Application of organic compound in preparation of medicine for preventing or treating neuroinflammation and related diseases

Abstract

The invention relates to application of an organic compound in preparation of a medicine for preventing or treating neuroinflammation related diseases, and belongs to the technical field of medicinal chemistry. It is found that the organic compound with the chemical structural formula shown in the formula (I)-(IV) can remarkably inhibit the expression level of proinflammatory factors and chemotactic factors in a microglial cell inflammation model and has a broad-spectrum anti-inflammatory effect, and therefore the organic compound has the effect of preventing or treating neuroinflammation related diseases. The invention develops new application of the organic compounds as shown in the formulas (I)-(IV), and also provides a new therapeutic drug for preventing or treating neuroinflammation related diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to the use of an organic compound in preparing a drug for preventing or treating neuroinflammatory diseases. Background Art

[0002] Microglia, as representatives of the resident macrophage population in the central nervous system (CNS), are believed to play a role in host defense and tissue repair. However, overactivation of microglia is thought to be the cause of inflammation-mediated brain tissue damage, and chronic activation of these cells is involved in the development and progression of various neurodegenerative diseases. Activated microglia can produce a variety of inflammation-related factors, including proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as chemokines such as macrophage inflammatory protein-1α (MIP-1α), monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), CXCL2, and CXCL3. These factors participate in the pathogenesis of diseases through neuroinflammatory responses.

[0003] With the in-depth exploration of the pathogenesis of various neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral infarction, progressive muscular dystrophy, Parkinson's disease and Huntington's disease in recent years, more and more research results have shown that chronic inflammatory response in the brain mediated by microglial activation is one of the pathological characteristics of neurological diseases.

[0004] Depression and neuroinflammation exhibit a bidirectional relationship, with inflammatory cytokines exacerbating depressive symptoms. Inflammation is a rapid, dynamic physiological response to stimulation. Inflammatory cytokines play a key role in this process and can induce depressive-like behaviors. Lipopolysaccharide (LPS) is a potent inducer of systemic inflammation that triggers microglial activation, cytokine release, and hippocampal neurodegeneration, thereby reproducing the key features of depression.

[0005] Although studies have shed light on a new avenue for treating neuroinflammatory diseases or symptoms, existing compounds, including anti-inflammatory drugs, particularly non-steroidal anti-inflammatory agents, still suffer from insufficient efficacy and limited safety, far from meeting the growing demand for the prevention and treatment of related diseases. Therefore, the development of new, more effective, and effective drug compounds targeting neuroinflammation has become an urgent need. Summary of the Invention

[0006] The present invention aims to overcome the shortcomings of the prior art and provide an organic compound for use in the preparation of a medicament for preventing or treating neuroinflammatory diseases. The present invention has discovered that organic compounds represented by chemical structures such as Formulas (I)-(IV) have the efficacy of preventing or treating neuroinflammatory diseases.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] In a first aspect, the present invention provides a use of an organic compound in the preparation of a medicament for preventing or treating a neuroinflammatory disease, wherein the organic compound is at least one of the organic compounds represented by formula (I) to (IV) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] In the organic compound represented by the chemical structure of formula (IV), R1, R2, and R3 are each independently selected from hydrogen, C1-C6 alkyl, or C1-C6 alkoxy. For example, the C1-C6 alkyl group may be methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), n-butyl (-CH2CH2CH2CH3), n-pentyl (-(CH2)4CH … ), n-hexyl (-(CH2)5CH3), isopropyl (-CH(CH3)2), sec-butyl (-CH(CH3)CH2CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-C(CH3)3), neopentyl (-CH2C(CH … )3). For example, the C1-C6 alkoxy group may be any one of a methoxy group (-OCH3), an ethoxy group (-OCH2CH3), a n-propoxy group (-OCH2CH2CH3), a n-butoxy group (-O(CH2)3CH3), a n-pentoxy group (-O(CH2)4CH3), a n-hexyloxy group (-O(CH2)5CH3), an isopropoxy group (-OCH(CH3)2), a sec-butoxy group (-OCH(CH3)CH2CH3), a tert-butoxy group (-OC(CH3)3), and a neopentoxy group (-OCH2C(CH3)3).

[0011] The organic compound represented by formula (I) of the present invention has a 1,4-benzothiazin-3-one structure; the organic compound represented by formula (II) has a 2-heteroaryl-4-aminoquinazoline structure; the organic compound represented by formula (III) has a pyridazinone, homopiperazine, and dihydroindole structure; and the organic compound represented by formula (IV) has a phthalazinone structure. The present invention has discovered that organic compounds containing these structures and represented by formulas (I)-(IV) have the effect of inhibiting the expression levels of proinflammatory factors (IL-1β, IL-6, TNF-α) and chemokines (MCP-1, CXCL2, CXCL3) in a microglial cell inflammation model. These factors are key markers of neuroinflammation. The organic compounds represented by formulas (I)-(IV) of the present invention all exhibit significant anti-neuroinflammatory activity and efficacy. Therefore, the use of organic compounds represented by formulas (I)-(IV) can effectively prevent or treat neuroinflammation-related diseases.

[0012] As a preferred embodiment of the first aspect, R1, R2, and R3 in the organic compound having the chemical structure shown in formula (IV) are all methyl groups, and the specific structure thereof is shown in formula (a):

[0013]

[0014] When R1, R2, and R3 of an organic compound represented by a chemical formula (IV) are all methyl groups, the compound has a chemical structure as represented by formula (a). When the compound represented by formula (a) is used, its effect on inhibiting the expression levels of proinflammatory factors and chemokines is superior to that when R1, R2, and R3 are other groups. Therefore, when R1, R2, and R3 are all methyl groups, the effectiveness of the organic compound represented by formula (IV) in preventing or treating neuroinflammatory diseases can be enhanced.

[0015] As a preferred embodiment of the first aspect, R1, R2, and R3 in the organic compound having the chemical structure shown in formula (IV) are all hydrogen, and its specific structure is shown in formula (b):

[0016]

[0017] When R1, R2, and R3 of the organic compound represented by the chemical formula (IV) are all hydrogen, the compound has the chemical structure represented by formula (b). The compound represented by formula (b) of the present invention also has the effect of inhibiting the expression levels of pro-inflammatory factors and chemokines. Therefore, when R1, R2, and R3 are all hydrogen, the compound represented by formula (b) also has the effect of preventing or treating neuroinflammatory diseases.

[0018] As a preferred embodiment of the first aspect, R1, R2, and R3 in the organic compound having the chemical structure shown in formula (IV) are all methoxy groups (-OCH3), and the specific structure thereof is shown in formula (c):

[0019]

[0020] When R1, R2, and R3 of the organic compound represented by the chemical formula (IV) are all methoxy groups, the compound has the chemical structure represented by formula (c). The compound represented by formula (c) of the present invention also has the effect of inhibiting the expression levels of proinflammatory factors and chemokines. Therefore, when R1, R2, and R3 are all methoxy groups, the compound represented by formula (c) also has the effect of preventing or treating neuroinflammatory diseases.

[0021] As a preferred embodiment of the first aspect, the organic compound having the chemical structure shown in formula (IV) wherein R1 is hydrogen, R2 is methyl, and R3 is methoxy, has a specific structure as shown in formula (d):

[0022]

[0023] When R1 of the organic compound represented by the chemical formula (IV) is hydrogen, R2 is methyl, and R3 is methoxy, it has the chemical structure represented by the formula (d). The compound represented by the formula (d) of the present invention also has the effect of inhibiting the expression levels of pro-inflammatory factors and chemokines. Therefore, when R1 is hydrogen, R2 is methyl, and R3 is methoxy, the compound represented by the formula (d) also has the effect of preventing or treating neuroinflammatory diseases.

[0024] As a preferred embodiment of the first aspect, the organic compound having the chemical structure shown in formula (IV) wherein R1 is a methoxy group, R2 is a methyl group, and R3 is hydrogen, has a specific structure as shown in formula (e):

[0025]

[0026] When R1 of an organic compound represented by a chemical formula (IV) is a methoxy group, R2 is a methyl group, and R3 is hydrogen, the compound has a chemical structure represented by formula (e). The compound represented by formula (e) of the present invention also has the effect of inhibiting the expression levels of pro-inflammatory factors and chemokines. Therefore, when R1 is a methoxy group, R2 is a methyl group, and R3 is hydrogen, the compound represented by formula (e) also has the effect of preventing or treating neuroinflammatory diseases.

[0027] As a preferred embodiment of the first aspect, in the organic compound having the chemical structure shown in formula (IV), R1 is n-butyl (-CH2CH2CH2CH3), R2 is ethoxy (-OCH2CH3), and R3 is isopropoxy (-OCH(CH3)2), and its specific structure is shown in formula (f):

[0028]

[0029] When R1 of the organic compound represented by the chemical structure of formula (IV) is a n-butyl group (-CH2CH2CH2CH3), R2 is an ethoxy group (-OCH2CH3), and R3 is an isopropoxy group (-OCH(CH3)2), it has a chemical structure represented by formula (f). The compound represented by formula (f) of the present invention also has the effect of inhibiting the expression levels of pro-inflammatory factors and chemokines. Therefore, when R1 is a n-butyl group (-CH2CH2CH2CH3), R2 is an ethoxy group (-OCH2CH3), and R3 is an isopropoxy group (-OCH(CH3)2), the compound represented by formula (f) also has the effect of preventing or treating neuroinflammatory-related diseases.

[0030] As a preferred embodiment of the first aspect, the neuroinflammation-related disease is at least one of Alzheimer's disease, Parkinson's disease, depression, anxiety, obsessive-compulsive disorder, and schizophrenia.

[0031] Studies have shown that Alzheimer's disease, Parkinson's disease, depression, anxiety, obsessive-compulsive disorder and schizophrenia are all caused by over-activated microglia producing inflammation-mediated neuroinflammation, which leads to brain tissue damage. High levels of pro-inflammatory factors (such as TNF-α, IL-1β and IL-6) and chemokines (such as MCP-1, CXCL2, CXCL3) can be detected in the patient's brain tissue. These factors participate in the pathogenesis of these diseases through neuroinflammatory reactions. Therefore, alleviating or inhibiting microglial inflammation as a target for treating neuroinflammatory-related diseases can achieve the purpose of treating Alzheimer's disease, Parkinson's disease, depression, anxiety, obsessive-compulsive disorder and schizophrenia. Since the organic compounds shown in formula (I)-(IV) of the present invention can significantly reduce pro-inflammatory factors and chemokines, the purpose of preventing or treating the above-mentioned neuroinflammatory-related diseases can be achieved.

[0032] In a second aspect, the present invention provides a pharmaceutical composition comprising at least one of the organic compounds represented by formula (I)-(IV) and a medically acceptable excipient.

[0033] As a preferred embodiment of the second aspect, the medically acceptable excipient is at least one of an emulsifier, a disintegrant, a glidant, a preservative, a sustained-release material, and a transdermal enhancer.

[0034] As a preferred embodiment of the second aspect, the pharmaceutical composition further comprises a second drug, which is any one of a drug for treating Alzheimer's disease, a drug for treating Parkinson's disease, a drug for treating depression, a drug for treating anxiety, a drug for treating obsessive-compulsive disorder, and a drug for treating schizophrenia.

[0035] The combined use of the organic compounds represented by formula (I)-(IV) of the present invention and other drugs for treating neuroinflammatory diseases has a synergistic effect, which can significantly improve the therapeutic effect and increase the utilization rate of the drugs.

[0036] As a preferred implementation manner of the second aspect, the drugs for treating Alzheimer's disease include donepezil, lencanerzumab, donepezil, mannuronate sodium, oxiracetam, and piracetam.

[0037] As a preferred implementation manner of the second aspect, the drugs for treating Parkinson's disease include levodopa, pramipexole, ropinirole, piribedil, rasagiline, selegiline, pracilizumab, and ambroxol.

[0038] As a preferred embodiment of the second aspect, the drugs for treating depression include atipamezole, mirtazapine, bazinaprine, benfuralin, difemelane, benedarine, biperatol, brofarmine, caroxadone, cypermethrin, cypromine, simoxadone, citalopram, clometholone, and clovotamine.

[0039] As a preferred implementation manner of the second aspect, the drugs for treating anxiety disorders include paroxetine, sertraline, escitalopram, fluoxetine, venlafaxine, duloxetine, alprazolam, lorazepam, and clonazepam.

[0040] As a preferred implementation manner of the second aspect, the drugs for treating obsessive-compulsive disorder include paroxetine, fluvoxamine, aripiprazole, and risperidone.

[0041] As a preferred implementation manner of the second aspect, the drugs for treating schizophrenia include haloperidol, chlorpromazine, perphenazine, penfluridol, clozapine, and quetiapine.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] The present invention finds that organic compounds with chemical structures such as those shown in formula (I)-(IV) can significantly inhibit proinflammatory factors and chemokines in microglial inflammation models, and have the effect of treating or preventing neuroinflammation-related diseases. The present invention has developed new uses for organic compounds such as those shown in formula (I)-(IV), which have the effect of treating or preventing neuroinflammation-related diseases. At the same time, the compounds of formula (I)-(IV) provided by the present invention have the ability to effectively antagonize microglia-mediated neuroinflammation. Based on the significant anti-neuroinflammatory activity exhibited in in vitro models and the close association between the inflammatory pathways they target and the pathological mechanism of depression, the compounds of formula (I)-(IV) have the potential to prevent and / or treat neuroinflammation-related diseases (including depression); the application prospects of developing the compounds for the treatment of depression mediated by excessive microglial activation and the release of proinflammatory cytokines. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is a graph showing the results of detecting the mRNA expression levels of key pro-inflammatory cytokines and chemokines in BV2 cells using real-time fluorescence quantitative PCR of organic compounds in Example 1;

[0045] Figure 2 This is a graph showing the results of detecting the mRNA expression levels of key pro-inflammatory cytokines and chemokines in BV2 cells using real-time fluorescence quantitative PCR of organic compounds in Example 2;

[0046] Figure 3 This is the result of detecting the mRNA expression levels of key pro-inflammatory cytokines and chemokines in BV2 cells by real-time fluorescence quantitative PCR using organic compounds in Example 3;

[0047] Figure 4 This is the result of real-time fluorescence quantitative PCR detection of key pro-inflammatory cytokines and chemokines in BV2 cells using organic compounds in Example 4. DETAILED DESCRIPTION

[0048] To better illustrate the purpose, technical solutions, and advantages of the present invention, the present invention will be further described below with reference to specific examples. In the examples, the following method was used to detect the inhibitory effects of different organic compounds on microglial BV2 inflammation. The experimental process is as follows:

[0049] 1. Experimental Materials

[0050] Culture medium: DMEM high glucose medium (Merck, D6429, DMEM-high glucose) containing 10% FBS + 1% penicillin / streptomycin (PS);

[0051] Cells: Microglial cells BV2;

[0052] Compounds: Examples 1-4, Examples.

[0053] 2. Experimental methods:

[0054] 2.1 Cell processing and grouping

[0055] (1) Cell pretreatment:

[0056] BV2 cells in the logarithmic growth phase were obtained, the old culture medium was aspirated, and 10% FBS + 1% PS DMEM high-glucose culture medium was added to disperse the cells; centrifugation was performed at 300×g for 3 minutes, and the supernatant was removed and the cells were resuspended in fresh culture medium.

[0057] (2) Cell counting and plating:

[0058] 20 μl of cell suspension was taken to detect the viability (>95%) using a cell counter, and then seeded into a 6-well plate with 350,000 cells per well (volume 2 ml / well).

[0059] (3) Hunger treatment:

[0060] After 24 hours of plating, BV2 microglial cells were starved for 3 hours with DMEM high-glucose basal medium containing 1% double-antibody without FBS.

[0061] (4) Lipopolysaccharide (LPS) stimulation and grouping:

[0062] Control (NC) group: treated with complete DMEM medium;

[0063] LPS group: LPS was added to complete DMEM medium to a final concentration of 1.0 μg / mL;

[0064] Groups of compounds of formula (I)-(IV): LPS and compounds of formula (I)-(IV) were added to complete DMEM medium to a final concentration of LPS of 1.0 μg / mL and a final concentration of compounds of formula (I)-(IV) of 10 μM.

[0065] 2.2 Detection of pro-inflammatory cytokines and chemokines expression levels:

[0066] After 3 hours of treatment, the mRNA expression levels of key proinflammatory cytokines and chemokines in BV2 cells were measured by real-time quantitative PCR (RT-qPCR). Proinflammatory cytokines included interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), while chemokines included monocyte chemoattractant protein-1 (MCP-1), CXCL2, and CXCL3. The specific steps are as follows:

[0067] (1) After BV2 cells were treated, the cells were collected and centrifuged at 3000 rpm for 3 min, the supernatant was discarded, and the (15596026, Invitrogen), the cells were lysed and collected into EP tubes. After vigorous shaking, they were allowed to stand at room temperature for 5 min.

[0068] (2) Towards Add 200 μL of chloroform to the extract, shake vigorously, and let it stand at room temperature for 10 minutes; centrifuge at 12,000 g for 15 minutes, and carefully transfer the supernatant to a new EP tube; add 500 μL of isopropanol to each tube, mix by inverting, and let it stand for 10 minutes; centrifuge at 12,000 g for 10 minutes; a small amount of white precipitate will be seen at the bottom of the EP tube;

[0069] (3) Remove the supernatant and retain the white precipitate. Add 1 mL of pre-cooled 75% ethanol (prepared with diethyl pyrocarbonate (DEPC) water) and shake. Centrifuge at 7500 g for 5 minutes, remove as much residual ethanol as possible, and dry at room temperature for 5-10 minutes. Add an appropriate volume of DEPC water to each tube and dissolve it with a pipette to obtain RNA.

[0070] (4) Detect RNA concentration using spectrophotometry at A260 / A280;

[0071] (5) Thaw dT primer, RT-buffer, and dNTP in advance; Place the PCR reaction tube on ice, then add 2 μg RNA, 1 μL oligodT primer, 2 μL random primer, and 13 μL RNase-free water, mix well, incubate at 70°C for 10 min, and then immediately place in an ice bath for at least 5 min; Place the PCR reaction tube on ice and continue to add: 4 μL RT-buffer (5×), 2 μL dNTP, 0.5 μ inhibitor, 0.5 μL RTase, and perform reverse transcription according to the program of 25°C for 10 min, 50°C for 60 min, and 90°C for 5 min to obtain cDNA;

[0072] (6) cDNA was diluted approximately 4 times and used as a template;

[0073] (7) Dissolve SYBR Green I Master (2×) on ice, calculate the qPCR system, and prepare the reaction system according to the following ratio: 10.0 μL The reaction system was obtained by adding 480 SYBR Green I Master (2×), 1 μL primer (10 μm), and 8.0 μL H O;

[0074] (8) Mix gently and centrifuge slightly. Take a 96-well qPCR plate and add 19 μL of the reaction system in step (7) above to each well according to the designed spotting sequence. Add 1 μL of diluted template cDNA to each well according to the designed spotting sequence. After spotting, apply a transparent film and scrape in one direction with a scraper to seal the 96-well plate. Centrifuge at 3000 rpm for 1 min. Put the plate on the machine and run the qPCR program. After the run, exclude outliers according to the Melt curve and calculate the relative expression of genes according to the Cp value.

[0075] The primer information for the qPCR detection of pro-inflammatory factors (IL-1β, IL6, TNF-α) and chemokines (MCP-1, CXCL2, CXCL3) mRNA levels used in the examples is as follows: Table 1:

[0076] Table 1

[0077]

[0078]

[0079] Example 1

[0080] Verification of the inhibitory effect of the organic compound represented by formula (I) on inflammation in microglial cells BV2

[0081] Compound: CAS number, source and brand information are shown in the table below:

[0082] Table 2

[0083]

[0084] The experimental results of this embodiment are shown in the attached Figure 1As shown, compared with the control group (NC), the mRNA expression levels of all inflammatory factors tested (IL-1β, IL-6, MCP-1, and TNF-α) in the LPS group were statistically significantly increased (****: P < 0.0001), indicating that LPS effectively activated the inflammatory response in BV2 cells. Compared with the model group (LPS), the mRNA expression levels of all inflammatory factors tested (IL-1β, IL-6, MCP-1, and TNF-α) in the K788-7115-treated group (10 μM) were statistically significantly decreased (#: p < 0.05; ####: P < 0.0001). These results demonstrate that the organic compound represented by formula (I) of the present invention significantly inhibits the mRNA expression levels of multiple key proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and chemokines (MCP-1) in the LPS-stimulated BV2 microglial cell inflammation model. This broad-spectrum anti-inflammatory effect, especially the inhibition of core factors such as IL-1β, IL-6, and TNF-α that are highly related to the pathology of depression, indicates that the organic compound represented by formula (I) has the ability to effectively antagonize microglia-mediated neuroinflammation.

[0085] Example 2

[0086] Verification of the inhibitory effect of the organic compound represented by formula (II) on inflammation in microglial cells BV2

[0087] Compound: CAS number, source and brand information are shown in Table 3

[0088] Table 3

[0089]

[0090]

[0091] The experimental results of this embodiment are shown in the attached Figure 2As shown, compared with the control group (NC), the mRNA expression levels of all inflammatory factors tested (IL-1β, MCP-1, TNF-α, CXCL2) in the LPS group were statistically significantly increased (****: P < 0.0001), indicating that LPS effectively activated the inflammatory response of BV2 cells. Compared with the model group (LPS), the mRNA expression levels of all inflammatory factors tested (IL-1β, MCP-1, TNF-α, CXCL2) in the G725-1830 treatment group (10 μM) were statistically significantly decreased (##: P < 0.01; ###: P < 0.001; ####: P < 0.0001). The results show that in the LPS-stimulated BV2 microglial cell inflammation model, the organic compound represented by formula (II) of the present invention can significantly inhibit the mRNA expression levels of multiple key proinflammatory cytokines (IL-1β, TNF-α) and chemokines (MCP-1, CXCL2). This broad-spectrum anti-inflammatory effect, especially the inhibition of core factors such as IL-1β and TNF-α that are highly related to the pathology of depression, indicates that the organic compound represented by formula (II) has the ability to effectively antagonize microglia-mediated neuroinflammation.

[0092] Example 3

[0093] Verification of the inhibitory effect of the organic compound represented by formula (III) on inflammation in microglial cells BV2

[0094] Compounds: CAS number, source and brand information are shown in Table 4

[0095] Table 4

[0096]

[0097] The experimental results of this embodiment are shown in the attached Figure 3As shown, compared with the control group (NC), the mRNA expression levels of all inflammatory factors tested (IL-1β, IL-6, MCP-1, TNF-α, CXCL2, CXCL3) in the LPS group were statistically significantly increased (*: p < 0.05; ****: P < 0.0001), indicating that LPS effectively activated the inflammatory response of BV2 cells. Compared with the model group (LPS), the mRNA expression levels of all inflammatory factors tested (IL-1β, IL-6, TNF-α, CXCL2, CXCL3) in the F977-0801 treatment group (10 μM) were statistically significantly decreased (#: p < 0.05; ##: p < 0.01; ####: P < 0.0001). The results show that in the LPS-stimulated BV2 microglial cell inflammation model, the organic compound represented by formula (III) of the present invention can significantly inhibit the mRNA expression levels of multiple key proinflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokines (CXCL2, CXCL3). This broad-spectrum anti-inflammatory effect, especially the inhibition of core factors such as IL-1β, IL-6, TNF-α that are highly related to the pathology of depression, indicates that the organic compound represented by formula (III) has the ability to effectively antagonize microglia-mediated neuroinflammation.

[0098] Example 4

[0099] Verify the inhibitory effect of the compound of formula (a) (i.e., the organic compound represented by formula (IV)) on the inflammation of microglial cells BV2

[0100] Compound: CAS number, source and brand information are shown in Table 5

[0101] Table 5

[0102]

[0103] The experimental results of this embodiment are shown in the attached Figure 4As shown, compared with the control group (NC), the mRNA expression levels of all inflammatory factors tested (IL-1β, IL-6, MCP-1, TNF-α, CXCL2, CXCL3) in the LPS group were statistically significantly increased (*: p < 0.05; ****: P < 0.0001), indicating that LPS effectively activated the inflammatory response of BV2 cells. Compared with the model group (LPS), the mRNA expression levels of all inflammatory factors tested (IL-1β, IL-6, MCP-1, TNF-α, CXCL2, CXCL3) in the 66016-3253 treatment group (10 μM) were statistically significantly decreased (#: p < 0.05; ##: p < 0.01; ###: p < 0.001; ####: P < 0.0001). The results show that in the LPS-stimulated BV2 microglial cell inflammation model, the organic compound represented by formula (IV) of the present invention can significantly inhibit the mRNA expression levels of multiple key proinflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokines (MCP-1, CXCL2, CXCL3). This broad-spectrum anti-inflammatory effect, especially the inhibition of core factors such as IL-1β, IL-6, TNF-α, which are highly related to the pathology of depression, indicates that the organic compound represented by formula (IV) has the ability to effectively antagonize microglia-mediated neuroinflammation.

[0104] In summary, based on the significant anti-neuroinflammatory activity exhibited by the organic compounds represented by Formulas (I)-(IV) in in vitro cell models and the close association between the inflammatory pathways they target and the pathological mechanisms of depression, the compounds of Formulas (I)-(IV) have the potential to prevent and / or treat neuroinflammatory-related diseases (including depression) and have application prospects as drugs for treating depression mediated by excessive microglial activation and the release of proinflammatory cytokines.

[0105] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. Use of an organic compound in the preparation of a drug for preventing or treating a neuroinflammatory disease, characterized in that: The organic compound is at least one of the organic compounds represented by formula (I)-(IV) and pharmaceutically acceptable salts thereof: In the organic compound having the chemical structure shown in formula (IV), R1, R2 and R3 are independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkoxy.

2. The use according to claim 1, characterized in that In the organic compound represented by the chemical structure of formula (IV), R1, R2 and R3 are all methyl groups.

3. The use according to claim 1, characterized in that In the organic compound having the chemical structure shown in formula (IV), R1, R2 and R3 are all hydrogen.

4. The use according to claim 1, wherein In the organic compound having the chemical structure shown in formula (IV), R1, R2 and R3 are all methoxy groups.

5. The use according to claim 1, wherein The organic compound having the chemical structure shown in formula (IV) is characterized in that R1 is hydrogen, R2 is methyl, and R3 is methoxy.

6. The use according to claim 1, wherein In the organic compound having the chemical structure shown in formula (IV), R1 is a methoxy group, R2 is a methyl group, and R3 is hydrogen.

7. The use according to claim 1, wherein The neuroinflammation-related disease is at least one of Alzheimer's disease, Parkinson's disease, depression, anxiety, obsessive-compulsive disorder, and schizophrenia.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one of the organic compounds represented by chemical structural formulae (I) to (IV) and medically acceptable excipients.

9. The pharmaceutical composition according to claim 8, wherein The medically acceptable excipient is at least one of an emulsifier, a disintegrant, a glidant, a preservative, a sustained-release material, and a transdermal enhancer.

10. The pharmaceutical composition according to claim 8, wherein The pharmaceutical composition further includes a second drug, which is any one of a drug for treating Alzheimer's disease, a drug for treating Parkinson's disease, a drug for treating depression, a drug for treating anxiety, a drug for treating obsessive-compulsive disorder, and a drug for treating schizophrenia.

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