SASPs) secreted by senescent cells are major drivers of neuroinflammation and further induce senescence in surrounding cells. This study investigated the effects of compound A1-A10 on neuroinflammation in senescent mouse brains by administering it via gavage and then using qPCR to detect the levels of inflammatory factors in the mouse brains.

[0062] Fresh mouse brain tissue was weighed using a grinding tube, and 1 ml of RNA extraction reagent and grinding beads (purchased from Novizan) were added. The mixture was then placed in a cryogenic grinder and ground at low temperature. After grinding, 200 μL of chloroform was added to the grinding tube. The mixture was vigorously shaken for 15 seconds to form an emulsion. After standing at 4°C for 5 minutes, it was centrifuged for 15 minutes (centrifugation conditions: 11200 rpm, 4°C). The grinding tube was then removed. At this point, the solution had separated into three layers: a colorless aqueous phase (upper layer), a white middle layer, and a red organic layer (lower layer). The upper aqueous phase was transferred to a new 1.5 ml centrifuge tube, and an equal volume of pre-chilled isopropanol was added. The mixture was inverted to mix thoroughly, and after standing at 4°C for 10 minutes, it was centrifuged for 10 minutes (centrifugation conditions: 11200 rpm, 4°C). A white precipitate was usually observed. The supernatant was discarded, and 1 ml of 75% ethanol was added. Gently tap the bottom of the tube to suspend the precipitate, and invert it several times. Let it stand at room temperature for 3-5 minutes, then centrifuge for 10 minutes (11200 rpm, 4℃), discarding the supernatant. Dry the precipitate in a clean, open environment at room temperature for 2-5 minutes. Add 20 μL of enzyme-free water to dissolve the precipitate. After complete dissolution, take a small amount for testing, and store the remainder at -85 to -65℃.

[0063] The extracted RNA was added to a reverse transcription reagent purchased from Novizan according to its concentration. II Q Select RT SuperMix for qPCR (+gDNA wiper) was used to prepare a reverse transcription system, and the reverse transcription was performed to cDNA according to the programmed procedure. Real-time quantitative PCR was performed using Taq Pro Universal SYBR qPCR premix from Novizan. The PCR protocol consisted of initial denaturation at 95°C for 30 seconds, followed by 40 amplification cycles, each consisting of denaturation at 95°C for 5 seconds, annealing at 60°C for 30 seconds, and extension at 72°C for 30 seconds. These PCR reactions were performed using a CFX96 real-time quantitative PCR detection system. To determine relative expression changes, 2... -ΔΔCt The method was used, and GAPDH was used as an endogenous control gene for normalization.

[0064] As shown in Figure 7A, qPCR results indicate that compared to young mice, the expression of the pro-inflammatory factor Il1β is increased in the brains of aged mice, and intervention with compound A1-A10 can significantly reduce the expression of Il1β. As shown in Figure 7B, qPCR results indicate the content of the pro-inflammatory factor Tnf in the brains of aged mice, suggesting that compound A1-A10 can significantly alleviate neuroinflammation in the brains of aged mice.

Claims

1. The application of the 2-aminothiazole derivatives shown in formula (I) in the preparation of anti-aging drugs. in, Z is H or a C1-C3 alkyl group; R 1 R 3 and R 4 It is H or halogen; R 2 -N(H)-C(O)-R, substituted or unsubstituted 5 R 5 Selected from C6~C 10 Aryl or C2~C 10 Heteroaryl; the substituent is selected from H, halogen, -CN, -NO2, -OH, -COOH, -NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -N(H)-C(O)-C1-C3 alkyl or C1-C6 alkylamino.

2. The application according to claim 1, characterized in that, in, Z is H, R 1 R 3 and R 4 For H, R 2 -N(H)-C(O)-R, substituted or unsubstituted 5 R 5 Selected from C6~C 10 Aryl or C2~C 10 Heteroaryl; the substituent is selected from H, halogen, -CN, -NO2, -OH, -COOH, -NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -N(H)-C(O)-C1-C3 alkyl or C1-C6 alkylamino.

3. The application according to claim 2, characterized in that, R 2 -N(H)-C(O)-R, substituted or unsubstituted 5 R 5 The substituent is selected from benzene, pyridine, pyrazine, thiophene, pyrazole, thiazole, pyrimidine, naphthalene, furan, pyrrole, indene, quinoline, or indole; the substituent is selected from H, halogen, -CN, -NO2, -OH, -COOH, -NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -N(H)-C(O)-C1-C4 alkyl, or C1-C4 alkylamino.

4. The application according to claim 3, characterized in that: The 2-aminothiazole derivatives mentioned above are selected from any one of the following:

5. The application according to claim 4, characterized in that, The application of the 2-aminothiazole derivatives in the preparation of drugs to improve age-related cognitive impairment and short- and long-term learning and memory impairment, and to alleviate neuroinflammation.

6. The application according to claim 4, characterized in that, The application of the 2-aminothiazole derivatives in the preparation of drugs that alleviate microglial senescence, reduce the accumulation of senescence-related β-galactosidase in senescent cells, reduce the secretion of senescence-related secretory phenotypes, and improve apoptosis and oxidative stress loss in senescent cells.

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