CN115581689A - Application of urolithin B amide derivatives - Google Patents
Application of urolithin B amide derivatives Download PDFInfo
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- CN115581689A CN115581689A CN202211265773.3A CN202211265773A CN115581689A CN 115581689 A CN115581689 A CN 115581689A CN 202211265773 A CN202211265773 A CN 202211265773A CN 115581689 A CN115581689 A CN 115581689A
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- urolithin
- acetamide
- benzo
- oxo
- amide derivatives
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- RIUPLDUFZCXCHM-UHFFFAOYSA-N urolithin-A Natural products OC1=CC=C2C3=CC=C(O)C=C3OC(=O)C2=C1 RIUPLDUFZCXCHM-UHFFFAOYSA-N 0.000 title claims abstract description 85
- -1 urolithin B amide Chemical class 0.000 title claims abstract description 47
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- AZVZZDLTZDNZEQ-UHFFFAOYSA-N n-(pyrazin-2-ylmethyl)acetamide Chemical compound CC(=O)NCC1=CN=CC=N1 AZVZZDLTZDNZEQ-UHFFFAOYSA-N 0.000 description 1
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- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Hospice & Palliative Care (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an application of a urolithin B amide derivative, belonging to the field of medicines. The urolithin B amide derivatives can be used for preventing or treating the neurogenic diseases related to the reduction of mitochondrial activity, including aging and neurodegenerative diseases, and the invention adopts caenorhabditis elegans as a model, and the test result shows that 20 mu M of urolithin B and N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] benzopyran-3-yl) oxy) -N- (pyrazine-2-ylmethyl) acetamide have the effects of prolonging the life span of caenorhabditis elegans and enhancing the cognitive ability or relieving the cognitive dysfunction. The invention provides a new idea for the application of amide derivatives of urolithin B in anti-aging and preventing neurodegenerative diseases.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of a urolithin B amide derivative in preparation of a medicine for preventing body aging.
Background
Alzheimer's Disease (AD), the most commonly recognized neurological disorder associated with cognitive decline, is a neurodegenerative disorder in which the degree of dementia gradually worsens with age.
The aging of the organism is in essential connection with the autophagy dysfunction of mitochondria, the instability of genome, the shortening of telomerase, the imbalance of protein homeostasis and the degradation of cell viability function. The mechanism of AD formation is unknown, and is pushed by senile plaque deposition to a β (amyloid β), which has numerous possible causes of formation. At present, clinically, test medicines such as cholesterol inhibitors, cholinesterase inhibitors and the like used for preventing the Alzheimer disease caused by aging only can prevent the disease from deteriorating at most, and no medicine or method capable of completely treating the disease exists. Since the cause of AD is not yet clear, better animal models are also lacking in research. Caenorhabditis elegans (C.elegans) as a model organism, only needs 3 days to develop from eggs to adults under the condition of rich nutrition at 20 ℃, the gene of the Caenorhabditis elegans has high conservation of 60-80 percent with related genes of human, and the experimental result plays an important role in prompting the anti-aging effect of human prevention; because the growth cycle of the nematodes is short, a large amount of sample nematodes can be used for experiments in a short period, and the experimental result is credible; in the research of neurodegenerative diseases, nematodes are easy to obtain an ideal disease-deficient system model, have transparent bodies, are easy to observe and detect phenotypic characteristics, have complete nervous, motor and reproductive systems, and form rich motor behaviors such as advancing, retreating, population tropism and the like by virtue of the mutual coordination among cells, so that the nematodes are easy to operate genetically and pharmacologically in the research of disease-related models, and have important significance for preventing and exploring pathogenesis and treatment methods of neurodegenerative diseases.
Ellagitannins (elagitannins), which are polyphenolic compounds currently present in certain fruits, nuts and plants, belong to the class of hydrolysable tannin compounds, which are metabolized by the human body via the intestinal flora into more readily absorbable urolithins, a process in which ellagic acid loses a lactone ring and gradually removes hydroxyl groups. The ellagic acid loses a lactone ring to obtain the urolithin M5 at first, and hydroxyl of the urolithin M5 is removed at different positions to obtain monohydroxy urolithin B. Patent No. CN 113387916 discloses a method for preparing urolithin B and amidated derivatives. A valuable contribution to the anti-aging field would be made if a novel urolithin inhibitor could be found that could effectively improve cognitive function, or improve cognitive performance, or even treat cognitive disorders.
The nomenclature and chemical structures of urolithin B and amide derivatives are as follows:
disclosure of Invention
Under the background, the invention discloses an anti-aging application of a urolithin B amide derivative, and aims to provide a new application of the urolithin B amide derivative in anti-aging drugs.
In order to achieve the above object, the present invention adopts the following technical solutions.
The application of the urolithin B amide derivative is that the urolithin B amide derivative is prepared from the following two compounds:
The use of amide derivatives of urolithin B, both compounds for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disease associated with decreased mitochondrial activity.
The use of amide derivatives of urolithin B, both compounds being useful in the preparation of a medicament for prolonging nematode life.
Further, the nematode is caenorhabditis elegans.
Furthermore, the two compounds have obvious anti-aging effect when the concentration is 20 mu M.
The technical scheme of the invention has the following advantages:
1. under the condition of lower dosage and concentration, the urolithin B amide derivative can be observed to have obvious prolonging effect on the life of the caenorhabditis elegans compared with the urolithin B, and can delay the aging process of the caenorhabditis elegans; the method is simple to operate and has the advantage of effect.
2. The motor behavior and the stress capability of the caenorhabditis elegans indicate that the stachyose B amide derivative has an obvious life prolonging effect, so that the senescence is delayed, and the application value and significance of the compound are good for far-reaching medical application.
3. The invention provides a certain theoretical basis for the application of the urolithin B and the amide derivative thereof in the anti-aging drugs, and lays a good foundation for the development of the drugs in the future.
Drawings
FIG. 1 is a graph showing the effect of different concentrations of urolithin B on the healthy life of nematodes. Wherein, (a) is the survival curve of the urolithin B nematodes with different concentrations and (B) is the average life span of the urolithin B nematodes with different concentrations.
FIG. 2 shows the effect of 20 μ M urolithin B and amide derivatives on nematode longevity. Wherein (a) the urolithin B nematode survival curve (B) is 20 μ M for 20 μ M N-hexyl-2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide nematode survival curve (c) is 20 μ M N-butyl-2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide survival curve (d) is 20 μ M2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- ((tetrahydrofuran-2-yl) methyl) acetamide survival curve (e) is 20 μ M2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (2- (thien-2-yl) ethyl) acetamide survival curve (f) is 20 μ M N- (furan-2-ylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide survival curve (g) is 20 μ M N- (furan-2-yl) benzyl) acetamide survival curve (M) is 20 μ M Cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide nematode survival curve (i) is 20 μ M N- ((5-methylfuran-2-yl) methyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide survival curve (j) is 20 μ M N- (3-chloro-5-fluorobenzyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide nematode survival curve (k) is 20 μ M N- (2- (benzyloxy) ethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide survival curve (l) is 20 μ M2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide survival curve (M) is 20 μ M2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) N- (pyrazin-2-ylmethyl) acetamide survival curve (M) is 20 μ M2-oxo-6H-benzo [ c ] chromen-3-yl) nematode survival curve (M) - ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (2- (piperidin-1-yl) ethyl) acetamide nematode survival curve (o) 20 μ M mean lifetime of urolithin B (p) 20 μ M mean lifetime of urolithin B and amide derivative nematodes.
FIG. 3 is a graph showing the effect of 20 μ M urolithin B and 71g,71k amide derivatives on nematode locomotor behavior at day 4,8, 12. Wherein (a) 20 μ M urolithin B body curvature on day 4 (B) 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide body curvature on day 4 (c) 20 μ M urolithin B head wobble on day 4 (d) 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide head wobble on day 4 (e) 20 μ M urolithin B body curvature on day 8 (f) 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide body curvature on day 8 (g) 20 μ M N- (cyclohexylmethyl) -2- (6H-oxo-6H-benzo [ c ] chromen-3-yl) acetamide body wobble on day 8 (c) oxy) acetamide mu.M urolithin B head wobble (H) 20. Mu.M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide head wobble (i) 20. Mu.M urolithin B body flexion on day 12 (j) 20. Mu.M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide body flexion on day 12 (k) 20. Mu.M urolithin B head wobble (l) 20. Mu.M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide head wobble (l) on day twelve 20. Mu.M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) acetamide and 6H-oxopyran-3-yl) acetamide on day twelve.
FIG. 4 is a graph showing the effect of 20 μ M urolithin B and 71g,71k amide derivatives on nematode oxidative stress ability. Wherein (a) is a 20 μ M urolithin B oxidative stress survival curve (B) is a 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide oxidative stress survival curve (c) is a 20 μ M2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide oxidative stress survival curve (d) is a 20 μ M urolithin B oxidative stress average lifetime (e) is a 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide and a 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide oxidative average lifetime.
FIG. 5 is a graph showing the effect of 20 μ M urolithin B and 71g,71k amide derivatives on the assessment of nematode heavy metal capacity. Wherein (a) is a 20 μ M urolithin B heavy metal survival curve (B) is a 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide heavy metal survival curve (c) is a 20 μ M2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide heavy metal survival curve (d) is a 20 μ M urolithin B average lifetime (e) is a 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide average lifetime.
FIG. 6 shows the effect of 20 μ M urolithin B and 71g,71k amide derivatives on the learning and memory abilities of nematodes. Wherein (a) is 20 μ M urolithin B learning memory (B) is 20 μ M N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide and 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide learning memory.
FIG. 7 shows the effect of 20 μ M urolithin B and 71g,71k amide derivatives on the growth status of E.coli. Wherein (a) is the effect of urolithin B on E.coli growth (B) is the effect of N- (cyclohexylmethyl) -2- (6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) acetamide on E.coli growth (c) is the effect of 2- ((6-oxo-6H-benzo [ c ] chromen-3-yl) oxy) -N- (pyrazin-2-ylmethyl) acetamide on E.coli growth status.
FIG. 8 is a schematic view of a test board.
Detailed Description
The present invention will be described in further detail with reference to examples. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
1. Test materials and reagents
The C.elegans strain and E.coli op50 to which they belong in the test were purchased from Caenorha bd itis Genetics Center (CGC);
c.elegans strain: wild type N2
Urolithin B and amide derivatives thereof: synthesized at Changzhou university
Paraquat was obtained from Sigma Aldrich trade company, inc., and other reagents were obtained from Shanghai Biotech company, inc
NGM culture medium: 3g NaCl,2.5g tryptone, 17g agar, 25ml phosphate buffer, 975ml distilled water, sterilization at 121 ℃ for 20min, cooling to about 50-70 ℃, adding 1mL cholesterol solution of 5mol/L after membrane sterilization, 1mL anhydrous MgSO (MgSO) of 1mol/L 4 Solution 1mL,1mol/L CaCl 2 1ml of the suspension was added to the medium, plated on a plate, cooled to solidify, and placed in a refrigerator at 4 ℃.
100mM NaCl 5.85g, peptone 2.5g, agar 17g, distilled water 1L.
Preparing an LB culture medium:
(1) liquid culture medium: separately weighing peptone, yeast extract and NaCl 10g, 5g and 10g, adding distilled water to a constant volume of 1L,121 deg.C, sterilizing for 20min, and refrigerating at 4 deg.C for use.
(2) Solid medium: respectively weighing 10g, 5g, 10g and 17g of peptone, yeast extract, naCl and agar powder, adding distilled water to a constant volume of 1L,121 ℃, sterilizing for 20min, pouring the mixture into a flat plate, and freezing for later use in a refrigerator at 4 ℃ after solidification.
M9 buffer solution: na (Na) 2 HPO 4 6g，KH 2 PO4 3g，NaCl5g，MgSO 4 .7H 2 O 0.25g，H 2 O 1L。
1mol/L phosphate buffer: k 2 HPO 4 3.56g，KH 2 PO4 10.83g，H 2 O 100ml。
1mg/mLMgSO 4 Solution: collecting MgSO4 powder 120.3g, adding distilled water, diluting to volume of 1L, sterilizing at 121 deg.C for 20 min.
1mg/mLCaCl 2 Solution: taking 110.9g of CaCl2 powder, adding distilled water, metering to 1L, sterilizing at 121 deg.C for 20 min.
5mol/L cholesterol solution: 0.25g of cholesterol was dissolved in 50mL of absolute ethanol and aseptically filtered through a membrane using a needle filter for use.
50% of glycerin: sterilizing 100% glycerol 5mL in 5mL distilled water at 121 deg.C for 20min, cooling, and storing in 4 deg.C refrigerator.
And (3) nematode freezing and storing liquid: 0.3g of NaCl, KH 2 PO4 0.055g,KH 2 PO 4 0.3g, 21.5mL of glycerin, 50mL of distilled water, 121 ℃ and 20min for sterilization.
2. Method of producing a composite material
Example 1 extension of caenorhabditis elegans longevity by Uretifolia B amide derivatives
Test drugs:
negative controls were prepared 0.1% DMSO.
Positive control urolithin B and its amide derivatives were dissolved in 0.1% DMSO to prepare stock solutions.
(1) Life test
And (3) performing constant-temperature culture by using synchronized L4-stage nematodes at 20 ℃. DMSO in the solvent control group was 0.1%, and the positive control group was 10-100. Mu.M of urolithin B. Counting can be carried out from the transfer moment, and the transfer moment is recorded as the 0 th day of the life test. The number of nematodes surviving, dead and lost was recorded daily, the mean life span of each group was obtained, and the data were analyzed for survival.
(2) Life test of urolithin B and its amide derivatives
Urolithin B was used as a control and compared to its amide derivatives at optimal concentrations, the number of nematodes alive, dead and lost was recorded daily, the mean life of each group was obtained, and the data was analyzed for survival.
Analysis of results
The results are shown in FIG. 1, which is the effect of 0.1. Mu.M-100. Mu.M urolithin B on nematode longevity. The lifetime test was carried out using 0.1. Mu.M, 1. Mu.M, 10. Mu.M, 20. Mu.M, 50. Mu.M and 100. Mu.M as administration groups of different concentrations and 0.1% DMSO as a control group. The results show that 20 μ M of urolithin B extends the average life span of wild-type nematodes, shifting the survival curve to the right. Wherein it can be seen from FIG. 1 that the average life span of N2 nematodes reaches 17.42% at 20 μ M, that the 71g,71k amide derivative in FIG. 2 is higher than the negative controls by 9.06% and 9.96% compared to urolithin B, and that the 71g,71k amide derivative is longer than urolithin B by the life span of the nematodes, this example demonstrates that urolithin B can prolong the life span of C.elegans, and that the anti-aging effect of urolithin B significantly improves the life span of nematodes at a dose of 20 μ M, but to a lesser extent than the 71g,71k amide derivative.
Example 2: urinary calculus B and amide derivatives improve nematode motility
Test drugs: negative controls were prepared 0.1% DMSO.
Positive control urolithin B and its amide derivatives were dissolved in 0.1% DMSO to prepare stock solutions.
Experimental methods
Determination of exercise Capacity
Intervention with nematode dosing synchronized to L4 phase on day four, day eight and day twelfth. 10 nematodes were placed on the blank NGM medium using M9 buffer, and after 1min recovery, the number of head swings within 1min and the number of body bends within 20s were recorded.
Analysis of results
The number of body bends and head swings within 1min for nematodes on the fourth, eighth and twelfth days of the dosing intervention in 20s are shown in figure 3. The 20 μ M urolithin B had better improvement in body bending times and head swinging times of nematodes on the fourth, eighth and twelfth days than the control group, respectively, and the amide derivative 71g,71k, as shown in FIG. 3, had a significant improvement effect compared with urolithin B. This example demonstrates that 71g,71k amide derivatives enhance nematode motility over urolithin B, leading to improved health and lateral effects in anti-aging.
Example 3: the stress ability of nematode is improved by the urolithin B and amide derivatives
Test drugs: the negative control was prepared in 0.1% DMSO.
Positive control urolithin B and its amide derivatives were dissolved in DMSO 0.1% to prepare a stock solution.
Experimental methods
Oxidizing stress of paraquat: after 48h of administration of the synchronized post-culture medium to L4 nematodes, they were transferred to liquid medium containing paraquat at a concentration of 160mM and the number of nematode deaths and survivals were recorded every 1 h.
Analysis of results
The results of nematode oxidative stress at 48h after administration of intervention are shown in figure 4. The results showed that 20 μ M urolithin B administered group increased nematode oxidative stress by 25.46% over the control group. 71g,71k amide derivatives are 25.92% and 29.32% higher than negative control respectively compared with urolithin B, and the 71g,71k amide derivatives can improve the survival time of nematode stress ability, and the results of the example show that the 71g,71k amide derivatives improve the stress ability of nematodes and have an anti-aging effect compared with urolithin B.
Example 4: the urolithin B and amide derivatives improve the heavy metal resistance of nematodes
Test drugs: the negative control was prepared in 0.1% DMSO.
Positive control urolithin B and its amide derivatives were dissolved in 0.1% DMSO to prepare stock solutions.
Experimental method
The synchronized L4 phase nematodes were dosed at 48h,48h followed by the addition of a final concentration of 180. Mu.M copper chloride solution, after which the number of nematodes surviving was recorded once a day until all of the nematodes died.
Results of the experiment
The anti-heavy metals of the nematodes after 48h administration are shown in FIG. 5. The results showed that the average life of 20. Mu.M urolithin B was 9.43% higher than that of the control, and that 71g of the 71k amide derivative was 11.54% higher than that of the negative control and 13.63% higher than that of urolithin B. The results of this example demonstrate that 71g,71k amide derivatives have better effect against heavy metals than urolithin B.
Example 5: the urolithin B and amide derivatives improve the learning ability of nematodes
Test drugs: negative controls were prepared 0.1% DMSO.
Positive control urolithin B and its amide derivatives were dissolved in 0.1% DMSO to prepare stock solutions.
Experimental methods
Chemotrending capacity assay
The synchronized L4-phase nematodes are respectively exposed to the experimental group and the control group for 72h to prepare 100mMThe NaCl culture medium is sterilized at high temperature and high pressure, and the nematodes M9 are washed for 2-3 times to be cultured in a new culture medium for 4 hours by starvation. Blank media and media containing 100mM NaCl were separately drilled out overnight for 14h using a cork drill in test plates, which were transferred to test plates as shown in FIG. 8 below: blank NGM and 100mM NaCl blank NGM were drilled at 0.5cm from both ends of the plate with a cork drill as sample and control marks, respectively, so that the two marks were aligned with the center point. Two straight lines are drawn at 2cm positions on two sides of the circle center. 0.5mol/L NaN was added before the test 3 The nematode is transferred to the starting point, and the trend index (chemotaxis index) = (N) is determined after 1h A -N C )/N；N A Number of Nacl group nematodes, N C Number of nematodes in control group, N = total number of nematodes.
Analysis of results
The learning ability of urolithin B and 71g,71k amide derivatives is shown in FIG. 6. It can be seen that the learning ability of the control group was 0.052, the learning ability of 20. Mu.M urolithin B was 0.32, and the learning abilities of 71g and 71k amide derivatives were 0.35 and 0.41. The results show that 20 mu M of urolithin B and 71g of amide derivatives of the urolithin B can obviously improve the learning ability of adult nematodes on the fourth day.
Example 6: effect of 20. Mu.M urolithin amide derivatives on growth status of Escherichia coli
Test drugs: negative controls were prepared 0.1% DMSO.
Positive control urolithin B and its amide derivatives were dissolved in 0.1% DMSO to prepare stock solutions.
Experimental method
Preparing an LB liquid culture medium after autoclaving, and treating the following steps: 1. blank group 2, add op50, add methoxy urolithin A and its 6, 7 amide derivatives 4, add op50 and methoxy urolithin A and its 6, 7 amide derivatives. And (3) taking a blank group as a control, firstly measuring the oxyurolithin A and the 6 and 7 amide derivative groups thereof, then placing the other two groups in a shaking table at 37 ℃, measuring the absorbance of the oxyurolithin A and the 6 and 7 amide derivatives thereof at the OD595 position every 30min within 390min, and recording and drawing the growth curve of the OD value of the escherichia coli.
Analysis of results
FIG. 7 is a graph showing the effect of 20. Mu.M methoxyurolithin A and its 71g,71k amide derivative on the growth state of E.coli. As shown in FIG. 7, OP50 growth curves in LB liquid medium with the addition of 20. Mu.M urolithin B and its 71g,71k amide derivative were similar to those of LB liquid medium without the addition of the administration group, and the results of this example demonstrate that the longevity-extending effect of 20. Mu.M urolithin B and its 71g,71k amide derivative is independent of its antimicrobial effect and food availability.
Claims (5)
1. The application of the urolithin B amide derivative is characterized in that the urolithin B amide derivative is two compounds as follows:
1g：
1k：
the two compounds are used for preparing anti-aging medicaments.
2. The use of the urolithin B amide derivative according to claim 1, wherein: the two urolithin B amide derivatives are used for preparing medicines for treating or preventing neurodegenerative diseases related to mitochondrial activity reduction.
3. The use of the urolithin B amide derivative according to claim 1, wherein: the two kinds of urolithin B amide derivatives are used for preparing the medicament for prolonging the life of the nematodes.
4. The use of the urolithin B amide derivative according to claim 3, wherein: the nematode is caenorhabditis elegans.
5. The use of the urolithin B amide derivative according to claim 1, wherein: the two kinds of urolithin B amide derivatives have the best anti-aging effect when the molecular weight is 20 mu M.
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