CN103910700A - Compound for inhibiting activity of acetylcholin esterase and its application - Google Patents
Compound for inhibiting activity of acetylcholin esterase and its application Download PDFInfo
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- CN103910700A CN103910700A CN201410103553.XA CN201410103553A CN103910700A CN 103910700 A CN103910700 A CN 103910700A CN 201410103553 A CN201410103553 A CN 201410103553A CN 103910700 A CN103910700 A CN 103910700A
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- acetylcholine esterase
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Abstract
The invention discloses a compound for inhibiting activity of acetylcholin esterase and its application, and the compound for inhibiting activity of acetylcholin esterase has the application in preparation of medicines for inhibiting acetylcholin esterase. The compound for inhibiting activity of acetylcholin esterase can perform important effect for treating neurodegenerative diseases such as alzheimer's disease.
Description
Technical field
The present invention relates to a kind of compound and application thereof, particularly relate to a kind of acetylcholine esterase inhibition (AchE) active compound and application thereof.
Background technology
Nerve degenerative diseases all belongs to a clinical medicine difficult problem and major disease category, the brain cell of the extensive death that alzheimer's disease main manifestations is brain cell, particularly basal ganglia region as alzheimer's disease, Huntington's disease and Parkinson's disease etc.Under normal circumstances, the Fiber Projections that send basal ganglia region is to the brain cortex relevant with memory and cognition, and it discharges vagusstoff.The formation of short-term memory must have the participation of vagusstoff, and patient's content of acetylcholine transferase compared with normal people reduces 90% than normal people.AchE is considered to the target spot of the screening anti-Alzheimer disease medicine of, utilizes medicine to suppress excessive AchE activity and will contribute to treat the nerve retrograde affections such as alzheimer's disease.Treating this sick medicine comprises vasodilator, improves choline system function class medicine, cerebral circulation protective material etc. according to its mechanism of action.The volume of blood flow that cerebral vasodilator is mainly used to improve brain function and increase brain reaches therapeutic purpose, such as gingko leaf preparation, acetylsalicylic acid, Statins, red sage root compound Chinese medicinal preparation etc., can lead to expansion capillary vessel and strengthen brain circulation of blood, cerebral metabolism conditioning agent is mainly the cognitive function for improving people; Cholinergic drug improves the levels of acetylcholine in patient body by suppressing Pseudocholinesterase (AchE), improve patient's cognition and behavior disorder, slow down the progress of disease, to improving short-term memory successful, as this bright etc. of selagine, E2020, profit belongs to anticholinesterase medicine, but curative effect is undesirable.Antioxidant vitamin E treatment has good security and tolerance, and stimulates the neurotransmitter relevant with cognition to improve brain environment.Also have some other medicine as selegiline, on-steroidal AID etc., the medicine of these all treatment senile dementias is all to be improved.
Existing clinical medicine can not meet treatment needs, there are problems: as pharmaceutical activity is strong, medicine time is long, side effect is obvious, resistance, curative effect decline, import drug price costliness etc. appear in patient, be badly in need of the new drug of the anti-Alzheimer disease of research high-efficiency low-toxicity, few side effects.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of compound and application thereof of acetylcholine esterase inhibition activity, and it plays a significant role in treatment A Ercaimo disease waits nerve retrograde affection.
The present invention solves above-mentioned technical problem by following technical proposals: a kind of compound of acetylcholine esterase inhibition activity, it is characterized in that, and the structural formula of the compound of described acetylcholine esterase inhibition activity is as follows:
Preferably, the compound of described acetylcholine esterase inhibition activity carries out high-throughput AchE inhibitor screening and system confirmatory experiment.
Preferably, the compound of described acetylcholine esterase inhibition activity suppresses AchE active appraisal experiment.
Preferably, the compound of described acetylcholine esterase inhibition activity adopts medicine rationality molecular designing means to evaluate active.
The present invention also provides a kind of compound of acetylcholine esterase inhibition activity in the application of preparing in acetylcholinesterase inhibitor thing.
Positive progressive effect of the present invention is: the present invention shows by a series of body outer screening tests, and the compounds of this invention has AchE enzyme has good inhibition active.Due to the vital role that AchE plays in A Ercaimo disease develops, by suppressing the activity of AchE, the compounds of this invention and preparation play a significant role in the nerve retrograde affections such as treatment A Ercaimo disease, have important application prospect.The present invention relates to compound and be the active skull cap components in the Chinese herbal medicines such as Radix Angelicae Sinensis, safe, patient easily accepts; Compound is high to AchE targeting simultaneously, has improved the targeting for the treatment of such disease, has reduced side effect, can improve curative effect; Import drug price costliness in addition, all causes heavy economical load to patient family and country, and the compounds of this invention is with low cost, can alleviate patient treatment cost.
Accompanying drawing explanation
Fig. 1 is angelicic acid (z)-Z-ligustilide-11-alcohol ester (P7) suppresses curve schematic diagram to AchE;
Fig. 2 is the schematic diagram of angelicic acid (z)-Z-ligustilide-11-alcohol ester (P7) to AchE kinetic inhibition type test-results.
Embodiment
The present invention relates to a kind of activeconstituents of high flux screening acquisition in the pharmacological action aspect the inhibition of AchE activity and anti-A Ercaimo disease and the effect in anti-A Ercaimo disease is treated and prevented thereof, relate to the application of compound in medicine, belong to Western medicine field.
The compound of a kind of acetylcholine esterase inhibition activity of the present invention is for to return the structural formula of acid (z)-Z-ligustilide-11-alcohol ester (angeloyls enkyunolide) as follows:
The compound of acetylcholine esterase inhibition activity of the present invention is in the application of preparing in acetylcholinesterase inhibitor thing.
To in the compound of the above-mentioned acetylcholine esterase inhibition activity of the present invention, add after various auxiliary materials or pharmaceutically acceptable vehicle or carrier required while preparing different dosage form, can be prepared into any suitable clinical preparation with conventional drug formulation process, for example, can be injection (powder pin, freeze-dried powder, liquid drugs injection, transfusion etc.), tablet, oral liquid, granule, capsule, soft capsule, dripping pill etc.Wherein, described auxiliary material can be antioxygen complexing agent, weighting agent, framework material etc.; Described pharmaceutically acceptable carrier is one or more in Xylitol, N.F,USP MANNITOL, lactose, fructose, dextran, glucose, polyvinylpyrrolidone, low molecular dextran, sodium-chlor, calglucon or calcium phosphate, is preferably N.F,USP MANNITOL or lactose.
Carry out high-throughput AchE inhibitor screening and system confirmatory experiment (test example 1), the high flux screening model of an AchE enzyme inhibitors has been set up in this test, this model is take vagusstoff as substrate, select commercial AchE for suppress object, on 96 orifice plates by the variation of 350nm place absorbancy being detected to the inhibition activity of sample to enzyme.Through primary dcreening operation and multiple sieve, the checking of concentration dependence-amount effect relation curve has screened the compound that can effectively suppress AchE activity from 3000 testing compounds.
AchE maximum inhibition measuring method:
Get inhibiting rate and be greater than 50% sample as positive.System checking adopts the curve plotting of enzyme mark.Positive control compound suppresses curve and half effective inhibition concentration (IC50), draw enzyme kinetics Harnes curve, enzyme mark curve is take unit of enzyme/milliliter as X-coordinate, absorbancy (OD) value is ordinate zou drawing, be fabulous linear relationship, prove that, in linearity range, the method is reliable as the method data that detect enzymic activity.
By positive control for compound dimethyl sulfoxide (DMSO) (DMSO) be mixed with 10mM solution, and 8 gradients of stepwise dilution.Use-testing example one measuring method for activity adds respectively testing sample, the 50 μ l enzyme liquid of 5 μ l of stepwise dilution in the sample determination hole of 96 orifice plates, and certain density substrate solution 50 μ l arrange contrast and blank well, establishes 3 each multiple holes.Measure in 30min for 37 ℃ and measure the absorbance difference (Δ OD) of each hole at 350nm wavelength place, suppress the mensuration of curve plotting and IC50.Positive control compound shows good inhibition activity, suppresses the S type that curve has been, and concentration dependence is obvious, and s is consistent with bibliographical information, proves that the method is reliable and stable.Enzymatic kinetic curve obtains according to relevant Harnes curve plotting method, and linear relation is obvious, sees Fig. 1 and Fig. 2.
Carry out the compounds of this invention and suppress AchE active appraisal experiment (test example 2), dimethyl sulfoxide (DMSO) for compound (DMSO) is mixed with to 10mM solution, and 8 gradients of stepwise dilution.In employing test example 1, positive control measuring method for activity used suppresses the mensuration of curve plotting and IC50.Through determination of activity, the compounds of this invention demonstrates AchE is suppressed to active.Suppress curve and see figure, this compound is as shown in table 1 below to the inhibiting IC50 of AchE.
Table 1 the compounds of this invention suppresses AchE determination of activity result
Experimental result shows: the compounds of this invention all has active effect of better inhibition AchE, and the AchE of people, mouse is all had to very strong inhibition activity, and IC50 is lower; Particularly coniferylfemlate is a rare inhibitor, and angelicic acid (z)-Z-ligustilide-11-alcohol ester activity is lower slightly, but also has very high inhibition activity.
Experimental result shows: the compounds of this invention has active effect of better inhibition AchE, and the AchE of people, mouse is all had to very strong inhibition activity, and IC50 is lower, has very high inhibition activity.
Restraining effect and the enzyme kinetics of the compounds of this invention to AchE enzyme suppresses type definite (test example 3), different according to from the enzyme mode of action and response feature, can be divided into reversible inhibition and Irreversible inhibition to the restraining effect of enzyme by enzyme inhibitors.Reversible inhibition is, between inhibitor and enzyme molecule, reversible combination occurs, and this combination is to be generally used for playing a role by non covalent bond or weak bond cooperation, and available dilution or gel-filtration method are removed inhibitor.The combination of general medicine and enzyme should be reversible inhibition, therefore judges whether compound is that reversible inhibition is the important indicator of assessing compound.
Take unit of enzyme/milliliter as X-coordinate, the mapping take absorbancy (OD) as ordinate zou, add and make inhibiting rate be respectively 20% and 50% compound to intersect at initial point with the straight line that does not add compound, can judge that the compounds of this invention is reversible AchE inhibitor (Fig. 2).
The kinetics type of the reversible inhibition of enzyme: can distinguish the reversible inhibition of inhibitor to enzyme with kinetics methodology, generally be divided into Four types: competitive inhibition, uncompetitive inhibitor effect, non-competitive inhibition and mixing competitive inhibition.
Competitive inhibition (competitive inhibition): inhibitor (I) is combined with the active centre of enzyme (E), can stop the combination of substrate and enzyme, the combination of substrate and enzyme active center simultaneously also can stop the combination of enzyme and inhibitor, be the same binding site of inhibitor and substrate competition enzyme, be called competitive inhibition.The enzyme inhibitors with competitive inhibition is called competitive reversible inhibitor.
Non-competitive inhibition (noncompetitive inhibition): the combination of substrate S and inhibitor I and enzyme is fully uncorrelated mutually, neither repels and does not also promote.S can with free E combination, also can with the combination of IE complex body.Same I can with free E combination, also can with the combination of ES complex body, but IES can not discharge product, same, non-competitive inhibition is not too common in single substrate reactions, is generally more common in the inhibition of bisubstrate reaction.
The active type that suppresses of substrate model AchE in Double bottom thing is determined: the testing sample, the 50 μ l enzyme liquid (from human placemta) that in the sample determination hole of 96 orifice plates, add respectively the 5 μ l of (or not adding) two concentration, in rear each hole, adding concentration is the GSH substrate 50 μ l of 2.5mmol/L and the 1-chloro-2 of different concns, 4-dinitrobenzene (CDNB) substrate solution 10 μ l, arrange contrast and blank well.Measure the interior absorbance difference (Δ OD) of each hole at 350nm wavelength place of measuring of 5min for 37 ℃, draw Harnes curve, can judge that according to curve shape compound involved in the present invention is reversibly-competitive inhibitor to the inhibitor type of substrate model, the inhibition type of positive drug is also competitive inhibitor simultaneously.
Adopt medicine rationality molecular designing means to evaluate the activity (test example 4) of the compounds of this invention, the nineties in 20th century, SARS drug design has got involved in (comprising molecular simulation and area of computer aided SARS drug design) links of drug research as a kind of practical instrument, become a kind of and practical instrument high flux screening complementation, join in the workflow (pipeline) of original new drug research, and become one of core technology of original new drug research.
Drug design method can be divided into two classes, based on micromolecular medicinal design (ligand-based drug design, LBDD) medicinal design (the structure-based drug design with based on receptor biological macromolecular structure, SBDD), if (molecular docking) method of the molecular docking based on biomacromolecule three-dimensional structure and the SBDD such as 3D-QSAR analytical procedure and database search method based on Medicine small molecule are according to acceptor or enzyme biomacromolecule (protein, nucleic acid etc.) three-dimensional structure, crystalline structure, nucleus magnetic resonance (NMR) structure, low temperature Electronic Speculum structure or computer simulation structure, set up the three-dimensional structure of small molecules and acceptor or enzyme complex with Theoretical Calculation and molecule simulation method, the interaction of research small molecules and acceptor.
The eighties in 20th century, Kuntz has developed molecular docking (docking) method: a kind of small molecules of simulating is combined the method for calculation of three-dimensional structure and bonding strength thereof with biomacromolecule, and has developed first molecular docking program DOCK.A series of molecular docking methods on the basis of DOCK, are developed, as FlexX AutoDock, GOLD and GAsDock etc.
The virtual screening method basic procedure of molecular docking is as follows: the information of the active small molecular compound structure in the present invention is carried out atomic type and chemical bond ownership by (1), 2D structural transformation is become to three-dimensional (3D) structure and carries out composition optimizes, composition 3D small molecules database; (2) biomacromolecule (protein) is carried out to protonated and atomic charge ownership, and carry out composition optimizes, determine small molecules binding site, build computing grid; (3) the each compound in 3D small molecules database is docked to the avtive spot of biomacromolecule, and gives a mark---calculate the bonding strength (in conjunction with free energy) of small molecules-biomacromolecule; (4) select compound (the higher molecule of giving a mark) according to the result of marking, carry out quasi-medicated property evaluation
Medicinal design (the Structure-based Drug Design of this test example experimental design based on structure of biological macromolecule, SBDD) virtual screening technology, adopt FLEX X molecular docking marking in rational drug design (Rati onal drug design) Triplos7.0 software package, AchE protein three-dimensional database is carried out to composition optimizes, select 6 dusts with interior macromolecular structure, related compound in this invention is docked with enzyme molecular activity site.
By molecular docking result, can find out the compounds of this invention obtaining by screening method described in embodiment, can be good at entering enzyme molecular activity chamber, marking result is higher, its marking result of the active high compound of screening is also high, demonstrate and the good complementarity of high flux screening result, two kinds of method evaluation results are consistent.
Molecular docking marking result take database file 1GLP result as reference.Test-results is in table 2.
The virtual screening result of the medicinal design of table 2. sample based on structure of biological macromolecule
| Sample title | Hydrogen bond number | Screening marking | The selection result |
| Angelicic acid (z)-Z-ligustilide-11-alcohol ester | 4 | -11.2 | Excellent |
In a word, all can show that by above embodiment the compounds of this invention has and has better inhibition active to AchE, suppress type and meet into property of medicine requirement, likely be developed as the nerve retrograde affection original new drugs such as anti-Alzheimer disease, there is important application prospect.
Body outer screening test shows (table 1), and the compounds of this invention, to AchE, especially have good inhibition active for acetylcholinesterase, and it is clear and definite to suppress type.The vital role playing in the developing of the nerve retrograde affections such as alzheimer's disease due to AchE, by suppressing the activity of AchE, suppress type prompting compound and there is the good one-tenth property of medicine, be worth further investigation, the compounds of this invention may have good application prospect in treatment nerve retrograde affection field.
Those skilled in the art can carry out various remodeling and change to the present invention.Therefore, the present invention has covered various remodeling and the change in the scope that falls into appending claims and equivalent thereof.
Claims (5)
1. a compound for acetylcholine esterase inhibition activity, is characterized in that, the structural formula of the compound of described acetylcholine esterase inhibition activity is as follows:
2. the compound of acetylcholine esterase inhibition activity as claimed in claim 1, is characterized in that, the compound of described acetylcholine esterase inhibition activity carries out high-throughput AchE inhibitor screening and system confirmatory experiment.
3. the compound of acetylcholine esterase inhibition activity as claimed in claim 1, is characterized in that, the compound of described acetylcholine esterase inhibition activity suppresses AchE active appraisal experiment.
4. the compound of acetylcholine esterase inhibition activity as claimed in claim 1, is characterized in that, the compound of described acetylcholine esterase inhibition activity adopts medicine rationality molecular designing means to evaluate active.
5. the compound of an acetylcholine esterase inhibition activity is in the application of preparing in acetylcholinesterase inhibitor thing.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101302208A (en) * | 2008-03-04 | 2008-11-12 | 刘庆山 | Compound inhibiting glutathion S-transferase activity, preparation and use thereof |
| CN101563080A (en) * | 2006-08-11 | 2009-10-21 | 帝斯曼知识产权资产管理有限公司 | Ligustilide derivatives for the treatment of disorders of the central nervous system |
| CN103360388A (en) * | 2012-04-10 | 2013-10-23 | 江苏先声药物研究有限公司 | 5-Amino-1,4-dihydro-1,8-naphthyridine derivatives and pharmaceutical compositions as well as uses thereof |
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2014
- 2014-03-20 CN CN201410103553.XA patent/CN103910700A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101563080A (en) * | 2006-08-11 | 2009-10-21 | 帝斯曼知识产权资产管理有限公司 | Ligustilide derivatives for the treatment of disorders of the central nervous system |
| CN101302208A (en) * | 2008-03-04 | 2008-11-12 | 刘庆山 | Compound inhibiting glutathion S-transferase activity, preparation and use thereof |
| CN103360388A (en) * | 2012-04-10 | 2013-10-23 | 江苏先声药物研究有限公司 | 5-Amino-1,4-dihydro-1,8-naphthyridine derivatives and pharmaceutical compositions as well as uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| LI-LING CHENG ET AL.: "Z-ligustilide isolated from Radix Angelicae sinensis ameliorates the memory impairment induced by scopolamine in mice", 《FITOTERAPIA》 * |
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