CN112843026A - Application of diphenyl ether compound in preparation of acetylcholinesterase inhibitor or medicament for treating Alzheimer disease - Google Patents
Application of diphenyl ether compound in preparation of acetylcholinesterase inhibitor or medicament for treating Alzheimer disease Download PDFInfo
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Abstract
The invention discloses an application of a diphenyl ether compound in preparing an acetylcholinesterase inhibitor or a medicament for treating Alzheimer disease. The invention separates the compounds expansol F (1), expansol C (2), expansol D (3) and corditol C (4) shown in formula (I) from the fermentation culture of marine fungus Aspergillus sp.BH4-11. The marine fungus Aspergillus sp.BH4-11 is preserved in Guangdong province microbial strain in 11/3/2020Collection Center (GDMCC), deposit number: GDMCC No: 61265. the four compounds have obvious inhibitory activity to acetylcholinesterase, provide alternative compounds for developing new acetylcholinesterase inhibitors, and have important significance for developing marine drug resources in China.
Description
The technical field is as follows:
the invention belongs to the field of natural products, and particularly relates to four diphenyl ether compounds and application thereof in preparation of acetylcholinesterase inhibitors or medicines for treating Alzheimer's disease.
Background art:
alzheimer's Disease (AD), i.e., senile dementia, is a cerebral degenerative disease characterized by progressive dementia, the most common age-related neurodegenerative disease, which seriously affects the cognitive function, memory function, visual function, social life ability, personal living ability, emotional personality, and the like of patients, and the number of patients with AD is increasing year by year with the rapid increase of the aged population in the world, and at present, about 4600 ten thousand of AD patients exist in the world. The number of AD patients in China is over 600 thousands, and the AD becomes the third killer threatening the health of human beings after cardiovascular and cerebrovascular diseases and malignant tumors. The currently believed most effective treatment for alzheimer's disease is to enhance cholinergic neurotransmission in the brain and reduce acetylcholine (ACh) hydrolysis. The acetylcholinesterase inhibitor can enable ACh to be accumulated and increased in content at synapses, ensures normal transmission of nerve signals in vivo, thereby improving functions of learning, memory and the like, and is a treatment medicament which is most widely clinically applied at present and achieves the purpose of relieving AD symptoms by improving the content of acetylcholine. However, the existing acetylcholinesterase inhibitor drugs have large side effects and are not beneficial to long-term administration of patients. Therefore, the search for a novel acetylcholinesterase inhibitor with more obvious activity, high selectivity and small toxic and side effects is particularly urgent. Biological resources in the special marine ecological environment become a new space for expanding natural medicinal resources, and are also the new field which is the most abundant and complete in storage and has the potential for developing new medicaments at present. The marine natural products are more and more valued and become the main source for finding important leading drugs and the basis for developing new drugs. Therefore, the natural products with acetylcholinesterase inhibition activity screened and found in the marine microorganisms have important significance for developing acetylcholinesterase inhibitors.
The invention content is as follows:
the invention aims to provide application of a diphenyl ether compound in preparation of acetylcholinesterase inhibitors or medicaments for treating Alzheimer's disease.
The diphenyl ether compound is a compound expansol F (1), expansol C (2), expansol D (3) or cordiyol C (4) shown in a formula (I).
The second object of the present invention is to provide an acetylcholinesterase inhibitor or a drug for treating alzheimer's disease, which comprises an effective amount of a diphenyl ether compound or a pharmaceutically acceptable salt thereof as an active ingredient. Preferably, a pharmaceutically acceptable carrier is also included.
Preferably, the diphenyl ether compound is a compound expansol F (1), expansol C (2), expansol D (3) or corditol C (4) shown in the formula (I).
The third purpose of the invention is to provide a preparation method of diphenyl ether compounds, which is characterized in that the diphenyl ether compounds are obtained by separating from fermentation cultures of marine fungi Aspergillus sp.BH4-11, the diphenyl ether compounds are compounds expansol F, expansol C, expansol D and/or cordiyol C shown in formula (I), the marine fungi Aspergillus sp.BH4-11 has a collection number of GDMCC No: 61265.
preferably, the method comprises the following steps:
extracting a fermentation culture of the marine fungus Aspergillus sp.BH4-11 with acetone, extracting with ethyl acetate, concentrating the extract to obtain a crude extract, separating the crude extract by medium-pressure silica gel column chromatography, and performing separation by using petroleum ether: gradient eluting ethyl acetate from volume ratio of 100: 0 to 1: 1, gradient eluting with petroleum ether, ethyl acetate and methanol from volume ratio of 20: 1 to 0: 100, and identifying and mixing the same fractions by thin layer chromatography; collecting petroleum ether/ethyl acetate at volume ratio of 85: 15, subjecting to reverse phase medium pressure chromatography at position Fr.4, wherein the mobile phase is methanol/water, gradient eluting from volume ratio of 20: 80 to 100: 0, collecting position Fr.4-8 eluted at methanol/water volume ratio of 60: 40, purifying by HPLC to obtain compound expansol F, collecting position Fr.4-9 eluted at methanol/water volume ratio of 70: 30, and purifying by HPLC to obtain compound expansol C and compound expansol D; collecting petroleum ether/ethyl acetate at volume ratio of 75: 25, subjecting to reverse phase medium pressure chromatography at a mobile phase of methanol/water, gradient eluting from volume ratio of 20: 80 to 100: 0, collecting methanol/water at volume ratio of 50:50, and purifying by HPLC at a position Fr.5-3 to obtain compound cordyol C.
Preferably, the fermentation culture of the marine fungus Aspergillus sp.BH4-11 is prepared by the following method: inoculating Aspergillus sp.BH4-11 into MB culture medium, culturing at 27 deg.C and 200rpm for 72 hr to obtain seed liquid, inoculating the seed liquid into rice culture medium, and culturing at 27 deg.C and standing for 70 days to obtain fermentation culture of Aspergillus sp.BH4-11.
A fourth object of the present invention is to provide the use of the marine fungus Aspergillus sp.bh4-11 for the preparation of diphenyl ether compounds, such as compounds expansol D, expansol E, expansol F and/or cordidyl C according to formula (i), wherein the marine fungus Aspergillus sp.bh4-11 has the accession number GDMCC No: 61265.
the compounds expansol F (1), expansol C (2), expansol D (3) and corditol C (4) are isolated from the fermentation culture of the marine fungus Aspergillus sp.BH4-11. The four compounds have obvious inhibitory activity to acetylcholinesterase, provide alternative compounds for developing new acetylcholinesterase inhibitors, and have important significance for developing marine drug resources in China.
The marine fungus Aspergillus sp.BH4-11 of the invention is deposited in Guangdong province microorganism culture Collection (GDMCC) at 11/3 of 2020, address: the preservation number of the Guangzhou city, Jielizhou 100 college No. 59 building 5, Guangdong province microbiological research institute: GDMCC No: 61265.
description of the drawings:
FIG. 1 shows molecular docking analysis of expansol F with recombinant human acetylcholinesterase (PDB ID: 4EY 7).
FIG. 2 shows molecular docking analysis of expansol C with recombinant human acetylcholinesterase (PDB ID: 4EY 7).
FIG. 3 shows molecular docking analysis of expansol D with recombinant human acetylcholinesterase (PDB ID: 4EY 7).
FIG. 4 shows molecular docking analysis of corditol C with recombinant human acetylcholinesterase (PDB ID: 4EY 7).
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: preparation and structural identification of expansol F, expansol C, expansol D and corditol C
Preparation of expansol F (1), expansol C (2), expansol D (3) and corditol C (4) represented by formula (I)
1. And (3) microorganism culture conditions:
inoculating Aspergillus sp.BH4-11 into a 100mL triangular flask, culturing for 72 hours at 27 ℃ and 200rpm in a seed culture medium (MB culture medium) 20 mL/flask to obtain a seed solution, inoculating the seed solution into a 1000mL triangular flask containing a rice culture medium, culturing for 30 bottles together, and culturing at 27 ℃ and standing for 70 days to obtain a rice culture product (namely a fermentation culture of Aspergillus sp.BH4-11) of the marine fungus. The seed culture medium is MB culture medium: the preparation method comprises the steps of uniformly mixing the components, adjusting the pH value to 7.0, subpackaging into 100mL triangular bottles, each bottle being 20mL, and carrying out autoclaving at 121 ℃ for 30 min. The preparation method of the rice culture medium comprises the following steps: every 1000mL of triangular flask is filled with 200g of rice, 2g of refined sea salt and 200mL of distilled water, and autoclaved at 121 ℃ for 30 min.
2. Extraction and separation:
soaking a culture product of rice of Aspergillus sp.BH4-11 in acetone with a volume twice that of the rice for 2 days, mashing the rice, performing ultrasonic treatment at an ultrasonic frequency of 40KHZ and an ultrasonic power of 360w for 15 minutes, and performing reduced pressure filtration by using 8 layers of gauze. The filtrate is decompressed and concentrated to remove acetone, then ethyl acetate with twice volume is used for extraction for 3 times, and ethyl acetate phase crude extract is obtained after the extract liquid is concentrated. Extracting the filter residue with ethyl acetate for 3 times, concentrating the extract, mixing the ethyl acetate phase crude extract to obtain total crude extract (120g), dissolving the total crude extract with 250mL of methanol, mixing with 100-200 mesh silica gel, separating by medium pressure silica gel column chromatography, wherein the mobile phase is petroleum ether and ethyl acetate, and the volume ratio is 100: 0 to 1: 1 (flow rate 50mL min.)-1) Gradient eluting to obtain first fraction, and eluting with petroleum ether, ethyl acetate and methanol at a volume ratio of 20: 1 to 0: 100 (flow rate of 50mL min)-1) Gradient elution provided a second fraction. The first fraction and the second fraction were identified by Thin Layer Chromatography (TLC) and the same fractions gave 7 elution sites Fr.1-7. Wherein Fr.4 (petroleum ether: ethyl acetate elution part with volume ratio of 85: 15) is subjected to reverse phase medium pressure chromatography (ODS), the mobile phase is methanol/water, 10 sub-elution parts Fr.4-1-Fr.4-10 and Fr.4-8 (methanol/water elution part with volume ratio of 60: 40) are subjected to semi-preparative High Performance Liquid Chromatography (HPLC) purification, YMC semi-preparative column (ODS-A,12nm, S-50 μm) is selected, the column temperature is 27 deg.C, the mobile phase is methanol/water volume ratio of 55: 45 and the flow rate is 3mL/min, fraction with retention time of 48min is collected to obtain compound 1(2.1mg), Fr.4-9 (methanol/water volume ratio of 70: 30) is subjected to semi-preparative HPLC purification, YMC semi-preparative column (ODS-A,12nm, S-50 μm) is selected, the column temperature is 27 ℃, and the mobile phase is methanol/waterThe volume ratio was 60: 40, the flow rate was 3mL/min, and the fraction with a retention time of 25min was collected to give Compound 2(1.7mg), and the fraction with a retention time of 33min was collected to give Compound 3(3.3 mg). Fr.5 (petroleum ether: ethyl acetate volume ratio of 75: 25 elution part) by reversed phase medium pressure chromatography (ODS), mobile phase methanol/water, from volume ratio of 20: 80 to 100: 0 gradient elution 8 elution parts Fr.5-1-Fr.5-8, Fr.5-3 (methanol/water volume ratio of 50:50 elution part) by semi-preparative high performance liquid purification, using YMC semi-preparative column (ODS-A,12nm, S-50 μm), column temperature of 27 deg.C, mobile phase methanol/water volume ratio of 50:50, flow rate of 3mL/min, collecting the retention time of 37min fraction to obtain compound 4(18.5 mg).
II, structural identification of Compound 1, Compound 2, Compound 3 and Compound 4
Compound 1: a light brown oil which is a white oil,1H-NMR、13C-NMR (Table 1) and reported expansol F data are in agreement, and low resolution mass spectrometry (LR-ESIMS) gives the excimer ion peak M/z 447.2([ M + H ]]+) This data is consistent with the molecular weight 288.1 of expansol F and is therefore identified as expansol F.
Compound 2: a light brown oil which is a white oil,1H-NMR、13C-NMR (Table 1) was in agreement with the reported expansol C data, and low resolution mass spectrometry (LR-ESIMS) gave the excimer ion peak M/z 447.2([ M + H ]]+) This data is consistent with the molecular weight 288.1 of expansol C and is therefore identified as expansol C.
Compound 3: a light brown oil which is a white oil,1H-NMR、13C-NMR (Table 1) and reported expansol D data are in agreement, and low resolution mass spectrometry (LR-ESIMS) gives the excimer ion peak M/z 447.2([ M + H ]]+) This data is consistent with the molecular weight 288.1 of expansol D and is therefore identified as expansol D.
Compound 4: a light brown oil which is a white oil,1H-NMR、13C-NMR (Table 2) was in agreement with the reported cordyol C data, and low resolution mass spectrometry (LR-ESIMS) gave the excimer ion peak M/z 247.1([ M + H ]]+) This data is consistent with the molecular weight 288.1 of cordiol C and is therefore identified as cordiol C.
TABLE 1 preparation of Compounds 1-31H NMR and13c NMR data
TABLE 2 preparation of Compound 41H NMR and13c NMR data
Example 2: determination of acetylcholinesterase inhibitory Activity of Compound 1, Compound 2, Compound 3 and Compound 4 first, computer molecular docking of Compound 1, Compound 2, Compound 3 and Compound 4, as shown in formula (I)
Use of
The software screens a number of diphenyl Ether natural products by high performance computerized molecular docking analysis, operating as described in the literature (Dai, Y.; Li, K.; She, J.; Zeng, Y.; Wang, H.; Liao, S.; Lin, X.; Yang, B.; Wang, J.; Tao, H.; Dai, H.; Zhou, X.; Liu U, Y. Lipopeptin excipients and a peptide Glycerol Ether with AChE inhibitor 2020, 18.). Compounds 1-4 were interfaced with an acetylcholinesterase target (PDB ID: 4EY7) and their interactions evaluated, and studies analyzed the molecular interactions between the ligand binding domain and the compounds, with the results shown in Table 3 and FIGS. 1-4. It can be seen that the screened compounds 1-4 all produce better interaction with the target protein, which indicates that the compounds have significant acetylcholinesterase inhibitory activity, wherein the compound 3 has the best binding score (the more negative the score is, the better the binding is), shows higher binding energy, and is matched with the original small molecule in the crystal complexBody E20 was scored similarly.
TABLE 3 in silico molecular docking evaluation of Compounds 1-4 with the acetylcholinesterase target (PDB ID: 4EY7)
Secondly, the acetylcholinesterase inhibition activity of the compound 1, the compound 2, the compound 3 and the compound 4 shown in the formula (I) is measured
The acetylcholinesterase Inhibitory activity of compounds 1-4 was further evaluated using the Ellman method, as described in the literature (Dai, Y.; Li, K.; She, J.; Zeng, Y.; Wang, H.; Liao, S.; Lin, X.; Yang, B.; Wang, J.; Tao, H.; Dai, H.; Zhou, X.; Liu, U., Y. Lipopeptin animals and a peptide Glycerol Ether with AChE inhibition drugs 2020, 18.). The results show that compounds 1-4 have significant inhibitory activity against acetylcholinesterase, the activity results are shown in table 4, and tacrine is a positive control.
TABLE 4 Compounds 1-4 have significant inhibitory Activity on acetylcholinesterase
| Compound (I) | 1 | 2 | 3 | 4 | Tacrine (D) |
| IC50(μg/ml) | 5.15 | 15.08 | 1.74 | 4.87 | 0.05455 |
Claims (9)
1. The diphenyl ether compound or the medicinal salt thereof can be applied to the preparation of acetylcholinesterase inhibitors or medicaments for treating Alzheimer's disease.
2. The use according to claim 1, wherein the diphenyl ether compound is compound expansol F, expansol C, expansol D or corditol C.
3. An acetylcholinesterase inhibitor or a medicament for treating Alzheimer disease, which is characterized by comprising an effective amount of diphenyl ether compounds or medicinal salts thereof as active ingredients.
4. The acetylcholinesterase inhibitor or the drug for treating Alzheimer's disease according to claim 3, wherein said diphenyl ether compound is compound expansol F, expansol C, expansol D or corditol C.
5. The acetylcholinesterase inhibitor or the drug for treating alzheimer's disease according to claim 3, further comprising a pharmaceutically acceptable carrier.
6. A preparation method of diphenyl ether compounds is characterized in that the diphenyl ether compounds are obtained by separating from fermentation cultures of marine fungi Aspergillus sp.BH4-11, the diphenyl ether compounds are compounds expansol F, expansol C, expansol D and/or corditol C, the marine fungi Aspergillus sp.BH4-11 have the collection number of GDMCC No: 61265.
7. the method of claim 6, comprising the steps of:
extracting a fermentation culture of the marine fungus Aspergillus sp.BH4-11 with acetone, extracting with ethyl acetate, concentrating the extract to obtain a crude extract, separating the crude extract by medium-pressure silica gel column chromatography, and performing separation by using petroleum ether: gradient eluting ethyl acetate from volume ratio of 100: 0 to 1: 1, gradient eluting with petroleum ether, ethyl acetate and methanol from volume ratio of 20: 1 to 0: 100, and identifying and mixing the same fractions by thin layer chromatography; collecting petroleum ether/ethyl acetate at volume ratio of 85: 15, subjecting to reverse phase medium pressure chromatography at position Fr.4, wherein the mobile phase is methanol/water, gradient eluting from volume ratio of 20: 80 to 100: 0, collecting position Fr.4-8 eluted at methanol/water volume ratio of 60: 40, purifying by HPLC to obtain compound expansol F, collecting position Fr.4-9 eluted at methanol/water volume ratio of 70: 30, and purifying by HPLC to obtain compound expansol C and compound expansol D; collecting petroleum ether/ethyl acetate at volume ratio of 75: 25, subjecting to reverse phase medium pressure chromatography at a mobile phase of methanol/water, gradient eluting from volume ratio of 20: 80 to 100: 0, collecting methanol/water at volume ratio of 50:50, and purifying by HPLC at a position Fr.5-3 to obtain compound cordyol C.
8. The method according to claim 7, wherein the fermentation culture of the marine fungus Aspergillus sp.bh4-11 is prepared by: inoculating Aspergillus sp.BH4-11 into MB culture medium, culturing at 27 deg.C and 200rpm for 72 hr to obtain seed liquid, inoculating the seed liquid into rice culture medium, and culturing at 27 deg.C and standing for 70 days to obtain fermentation culture of Aspergillus sp.BH4-11.
9. Application of marine fungus Aspergillus sp.BH4-11 in preparing diphenyl ether compounds, wherein the diphenyl ether compounds are compounds expansol D, expansol E, expansol F and/or cordiol C, and the marine fungus Aspergillus sp.BH4-11 has a collection number of GDMCC No: 61265.
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