CN103980180B - A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug - Google Patents
A kind of indoles-a-amino acid compounds and preparing the application in anti-AIDS drug Download PDFInfo
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- 229940124321 AIDS medicine Drugs 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- -1 2-amino-2- (6-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester Chemical compound 0.000 claims description 72
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 43
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 150000002475 indoles Chemical class 0.000 abstract description 11
- 239000002253 acid Substances 0.000 abstract 1
- 238000007171 acid catalysis Methods 0.000 abstract 1
- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 239000000047 product Substances 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 18
- 230000000694 effects Effects 0.000 description 15
- 239000003814 drug Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 208000030507 AIDS Diseases 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 9
- 108060001084 Luciferase Proteins 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 7
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 7
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 7
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- 102100034343 Integrase Human genes 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002777 nucleoside Substances 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000031886 HIV Infections Diseases 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229960000689 nevirapine Drugs 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- GHPFVEIYABXUGH-UHFFFAOYSA-N 1-(3-methylbutyl)indole Chemical compound C1=CC=C2N(CCC(C)C)C=CC2=C1 GHPFVEIYABXUGH-UHFFFAOYSA-N 0.000 description 3
- MZBSJLAGBUNNLH-UHFFFAOYSA-N 3,3,3-trifluoropropanamide Chemical class NC(=O)CC(F)(F)F MZBSJLAGBUNNLH-UHFFFAOYSA-N 0.000 description 3
- KSNKQSPJFRQSEI-UHFFFAOYSA-N 3,3,3-trifluoropropanoic acid Chemical compound OC(=O)CC(F)(F)F KSNKQSPJFRQSEI-UHFFFAOYSA-N 0.000 description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000011225 antiretroviral therapy Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- BESVJAAMVQYJDM-UHFFFAOYSA-N ethyl 2-amino-3,3,3-trifluoro-2-(1H-indol-3-yl)propanoate Chemical compound C1=CC=C2C(C(N)(C(=O)OCC)C(F)(F)F)=CNC2=C1 BESVJAAMVQYJDM-UHFFFAOYSA-N 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- XWLFYDWQYPOMKM-UHFFFAOYSA-N methyl 3-(2-amino-3-ethoxy-1,1,1-trifluoro-3-oxopropan-2-yl)-1H-indole-5-carboxylate Chemical compound C1=C(C(=O)OC)C=C2C(C(N)(C(=O)OCC)C(F)(F)F)=CNC2=C1 XWLFYDWQYPOMKM-UHFFFAOYSA-N 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- YXZFFTJAHVMMLF-UHFFFAOYSA-N 1-bromo-3-methylbutane Chemical compound CC(C)CCBr YXZFFTJAHVMMLF-UHFFFAOYSA-N 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- KJHQVUNUOIEYSV-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-oxopropanoate Chemical compound CCOC(=O)C(=O)C(F)(F)F KJHQVUNUOIEYSV-UHFFFAOYSA-N 0.000 description 2
- MTTMADXARZWTLP-UHFFFAOYSA-N ethyl 3,3,3-trifluoropropanimidate Chemical compound CCOC(=N)CC(F)(F)F MTTMADXARZWTLP-UHFFFAOYSA-N 0.000 description 2
- 229960002049 etravirine Drugs 0.000 description 2
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960002814 rilpivirine Drugs 0.000 description 2
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 102000006481 HIV Receptors Human genes 0.000 description 1
- 108010083930 HIV Receptors Proteins 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 101710149951 Protein Tat Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to medical art, specifically disclose a kind of indoles-a-amino acid compounds.Fu-Ke of the indoles of Louis acid catalysis and trifluoropropyl acid esters-imines reaction is adopted to prepare this indoles-a-amino acid analog derivative.This patent mainly introduces preparation method and this compounds is preparing the application in anti-AIDS drug.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an indole-alpha-amino acid compound and application thereof in preparing anti-AIDS medicines.
Background
Acquired immunodeficiency syndrome (AIDS) was first discovered and identified since the 80's of the 20 th century, a rapidly epidemic in China and worldwide that is a major epidemic causing death worldwide. Recent data from the world health organization indicates that approximately three million people worldwide have died of aids and that currently, there are still thirty million patients struggling with aids. Therefore, the development of novel high-efficiency and low-cost therapeutic drugs is still the urgent need for preventing and treating AIDS. Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome, and its replication cycle is completed mainly by reverse transcriptase, integrase and protease upon infection of the host. Because HIV is subject to variation during its replication, it has presented a great challenge to drug development and vaccine development. At present, several drugs with different action mechanisms are mainly used in combination clinically, namely, the high-efficiency antiretroviral therapy. The popularization and the use of the high-efficiency antiretroviral therapy effectively relieve the illness state of patients and prolong the average life of AIDS patients, but the treatment cost is higher, and unbearable adverse reactions and drug resistance are generated after long-term use. At present, effective anti-AIDS vaccines are still lacked, and the development of high-efficiency and low-cost therapeutic drugs is still urgent.
The currently marketed aids drugs can be classified according to different action targets: reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, entry inhibitors, and the like. Among them, reverse transcriptase inhibitors play an important role in the treatment of aids, especially in the highly active antiretroviral therapy, whose target of action is the Reverse Transcriptase (RT) of HIV-1. Reverse transcriptase inhibitors can be classified into Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) depending on the mechanism of action. Nucleoside reverse transcriptase inhibitors are incorporated into the reverse transcription products of the virus by competing with normal nucleotide substrates during viral replication, thereby terminating the extension of the viral genome. Unlike nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors are a class of small drug molecules that act by binding to the hydrophobic binding pocket near the polymerization site of HIV reverse transcriptase.
Over 20 years of non-nucleoside reverse transcriptase inhibitor research, at least 50 structurally diverse non-nucleoside reverse transcriptase inhibitors have been discovered. The first generation of non-nucleoside anti-aids drugs are nevirapine (nevirapine) and delavirdine (delavirdine), and the second generation of non-nucleoside anti-aids drugs are efavirenz (efavirenz), etravirine (etravirine) and rilpivirine (rilpivirine). There are a number of additional non-nucleoside drug candidates in clinical research. The non-nucleoside drugs have the advantages of strong activity and good specificity, do not affect the DNA synthesis of cells or mitochondria, but limit the clinical application of the drugs due to the emergence of drug-resistant mutant strains. Therefore, there is an urgent need to develop novel non-nucleoside inhibitors and broaden the clinical drug choices. Recently, some indole compounds have been reported in documents to have certain anti-HIV reverse transcriptase activity, but most indole compounds have complex structures and high synthesis difficulty, and the activity is not particularly good, so that the possibility of drug formation is limited. In 2013, a subject group reports that an indole derivative containing trifluoromethyl is a good non-nucleoside reverse transcriptase inhibitor, can effectively inhibit the activity of reverse transcriptase, provides a new idea for developing anti-AIDS drugs, and designs an alpha amino acid compound based on the indole as an HIV-1 reverse transcriptase inhibitor on the basis of the new idea.
Disclosure of Invention
The technical problem to be solved by the invention is to provide an indole-alpha-amino acid compound and application thereof in preparing anti-AIDS medicaments.
The indole-alpha-amino acid compound provided by the invention has a structure shown in the following general formula:
wherein,
R1is H, 5-F, 5-Cl, 5-Br, 5-NO2、5-CN、5-CHO、5-COOMe、6-F、6-Cl、6-Br、6-NO26-CN, 5-Me, 6-Me or 5-OMe;
R2is H or isoamyl;
R3me or Et.
In vitro anti-HIV-1 activity experiments show that the indole-alpha-amino acid compound can be used as an HIV-1 non-nucleoside reverse transcriptase inhibitor for preparing anti-AIDS drugs. Preferred, in particular, are the following compounds:
ethyl 2-amino-2- (6-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX1),
Ethyl 2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX2),
Ethyl 2-amino-2- (6-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX3),
Ethyl 2-amino-2- (5-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX4),
Ethyl 2-amino-2- (6-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX5),
Ethyl 2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX6),
Ethyl 2-amino-2- (6-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX7) or
Ethyl 2-amino-2- (5-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX 8).
The invention also provides a preparation method of the indole-alpha-amino acid compound represented by the structural formula.
When R is3Et, synthesized by the reaction of formula i to give the R band3Trifluoropropionate-imine compounds of (a).
The specific operation steps can be as follows:
ethyl trifluoropyruvate (170mg,1mmol) and p-anisidine PMP (129mg,1.05eq.) were dissolved in 10mL of benzene solution, p-toluenesulfonic acid (8.6mg, 5% eq.) was added to the solution at 85 ℃ for reflux reaction, monitored by TLC. After 6h, the solvent benzene was distilled off, and column chromatography separation was performed to obtain a reaction product trifluoropropionate-imine as a raw material for the reaction (iii), which was a pale yellow liquid with a yield of 85%.
When R is1=H,R2Is synthesized by the reaction shown in the following formula ii to give a band R1,R2The indole derivative of (1). The specific operation steps can be as follows:
indole (232mg, 2mmol) was dissolved in 10mL DMF, 8mL DMF solution containing 96mg (2.4mmol) NaH (60% dispersion administration) was added at 5 deg.C, the mixture was stirred at room temperature for 30min and then cooled to 5 deg.C, 5mL DMF solution containing 362.5mg isoamyl bromide (2.4mmol) was added dropwise, the reaction was carried out at room temperature, and TLC was used for monitoring. After 16h, the mixture was cooled to 5 ℃ and 15mL of water was added to quench the reaction, the product was extracted with ether and separated by column chromatography to give the reaction product as the starting material for reaction (iii) as a pale yellow liquid with 93% and 94% yields, respectively.
With R other than that obtained by reaction ii above1,R2The indole derivatives of (4) are all commercially available.
Obtaining the band R by synthesizing or purchasing commodities1,R2Then taking equivalent amount of the band R1,R2The indole derivative and the trifluoropropionic acid ester-imine are dissolved in dichloromethane and fully dissolved, and then proper amount of AlCl is added3Catalytic Friedel-crafts reaction, TLC monitoringThe preparation method comprises the following steps of carrying out basic reaction on raw materials, and carrying out column chromatography separation to obtain the target compound.
The reaction formula is shown in the following formula (iii).
R1Is H, 5-F, 5-Cl, 5-Br, 5-NO2、5-CN、5-CHO、5-COOMe、6-F、6-Cl、6-Br、6-NO26-CN, 5-Me, 6-Me or 5-OMe;
R2is H or isoamyl;
R3me or Et.
The specific operation process can be as follows:
0.2mmol of reaction ii or of the commercial tape R is taken1,R2The indole derivative (2) and 0.2mmol of trifluoropropionic acid ester-imine are added into a single-neck round-bottom flask containing magnetons, 5mL of dichloromethane are added to dissolve the indole derivative and the trifluoropropionic acid ester-imine, the mixture is stirred evenly, and 0.2mmol of AlCl is added3The catalytic Friedel-crafts reaction was carried out and the progress of the reaction was monitored by TLC. After the raw materials are basically reacted completely, the pure target compound is obtained by column chromatography separation.
Pharmacological experiments show that the compound can be used as an HIV-1 non-nucleoside reverse transcriptase inhibitor for preparing anti-AIDS medicaments. Accordingly, the present invention also provides an anti-AIDS pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable carriers or excipients, which may be prepared according to conventional pharmaceutical techniques.
Detailed Description
Example 1: preparation of ethyl 2-amino-2- (6-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX1)
Adding 0.2mmol of 6-bromoindole and 0.2mmol of trifluoropropionate-imine into a single-neck round-bottom flask containing magnetons, adding 5mL of dichloromethane for dissolving, stirring, adding 0.2mmol of AlCl3The catalytic Friedel-crafts reaction was carried out and the progress of the reaction was monitored by TLC. After the raw materials are fully reacted, pure solid compound HX1 is obtained by column chromatography separation, the product is yellow solid, and the yield is 91%.1HNMR(400MHz,CDCl3)8.30(s,1H),7.76(d,J=8.7Hz,1H),7.47(s,1H),7.41(d,J=2.5Hz,1H),7.26–7.23(m,1H),4.45–4.36(m,2H),1.33(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)169.15,137.14,125.03,124.84,124.07,123.90,122.54,116.33,114.30,108.87,76.12(q),64.44,13.94.
Example 2: preparation of ethyl 2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX2)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 91%.1HNMR(400MHz,CDCl3)8.34(s,1H),8.00(s,1H),7.35(s,1H),7.18(d,J=10.3Hz,1H),7.11(d,J=8.6Hz,1H),4.40–4.27(m,3H),1.28(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)169.09,135.02,127.65,126.78,125.65,125.29,123.94,113.94,112.79,108.33,64.52,62.69(q),13.92.
Example 3: preparation of ethyl 2-amino-2- (6-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX3)
The preparation is as in example 1, the product is a pale yellow solid with a yield of 89%.1HNMR(400MHz,Acetone-d6)10.64(s,1H),7.93–7.86(m,1H),7.59(s,1H),7.19(d,J=9.8Hz,1H),6.95–6.86(m,1H),4.37(dtt,J=10.8,7.4,3.7Hz,2H),1.29(t,J=7.1Hz,3H).13CNMR(101MHz,Acetone-d6)169.09,160.54(d,1JC-F=237.35Hz),137.69,126.59,126.35,123.22,123.12,109.81,109.04(d,2JC-F=24.24Hz),98.35(d,3JC-F=25.25Hz),78.14,63.67,14.26.
Example 4: preparation of ethyl 2-amino-2- (5-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX4)
The preparation is as in example 1, the product is a pale yellow solid with a yield of 93%.1HNMR(400MHz,CDCl3)8.33(s,1H),7.58(dt,J=12.2,6.1Hz,1H),7.50(d,J=2.6Hz,1H),7.28–7.25(m,1H),6.97(td,J=9.0,2.5Hz,1H),4.46–4.37(m,2H),1.36(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)169.18,158.12(d,1JC-F=235.33Hz),132.88,126.10,125.62,119.49,113.92,111.99(d,2JC-F=10.10Hz),111.31(d,3JC-F=27.27Hz),106.33,64.39,63.34(q),55.38,13.92.
Example 5: preparation of ethyl 2-amino-2- (6-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX5)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 87%.1HNMR(400MHz,Acetone-d6)10.75(s,1H),7.95(d,J=1.3Hz,1H),7.66(d,J=2.5Hz,1H),7.47(d,J=8.7Hz,1H),7.15(dd,J=8.7,2.1Hz,1H),4.38(qd,J=7.1,4.0Hz,2H),1.31(t,J=7.1Hz,3H).13CNMR(101MHz,Acetone-d6)168.98,136.22,127.59,127.52,125.86,123.72,122.91,121.38,113.98,109.44,77.86(q),63.78,14.24.
Example 6: preparation of ethyl 2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX6)
The preparation is as in example 1, the product being a white solid with a yield of 90%.1HNMR(400MHz,CDCl3)8.36(s,1H),7.92(s,1H),7.50(d,J=2.6Hz,1H),7.26(d,J=4.6Hz,1H),7.18(dd,J=8.7,1.9Hz,1H),4.47–4.39(m,2H),1.37(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)169.10,134.74,126.36,126.19,125.77,123.13,120.99,112.29,108.56,72.39(q),64.46,13.92.
Example 7: preparation of ethyl 2-amino-2- (6-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX7)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 89%.1HNMR(400MHz,Acetone-d6)11.24(s,1H),8.98(d,J=1.8Hz,1H),8.09(dd,J=9.0,2.3Hz,1H),7.87(d,J=2.5Hz,1H),7.67(d,J=9.0Hz,1H),4.45–4.38(m,2H),1.35(d,J=7.1Hz,3H).13CNMR(101MHz,Acetone-d6)168.70,142.79,140.78,129.75,126.41,125.73,123.57,119.26,118.07,113.13,112.10,77.79(q),64.06,14.20.
Example 8: preparation of ethyl 2-amino-2- (5-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX8)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 89%.1HNMR(400MHz,CDCl3)10.58(s,1H),8.97(s,1H),8.10(d,J=9.1Hz,1H),7.72(s,1H),7.50–7.44(m,1H),5.16(s,1H),4.52–4.38(m,2H),2.44(s,1H),1.40(td,J=7.1,1.3Hz,3H).13CNMR(101MHz,CDCl3)168.50,141.95,139.72,128.19,124.52,118.81,117.53,111.69,110.69,67.01(q),64.13,13.73.
Example 9: 2-amino-2- (6-cyano-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester (HX9)
Preparation of
The preparation is as in example 1, the product is a white solid with a yield of 92%.1HNMR(400MHz,CDCl3)9.14(s,1H),8.36(s,1H),7.63(d,J=2.6Hz,1H),7.44(dt,J=8.5,4.8Hz,2H),4.59(s,1H),4.50–4.37(m,2H),1.37(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)167.73,137.18,126.49,125.91,124.26,124.09,123.67,120.83,119.65,111.56,108.34,102.37,69.48(q),63.61,12.89.
Example 10: preparation of ethyl 2-amino-2- (6-methyl-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX10)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 93%.1HNMR(400MHz,CDCl3)8.12(s,1H),7.65(s,1H),7.28(d,J=2.3Hz,1H),7.16(d,J=8.3Hz,1H),7.03(dd,J=8.3,0.9Hz,1H),4.46–4.39(m,2H),2.43(s,3H),1.32(d,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)169.49,134.65,129.83,125.34,125.04,124.48,124.34,120.55,111.09,107.92,67.10(q),64.23,21.63,13.88.
Example 11: preparation of ethyl 2-amino-2- (5-cyano-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX11)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 94%.1HNMR(400MHz,CDCl3)9.08(s,1H),8.36(s,1H),7.64(d,J=2.7Hz,1H),7.49–7.40(m,2H),4.55(d,J=16.2Hz,1H),4.51–4.36(m,2H),1.38(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)168.76,138.17,127.56,126.90,125.35,125.11,124.69,120.63,112.54,109.47,103.54,68.89(q),64.66,13.94.
Example 12: preparation of ethyl 2-amino-2- (5-formyl-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX12)
The preparation is as in example 1, and the product is a pale yellow oil with a yield of 91%.1HNMR(400MHz,Acetone-d6)11.03(s,1H),10.05(s,1H),8.55(s,1H),7.80–7.70(m,2H),7.63(d,J=8.5Hz,1H),4.46–4.36(m,2H),1.32(t,J=7.1Hz,3H).13CNMR(101MHz,Acetone-d6)192.72,168.90,140.97,131.01,128.11,127.94,127.52,126.32,126.29,122.62,113.38,113.33,77.84(q),63.90,14.25.
Example 13: preparation of ethyl 2-amino-2- (5-carbomethoxy-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX13)
The preparation is as in example 1, the product is a white solid with a yield of 91%.1HNMR(400MHz,Acetone-d6)10.90(s,1H),8.75(s,1H),7.85(dd,J=8.6,1.6Hz,1H),7.72(d,J=2.3Hz,1H),7.54(d,J=8.6Hz,1H),6.24(s,1H),4.44–4.35(m,2H),3.88(s,3H),1.33(t,J=7.1Hz,3H).13CNMR(101MHz,Acetone-d6)169.03,168.20,140.33,127.73,126.54,125.98,125.07,123.90,122.84,112.43,64.30(q),63.84,51.98,14.21.
Example 14: preparation of ethyl 2-amino-2- (5-methyl-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX14)
The procedure is as in example 1, the product being a yellow solid in 90% yield.1HNMR(400MHz,Acetone-d6)10.40(s,1H),7.69(s,1H),7.51(d,J=2.5Hz,1H),7.32(d,J=8.3Hz,1H),6.98(d,J=8.3Hz,1H),5.98(s,1H),4.40–4.29(m,2H),2.39(s,3H),1.29(d,J=7.1Hz,3H).13CNMR(101MHz,Acetone-d6)169.39,136.16,129.26,126.72,126.69,125.81,124.38,123.88,121.52,112.18,64.3(q),63.53,21.80,14.28.
Example 15: preparation of ethyl 2-amino-2- (5-methoxy-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX15)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 92%.1HNMR(400MHz,CDCl3)8.31(s,1H),7.36(dd,J=5.3,2.3Hz,2H),7.20(d,J=8.9Hz,1H),6.87(dd,J=8.8,2.4Hz,1H),4.47–4.31(m,2H),3.84(s,3H),1.33(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)169.39,154.44,131.43,125.66,124.96,122.20,113.16,112.11,108.10,102.70,64.23,63.02(q),55.82,13.99.
Example 16: preparation of ethyl 2-amino-2- (1-isopentyl-indol-3-yl) -3,3, 3-trifluoropropionate (HX16)
The preparation is as in example 1, the product is a pale yellow solid with a yield of 90%.1HNMR(400MHz,CDCl3)7.34–7.29(m,2H),7.15(d,J=7.7Hz,1H),7.09(s,1H),6.94(t,J=7.6Hz,1H),4.26–4.05(m,4H),1.70(d,J=7.2Hz,2H),1.61–1.55(m,1H),1.08(dd,J=34.7,27.6Hz,3H),0.96–0.91(m,6H).13CNMR(101MHz,CDCl3)168.69,136.19,129.24,126.92,121.94,121.37,119.14,109.39,108.00,65.78(q),61.98,44.77,38.93,25.75,22.49,22.39,13.91.
Example 17: preparation of ethyl 2-amino-2- (1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX17)
The preparation is as in example 1, the product is a white solid with a yield of 92%.1HNMR(400MHz,CDCl3)8.24(s,1H),7.88(d,J=8.0Hz,1H),7.36(s,1H),7.30(d,J=8.1Hz,1H),7.24–7.19(m,1H),7.18–7.11(m,1H),4.45–4.34(m,2H),1.66(s,0H),1.31(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)168.37,135.28,124.03,123.94,123.41,121.63,121.09,120.00,119.46,110.38,107.46,63.63(q),63.21,12.85.
Example 18: preparation of methyl 2-amino-2- (1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX18)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 91%.1HNMR(400MHz,CDCl3)8.27(s,1H),7.84(d,J=8.0Hz,1H),7.36(d,J=2.4Hz,1H),7.31(d,J=8.1Hz,1H),7.21(dd,J=11.7,4.6Hz,1H),7.18–7.12(m,1H),4.40(s,1H),3.91(s,3H).13CNMR(101MHz,CDCl3)169.98,136.31,125.08,124.93,124.42,122.76,120.83,120.67,111.47,108.45,64.42(q),54.49.
Example 19: 2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid methyl ester (HX19)
Preparation of
The preparation is as in example 1, the product being a pale yellow solid with a yield of 90%.1HNMR(400MHz,CDCl3)8.39(s,1H),7.86(d,J=1.2Hz,1H),7.43(d,J=2.6Hz,1H),7.24(d,J=8.6Hz,1H),7.16(dd,J=8.7,1.9Hz,1H),4.42(s,1H),3.95(s,3H).13CNMR(101MHz,CDCl3)169.66,134.65,126.44,126.17,125.71,123.20,121.91,120.56,112.41,108.18,63.97(q),54.65.
Example 20: preparation of methyl 2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionate (HX20)
The preparation is as in example 1, the product being a pale yellow solid with a yield of 91%.1HNMR(400MHz,CDCl3)8.40(s,1H),8.04(s,1H),7.43(d,J=2.6Hz,1H),7.30(dd,J=8.7,1.8Hz,1H),7.24–7.22(m,1H),4.40(s,1H),3.95(s,3H).13CNMR(101MHz,CDCl3)169.62,134.93,126.84,125.78,125.53,125.39,123.70,123.56,114.08,112.79,64.15(q),54.65.
Example 21: preparation of 1-isopentyl-1H-indole (HX21)
Indole (232mg, 2mmol) was dissolved in 10mL DMF, 8mL DMF solution containing 96mg (2.4mmol) NaH (60% dispersion administration) was added at 5 deg.C, the mixture was stirred at room temperature for 30min and then cooled to 5 deg.C, 5mL DMF solution containing 362.5mg isoamyl bromide (2.4mmol) was added dropwise, the reaction was carried out at room temperature, and TLC was used for monitoring. After 16h, the mixed solution is cooled to 5 ℃, 15mL of water is added to quench the reaction, the product is extracted by ether, and the 1-isoamyl indole is obtained by column chromatography separation, and the product is light yellow oily matter with the yield of 93 percent.1HNMR(400MHz,CDCl3)7.62(d,J=7.9Hz,1H),7.32(d,J=8.2Hz,1H),7.18(d,J=8.6Hz,1H),7.08(dd,J=10.9,5.2Hz,2H),6.47(d,J=2.9Hz,1H),4.12–4.07(m,2H),1.70(d,J=7.6Hz,2H),1.58(s,1H),0.95(d,J=6.6Hz,6H).13CNMR(101MHz,CDCl3)135.99,128.67,127.74,121.40,121.06,119.26,109.45,100.99,44.66,39.13,25.82,22.56.
Example 22: preparation of ethyl trifluoropropionate-imine (HX22)
Ethyl trifluoropyruvate (170mg,1mmol) and p-anisidine PMP (129mg,1.05eq.) were dissolved in 10mL of benzene solution, p-toluenesulfonic acid (8.6mg, 5% eq.) was added to the solution at 85 ℃ for reflux reaction, monitored by TLC. After 6h, the solvent benzene is distilled off, and column chromatography separation is carried out to obtain a reaction product trifluoropropionylimine which is used as a raw material of the reaction (iv), wherein the product is light yellow liquid, and the yield is 85%.1HNMR(400MHz,CDCl3)7.01(d,J=8.9Hz,2H),6.89(d,J=8.9Hz,2H),4.25(q,J=7.1Hz,2H),3.82(s,3H),1.18(t,J=7.1Hz,3H).13CNMR(101MHz,CDCl3)160.36,159.43,139.04,122.27,114.34,77.34,77.03,76.71,62.74,55.49,13.72.
TABLE 1 chemical Structure of the target compound HX1-20 synthesized by the method of the present invention
Compounds | R1 | R2 | R3 |
HX1 | 6-Br | H | Et |
HX2 | 5-Br | H | Et |
HX3 | 6-F | H | Et |
HX4 | 5-F | H | Et |
HX5 | 6-Cl | H | Et |
HX6 | 5-Cl | H | Et |
HX7 | 6-NO2 | H | Et |
HX8 | 5-NO2 | H | Et |
HX9 | 6-CN | H | Et |
HX10 | 6-Me | H | Et |
HX11 | 5-CN | H | Et |
HX12 | 5-CHO | H | Et |
HX13 | 5-COOMe | H | Et |
HX14 | 5-Me | H | Et |
HX15 | 5-OMe | H | Et |
HX16 | H | 1-isopentyl | Et |
HX17 | H | H | Et |
HX18 | H | H | Me |
HX19 | 5-Cl | H | Me |
HX20 | 5-Br | H | Me |
Experimental example 22: pharmacological experiment of indole-alpha amino acid compound
(1) And (3) determining the cytotoxicity of the indole-alpha amino acid compound:
yellow thiazole blue, MTT for short, can penetrate through cell membranes to enter cells, amber dehydrogenase in mitochondria of living cells can enable exogenous MTT to be reduced into water-insoluble needle-shaped Formazan crystals and deposited in the cells, the crystals can be dissolved by 20 percent (mass to volume) SDS, an enzyme linked immunosorbent detector is used for measuring the light absorption value at 595nm wavelength, and the cell number can be indirectly reflected.
For the experiment, TZM-bl (provided by American health institute) cells were transferred to a 96-well plate, after 24 hours, the compound was added to the cells at a certain dilution, the cells were cultured at 37 ℃ for 72 hours, 100. mu.L of the supernatant was aspirated, 20. mu.L of LMTT was added, the cells were cultured at 37 ℃ for 4 hours, 100. mu.L of 20% SDS was added, and after 18 hours of culture, the OD value at 595nm was measured using a microplate reader. Inhibition ratio (%) of compound [1- (E-N)/(P-N)]× 100, wherein "E" represents the OD value of the administered group, "P" represents the OD value of the non-administered group, "N" represents the OD value of the blank group50) As an indicator of the cytotoxicity of the compound.
(2) In vitro anti-HIV-1 activity of indole-alpha amino acid compounds:
HIVIIIBthe strain is a classical HIV drug screening experimental strain, TZM-bl (provided by the American health research institute) cells are modified Hela (provided by the American type Collection) cell strains, HIV receptors and auxiliary receptors are stably expressed on cell membranes, and luciferase genes started by HIV long terminal repetitive sequences are stably integrated in cell nuclei. HIVIIIBAfter TZM-b1 cells are infected, the TAT protein expressed by the virus can activate the expression of luciferase gene in the cells, and the replication level of the virus can be judged by detecting the activity of luciferase in the cells. By detecting luciferase in cells after drug treatment, the activity of the drug in inhibiting HIV-1 virus can be accurately quantified.
In the experiment, HIV was administeredIIIBMixing the virus and the drug, adding into TZM-bl cells (60% (area ratio) and fully spreading), adsorbing the cells with the virus for 2 hours, removing the mixture, adding fresh culture medium (DMEM, 90% (volume ratio), fetal bovine serum10% (volume ratio), G418, 500. mu.g/mL; hygromycin, 100. mu.g/mL; puromycin, 1 μ g/ml, wherein the percentage is volume percentage) was continued and 8 replicate wells were made for each dilution. After incubation at 37 ℃ for 24 hours, luciferase activity in the cells was detected. Inhibition ratio (%) of compound [1- (E-N)/(P-N)]× 100 wherein "E" represents the activity of luciferase in the experimental group, "P" represents the activity of luciferase in the positive group, "N" represents the activity of luciferase in the negative group50) As an indicator of its antiviral activity.
In the invention, the cytotoxicity and anti-HIV-1 activity of 20 synthesized compounds are checked by using Nevirapine (NVP) as a control, and the selectivity index SI of the compounds is calculated, and the results are shown in Table 2.
TABLE 2 results of cytotoxicity and anti-HIV-1 Activity of HX1-20, a target Compound synthesized according to the invention
compounds | IC50(μM) | CC50(μM) | SI(CC50/IC50) |
HX1 | 0.045 | 49.295 | 1095.4 |
HX2 | 0.060 | >109.545 | >1825.8 |
HX3 | 0.342 | >131.475 | >384.4 |
HX4 | 0.434 | >131.475 | >302.9 |
HX5 | 0.574 | >124.729 | >217.3 |
HX6 | 1.715 | >124.729 | >72.7 |
HX7 | 0.785 | 48.302 | 61.5 |
HX8 | 1.057 | 78.491 | 74.3 |
HX9 | 1.606 | 64.255 | 40.0 |
HX10 | 8.659 | 69.936 | 8.1 |
HX11 | 2.120 | 89.957 | 42.4 |
HX12 | 1.909 | >127.283 | 66.7 |
HX13 | 0.813 | >116.183 | >142.9 |
HX14 | 2.398 | >133.321 | >55.6 |
HX15 | 2.055 | >126.472 | >61.5 |
HX16 | 9.821 | >112.239 | >11.4 |
HX17 | 2.445 | 69.869 | 28.6 |
HX18 | 3.139 | 95.510 | 30.4 |
HX19 | 4.239 | 130.434 | >30.8 |
HX20 | 1.481 | 113.921 | >76.9 |
NVP | 0.034 | 150.208 | 4417.9 |
The above experimental results show that: most of the synthesized compounds have good anti-HIV-1 activity, such as compound HX1 (IC)50=0.045μM,SI=1095.4)、HX2(IC50=0.060μM,SI>1825.8)、HX3(IC50=0.342μM,SI>384.4)、HX4(IC50=0.434μM,SI>302.9), etc.
Claims (3)
1. An application of indole-alpha-amino acid compounds in preparing anti-AIDS drugs, wherein the indole-alpha-amino acid compounds have a structure shown as the following general formula:
wherein,
R1is H, 5-F, 5-Cl, 5-Br, 5-NO2、5-CN、5-CHO、5-COOMe、6-F、6-Cl、6-Br、6-NO26-CN, 5-Me, 6-Me or 5-OMe;
R2is H or isoamyl;
R3me or Et.
2. Use according to claim 1, wherein the indole- α -amino acid compound is:
2-amino-2- (6-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (5-bromo-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (6-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (5-fluoro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (6-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (5-chloro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester,
2-amino-2- (6-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester or
2-amino-2- (5-nitro-1H-indol-3-yl) -3,3, 3-trifluoropropionic acid ethyl ester.
3. An anti-aids pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
Priority Applications (1)
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Citations (1)
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CN103113285A (en) * | 2013-03-11 | 2013-05-22 | 武汉大学 | Indole compound and application thereof as HIV-1 reverse transcriptase inhibitor |
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Non-Patent Citations (3)
Title |
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Enantioselective inhibition of reverse transcriptase (RT) of HIV-1 by non-racemic indole-based trifluoropropanoates developed by asymmetric catalysis using recyclable organocatalysts;Xin Han,等;《Organic & Biomolecular Chemistry》;20131009;第11卷(第48期);第8464页方案3、第8465-8466页表1 * |
Enhanced efficiency of recyclable C3-symmetric cinchonine-squaramides in the asymmetric Friedel–Crafts reaction of indoles with alkyl trifluoropyruvate;Xin Han,等;《Tetrahedron: Asymmetry》;20121015;第23卷(第18-19期);第1332-1337页 * |
Structure–Activity Relationships of Organofluorine Inhibitors of b-Amyloid Self-Assembly;Bela Torok,等;《ChemMedChem》;20120220;第7卷(第5期);第913页图1 * |
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