CN109810044A - A compound with HIV-1 integrase inhibitory activity and its preparation and application - Google Patents
A compound with HIV-1 integrase inhibitory activity and its preparation and application Download PDFInfo
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- CN109810044A CN109810044A CN201910146182.6A CN201910146182A CN109810044A CN 109810044 A CN109810044 A CN 109810044A CN 201910146182 A CN201910146182 A CN 201910146182A CN 109810044 A CN109810044 A CN 109810044A
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- hiv
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- inhibitory activity
- integrase inhibitory
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- 108700020129 Human immunodeficiency virus 1 p31 integrase Proteins 0.000 title claims abstract description 54
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
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- 238000006243 chemical reaction Methods 0.000 claims description 67
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- 238000003786 synthesis reaction Methods 0.000 claims description 12
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- 238000003756 stirring Methods 0.000 claims 3
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- 238000004090 dissolution Methods 0.000 claims 1
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Abstract
The present invention relates to pharmaceutical technology field, specifically a kind of compound and preparation method thereof with HIV-1 integrase inhibiting activities.The present invention is using open-chain crown ether as raw material, it is synthesized by a series of step, having finally obtained one kind has significant antiviral activity, and influences the lesser compound with HIV-1 integrase inhibiting activities to normal cell, and compound is indicated with leading to formula (I) as follows:In the logical formula (I), R1, R2 are hydroxyl, alkoxy, amino, hydrogen atom；R3 is hydrogen atom, halogen atom, alkyl, nitro, hydroxyl, amino.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically a kind of compound with HIV-1 integrase inhibiting activities and its
Preparation and application.
Background technique
AIDS, also known as acquired immunodeficiency syndrome (acquired immune deficiency syndrome,
It AIDS), is systemic caused by human immunodeficiency virus (human immune deficiency virus, HIV) infection
The badly damaged communicable disease being characterized of immune system.Since the U.S. in 1981 reports Patient With Aids case, constantly
To spreading all over the world and wreaking havoc prevalence in the world, life and health and social development to the mankind cause extremely serious
Harm, oneself cause national governments and society common concern.HIV-1 drug resistance is since viral gene mutates, so that medicine
The biochemistry or structure feature of object action target spot change, and cause virus-drug insensitive or sensibility decline.
HIV-1 integrase (Integrase) is one of three key enzymes of virus replication, can mediate retroviral
DNA is integrated into host genome DNA.If integration process is blocked, viral duplication will be interrupted, therefore integration process is
HIV-1 Virus entry target cell ultimately forms the last one committed step of irreversible infection, and integrase has become containment virus
The important target of propagation.
However, there is the problem of drug resistance in integrase chain tra nsfer inhibitor currently on the market.Therefore, a kind of structure is found
The HIV-1 integrase inhibition novel, toxicity is low, antiviral activity is high is current urgent problem.
Summary of the invention
In order to solve the above technical problems existing in the prior art, the present invention provides a kind of with the suppression of HIV-1 integrase
Active compound is made, specific as follows:
A kind of compound with HIV-1 integrase inhibiting activities is indicated with leading to formula (I) as follows:
Preferably, in the logical formula (I), R1, R2 are hydroxyl, alkoxy, amino, hydrogen atom.Compound at this time has
Preferable antiviral activity.
Preferably, in the logical formula (I), R3 is hydrogen atom, halogen atom, alkyl, nitro, hydroxyl, amino.Change at this time
Closing object has preferable antiviral activity.
It is further preferred that in the logical formula (I), R1 OH, R2 OCH2CH3, R3 H.Compound at this time has
Preferable antiviral activity, and cytotoxicity is relatively low, and whole effect is preferable.
The preparation method of the compound with HIV-1 integrase inhibiting activities, includes the following steps:
(1) synthesis is to methoxyl group diazonium benzene hydrochloride (compound b): by 1 times of equivalents of compound a (open-chain crown ether) with dense
Hydrochloric acid is completely dissolved, after 2h is stirred at room temperature；It moves into 0 DEG C to -10 DEG C of reaction system, it is constant to temperature, it is slowly added to 2 times and works as
Sodium nitrite is measured, is stirred to react, reacts 2-5h at such a temperature to get compound b is arrived；
(2) synthesize (Z) -2- acetyl group -2- ((4- methoxyphenyl) diazenyl) ethyl glutarate (compound c):
Excessive dense H is added after being completely dissolved the raw material 2- acetyl ethyl glutarate of 1.2 times of equivalents with dehydrated alcohol2SO4, fill it
Divide and mix, compound b is added in slow constant speed, reacts at room temperature 2-3h, carries out experiment post-processing after reaction: adjusting pH to weak base
Property, it is extracted with ethyl acetate (EthylAcetate, EA), concentrated extract, with silica gel column chromatogram separating purification target product, i.e.,
It isolates and purifies to obtain compound c；
(3) synthesis (Z) -2- (2- (4- methoxyphenyl) hydrazono-) ethyl glutarate (compound d): will separate
Compound c be completely dissolved with dehydrated alcohol after, excessive dense HCl is added, 2-5h is stirred at room temperature, to after reaction, separation,
It is purified into compound d；
(4) synthesize 3- (2- ethyoxyl -2- oxoethyl) -5- methoxyl group -1H- indole -2-carboxylic ethyl ester (compound e):
After compound d is completely dissolved with dehydrated alcohol, it is passed through dry HCl gas, 2-7h is stirred at room temperature, to after reaction, into
Row experiment post-processing, then separates, is purified into compound e, is the compound with HIV-1 integrase inhibiting activities.
Preferably, in the reaction process of step (1)-(4), thin-layered chromatography (Thin Layer is carried out
Chromatography, TLC) monitoring extent of reaction, if reaction not completely if the reaction was continued, until the reaction is complete.TLC is chemistry
Common method in synthesis, advantage are, simply, quickly, sensitive, can real-time monitoring.
Preferably, experiment post-processing is to adjust reaction solution pH, extracted with ethyl acetate (Ethyl Acetate, EA)
The operation such as take, be concentrated, separating.It is further preferred that the tune reaction solution pH, with EA extraction, concentration, separation etc. operation, specifically
It is to adjust pH to alkalescent, is extracted with EA, concentrated extract, column is filled, with TLC separation purification of target product.
Preferably, the tune pH is alkalescent, is adjusted with natrium carbonicum calcinatum.
Application of the compound with HIV-1 integrase inhibiting activities in the drug for being used to prepare AntiHIV1 RT activity.Especially
It is by the compound in the application being used in HIV-1 type integrase inhibitor.
Compared with prior art, the technical effect of the invention is embodied in:
The present invention passes through early-stage study discovery, the compound of the parent nucleus containing 2- indolecarboxylic acid, 2- indolecarboxylic acid therein
Parent nucleus is not yet reported in HIV-1 integrase inhibitor.Meanwhile there is most significant antiviral activity, and indoles right and wrong
An often important class formation, the structure of peptide can be imitated and in conjunction with target proteins, more accessible to integrase active region, to mention
Rise its antiviral effect.Therefore, inventor thinks that the novel integrase inhibitor of 2- indolecarboxylic acid class may be easier to and integrase
Active site region, which combines, reaches more significant antiviral effect, and using open-chain crown ether as raw material, passes through a series of step
Suddenly it is synthesized, has been finally obtained a kind of with significant antiviral activity and lesser with HIV- on normal cell influence
The compound and its derivative of 1 integrase inhibiting activities, the compound of the present invention and preparation method thereof have raw material simplicity be easy to get,
The advantages that reaction condition is simple and easy, and yield is high.
Detailed description of the invention
Fig. 1 is the synthesis technology schematic diagram with the compound and its derivative of HIV-1 integrase inhibiting activities；
Fig. 2 is the structural schematic diagram of the compound with HIV-1 integrase inhibiting activities of the invention；
Specific embodiment
It is limited below with reference to specific embodiment technical solution of the present invention is further, but claimed
Range is not only limited to made description.
Embodiment 1
(1) synthesis is to methoxyl group diazonium benzene hydrochloride (compound b): by the dense salt of compound a (open-chain crown ether) 1.00g
Acid is completely dissolved, after 2h is stirred at room temperature；It moves into 0 DEG C to -10 DEG C reaction system, it is constant to temperature, it is slowly added to the Asia 0.8404g
Sodium nitrate is stirred to react, and reacts 3.5h at such a temperature to get compound b is arrived
(2) synthesize (Z) -2- acetyl group -2- ((4- methoxyphenyl) diazenyl) ethyl glutarate (compound c):
Excessive dense H is added after being completely dissolved 2.24g 2- acetyl ethyl glutarate with dehydrated alcohol2SO4, it is mixed well, is delayed
The ethanol solution of 1.7g compound b is added dropwise in slow constant speed, room temperature reaction 2.5h is added dropwise, after being tested after reaction
Reason, that is, isolate and purify to obtain compound c；
(3) (Z) -2- (2- (4- methoxyphenyl) hydrazono-) ethyl glutarate (compound d): by 1g chemical combination is synthesized
After object c is completely dissolved with dehydrated alcohol, excessive dense HCl is added, 3.5h is stirred at room temperature, to after reaction, after being tested
Processing, then separates, is purified into compound d；
(4) synthesize 3- (2- ethyoxyl -2- oxoethyl) -5- methoxyl group -1H- indole -2-carboxylic ethyl ester (compound e):
After 1g compound d is completely dissolved with dehydrated alcohol, it is passed through dry HCl gas, 4.5h is stirred at room temperature, to after reaction,
Experiment post-processing is carried out, then separates, be purified into compound e, is the compound e with HIV-1 integrase inhibiting activities.
In the reaction process of step (1)-(4), progress thin-layered chromatography (Thin Layer Chromatography,
TLC) monitor extent of reaction, if reaction not completely if the reaction was continued, until the reaction is complete.
The described experiment post-processing is that pH is adjusted to be extracted 3 times with ethyl acetate (EthylAcetate, EA) to alkalescent,
Concentrated extract fills column, with TLC separation purification of target product.
The tune pH is alkalescent, is adjusted with natrium carbonicum calcinatum.
Compound e with HIV-1 integrase inhibiting activities
Embodiment 2
(1) synthesis is to methoxyl group diazonium benzene hydrochloride (compound b): by the dense salt of compound a (open-chain crown ether) 1.00g
Acid is completely dissolved, after 2h is stirred at room temperature；It moves into 0 DEG C to -10 DEG C reaction system, it is constant to temperature, it is slowly added to the Asia 0.8404g
Sodium nitrate is stirred to react, and reacts 2h at such a temperature to get compound b is arrived
(2) synthesize (Z) -2- acetyl group -2- ((4- methoxyphenyl) diazenyl) ethyl glutarate (compound c):
Excessive dense H is added after being completely dissolved 2.24g 2- acetyl ethyl glutarate with dehydrated alcohol2SO4, it is mixed well, is delayed
The ethanol solution of 1.7g compound b is added dropwise in slow constant speed, and room temperature reaction 2h is added dropwise, carries out experiment post-processing after reaction,
It isolates and purifies to obtain compound c；
(3) (Z) -2- (2- (4- methoxyphenyl) hydrazono-) ethyl glutarate (compound d): by 1g chemical combination is synthesized
After object c is completely dissolved with dehydrated alcohol, excessive dense HCl is added, 2h is stirred at room temperature, to after reaction, after being tested
Reason, then separates, is purified into compound d；
(4) synthesize 3- (2- ethyoxyl -2- oxoethyl) -5- methoxyl group -1H- indole -2-carboxylic ethyl ester (compound e):
After 1g compound d is completely dissolved with dehydrated alcohol, it is passed through dry HCl gas, 2h is stirred at room temperature, to after reaction, into
Row experiment post-processing, then separates, is purified into compound e, is the compound e with HIV-1 integrase inhibiting activities.
In the reaction process of step (1)-(4), progress thin-layered chromatography (Thin Layer Chromatography,
TLC) monitor extent of reaction, if reaction not completely if the reaction was continued, until the reaction is complete.
The described experiment post-processing is that pH is adjusted to be extracted 3 times with ethyl acetate (EthylAcetate, EA) to alkalescent,
Concentrated extract fills column, with TLC separation purification of target product.
The tune pH is alkalescent, is adjusted with natrium carbonicum calcinatum.
Compound e with HIV-1 integrase inhibiting activities
Embodiment 3
(1) synthesis is to methoxyl group diazonium benzene hydrochloride (compound b): by the dense salt of compound a (open-chain crown ether) 1.00g
Acid is completely dissolved, after 2h is stirred at room temperature；It moves into 0 DEG C to -10 DEG C reaction system, it is constant to temperature, it is slowly added to the Asia 0.8404g
Sodium nitrate is stirred to react, and reacts 5h at such a temperature to get compound b is arrived
(2) synthesize (Z) -2- acetyl group -2- ((4- methoxyphenyl) diazenyl) ethyl glutarate (compound c):
Excessive dense H is added after being completely dissolved 2.24g 2- acetyl ethyl glutarate with dehydrated alcohol2SO4, it is mixed well, is delayed
The ethanol solution of 1.7g compound b is added dropwise in slow constant speed, and room temperature reaction 3h is added dropwise, carries out experiment post-processing after reaction,
It isolates and purifies to obtain compound c；
(3) (Z) -2- (2- (4- methoxyphenyl) hydrazono-) ethyl glutarate (compound d): by 1g chemical combination is synthesized
After object c is completely dissolved with dehydrated alcohol, excessive dense HCl is added, 5h is stirred at room temperature, to after reaction, after being tested
Reason, then separates, is purified into compound d；
(4) synthesize 3- (2- ethyoxyl -2- oxoethyl) -5- methoxyl group -1H- indole -2-carboxylic ethyl ester (compound e):
After 1g compound d is completely dissolved with dehydrated alcohol, it is passed through dry HCl gas, 7h is stirred at room temperature, to after reaction, into
Row experiment post-processing, then separates, is purified into compound e, is the compound e with HIV-1 integrase inhibiting activities.
In the reaction process of step (1)-(4), progress thin-layered chromatography (Thin Layer Chromatography,
TLC) monitor extent of reaction, if reaction not completely if the reaction was continued, until the reaction is complete.
The described experiment post-processing is that pH is adjusted to be extracted 3 times with ethyl acetate (EthylAcetate, EA) to alkalescent,
Concentrated extract fills column, with TLC separation purification of target product.
The tune pH is alkalescent, is adjusted with natrium carbonicum calcinatum.
Compound e with HIV-1 integrase inhibiting activities
Embodiment 4
(1) synthesis is to methoxyl group diazonium benzene hydrochloride (compound b): by compound a (open-chain crown ether) 1.00g
(1.00eq.) is completely dissolved with concentrated hydrochloric acid, after 2h is stirred at room temperature；It moves into 0 DEG C to -10 DEG C reaction system, it is constant to temperature,
It is slowly added to 0.8404g sodium nitrite, is stirred to react, reacts 3.5h at such a temperature to get compound b is arrived
(2) synthesize (Z) -2- acetyl group -2- ((4- methoxyphenyl) diazenyl) ethyl glutarate (compound c):
Excessive dense H is added after being completely dissolved 2.24g 2- acetyl ethyl glutarate with dehydrated alcohol2SO4, it is mixed well, is delayed
The solution of compound b is added dropwise in slow constant speed, and room temperature reaction 2.5h is added dropwise, carries out experiment post-processing after reaction, that is, separates
Purifying obtains compound c；
(3) (Z) -2- (2- (4- methoxyphenyl) hydrazono-) ethyl glutarate (compound d): by 1g chemical combination is synthesized
After object c is completely dissolved with dehydrated alcohol, excessive dense HCl is added, 3.5h is stirred at room temperature, to after reaction, after being tested
Processing, then separates, is purified into compound d；
(4) synthesize 3- (2- ethyoxyl -2- oxoethyl) -5- methoxyl group -1H- indole -2-carboxylic ethyl ester (compound e):
After 1g compound d is completely dissolved with dehydrated alcohol, it is passed through dry HCl gas, 4.5h is stirred at room temperature, to after reaction,
Experiment post-processing is carried out, then separates, be purified into compound e, is the compound e with HIV-1 integrase inhibiting activities；
(5) synthesizing 3- (carboxymethyl) -5- methoxyl group -1H- indole-2-carboxylic acid (has HIV-1 integrase inhibiting activities
Compound f): to equipped with acetone: water is that sodium hydroxide 78.60mg room temperature is added in the reactor of 2:1 and substance e 100.00mg
It is stirred to react, when raw material end of reaction, then can handle reaction, i.e., pour into reaction solution in beaker, then adjusting pH is alkalescent, acetic acid
Ethyl ester extracts 4 times, concentration, and the compound f with HIV-1 integrase inhibiting activities can be obtained with silica gel column chromatography separation.
In the reaction process of step (1)-(4), progress thin-layered chromatography (Thin Layer Chromatography,
TLC) monitor extent of reaction, if reaction not completely if the reaction was continued, until the reaction is complete.
The described experiment post-processing is that pH is adjusted to be extracted 3 times with ethyl acetate (EthylAcetate, EA) to alkalescent,
Concentrated extract fills column, with TLC separation purification of target product.
The tune pH is alkalescent, is adjusted with natrium carbonicum calcinatum.
Compound f with HIV-1 integrase inhibiting activities
Embodiment 5
The resulting compound f with HIV-1 integrase inhibiting activities of Example 4 will have in 100 mL reactors
There is compound f50.00mg and the 15mL distilled water of HIV-1 integrase inhibiting activities to mix, magnetic agitation, oil bath heating to 40
DEG C, 30% sodium hydroxide solution is then added, makes pH value control between 11-11.5, is heated to 85-95 DEG C and is allowed to dissolve, add
Active carbon is a small amount of, and decolourize 15min, filters, and filtrate is cooled to 25 DEG C of filterings, smoke filtrate is allowed to be cooled to room temperature nature crystallization, crystal
It is washed with a small amount of ice water, it is dry at 80 DEG C, obtain the compound g with HIV-1 integrase inhibiting activities.
Compound g with HIV-1 integrase inhibiting activities
Embodiment 6
Raw material a open-chain crown ether in embodiment 4 is changed to 3- hydroxyl -4- aminoanisole, remaining step is identical, finally
Obtain the compound h with HIV-1 integrase inhibiting activities.
Compound h with HIV-1 integrase inhibiting activities
Embodiment 7
2 acyl ethyl glutarate of raw material in embodiment 4 is changed to 2- acetyl group -5- methoxyl group -4- ketoglutaric acid,
Remaining step is identical, finally obtains the compound i with HIV-1 integrase inhibiting activities.
Compound i with HIV-1 integrase inhibiting activities
Embodiment 8
2 acyl ethyl glutarate of raw material in embodiment 4 is changed to 2- acetyl group -5- ethyoxyl -4- ketoglutaric acid,
Remaining step is identical, finally obtains the compound j with HIV-1 integrase inhibiting activities.
Compound j with HIV-1 integrase inhibiting activities
Embodiment 9
Raw material a open-chain crown ether in embodiment 4 is changed to the fluoro- 4- aminoanisole of 3-, remaining step is identical, finally
To the compound k with HIV-1 integrase inhibiting activities.
Compound k with HIV-1 integrase inhibiting activities
Embodiment 10
Raw material a open-chain crown ether in embodiment 4 is changed to 3- chloro-4-methoxy aniline, remaining step is identical, finally
To the compound l with HIV-1 integrase inhibiting activities.
Compound l with HIV-1 integrase inhibiting activities
The compound with HIV-1 integrase inhibiting activities resulting to embodiment 1-10 is determined as follows:
(1) integrase chain transfer activity measures
This experiment is carried out in the dark in 96 hole microwell plate of black polystyrene, and reaction system is 50 μ L.First with 1 × reaction
Buffer (25mM PIPES, 10mM beta -mercaptoethanol, 0.1 g/LBSA, 10mM MnCl2, 5% glycerol, pH 7.0) and board-washing one
Secondary, then every hole is added 25 μ L and is free of MnCl22 × reaction buffer, 550nM purifying integrase recombinant protein and 5 μ L it is molten
In the untested compound of DMSO, in 37 DEG C of incubations 20min, positive controls DTG after mixing.Add final concentration of 10mM's
MnCl2, 30nM donor dna and 300nM target DNA, and sterilizing distilled water is added and supplies volume to 50 μ L, be incubated for after mixing in 37 DEG C
1h.Be added later 1.5 μ L 10mg/mL Streptavidin MagneSphere and 51.5 μ L magnetic bead combination buffers (10mM Tris-HCl,
2M NaCl, 20mM EDTA, 0.1%Tween-20, pH 7.6), in 20 DEG C of incubations 15 min, every 5min after thoroughly oscillation mixes
Oscillation mixes once, and microwell plate is placed in magnetic bead collector and stands 90s, abandons supernatant, and washed with the PBS containing 0.05%Tween-20
Magnetic bead is three times.The relative fluorescence (RFU) that every hole is finally detected with fluorescence analyser, selects excitation wavelength 485nm, launch wavelength
528nm calculates the inhibiting rate of sample to be tested.
(2) compound is to C8166 and PBMC cytotoxicity experiment
Untested compound is carried out 5 with RPMI-1640 complete medium (containing 10%FBS) on 96 hole microtest plates
Times doubling dilution, totally 6 dilutions, each dilution set 3 holes, every 100 μ L of hole.The control wells of not drug containing are set simultaneously.Often
Hole is added 4 × 105The C8166 cell of/mL or 5 × 106The 100 μ L of PBMC of/mL.37 DEG C, 5%CO2Culture 3 days uses
MTT colorimetric determination cytotoxicity.Microplate reader measures OD value, and measurement wavelength is 595nm, and CC is calculated50Value.
(3) compound is to HIV-1IIIBThe Inhibition test of cytopathogenic effect (CPE)
Untested compound is carried out 5 times of doubling dilutions with RPMI-1640 complete medium on 96 hole microtest plates (to rise
Begin final concentration of 20 μM), each dilution sets 3 repeating holes, every 100 μ L of hole, while the control wells of not drug containing are arranged.Every hole
It is added 8 × 105The 50 μ L of C8166 cell of/mL, is then added the HIV-1 of 50 μ LIIIBDilute supernatant, 50/ hole 1300 TCID.
37 DEG C, 5%CO2Culture 3 days, (100 ×) count the formation of plasomidum under inverted microscope.EC50To inhibit Syncytium formation
Compound concentration when 50%.
The activity of the resulting compound with HIV-1 integrase inhibiting activities of embodiment 1-10 is as follows:
The above active testing the result shows that, the antiviral work of compound with HIV-1 integrase inhibiting activities of the invention
Property it is significant, while cytotoxicity is low, provides new selection to treat the exploitation of AIDS-treating medicine.
Finally it is pointed out that above embodiments are only the more representational examples of the present invention.Obviously, technology of the invention
Scheme is not limited to above-described embodiment, and acceptable there are many deformations.Those skilled in the art can be from disclosed by the invention
All deformations that content is directly exported or associated, are considered as protection scope of the present invention.
Claims (10)
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1294580A (en) * | 1998-03-26 | 2001-05-09 | 盐野义制药株式会社 | Indole derivatives with antiviral activity |
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2019
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1294580A (en) * | 1998-03-26 | 2001-05-09 | 盐野义制药株式会社 | Indole derivatives with antiviral activity |
Non-Patent Citations (1)
| Title |
|---|
| FINDLAY, STEPHEN P.; DOUGHERTY, GREGG: "《The synthesis of certain substituted indoleacetic acids》", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
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