CN101108848A - Furoquinoline compound and application of the same in manufacturing anti-virus medicament - Google Patents
Furoquinoline compound and application of the same in manufacturing anti-virus medicament Download PDFInfo
- Publication number
- CN101108848A CN101108848A CNA2006100291746A CN200610029174A CN101108848A CN 101108848 A CN101108848 A CN 101108848A CN A2006100291746 A CNA2006100291746 A CN A2006100291746A CN 200610029174 A CN200610029174 A CN 200610029174A CN 101108848 A CN101108848 A CN 101108848A
- Authority
- CN
- China
- Prior art keywords
- compound
- cypa
- hiv
- virus
- aids
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the chemical engineering field, which relates to a small molecule compound with anti-HIV activity, the preparation method and the application. The CyPA can combine with Gag polyprotein of the human immunodeficiency virus (HIV-1). Adoption of the RNAi technology silences CypA or inhibits the activity of the CypA which can disturb the replication of the HIV-1 virus. The small molecule compound of the invention is CyPA inhibitor and has the function of resisting the HIV-1 virus, which is designed aiming at the cell targets, does not easily form drug resistance and is suitable for the requirements of the drug use for long life of AIDS sufferers. Therefore, the small molecule compound can be developed as the novel drug resisting the AIDS and provides a novel approach and means for treating and healing the AIDS.
Description
Technical field
The present invention relates to chemical field, relate to a kind of micromolecular compound with HIV (human immunodeficiency virus)-resistant activity, its preparation method and application.
Background technology
Cyclophilin Cycliphilins (CyPs) is the intracellular protein of widespread distribution, all exists in plant, bacterium and Mammals, has high conservative, is found as the cell receptor of ciclosporin A at first.(CyclosporinA is to separate 11 the amino acid whose ring type polypeptides that contain that obtain from fungus metabolite CsA) to ciclosporin A, is usually used in treating rejection and the autoimmunization systemic disease that is produced after the organ transplantation clinically as immune suppressant drug.The CyPs that has at present found and cloned has more than 130 kind of isomer [GalatA, Metcalfe SM.Peptidyl proline cis-trans iso-merases.Prog Biophys Molec Biol, 1995; 63:67.], they have constituted Cyclophilins family.CyPs has peptide cis-trans propyl isomerism enzyme (PPIase) activity, the catalytic proteins folding process, especially the protein folding of proline rich, and play molecular chaperones effect [Ivery MT.Immunophilins:switched on protein binding domains? Med Res Rev.2000; 20 (6): 452-484.].Meanwhile, CyPs is relevant biological procedures such as apoptosis [the Lee JP of wide participation also, Palfrey HC, Bindokas VP, et al.The role of immunophilins in mutant superoxidedismutas-1 linked familial amyotrophic lateral sclerosis.Proc Natl Acad Sci USA.1999; 96 (6): 3251-3256.] and intercellular signal conduction [Jin ZJ, Melaragno MG, Liao DF, et al.CyclophilinA is a secreted growth factor induced by oxidative stress.Circ Res.2000; 87 (9): 789-796.] etc.
Many studies show that arranged, and CyPA can combine with the Gag polyprotein (Gag polyprotein) of human immunodeficiency virus (HIV-1).This combination makes CypA to be packaged into specifically in the HIV-1 virosome, and be not wrapped into [Franke EK in other retrovirus, Yuan HE, Luban J.Specificincorporation of cyclophilin A into HIV-1 virions.Nature.1994; 372 (6504): 359-362.].In HIV-1 C-type virus C self assembling process, CyPA enters virus as specific integral part, commitment at the HIV-1 cells infected [the Braaten D that plays a role, Franke EK, Luban J.Cyclophilin A isrequired for an early step in the life cycle of human immunodeficiency virus type 1before the initiation of reverse transcription.J Virol.1996; 70 (6): 3551-3560.].CypA and Gag make the N end CA structural domain that the site has been defined in Gag at present (this structural domain after the HIV-1 maturation through being cut into the p24 coat protein) mutually, the proline isomerase activity of CypA can be assisted the shell process of undressing [the Gamble TR after virus is finished cells infected, Vajdos FF, Yoo S, Worthylake DK, Houseweart M, Sundquist WI, Hill CP.Crystal structure of human cyclophilin A boundto the amino-terminal domain of HIV-1 capsid.Cell.1996; 87 (7): 1285-1294.].[as demonstrated by gene targeting in human T cells.EMBO J.2001 for Braaten D, Luban J.Cyclophilin A regulates HIV-1infectivity in the expression of the reticent CypA of use RNAi technology; 20 (6): 1300-1309; Sokolskaja E, Sayah DM, Luban J.Target cell cyclophilin Amodulates human immunodeficiency virus type 1 infectivity.J Virol.2004; 78 (23): 12800-12808.], perhaps use CsA and derivative thereof [Sokolskaja E, Sayah DM, Luban J.Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity.JVirol.2004; 78 (23): 12800-12808.; Bartz SR, Hohenwalter E, Hu MK, Rich DH, Malkovsky M.Inhibition of human immunodeficiency virus replication bynonimmunosuppressive analogs of cyclosporin A.Proc Natl Acad Sci U S is A.1995; 92 (12): 5381-5385.; Steinkasserer A, Harrison R, Billich A, Hammerschmid F, Werner G, Wolff B, Peichl P, Palfi G, Schnitzel W, Mlynar E, et al.Mode of action of SDZ NIM811, a nonimmunosuppressive cyclosporin A analog with activity against humanimmunodericiency virus type 1 (HIV-1): interference with early and late events inHIV-1 replication.J Virol.1995; 69 (2): 814-824.] suppress the activity of CypA, all can disturb duplicating of HIV-1 virus.
Yet up to the present, the someone reports the CypA inhibitor with anti HIV-1 virus as yet.
Summary of the invention
The purpose of this invention is to provide a kind of micromolecular compound with HIV (human immunodeficiency virus)-resistant activity.
Another object of the present invention provides the preparation method of above-mentioned micromolecular compound.
A further object of the present invention provides the application of above-mentioned micromolecular compound.
The invention provides a kind of furoquinoline compounds, its structural formula is:
Wherein, X is O, S or NH; R is N, N-diethylin, N, N-dimethylamino, 1H-pyrroles-1-base or 1-Pyrrolidine base.The present invention comprises that also this compounds is carried out routine substitutes resulting compound, is referred to as FD12.
Among the present invention, X can be O, i.e. Sauerstoffatom.
Among the present invention, R can be the N-dimethylamino.
In one embodiment of the present of invention, R is the N-dimethylamino, and X is O.Like this, compound is N-[(2,3-two-2-furoquinoline-6-yl) amino]-(dimethylamino)-methyl alcohol (N-[(2,3-di-2-furylquinoxalin-6-yl) amino] (dimethylamino) methanol), its structural formula is:
May disturb duplicating of HIV-1 virus in view of suppressing the active material of CypA, the avtive spot that the present invention is directed to CypA has designed some micromolecular inhibitors.Owing to be medicine, and cell target spot mutation rate with respect to viral target spot is relatively slow at the design of cell target spot, therefore be difficult for forming resistance, be fit to the demand of the lifelong medication of AIDS patient.
At first, the present invention has carried out virtual screening to the CypA micromolecular inhibitor.
Cyclophilin A (CypA, PPIA) gene is logged in the human genome database, and its typing number is NM _ 021130.In PDB protein structure database, retrieved the proteic X-ray diffraction crystal of human CypA structure (PDB code: 1CWA).This structure is the compound crystal structure of CypA and its natural inhibitor cyclosporin A (CsA).From this structure, determined the avtive spot of CypA, and determined in the avtive spot, can be by some key amino acids site that CsA suppressed.According to these structural informations, we and Chinese Academy of Sciences's Shanghai medicine are cooperated, and at the CypA avtive spot, some small molecules databases are screened.The small molecules database that is used to screen mainly comprises SPECS and CNPD.At last, filtered out FD12 of the present invention.Whole computation process is to carry out on Chinese Academy of Sciences's Shanghai medicine institute 64CPU-SGI ORIGN3800 computer and super calculation center, Shanghai 392CPU-martial prowess I supercomputer.
Secondly, the present invention utilizes the BIAcore molecule to make instrument checking virtual screening result mutually
The BIAcore molecule is based on surface plasma resonance technology as instrument mutually and realizes following the tracks of interaction between biomolecules, need not any marker, has therefore guaranteed the verity of experimental result to greatest extent.During experiment, biological molecules of interest (CypA albumen) is fixed on the sensing chip surface, then micromolecular compound is dissolved in solvent and flows through chip surface.Monitor can real-time follow-up detects combine, the dissociate variation of whole process of molecule and chip surface biological molecules of interest in the solution.By the binding data of BIAcore, we have determined that finally 12 can the bonded micromolecular compound take place with CypA, and have calculated these micromolecular compounds and CypA bonded balance-dissociation constant KD.
Once more, the present invention utilizes enzyme work to experimental results show that the ability that micromolecular compound is lived and suppressed the CypA enzyme, thereby seeks out the inhibitor of CypA.
It is a lot of to measure the active method of CyP, but the most frequently used with alpha-chymotrypsin activation measurement (α-chymotrypsin-coupled enzymic assay).Its principle is the oligopeptides substrate that contains proline(Pro), be in balance as N-succinyl--Ala-Ala-Pro-Phe p-Nitroaniline (N-Succinyl-Ala-Ala-Pro-Phe p-nitroanilide) its cis, transconfiguration in solution, this substrate generation cis-trans isomerism effect of CyP energy catalysis, promptly the catalysis proline(Pro) is become trans by cis; When it was in transconfiguration, C end p-nitroanilide was discharged pigment group p-Nitroaniline by the alpha-chymotrypsin cracking, can learn the PPIase activity of CyP in the variation of 390nm METHOD FOR CONTINUOUS DETERMINATION light absorption value.
We react in contrast with the reaction that does not add micromolecular inhibitor, measure the inhibiting rate that each small molecules part is lived and reacted enzyme under different concns, thereby calculate the IC of each small molecules part
50Value (ug/ml).The result shows, the IC of FD12 of the present invention
50Value illustrates also that less than 100 FD12 of the present invention has the active effect of PPIase that suppresses CyP.
At last, the present invention has also measured the influence of CypA micromolecular inhibitor to the HIV-1 virus replication.
Compound anti-HIV-1 virus increment test: briefly, utilize the double antibodies sandwich method to measure the amount that p24 albumen produces in each hole exactly.Absorbance value with the blank hole is reference, calculates each compound and suppresses the IC that HIV-1 virus p24 albumen produces
50Value.The result shows that FD12 has the ability that suppresses the HIV-1 virus replication, can be used as new anti-AIDS drug and develops.
On the other hand, the present invention also provides the preparation method of above-mentioned micromolecular compound.Micromolecular compound of the present invention can adopt preparation method's preparation of various routines.For example, synthetic by following two-step approach:
(1)
(2) with (1) gained compound reduction amido bond, promptly get the described compound of claim 1.
Wherein, X is O, S or NH; R is N, N-diethylin, N, N-dimethylamino, 1H-pyrroles-1-base or 1-Pyrrolidine base.
According to the method described above, adopt the synthetic N-[(2 of following method in one embodiment of the present of invention, 3-two-2-furoquinoline-6-yl) amino]-(dimethylamino)-methyl alcohol:
(1)
(2) with (1) gained compound reduction amido bond, promptly.
The present invention also provides the application of above-mentioned micromolecular compound in the preparation anti-AIDS drug.
Utilize micromolecular compound of the present invention,, can filter out with FD12 interactional material takes place, as inhibitor or antagonist etc. by various conventional screening methods.
FD12 of the present invention and inhibitor, antagonist etc. when using (administration) in treatment, can provide different effects.Usually, can these materials are formulated in nontoxic, inert and the pharmaceutically acceptable aqueous carrier medium, wherein pH is about 5-8 usually, and preferably pH is about 6-8, although the pH value can be with being changed to some extent by preparation Substance Properties and illness to be treated.The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, intracutaneous or topical.
With FD12 of the present invention is example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains protein and the pharmaceutically acceptable carrier or the vehicle for the treatment of significant quantity.This class carrier comprises (but being not limited to): salt solution, damping fluid, glucose, water, glycerine, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.FD12 of the present invention can be made into the injection form, for example is prepared by ordinary method with the physiological saline or the aqueous solution that contains glucose and other assistant agents.Pharmaceutical composition such as tablet and capsule can be prepared by ordinary method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of activeconstituents is the treatment significant quantity, for example every day about 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, FD12 of the present invention also can use with the other treatment agent.
Among the present invention, use N-[(2,3-two-2-furoquinoline-6-yl) amino]-anti-AIDS drug of (dimethylamino)-methyl alcohol preparation can be injection or tablet.
When FD12 polypeptide of the present invention is used as medicine, this polypeptide of treatment effective dose can be applied to Mammals, wherein should treat effective dose usually at least about 10 micrograms/kg body weight, and in most of the cases be no more than about 8 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
Acquired immune deficiency syndrome (AIDS) (AIDS) is a kind of by hiv virus, be HIV (human immunodeficiency virus) (humanimmunodeficiencyvirus, abbreviation HIV) destroys immune function of human body behind the intrusion human body, make human body that the multiple infection that can not cure and tumour take place, cause a kind of serious transmissible disease of infected person's death at last.The acquired immune deficiency syndrome (AIDS) that is called as " contemporary pestilence " and " super cancer " has caused the great attention of The World Health Organization (WHO) and national governments, the input that no matter is personnel and funds is all put in the first place, China has listed it in the Class B Notifiable disease, and is one of border monitoring of hygiene transmissible disease.Yet, up to the present, still do not have and can cure this sick active drug.Micromolecular compound FD12 of the present invention has the ability that suppresses the HIV-1 virus replication, and is the medicine at the design of cell target spot, is difficult for forming resistance, is fit to the demand of the lifelong medication of AIDS patient.Therefore, FD12 of the present invention can be used as new anti-AIDS drug and develops, for the treatment and treatment of AIDS a kind of new approach and means are provided.
Embodiment
The virtual screening of embodiment 1 CypA micromolecular inhibitor
Cyclophilin A (CypA, PPIA) gene is logged in the human genome database, and its typing number is NM_021130.In PDB protein structure database, we have retrieved the proteic X-ray diffraction crystal of human CypA structure (PDB code: 1CWA).This structure is the compound crystal structure of CypA and its natural inhibitor cyclosporin A (CsA).From this structure, we have determined the avtive spot of CypA, and have determined in the avtive spot, can be by some key amino acids site that CsA suppressed.According to these structural informations, we and Chinese Academy of Sciences's Shanghai medicine are cooperated, and at the CypA avtive spot, some small molecules databases are screened.The small molecules database that is used to screen mainly comprises SPECS and CNPD.At last, we have filtered out FD12 of the present invention.Whole computation process is to carry out on Chinese Academy of Sciences's Shanghai medicine institute 64CPU-SGI ORIGN3800 computer and super calculation center, Shanghai 392CPU-martial prowess I supercomputer.
Embodiment 2 utilizes the BIAcore molecule to make instrument checking virtual screening result mutually
The BIAcore molecule is based on surface plasma resonance technology as instrument mutually and realizes following the tracks of interaction between biomolecules, need not any marker, has therefore guaranteed the verity of experimental result to greatest extent.During experiment, biological molecules of interest (CypA albumen) is fixed on the sensing chip surface, then micromolecular compound is dissolved in solvent and flows through chip surface.Monitor can real-time follow-up detects combine, the dissociate variation of whole process of molecule and chip surface biological molecules of interest in the solution.By the binding data of BIAcore, we have determined that finally 12 can the bonded micromolecular compound take place with CypA, and have calculated these micromolecular compounds and CypA bonded balance-dissociation constant KD.Its equilibrium dissociation constant of FD12 of the present invention KD (M) is KD=3.19 ± 0.22 * 10
-6, Chi
2=0.427.Wherein, Chi
2Be data that are used for the test experience error in the BIAcore statistical software.
Embodiment 3 N-[(2,3-two-2-furoquinoline-6-yl) amino]-(dimethylamino)-methyl alcohol synthetic
2,3-(2-two furans)-6-aminoquinoxaline and dimethylaminoethyl chloride with the methylene dichloride be solvent at room temperature stir rapidly can generate N-[(2,3-2-two furoquinolines-6-yl) amino]-(N ', N '-dimethylamino)-methane amide.
The above-mentioned N-[(2 that obtains, 3-2-two furoquinolines-6-yl) amino]-(N ', N '-dimethylamino)-methane amide is through LiAlH
4/ THF reduction get final product target compound (being N-[(2,3-2-two furoquinolines-6-yl) amino]-(dimethylamino)-methyl alcohol).
Embodiment 4 N-[(2,3-2-two furoquinolines-6-yl) amino]-(1-pyrryl)-methyl alcohol synthetic
The first step: the pyrroles under the ether existence condition with CO
2And the n-Butyl Lithium reaction generates the 1-minaline;
Second the step: the 1-minaline in THF (tetrahydrofuran (THF)) with DMF (N, dinethylformamide) for catalyzer be 1-pyrroyl chlorine by the oxalyl chloride acidylate;
The 3rd the step: 2,3-(2-two furans)-6-aminoquinoxaline and 1-pyrroyl chlorine with the methylene dichloride be solvent at room temperature rapidly the stirring can generate compound N-[(2,3-2-two furoquinolines-6-yl) amino]-(1-pyrroles)-methane amide;
The 4th step: above-mentioned the 3rd step gained compound is through LiAlH
4/ THF reduction get final product target compound, i.e. N-[(2,3-2-two furoquinolines-6-yl) amino]-(1-pyrryl)-methyl alcohol).
Embodiment 5 N-[(2,3-2-two furoquinolines-6-yl) amino]-(N ', N '-diethylin)-methyl alcohol synthetic
The first step: 2,3-(2-two furans)-6-aminoquinoxaline and N, N-diethylin formyl chloride with the methylene dichloride be solvent at room temperature stir rapidly can generate compound N-[(2,3-2-two furoquinolines-6-yl) amino]-(N ', N '-diethylin)-methane amide);
Second step: above-mentioned the first step gained compound is through LiAlH
4/ THF reduction get final product target compound, i.e. N-[(2,3-2-two furoquinolines-6-yl) amino]-(N ', N '-diethylin)-methyl alcohol).
Embodiment 6 N-[(2,3-2-two furoquinolines-6-yl) amino]-(1-Pyrrolidine alkyl)-methyl alcohol synthetic
The first step: 2,3-(2-two furans)-6-aminoquinoxaline and 1-Pyrrolidine alkyl formyl chloride are that solvent at room temperature stirs rapidly and can generate compound N-[(2,3-2-two furoquinolines-6-yl) amino]-(1-Pyrrolidine alkyl)-methane amide with the methylene dichloride;
Second step: above-mentioned the first step gained compound is through LiAlH
4/ THF reduction get final product target compound, i.e. N-[(2,3-2-two furoquinolines-6-yl) amino]-(1-Pyrrolidine alkyl)-methyl alcohol.
Embodiment 7 utilizes enzyme work to experimental results show that the ability that micromolecular compound is lived and suppressed the CypA enzyme
It is a lot of to measure the active method of CyP, but the most frequently used with alpha-chymotrypsin activation measurement (α-chymotrypsin-coupled enzymic assay).Its principle is the oligopeptides substrate that contains proline(Pro), be in balance as N-succinyl--Ala-Ala-Pro-Phe p-Nitroaniline (N-Succinyl-Ala-Ala-Pro-Phep-nitroanilide) its cis, transconfiguration in solution, this substrate generation cis-trans isomerism effect of CyP energy catalysis, promptly the catalysis proline(Pro) is become trans by cis; When it was in transconfiguration, C end p-nitroanilide was discharged pigment group p-Nitroaniline by the alpha-chymotrypsin cracking, can learn the PPIase activity of CyP in the variation of 390nm METHOD FOR CONTINUOUS DETERMINATION light absorption value.
We react in contrast with the reaction that does not add micromolecular inhibitor, measure the inhibiting rate that each small molecules part is lived and reacted enzyme under different concns, thereby calculate the IC of each small molecules part
50Value.Its enzyme of FD12 of the present invention is lived and is suppressed IC
50Value (μ M) is 3.47 ± 0.92.
Embodiment 8 compound anti-HIV-1s virus increment test
MT-2 cell kind in 96 orifice plates, every hole 10
4Individual.Substratum is RPMI 1640 substratum that contain 10% foetal calf serum.HIV-1 virus is come cells infected with 100 50% tissue infection equivalents, adds the compound overnight incubation (is blank with the hole that does not add compound) of different concns gradient simultaneously.Next day, change the fresh culture that does not contain micromolecular compound.The 4th day, get 100uL nutrient solution supernatant, after handling, the Triton-X100 that adds 5% volume obtains employing virus cracking liquid, measure p24 protein content (p24 is the coat protein of HIV-1, can be used as the index of measurement virus particle quantity) with the ELISA method then.Briefly, utilize the double antibodies sandwich method to measure the amount that p24 albumen produces in each hole exactly.To resist HIV immunoglobulin (Ig) wrapper sheet to spend the night (pH9.6 carbonic acid buffer, 4 ℃), add the PBS sealing that contains 4% skim-milk then; Hatched usefulness precooling PBS flushing several times 1 hour in 37 ℃ after adding the 100uL employing virus cracking liquid; Add the anti-p24 monoclonal antibody of horseradish peroxidase-labeled, develop the color a quarter with TMB; The sulphuric acid soln termination reaction that adds 1N then, the absorbance value when on microplate reader, reading 450nm.Absorbance value with the blank hole is reference, calculates each compound and suppresses the IC that HIV-1 virus p24 albumen produces
50Value.
Result: FD12 suppresses the I that HIV-1 virus p24 albumen produces
50Be worth following (ug/ml): 25.34 ± 2.11.
Claims (7)
1. furoquinoline compounds compound is characterized in that its structural formula is:
Wherein, X is O, S or NH; R is N, N-diethylin, N, N-dimethylamino, 1H-pyrroles-1-base or 1-Pyrrolidine base.
2. compound as claimed in claim 1 is characterized in that, X is O.
3. compound as claimed in claim 1 is characterized in that, R is the N-dimethylamino.
4. compound as claimed in claim 1 is characterized in that, R is the N-dimethylamino, and X is O.
5. the preparation method of compound according to claim 1 is characterized in that this preparation method may further comprise the steps:
(1)
With
Synthetic;
(2) with (1) gained compound reduction amido bond, promptly get the described compound of claim 1.
6. the application of compound in the preparation anti-AIDS drug according to claim 1.
7. application as claimed in claim 6 is characterized in that, this anti-AIDS drug is injection or tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100291746A CN101108848A (en) | 2006-07-20 | 2006-07-20 | Furoquinoline compound and application of the same in manufacturing anti-virus medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100291746A CN101108848A (en) | 2006-07-20 | 2006-07-20 | Furoquinoline compound and application of the same in manufacturing anti-virus medicament |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101108848A true CN101108848A (en) | 2008-01-23 |
Family
ID=39041132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100291746A Pending CN101108848A (en) | 2006-07-20 | 2006-07-20 | Furoquinoline compound and application of the same in manufacturing anti-virus medicament |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101108848A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241672A (en) * | 2011-06-29 | 2011-11-16 | 泰山医学院 | 2,3-dipyrrolyl-6-acylaminoquinoxaline compounds and preparation method thereof |
| CN103772371A (en) * | 2013-04-28 | 2014-05-07 | 复旦大学 | 6-furyl quinazoline-4-amine compound as well as preparation method and application thereof |
-
2006
- 2006-07-20 CN CNA2006100291746A patent/CN101108848A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241672A (en) * | 2011-06-29 | 2011-11-16 | 泰山医学院 | 2,3-dipyrrolyl-6-acylaminoquinoxaline compounds and preparation method thereof |
| CN103772371A (en) * | 2013-04-28 | 2014-05-07 | 复旦大学 | 6-furyl quinazoline-4-amine compound as well as preparation method and application thereof |
| CN103772371B (en) * | 2013-04-28 | 2016-08-17 | 复旦大学 | 6-furyl quinazoline-4-amines and its production and use |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Poduri et al. | Drugs targeting various stages of the SARS-CoV-2 life cycle: Exploring promising drugs for the treatment of Covid-19 | |
| Barrientos et al. | The highly specific carbohydrate-binding protein cyanovirin-N: structure, anti-HIV/Ebola activity and possibilities for therapy | |
| Pan et al. | HIV-1 gp41 fusion intermediate: a target for HIV therapeutics | |
| Dakal | SARS-CoV-2 attachment to host cells is possibly mediated via RGD-integrin interaction in a calcium-dependent manner and suggests pulmonary EDTA chelation therapy as a novel treatment for COVID 19 | |
| Zhang et al. | Overview of targets and potential drugs of SARS-CoV-2 according to the viral replication | |
| MXPA02001349A (en) | Protein polymerization inhibitors and methods of use. | |
| CN111402968B (en) | New application of kaempferol in COVID-19 virus based on molecular simulation | |
| Chang et al. | Targeting protein-protein interaction interfaces in COVID-19 drug discovery | |
| Al-Azzam et al. | Peptides to combat viral infectious diseases | |
| Mule et al. | Drug repurposing strategies and key challenges for COVID-19 management | |
| Han et al. | Advances and challenges in the prevention and treatment of COVID-19 | |
| US20020094991A1 (en) | Methods and compositions for treating microtubule-mediated viral infections and lesions | |
| CN100502869C (en) | Application of a compound in preparing anti-virus medicament | |
| Xiang et al. | Potential therapeutic approaches for the early entry of SARS-CoV-2 by interrupting the interaction between the spike protein on SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) | |
| US11517581B2 (en) | Zika virus protease inhibitors and methods of use thereof | |
| CN101108848A (en) | Furoquinoline compound and application of the same in manufacturing anti-virus medicament | |
| CN101108178B (en) | Application of cyclophilin A restrainer in preparing anti-virus medicament | |
| CN100502865C (en) | Application of a compound in preparing anti-AIDS medicament | |
| CN100502879C (en) | Application of a compound in preparing anti-virus medicament | |
| CN101108183A (en) | Application of cyclophilin A restrainer in preparing anti-virus medicament | |
| CN101334411B (en) | Screening for CXCR4 receptor antagonism polypeptides for treating breast carcinoma and its uses | |
| CN100502855C (en) | Application of a compound in preparing anti-AIDS medicament | |
| CN100577170C (en) | Application of pyrazolopyrimidine Src family tyrosine kinase inhibitor in preparing medicament for curing myocardial infarction | |
| CN106535924A (en) | Treatment and prevention of alzheimer's disease (AD) | |
| US6537967B1 (en) | Pentamer peptide amide, ALGPGNH2, which inhibits viral infectivity and methods of use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |