CN104000824A - Application of five membered benzohetercyclic compounds to preparation of HIV-1 (Human Immunodeficiency Virus-1)-resistant drugs - Google Patents
Application of five membered benzohetercyclic compounds to preparation of HIV-1 (Human Immunodeficiency Virus-1)-resistant drugs Download PDFInfo
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- CN104000824A CN104000824A CN201410232554.4A CN201410232554A CN104000824A CN 104000824 A CN104000824 A CN 104000824A CN 201410232554 A CN201410232554 A CN 201410232554A CN 104000824 A CN104000824 A CN 104000824A
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Abstract
The invention discloses an application of five membered benzohetercyclic compounds to preparation of HIV-1 (Human Immunodeficiency Virus-1)-resistant drugs. The compounds have the general formula as shown in the specification. Based on the interaction of Vif-APOBEC3G, the inventor proves that the expression quantity of green fluorescent proteins in a screening system is to be recovered because the compounds as shown in the general formula and particularly the five membered benzohetercyclic compounds disclosed by the invention can inhibit the degrading activity of Vif proteins to A3G. Wild HIV-1 infection experiments carried out in human primary CD4+T lymphocytes and CD4+T lymphocytic systems such as H9, SupT1 and the like prove that the five membered benzohetercyclic compounds have relatively good antiviral effects. The five membered benzohetercyclic compounds are used for providing powerful theoretical and practice basis for further researching and developing antiviral drugs so as to have important research and development values and development significance.
Description
Technical field
The present invention relates to a kind of new application of compound, the particularly application of benzo five-membered heterocycle compound in preparing anti-HIV-1 virus drugs.
Background technology
HIV-1 virus is found at first the 1981 Nian U.S. and finds, by a series of unknown causes, after the syndrome that the cellular immunity deficiency of take is feature occurs, research worker has started the searching to its etiology.Nineteen eighty-three France research group, from a lymph enlargement syndrome patient lymph node, is isolated HIV-1 virus.It is a kind of slow virus that infects human immunity system cells, this virus is destroyed the immunity of human body, cause immune system to lose resistance, and cause various diseases and cancer to be able to survive in human body, thereby cause acquired immune deficiency syndrome (AIDS)---acquired immune deficiency syndrome (AIDS).At present, universal insufficient due to AIDS education, the HIV in the whole world infects still in rising trend, especially in China, has entered especially the rapid growth phase.Stop as early as possible acquired immune deficiency syndrome (AIDS) to become an instant major issue at China popular.Therefore; continue to expand our understanding to HIV-1 mechanism of causing a disease; develop more effective; more economical; still less the antiviral drugs of side effect copies to remove remaining HIV-1 completely; and the vaccine of developing strong and long-acting anti-HIV-1 is with protection Susceptible population, will be the key that can we finally defeat acquired immune deficiency syndrome (AIDS).
The benzo five-membered heterocycle compound with following general formula:
or
In formula I:
R
1for the alkyl of H, C1～C4, or containing the sulfo group that is connected with phenyl ring, be positioned at 1 or No. 2 position of phenyl ring; R
2for the alkyl of H, C1～C4, or with pentacyclic carbonamido; R
1, R
2when different, be H, C1～C4;
X is S or O;
In formula II:
In formula II:
for singly-bound or two key;
X
1for N, S or O; X
2for S or O;
R
1for with pentacyclic carbonamido or be connected with the sulfo group of phenyl ring, be positioned at 1 or No. 2 position of phenyl ring; R
2for H, methyl, ethyl, when
during for two key, R
2for O; Work as X
1during for N, R
3for H or be connected with 3 ° of amidos of phenyl ring, as
(3-({ [(2-chloro-6-fluorophenyl) methyl] (methyl) amino } methyl)-2,3-dihydro-1,3-benzoxazoles-2-ketone, 6-(6-methoxy-3,4-dihydroquinolin-1 (2H)-ylsulfonyl) benzo[d] oxazol-2 (3H)-one),
(5-bromo-2-ethyoxyl-N-(2-methyl isophthalic acid, 3-benzoxazoles-5-yl) benzene-1-sulfonamide, 5-bromo-2-ethoxy-N-(2-methylbenzo[d] oxazol-5-yl) benzenesulfonamide),
(N-(1,3-benzothiazole-2-yl)-1-(furan-2-ylmethyl)-5-oxo-pyrrolidine-3-Methanamide, 2-((5-(benzo[d] [1,3] dioxol-5-yl)-1,3,4-oxadiazol-2-yl) thio)-N-(furan-2-ylmethyl) propanamide),
(6-(6-methoxyl group-1; 2; 3; 4-tetrahydroquinoline-1-sulfonyl)-2; 3-dihydro-1; 3-benzoxazoles-2-ketone, 3-(((2-chloro-6-fluorobenzyl) be amino (methyl)) methyl) benzo[d] oxazol-2 (3H)-one) or
(2-{[5-(2 hydrogen-1,1,3-benzo dioxolanes-5-yl)-1,3,4-oxadiazoles-2-yl] sulfenyl }-N-(furan-2-ylmethyl) propionic acid amide., N-(benzo[d] thiazol-2-yl)-1-(furan-2-ylmethyl)-5-oxopyrrolidine-3-carboxamide) can be purchased from Enamine company or carry out on its basis synthetic, do not report that at present this compounds is for antiviral experiment or other similar effects.
Summary of the invention
The object of the present invention is to provide benzo five-membered heterocycle compound to apply in preparing anti-HIV-1 virus drugs.
Benzo five-membered heterocycle compound used in the present invention has following general formula:
or
In formula I:
R
1for the alkyl of H, C1～C4, or containing the sulfo group that is connected with phenyl ring, be positioned at 1 or No. 2 position of phenyl ring; R
2for the alkyl of H, C1～C4, or with pentacyclic carbonamido; R
1, R
2when different, be H, C1～C4;
X is S or O;
In formula II:
for singly-bound or two key;
X
1for N, S or O; X
2for S or O;
Preferably, the R of above-mentioned benzo five-membered heterocycle compound
1for with pentacyclic carbonamido or be connected with the sulfo group of phenyl ring, be positioned at 1 or No. 2 position of phenyl ring; R
2for H, methyl, ethyl, when
during for two key, R
2for O; Work as X
1during for N, R
3for H or be connected with 3 ° of amidos of phenyl ring.
Preferably, in the formula I or formula II of above-mentioned benzo five-membered heterocycle compound, the sulfo group that is connected with phenyl ring is:
or
, in formula, R is methyl or ethyl;
In formula III
be positioned at 4 or No. 5 positions of phenyl ring; Y is halogen, is positioned at 1～No. 3 position of phenyl ring;
In formula IV,
be positioned at 1～No. 3 position of phenyl ring
Preferably, in the formula I or formula II of above-mentioned benzo five-membered heterocycle compound, the sulfo group that is connected with phenyl ring is:
or
.
Preferably, above-mentioned benzo five-membered heterocycle compound with pentacyclic carbonamido is:
or,
;
In formula, the integer that n is 1～3, the alkyl that R is C1～C3, X
3for N, S or O.
Preferably, the X of above-mentioned benzo five-membered heterocycle compound
3for O, n=1.
Preferably, the R of above-mentioned benzo five-membered heterocycle compound
3for
, in formula, Y
1, Y
2for halogen, R
1the R of '～solely
3' found the chain alkylene into C1～C3.
Preferably, above-mentioned benzo five-membered heterocycle compound is selected from
,
,
,
or
.
Inventor utilizes the interaction of Vif-APOBEC3G, confirm the benzo five-membered heterocycle compound of above-mentioned general formula, particularly proved is invented the activity that benzo five-membered heterocycle compound can suppress Vif protein degradation A3G, causes the expression of screening system Green fluorescin to go up.By carrying out the infection experiment of wild type HIV-1 virus in the CD4+ T lymphocyte series such as the primary CD4+ T lymphocyte people and H9, SupT 1, confirm, the benzo five-membered heterocycle compound of the present invention has good antivirus action, for strong theoretical basis and the practical basis that further antiviral drugs research and development provide, there are important research and development and be worth and develop meaning.
Accompanying drawing explanation
Fig. 1: the structure principle of cell screening model;
Fig. 2: the benzo five-membered heterocycle compound of the present invention has the effect that suppresses Vif activity;
Fig. 3: the benzo five-membered heterocycle compound of the present invention suppresses the print effect of wild type HIV-1 in expressing the H9 cell of A3G albumen and not expressing the SupT1 cell of A3G albumen.
The specific embodiment
Vif is one of indispensable protein of HIV, and its major function is antiviral agent APOBEC3G natural in antagonism host.APOBEC3G is that one of H IV-1 virus threatens greatly, and it is present in the natural host cell of HIV-1 (as CD4+ T cell and macrophage), can be wrapped the virion into HIV-1, brings into play its extremely strong antivirus action in HIV-1 reverse transcription process.For this reason, HIV-1 self the Vif albumen of having encoded carrys out the antiviral activity of specificity antagonism APOBEC3G, and it can import APOBEC3G ubiquitin system and degraded (Figure 1A).Therefore, how deactivation Vif, is a very important target of research and development anti-HIV-1 virus drugs.
According to the molecule mechanism of Vif antagonism APOBEC3G, the Vif that filters out some HIV of the allowing small-molecule drug of APOBEC3G of cannot degrading.We are setting up a kind of easy living cells screening system for this reason, as shown in Fig. 1 B, by the plasmid co-transfection of expressing APOBEC3G-GFP fusion rotein and expressing Vif in cell.With APOBEC3G-GFP fusion rotein, whether be degraded to index.As long as certain compound can also make APOBEC3G-GFP fusion rotein not be degraded (being that GFP fluorescence also exists) in the situation that Vif exists, this compound is exactly the inhibitor of Vif.By the further evaluation to Vif target, confirm that compound acts on host cell or acts on the Vif of virus protein.
In order to understand better essence of the present invention, below in conjunction with experiment and result, illustrate that the benzo five-membered heterocycle compound of the present invention applies in preparing anti-HIV-1 virus drugs.
Below, in experiment, for the purpose of facilitating, compound 1～5 refers to respectively:
2-{[5-(2 hydrogen-1,1,3-benzo dioxolanes-5-yl)-1,3,4-oxadiazoles-2-yl] sulfenyl }-N-(furan-2-ylmethyl) propionic acid amide. (compound 1),
6-(6-methoxyl group-1,2,3,4-tetrahydroquinoline-1-sulfonyl)-2,3-dihydro-1,3-benzoxazoles-2-ketone (compound 2),
5-bromo-2-ethyoxyl-N-(2-methyl isophthalic acid, 3-benzoxazoles-5-yl) benzene-1-sulfonamide (compound 3),
3-({ [(2-chloro-6-fluorophenyl) methyl] (methyl) amino } methyl)-2,3-dihydro-1,3-benzoxazoles-2-ketone (compound 4),
N-(1,3-benzothiazole-2-yl)-1-(furan-2-ylmethyl)-5-oxo-pyrrolidine-3-Methanamide (compound 5).
experiment one
1) get cell strain 239t cell on well-grown people's kidney, be inoculated in the 96 transparent flat undersides in hole every hole 5 * 10
4cell.The culture medium of using is complete medium: DMEM in high glucose, and 10% hyclone and 1% dual anti-, condition of culture is 5% carbon dioxide, 37 ℃;
2) 24h adherent after, two kinds of plasmids of cotransfection PEGFP-A3G and pcDNA3.1-Vif.Transfection adopts liposome transfection, and reagent is used lipo2000, transfection liquid 20 μ l;
3) after transfection 4h, add compound to be screened, every hole 2 μ l, final concentration is 50 μ M;
4) cultivate after 48h, detect the expression of green fluorescent protein GFP.If there is green fluorescent protein GFP, express the situation rising, this compound may become antiviral drug candidate.
Experimental result as shown in Figure 2, can find out from experimental result, and the benzo five-membered heterocycle compound of the present invention all has the effect that suppresses Vif activity.
experiment two
Vif albumen has important function in HIV-1 virus replication, and the HIV virus of vif defect can not copy in CD4+T cell, macrophage, can not be in above-mentioned " non-permission " time multiplexed cell system; And the wild strain virus that contains vif gene can be in above-mentioned time multiplexed cell system.After some target cell of Vif gene-deleted strain cell entry, reverse transcription can be carried out, but proviral DNA can not be synthesized.Studies show that HIV copies appearance or the disappearance of putting to death in a kind of cytostatic factor, this endogenic inhibitive factor is APOBEC3G, it belongs to intracellular rna editing enzymes, can make the cytosine deaminizating in mRNA form uracil, cause the accumulation of G and A mutant, and then be viral DNA degraded, vif forms the inhibition activity of complex blocking-up APOBEC3G by being combined with APOBEC3G.The cell line existing at APOBEC3G as H9 cell in, APOBEC3G and vif protein binding are degraded by ubiquitination system, if compound can suppress APOBEC3G by vif protein degradation, host cell can not be infected by HIV-1; And the non-existent feelings cell line of APOBEC3G as SupT1 cell in, HIV-1 albumen can normally infect this host cell; This compound will likely become the compound of anti-HIV-1 Vif albumen so.
APOBEC3G is the self-protective mechanism of cell, but vif is the albumen of HIV-1 virus antagonism APOBEC3G function, causes HIV-1 virus to escape self-reset procedure in cell.Utilize the permission cell of HIV-1 and do not allow the effect comparison of antiviral in cell experiment, thereby can further in wild type Viral experiment, determine the Vif albumen that target compound can antagonism HIV-1, suppress copying of HIV-1 virus.
1) get well-grown lymphocyte series H9 and Supt 1, cell consumption is 2 * 10
5/hole, infects respectively packaged HIV-1 virus supernatant, and viral consumption is 10ng/1 * 10
6cell; (during infection, using the short reagent polybrene that infects);
2) after infection 3h, change liquid, use PBS to clean three times, abandon supernatant, use 1640 culture medium (10% hyclone, 1% is dual anti-) to cultivate, the every hole 200 μ l of culture medium, the every hole 2 μ l(final concentration 50 μ M of compound);
3) use 2%Triton X-100 to process the supernatant of receiving sample, receive the cell conditioned medium of having cultivated 4day, survey P24 Elisa.
Experimental result as shown in Figure 3.From experimental result, can find out, the benzo five-membered heterocycle compound of the present invention has good anti-HIV-1 virus function in H9 cell, and there is no effect in SupT1 cell.
experiment three
1) get well-grown lymphocyte series H9, cell consumption is 2 * 10
5/ hole, infects packaged HIV-1 virus supernatant, and viral consumption is 10ng/1 * 10
6cell; (during infection, using the short reagent polybrene that infects);
2) after infection 3h, change liquid, use PBS to clean three times, abandon supernatant, use 1640 culture medium (10% hyclone, 1% is dual anti-) to cultivate, the every hole 200 μ l of culture medium, add the every hole 2 μ l of compound, final concentration is respectively 50 μ M, 5 μ M, 0.5 μ M, 0.05 μ M, 0.005 μ M, 0.0005 μ M, 0 μ M;
3) use 2%Triton X-100 to process the supernatant of receiving sample, receive sample 4day, survey P24 Elisa.
Experimental result is as shown in the table, the IC of the benzo five-membered heterocycle compound of the present invention
50be worth as shown in the table:
| Compound number | IC 50 (μM) |
| 1 | 1.51 |
| 2 | 0.89 |
| 3 | 3.41 |
| 4 | 1.85 |
| 5 | 0.99 |
From experimental result, benzo five-membered heterocycle compound of the present invention has the viral effect of good inhibition.
?
experiment four
(3-(4 for MTS, 5-dimethylthiazol-2-yl)-5 (3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium, inner salt) be a kind of new synthetic tetrazole compound, it is identical with the application principle of MTT, by the multiple dehydrogenase in living cells mitochondrion, be reduced into separately coloured first a ceremonial jade-ladle, used in libation product, the viable count of its shade and some sensitive cells strain is height correlation within the specific limits.According to the absorbance of the 490n recording (OD value), judge living cells quantity, OD value is larger, and cytoactive is stronger, represents that drug toxicity is less.
1) inoculating cell, is made into individual cells suspension with the DMEM culture fluid containing 10% tire calf serum by 293t, is inoculated into 96 orifice plates, every pore volume 200 μ l with 1000, every hole cell;
2) 24h adds compound after adherent, every hole 2 μ l, and final concentration is respectively 50 μ M, 5 μ M, 0.5 μ M, 0.05 μ M, 0.005 μ M, 0.0005 μ M, 0 μ M;
3) cultivate after 48h, every hole adds MTS solution 20 μ l, continues to hatch 2～4 h in incubator;
4) select 490nm wavelength, on enzyme linked immunological monitor, measure each hole absorbance value, observe the cytotoxicity of compound to 293t cell.
Experimental result is as shown in the table, the CC of the benzo five-membered heterocycle compound of the present invention
50be worth as shown in the table:
| Compound number | CC 50 (μM) |
| 1 | >50 |
| 2 | >50 |
| 3 | >50 |
| 4 | >50 |
| 5 | >50 |
From experimental result, can find out, the benzo five-membered heterocycle compound toxicity of the present invention is lower, is all ready-made acellular malicious phenomenon in 293t cell.
Claims (7)
1. the application of benzo five-membered heterocycle compound in preparing anti-HIV-1 virus drugs, described benzo five-membered heterocycle compound has following general formula:
or
In formula I:
R
1for the alkyl of H, C1～C4, or containing the sulfo group that is connected with phenyl ring, be positioned at 1 or No. 2 position of phenyl ring; R
2for the alkyl of H, C1～C4, or with pentacyclic carbonamido; R
1, R
2when different, be H, C1～C4;
X is S or O;
In formula II:
For singly-bound or two key;
X
1for N, S or O; X
2for S or O;
R
1for with pentacyclic carbonamido or be connected with the sulfo group of phenyl ring, be positioned at 1 or No. 2 position of phenyl ring; R
2for H, methyl, ethyl, when
during for two key, R
2for O; Work as X
1during for N, R
3for H or be connected with 3 ° of amidos of phenyl ring.
2. application according to claim 1, is characterized in that: in formula I or formula II, the sulfo group that is connected with phenyl ring is:
or
, in formula, R is methyl or ethyl;
In formula III
be positioned at 4 or No. 5 positions of phenyl ring; Y is halogen, is positioned at 1～No. 3 position of phenyl ring;
In formula IV,
be positioned at 1～No. 3 position of phenyl ring.
3. application according to claim 2, is characterized in that: in formula I or formula II, the sulfo group that is connected with phenyl ring is:
or
.
4. application according to claim 1 and 2, is characterized in that: with pentacyclic carbonamido, be:
or,
;
In formula, the integer that n is 1～3, the alkyl that R is C1～C3, X
3for N, S or O.
5. application according to claim 4, is characterized in that: X
3for O, n=1.
6. according to the application described in claim 1,2 or 5, it is characterized in that: R
3for
, in formula, Y
1, Y
2for halogen, R
1the R of '～solely
3' found the chain alkylene into C1～C3.
7. application according to claim 1, is characterized in that: benzo five-membered heterocycle compound is selected from
,
,
,
or
.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230067A (en) * | 2001-02-14 | 2008-07-30 | 泰博特克药品有限公司 | Broadspectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors |
| CN101293876A (en) * | 2008-06-16 | 2008-10-29 | 山西医科大学 | Benzoxazole ketones derivative and preparation method thereof |
| CN101878210A (en) * | 2007-12-06 | 2010-11-03 | 泰博特克药品公司 | Amide compound as boosters |
-
2014
- 2014-05-28 CN CN201410232554.4A patent/CN104000824B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230067A (en) * | 2001-02-14 | 2008-07-30 | 泰博特克药品有限公司 | Broadspectrum 2-(substituted-amino)-benzothiazole sulfonamide HIV protease inhibitors |
| CN101878210A (en) * | 2007-12-06 | 2010-11-03 | 泰博特克药品公司 | Amide compound as boosters |
| CN101293876A (en) * | 2008-06-16 | 2008-10-29 | 山西医科大学 | Benzoxazole ketones derivative and preparation method thereof |
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