CN104230929B - A kind of non-nucleoside HIV-1 RT inhibitor - Google Patents
A kind of non-nucleoside HIV-1 RT inhibitor Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a kind of non-nucleoside HIV-1 RT inhibitor, shown in (1).The combination of the non-nucleoside HIV-1 RT inhibitor that the present invention is novel and HIV-1RT is more closely stablized, not only there is good restraining effect for wild-type virus, and the virus after variation is had to the restraining effect of improvement, greatly improve the curative effect of anti-AIDS new drug.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of non-nucleoside HIV-1 RT inhibitor.
Background technology
The research and development of anti-AIDS new drug are the focuses that the whole world is paid close attention to always, according to 5 stage characteristics of HIV cell, the AntiHIV1 RT activity chemicals of design and synthesis can be divided into 5 classes, that is: intrusion/fusion inhibitor, integrase inhibitor, proteinase inhibitor, efabirenz, non-nucleoside reverse transcriptase inhibitor.
Nevirapine (nevirapine, as shown in following formula (A)) is the Non-nucleoside-type inhibitors for HIV1-RT (RT) of first-generation FAD certification.The Main Function of HIV-1RT is exactly the DNA rna transcription of virus being become double-strand, thus realizes constantly copying of virus.Compared with nucleoside inhibitor, although the drug effect of Nevirapine is better and side effect is less, the activity of medicine soon limit by the drug-resistant virus that occurs because of variation.Be very effective for the HIV-1RT after variation, Nevirapine reduces.
Due to the variation property that virus of AIDS is higher, most have inhibiting medicine to wild-type virus, and when virus of AIDS after variation, drug effect just can be had a greatly reduced quality, and this is also the important problem of puzzlement anti-AIDS new drug development always.Therefore, need a kind of anti-AIDS new drug badly, not only there is the restraining effect of wild-type virus, also there is the inhibition to the virus that may morph.
Summary of the invention
Undesirable for the suppression drug effect of Non-nucleoside-type inhibitors in prior art to variation virus of AIDS, the present invention proposes a kind of novel non-nucleoside HIV-1 RT inhibitor, not only there is better inhibition to wild-type virus, and good curative effect is kept equally for the virus after variation.
Non-nucleoside HIV-1 RT inhibitor of the present invention, as shown in following formula (1):
Wherein, R is N or CH.
Above-mentioned formula (1) Suo Shi in the compounds of this invention, work as R=N, the compound structure of non-nucleoside HIV-1 RT inhibitor of the present invention is as shown in following formula (1-I):
The molecular formula of above-mentioned formula (1-I) compound (Mnevirapine) is C
15h
14n
4o
2, molecular weight is 282.30.
Above-mentioned formula (1) Suo Shi in the compounds of this invention, work as R=CH, the compound structure of non-nucleoside HIV-1 RT inhibitor of the present invention is as shown in following formula (1-II):
The molecular formula of above-mentioned formula (1-II) compound (Mnev1) is C
16h
15n
3o
2, molecular weight is 281.30.
The invention allows for the preparation method of described non-nucleoside HIV-1 RT inhibitor.
Wherein, the preparation process of formula (1-I) inhibitor is: 2-amino-4-hydroxy pyridine is through diazotization, nitrated, chloro-4 pyridones (IV) of halogenating reaction generation intermediate product 3-amino-2-; intermediate product IV continues and the replacement of the chloro-5-methyl of 3--4-formyl chloride pyridine through acylation reaction and cyclopropylamine, and is hydrogenated sodium reduction production (1-I) compound Mnevirapine.Particularly, the preparation method of formula (1-I) is: 2-amino-4-hydroxy pyridine and Sodium Nitrite react and generate 2-amino-4-hydroxy pyridine diazonium salt under 0-5 degree Celsius, under the effect of dilute sulphuric acid, hydrolysis generation 2,4-dihydroxy-pyridine (I); 2,4-dihydroxy-pyridine generates 2 through nitration reaction under the effect of concentrated nitric acid and the vitriol oil, 4-dihydroxyl-3-nitropyridine (II), intermediate product II and phosphoryl chloride, phosphorus pentachloride, under the condition refluxed, generate 2-chloro-4-hydroxyl-3-nitropyridine (III); Hydrogen is under the catalysis of Raney nickel, and the intermediate product III that reduces under boron hydroxide weak basic condition obtains chloro-4 pyridones (IV) of 3-amino-2-; With pyridine and cyclohexane give solvent under 60-65 degree Celsius, chloro-4 pyridones of 3-amino-2-and 3-chloro-5-methyl-4-formyl chloride pyridine nucleo philic substitution reaction obtain the chloro-5-methyl of 3--N-(2-chloro-4-hydroxyl-3 pyridyl)-Isonicotinamide (V); Product V and cyclopropylamine generation substitution reaction, generate N-(4-hydroxyl)-2-(cyclopropylamino)-3-chloro-5-methyl-4 pyridine carboxamide (VI), reduced, through nucleophilic reaction production (1-I) compound by sodium hydride.
The preparation process of formula (1-II) inhibitor is: phenol is through the halogenation of sulfur oxychloride, the vitriol oil and the nitration reaction of concentrated nitric acid, the reduction reaction of hydrogen; generate intermediate product 2-amino-3-chlorophenol (III); intermediate product III and 3-chloro-5-methyl-4-formyl chloride pyridine generation acylation reaction generates N-(the chloro-2-phenylol of 3-)-3-chloro-5-methypyridine methane amide (IV); the replacement of intermediate product IV through cyclopropylamine and the reduction of sodium hydride, production (1-II) compound Mnev1.Particularly, the preparation method of formula (1-II) is: phenol generates 3-chlorophenol (I) under the effect of 30-40 degree Celsius of lower sulfur oxychloride and sodium carbonate, and intermediate product I and the vitriol oil and concentrated nitric acid generation nitration reaction generate the chloro-2-nitrophenols (II) of 3-; Under boron hydroxide weak basic condition, intermediate product II is 2-amino-3-chlorophenol (III) by hydrogen reducing under the catalysis of Raney nickel; With pyridine and cyclohexane give solvent, intermediate product III and 3-chloro-5-methyl-4-formyl chloride pyridine nucleo philic substitution reaction generates product (IV) N-(the chloro-2-phenylol of 3-)-3-chloro-5-methypyridine methane amide; Intermediate product IV and cyclopropylamine nucleo philic substitution reaction generate N-(the chloro-phenylol of 3-)-3-(cyclopropylamino)-5-methyl-Isonicotinamide (V); When pyridine makees solvent, intermediate product V and sodium hydride through reduction reaction, with cyclopropyl through nucleophilic addition(Adn), production (1-II) compound.
The invention allows for the application of described non-nucleoside HIV-1 RT inhibitor in preparation suppression HIV-1 viral protein medicine.Wherein, HIV-1 viral protein comprises HIV-1RT (PDBID:1VRT, see HighresolutionstructuresofHIV-1RTfromfourRT-inhibitorcom plexes, Journal:(1995) Nat.Struct.Biol.2:293-302), Lys103Asp (K103N, PDBID:1FKP, see Structuralbasisfortheresilienceofefavirenz (DMP-266) todrugresistancemutationsinHIV-1reversetranscriptase.Jou rnal:(2000) StructureFold.Des.8:1089-1094), Tyr181Cys (Y181C, PDBID:1JLB, see Structuralmechanismsofdrugresistanceformutationsatcodons 181and188inHIV-1reversetranscriptaseandtheimprovedresili enceofsecondgenerationnon-nucleosideinhibitors.Journal:(2001) J.Mol.Biol.312:795-805).
The generation of drug-resistant virus be due to medicine binding pocket inside some amino acid morph, reduce the combination of medicine and viral protein, thus the effect of medicine had a greatly reduced quality.HIV-1RTK103N is a very important variation, and it makes the combination of nevirapine and viral protein decrease the activity of about 40 times.In addition, the sulphur atom on the Cys residue after Y181C variation makes variation and the carbon atom on Nevirapine produce and significantly repel, and make the combination of albumen and medicine can decrease the activity of about 113 times.Studied discovery, Nevirapine combines by means of only several faint hydrogen bond and viral protein in the past, interacts the strongest in it with His235, Pro236, Lys101.So due to the interaction of hydrogen bond that Nevirapine does not have and viral protein generation is stronger, develop immunity to drugs after viral protein morphs, the drug effect of Nevirapine just greatly reduces.
For this phenomenon, the present invention obtains a kind of new non-nucleoside HIV-1 RT inhibitor by the structure construction changing Nevirapine.It can form strong hydrogen bond with viral protein, thus improves the effect of inhibitor, contains the resistance owing to producing after viral protein variation.
Compared with existing medicine Nevirapine (such as formula (A) Suo Shi), the compounds of this invention improvement structurally comprises: be connected with the C13 on Nevirapine with a hydroxyl, carry out the hydrogen atom that alternative original Nevirapine is connected with C13, make this hydroxyl can form stronger hydrogen bond with His235 and the Tyr318 residue on viral protein (comprising wild-type and anomaly).In order to prevent the C10=O1 of this hydroxyl and compound N evirapine (formula (A)) from forming interior hydrogen bond and affecting the interaction of inhibitor and viral protein, the present invention is by the evolution of C10-O1 and N3-H on Nevirapine.Meanwhile, the repulsive interaction that C4 atom is strong on the sulphur atom on the rear Cys residue of Tyr181Cys variation and Nevirapine, the present invention also converts the relative position of N2, C4 atom on Nevirapine further.Obtain thus such as formula the non-nucleoside HIV-1 RT inhibitor (Mnevirapine) of the present invention shown in (1-I).On the other hand, because the solvation number of polar atom is often higher, be unfavorable for that medicine and albumen combine under liquid phase, so the present invention proposes to improve further on the basis of above-mentioned formula (1-I) Mnevirapine, replace the N4 atom on Mnevirapine with a C atom, obtain such as formula the inhibitor of the present invention (Mnev1) shown in (1-II).
The present invention, by the binding pattern of research Nevirapine and HIV-1RT, obtains series of new non-nucleoside HIV-1 RT inhibitor by changing the molecular structure of Nevirapine, and the combination of itself and HIV-1RT is more closely stablized.Calculated by molecular dynamics simulation (MD) and MM/GBSA and find, the present invention's novel non-nucleoside HIV-1 RT inhibitor not only has good restraining effect for wild-type virus, and there is good restraining effect equally for the virus after variation, drastically increase the curative effect of anti-AIDS new drug.
Accompanying drawing explanation
Fig. 1 is HIV1-RT (RT) crystalline structure schematic diagram.
Embodiment
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The non-nucleoside HIV-1 RT inhibitor that the present invention proposes, its structure is as shown in following general formula (1):
Wherein, R is N or CH.
Embodiment 1 inhibitor of the present invention and viral protein binding pattern are tested and Conjugated free energy calculation result
The crystalline structure of wild-type virus albumen HIV-1RT (PDBID:1VRT), varient Lys103Asp (K103N, PDBID:1FKP), Tyr181Cys (Y181C, PDBID:1JLB) is obtained from PDB library inquiry.Calculate the Conjugated free energy of existing medicine Nevirapine and three kind of albumen respectively by the method for molecular dynamics simulation (MD) and MM/GBSA, result is as shown in table 1.Visible according to result, for the albumen after variation, Nevirapine and its Conjugated free energy obviously raise, and the fact that after this and virus of AIDS make a variation, Nevirapine drug effect obviously reduces is consistent.
To Mnevirapine (formula (1-I)) proposed by the invention and Mnev1 (formula (1-II)), in Autodock software, it is docked with viral protein respectively, obtain the binding pattern of novel inhibitors of the present invention and HIV-1RT and varient.The configuration of novel inhibitors obtained by observing Dock can find, His235, Tyr318 portion on the hydroxyl on inhibitor of the present invention and HIV-1RT and varient defines stable hydrogen bond.
Then, sampled by molecular dynamics simulation (MD), calculate the Conjugated free energy of novel inhibitors of the present invention and albumen by MM-GBSA method, and compare with the Conjugated free energy of albumen with Nevirapine, verify inhibitor of the present invention and viral protein in conjunction with effect.The Conjugated free energy that MM-GBSA calculates albumen and part (comprising Nevirapine and two kinds of new inhibitor small molecules of the present invention) is according to following formulae discovery:
ΔG
bind＝G
complex-G
receptor-G
ligand＝ΔE
MM+ΔG
GB+ΔG
np-TΔS(1)
Wherein, Δ E
mMthe electrostatic under gas phase and Van der Waals energy, Δ G
gBpolar solvent free energy, Δ G
npbe non-polar solvent free energy, T Δ S is that Entropy Changes is to the contribution combined by energy.
Before carrying out MD, first use Gaussian09 software at the configuration of HF/6-31G* level optimization inhibitor, and with RESP method matching inhibitor atomic charge.The viral protein Amberff99SB field of force describes.MD carries out in explicit water model, and the size of water box is
the time of MD is 1ns, and from the MD track of last 200ps, on average gets 50 structures calculate for MM-GBSA.Entropy Changes adopts normal-mode to calculate to the contribution of Conjugated free energy, and when considering the calculating special charges of normal-mode to large system, actual getting exists with the closest range of inhibitor
within residue carry out normal-mode calculating.Calculation result is as shown in following table 1-3:
The existing medicine Nevirapine of table 1 and HIV-1 viral protein Conjugated free energy
| System | ΔE ele | ΔE vdw | ΔG GB | ΔG np | TΔS | ΔG bind |
| Wild-type | -7.43 | -42.48 | 22.04 | -4.80 | -18.08 | -14.58 |
| K103N | -4.47 | -43.18 | 20.09 | -4.80 | -20.14 | -12.22 |
| Y181C | -5.72 | -42.78 | 20.79 | -4.80 | -19.24 | -13.28 |
Table 2 formula (1-I) compound and HIV-1 viral protein Conjugated free energy
| System | ΔE ele | ΔE vdw | ΔG GB | ΔG np | TΔS | ΔG bind |
| Wild-type | -15.32 | -40.25 | 31.34 | -5.02 | -16.27 | -12.98 |
| K103N | -19.35 | -43.67 | 36.52 | -4.70 | -15.73 | -15.47 |
| Y181C | -12.09 | -44.33 | 30.06 | -4.90 | -15.76 | -15.50 |
Table 3 formula (1-II) compound and HIV-1 viral protein Conjugated free energy
| System | ΔE ele | ΔE vdw | ΔG GB | ΔG np | TΔS | ΔG bind |
| Wild-type | -8.33 | -43.27 | 24.96 | -4.97 | -19.67 | -11.94 |
| K103N | -15.08 | -43.77 | 30.35 | -4.91 | -18.51 | -14.90 |
| Y181C | -8.85 | -44.57 | 24.80 | -4.83 | -17.13 | -16.32 |
Visible according to above test result, compared with Nevirapine, formula (1-I) the compound Mnevirapine obtained after structure of modification, not only lower with the Conjugated free energy of wild-type virus albumen, and lower with the Conjugated free energy of variant protein K103N, Y181C, demonstrate good drug effect.Formula (1-II) the compound Mnev1 that further improvement obtains, to obtain the data of Conjugated free energy better, visible more tight with the combination of viral protein, stablize.
As can be seen here, new inhibitor Mnevirapine, Mnev1 and the Nevirapine of the present invention compares, and not only has the combination more stable with wild-type HIV-1 viral protein, effectively can suppress the viral protein after making a variation simultaneously.
The preparation of compound shown in embodiment 2 formula (1-I)
Above-mentioned formula (1) Suo Shi in compound, work as R=N, the compound structure of non-nucleoside HIV-1 RT inhibitor of the present invention is as shown in following formula (1-I):
The molecular formula of above-mentioned formula (1-I) compound is C
15h
14n
4o
2, molecular weight is 282.30.
It is as follows such as formula the reaction scheme of the preparation process of compound (1-I) Suo Shi that the present embodiment describes the present invention in detail.
2-amino-4-hydroxy pyridine and Sodium Nitrite react at 0-5 degree Celsius and generate 2-amino-4-hydroxy pyridine diazonium salt, 2-amino-4-hydroxy pyridine diazonium salt is under the effect of dilute sulphuric acid, at 0-25 degree Celsius range, hydrolysis generation 2,4-dihydroxy-pyridine (I).The transformation efficiency of reaction I reaches 80%.Product 2,4-dihydroxy-pyridine (I) is through nitration reaction under the effect of concentrated nitric acid and the vitriol oil, and generate 2,4-dihydroxyl-3-nitropyridine (II), this reaction conversion ratio is 85-95%.Intermediate product II and phosphoryl chloride and phosphorus pentachloride, under reflux conditions obtain 2-chloro-4-hydroxyl-3-nitropyridine (III), reaction conversion ratio is 90%.Under the catalysis and boron hydroxide weak basic condition of Raney nickel, intermediate product III is obtained by reacting chloro-4 pyridones (IV) of 3-amino-2-through hydrogen reducing.Under 60-65 degree Celsius, chloro-4 pyridones of 3-amino-2-and the chloro-5-methyl of 3--4-formyl chloride pyridine generation nucleophilic substitution reaction, generate the chloro-5-methyl of 3--N-(2-chloro-4-hydroxyl-3 pyridyl)-Isonicotinamide (V), this reaction needed pyridine and cyclohexane give solvent, thus the carrying out promoting reaction nucleophilic reaction.Chlorine in product V and cyclopropylamine generation substitution reaction, generate N-(4-hydroxyl)-2-(cyclopropylamino)-3-chloro-5-methyl-4 pyridine carboxamide (VI).Another chlorine in VI product can be hydrogenated sodium reduction, sloughs chlorine atom, Formed positive ion, and the nitrogen generation nucleophilic reaction in carbonium ion and VI, generate final product (1-I)-Mnevirapine.
The compound of above-mentioned product and intermediate product etc. is by gel gravimetric chromatography chromatography, and the fusing point of compound passes through
510 devices are approximate to be obtained.BrukerWM-250 (250-MHz) spectrometer record
1the NMR spectrum of H, BrukerAC-270 (69.2-MHz) spectrometer record
13the NMR spectrum of C, uses tetramethylsilane as internal standard substance.Before resonance signal being placed in Observable pulse 1 second, measure NOE reinforcing effect, the NOE reinforcing effect of detection is all greater than 5%.The mass spectrum of Finnegan4023GC/MS/DS spectrometer record compound.According to the measurement result of the method for NMR (Nuclear Magnetic Resonance) spectrum and X-ray diffraction, determine that the finalization compound obtained is that structure is such as formula compound-Mnevirapine (1-I) Suo Shi.
The preparation of compound shown in embodiment 3 formula (1-II)
Above-mentioned formula (1) Suo Shi in compound, work as R=CH, the compound structure of non-nucleoside HIV-1 RT inhibitor of the present invention is as shown in following formula (1-II):
The molecular formula of above-mentioned formula (1-II) compound is C
16h
15n
3o
2, molecular weight is 281.30.
It is as follows such as formula the reaction scheme of the preparation process of compound (1-II) Suo Shi that the present embodiment describes the present invention in detail.
Phenol generates 3-chlorophenol (I) under the effect of sulfur oxychloride and sodium carbonate, and temperature of reaction condition constant temperature is at 30-40 degree Celsius.Product I continues and the vitriol oil and concentrated nitric acid generation nitration reaction, generates the chloro-2-nitrophenols (II) of 3-.Under the catalysis of Raney nickel, product II is 2-amino-3-chlorophenol (III) by hydrogen reducing under this weak basic condition of BOH.Compound III and the chloro-5-methyl of 3--4-formyl chloride pyridine generation nucleophilic substitution reaction, generate product N-(the chloro-2-phenylol of 3-)-3-chloro-5-methypyridine methane amide (IV), react the productive rate improving nucleophilic reaction with pyridine and cyclohexane give solvent.Compound IV and cyclopropylamine continue nucleophilic substitution reaction occurs, and generate N-(the chloro-phenylol of 3-)-3-(cyclopropylamino)-5-methyl-Isonicotinamide (V).Compound V is when pyridine solvent, with sodium hydride generation reduction reaction, negative hydrogen ion in sodium hydride sloughs the chlorine Formed positive ion in (V), so with the nitrogen generation nucleophilic addition(Adn) of cyclopropylamino, generate final product (1-II)-Mnev1.
The compound of above-mentioned product and intermediate product etc. is by gel gravimetric chromatography chromatography, and the fusing point of compound passes through
510 devices are approximate to be obtained.BrukerWM-250 (250-MHz) spectrometer record
1the NMR spectrum of H, BrukerAC-270 (69.2-MHz) spectrometer record
13the NMR spectrum of C, uses tetramethylsilane as internal standard substance.Before resonance signal being placed in Observable pulse 1 second, measure NOE reinforcing effect, the NOE reinforcing effect of detection is all greater than 5%.The mass spectrum of Finnegan4023GC/MS/DS spectrometer record compound.According to the measurement result of the method for NMR (Nuclear Magnetic Resonance) spectrum and X-ray diffraction, determine that the finalization compound obtained is that structure is such as formula compound-Mnev1 (1-II) Suo Shi.
Shown in embodiment 4 formula (1-I), compound is tested the inhibit activities of HIV1-RT (RT)
The dimer that wild-type HIV-1RT albumen (PDBID:1VRT) is made up of P66 and P51 two peptide chains, length is respectively 539,428 amino acid, and crystalline structure as shown in Figure 1.The present embodiment detects formula (1-I) compound on a cellular level to the inhibit activities of HIV1-RT (RT).Concrete experimental technique is as follows:
Reaction mixture is by 50mM 32,3-dibromopropyl phosphoric acid ester (pH=7.8), 50mM L-glutamic acid, 1mM, dithiothreitol (DTT) (DTT), 2mMMgCl
2, 0.02% 3-[3-(courage acyl aminopropyl) dimethylamino] propanesulfonic acid inner salt (CHAPS), 0.8 μ g/mL poly rC: oligomeric dG and 500nM deoxyguanosine triphosphate (dGTP) composition, the cumulative volume of the reaction mixture be configured to is 60 μ L.In 0.5nMHIV-1RT environment, formula (1-I) inhibitor small molecules carries out the active testing in inhibitor molecules level respectively under concentration is 10 μ g/mL.
Formula (1-I) inhibitor is dissolved in DMSO solution, then adds HIV-1RT reversed transcriptive enzyme, react 1 hour under room temperature environment.Then add the liquid trichoroacetic acid(TCA) of 10% and the liquid tripoly phosphate sodium STPP of 2% of 50 μ L zero degrees celsius, under the environment of 4 degrees Celsius, cool 15 minutes.Acid insoluble product is obtained by #30 glass fibre filter, and the number of dry strainer is by the numeration of LKB1205 β sensitive film liquid scintillation counter.
By contrast in the effect containing inhibitor and the flow measurement inhibitor not containing resultant of reaction in inhibitor situation, and calculate IC
50.Experimental result shows, formula (1-I) inhibitor has good inhibition to HIV1-RT (RT) (PDBID:1VRT).
Shown in embodiment 5 formula (1-II), compound is tested the inhibit activities of HIV1-RT (RT)
The present embodiment detects formula (1-II) compound on a cellular level to the inhibit activities of HIV1-RT (RT).Basic experiment process is substantially the same manner as Example 4.
Experimental result shows, formula (1-II) inhibitor has good inhibition to HIV1-RT (RT) (PDBID:1VRT).
Embodiment 6 inhibitor of the present invention and existing medicine are to the inhibiting contrast experiment of HIV-1RT after making a variation
Experiment primary process comprises: in experimental group, be dissolved in DMSO solution respectively, then add Lys103Asp, Tyr181Cys reversed transcriptive enzyme by formula (1-I), (1-II) inhibitor, reacts 1 hour under room temperature environment.Then add the liquid trichoroacetic acid(TCA) of 10% and the liquid tripoly phosphate sodium STPP of 2% of 50 μ L zero degrees celsius, under the environment of 4 degrees Celsius, cool 15 minutes.Acid insoluble product is obtained by #30 glass fibre filter, and the number of dry strainer is by the numeration of LKB1205 β sensitive film liquid scintillation counter.With Nevirapine as a control group.By contrast in the effect containing inhibitor of the present invention and the flow measurement inhibitor containing resultant of reaction in existing medicine Nevirapine inhibitor situation, and calculate IC
50.
Experimental result shows, in control group, existing medicine is to the Lys103Asp (K103N after variation, and Tyr181Cys (Y181C PDBID:1FKP), PDBID:1JLB) restraining effect is not obvious, and formula (1-I), (1-II) inhibitor are to the Lys103Asp (K103N after variation, PDBID:1FKP) and Tyr181Cys (Y181C, PDBID:1JLB) there is good inhibition.
Therefore, inhibitor of the present invention not only has good restraining effect for wild-type virus, and has good restraining effect equally for the virus after variation, thus greatly improves the curative effect of anti-AIDS new drug.As can be seen here, formula (1-I), (1-II) inhibitor are applicable to prepare anti-HIV-1 viral protein medicine.
Protection content of the present invention is not limited to above embodiment.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.
Claims (6)
1. a non-nucleoside HIV-1 RT inhibitor, is characterized in that, as shown in following formula (1):
Wherein, R is N or CH.
2. non-nucleoside HIV-1 RT inhibitor as claimed in claim 1, is characterized in that, R=N, as shown in following formula (1-I):
3. non-nucleoside HIV-1 RT inhibitor as claimed in claim 1, is characterized in that, R=CH, as shown in following formula (1-II):
4. the preparation method of non-nucleoside HIV-1 RT inhibitor as claimed in claim 2; it is characterized in that; comprise the following steps: 2-amino-4-hydroxy pyridine is through diazotization, nitrated, chloro-4 pyridones of halogenating reaction generation intermediate product 3-amino-2-; chloro-4 pyridones of intermediate product 3-amino-2-and the chloro-5-methyl of the 3--4-replacement of formyl chloride pyridine through acylation reaction, cyclopropylamine and the reduction of sodium hydride, production (1-I) compound.
5. the preparation method of non-nucleoside HIV-1 RT inhibitor as claimed in claim 3, it is characterized in that, comprise the following steps: phenol is through the halogenation of sulfur oxychloride, the nitration reaction of the vitriol oil and concentrated nitric acid, the reduction reaction of hydrogen, generate intermediate product 2-amino-3-chlorophenol (III), intermediate product (III) and 3-chloro-5-methyl-4-formyl chloride pyridine generation acylation reaction generate N-(the chloro-2-phenylol of 3-)-3-chloro-5-methypyridine methane amide, intermediate product N-(the chloro-2-phenylol of the 3-) replacement of-3-chloro-5-methypyridine methane amide through cyclopropylamine and the reduction of sodium hydride, production (1-II) compound.
6. non-nucleoside HIV-1 RT inhibitor suppresses the application in HIV-1 viral protein medicine in preparation as claimed in claim 1.
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| CN1759104A (en) * | 2003-03-24 | 2006-04-12 | 弗·哈夫曼-拉罗切有限公司 | Non-nucleoside reverse transcriptase inhibitors I for treating HIV mediated diseases |
| CN101597263A (en) * | 2008-06-05 | 2009-12-09 | 首都医科大学 | Preparation of novel S-DABO HIV-1 reverse transcriptase inhibitor and uses thereof |
| CN102134223A (en) * | 2010-01-22 | 2011-07-27 | 首都医科大学 | Preparation and application of novel chiral 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine (S-DABO) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1759104A (en) * | 2003-03-24 | 2006-04-12 | 弗·哈夫曼-拉罗切有限公司 | Non-nucleoside reverse transcriptase inhibitors I for treating HIV mediated diseases |
| CN101597263A (en) * | 2008-06-05 | 2009-12-09 | 首都医科大学 | Preparation of novel S-DABO HIV-1 reverse transcriptase inhibitor and uses thereof |
| CN102134223A (en) * | 2010-01-22 | 2011-07-27 | 首都医科大学 | Preparation and application of novel chiral 3,4-dihydro-2-alkoxyl-6-benzyl-4-oxopyrimidine (S-DABO) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor |
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