CN116617226B - Application of novel indole quinoline derivative as enterovirus 71 inhibitor - Google Patents
Application of novel indole quinoline derivative as enterovirus 71 inhibitor Download PDFInfo
- Publication number
- CN116617226B CN116617226B CN202310737143.XA CN202310737143A CN116617226B CN 116617226 B CN116617226 B CN 116617226B CN 202310737143 A CN202310737143 A CN 202310737143A CN 116617226 B CN116617226 B CN 116617226B
- Authority
- CN
- China
- Prior art keywords
- indole quinoline
- enterovirus
- novel indole
- novel
- application
- 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.)
- Active
Links
- 241001529459 Enterovirus A71 Species 0.000 title claims abstract description 33
- RPXVPCHYVYRQNW-UHFFFAOYSA-N 1h-indole;quinoline Chemical class C1=CC=C2NC=CC2=C1.N1=CC=CC2=CC=CC=C21 RPXVPCHYVYRQNW-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 230000000120 cytopathologic effect Effects 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 15
- 241000700605 Viruses Species 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 10
- 238000002474 experimental method Methods 0.000 abstract description 3
- -1 indole quinoline compound Chemical class 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 239000003443 antiviral agent Substances 0.000 abstract description 2
- 230000004083 survival effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 18
- 230000005764 inhibitory process Effects 0.000 description 12
- MZXDPTWGJXNUMW-UHFFFAOYSA-N 7h-pyrido[3,2-c]carbazole Chemical class C1=CC=NC2=C3C4=CC=CC=C4NC3=CC=C21 MZXDPTWGJXNUMW-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 230000003833 cell viability Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000709661 Enterovirus Species 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 241000709664 Picornaviridae Species 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 0.000 description 1
- 208000006740 Aseptic Meningitis Diseases 0.000 description 1
- 206010051093 Cardiopulmonary failure Diseases 0.000 description 1
- 241000709675 Coxsackievirus B3 Species 0.000 description 1
- 239000012625 DNA intercalator Substances 0.000 description 1
- 102100028554 Dual specificity tyrosine-phosphorylation-regulated kinase 1A Human genes 0.000 description 1
- 101000838016 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 1A Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 206010027201 Meningitis aseptic Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 238000011053 TCID50 method Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 231100001134 median toxic concentration Toxicity 0.000 description 1
- 208000030194 mouth disease Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses an application of a novel indole quinoline compound as an enterovirus 71 inhibitor, belonging to the technical field of antiviral drugs. The novel indole quinoline derivatives are JL-70, JL-72 and JL-86, and the novel indole quinoline derivatives are found through anti-EV 71 activity research experiments, so that the novel indole quinoline derivatives can inhibit cytopathic effect (CPE) generated by EV71 on host cells RD, enhance cell survival rate, reduce yield of progeny viruses, and have potential to be widely applied to preparation of anti-EV 71 virus medicines.
Description
Technical Field
The invention belongs to the technical field of antiviral drugs, and particularly relates to application of a novel indoquinoline derivative as an enterovirus 71 inhibitor.
Background
Enterovirus 71 (EV 71) is a member of enterovirus genus (Enterovirus) of picornaviridae (Picornaviridae), is one of the most important pathogens causing infant hand-foot-mouth disease, and sometimes is accompanied by serious central nervous system complications including aseptic meningitis, encephalitis, poliomyelitis-like paralysis, neuropathic cardiopulmonary failure and the like, and even causes death. At present, no specific medicine is available for treating the EV 71-infected diseases, and related vaccines are marketed in 2015, and the prevention effect of the vaccines is still to be further investigated.
The indole quinoline derivative is an alkaloid, and the indole quinoline derivative widely exists in natural products and synthetic medicines with broad-spectrum biological activity and attracts great attention. The 11 h-indolo [3,2-c ] quinoline compound not only can be used as a candidate drug for resisting malaria and tumors and a high-efficiency inhibitor of dual-specificity tyrosine phosphorylation regulating kinase 1A (DYRK 1A), but also can be used as a DNA intercalator for inhibiting the replication and transcription of DNA, and has important application value in the fields of biology, medicine and the like. In addition, the indole quinoline derivatives have potential antibacterial, antiviral, antimalarial, antihyperglycemic and antitumor effects and are also key intermediates for synthesizing some important compounds. Indoloquinoline derivatives have been recently reported for use in anti-enterovirus therapy.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art, and aims to provide an application of a novel indole quinoline derivative as an enterovirus 71 inhibitor. The novel indole quinoline derivative provided by the invention is used as an anti-EV 71 virus compound and a non-nucleoside reverse transcriptase inhibitor, and has application in preparation of anti-enterovirus EV71 drugs.
The aim of the invention is achieved by the following technical scheme:
novel indoloquinoline derivatives, which are JL-70, JL-72 and JL-86 having the following chemical structural formula:
a pharmaceutically acceptable salt of the novel indoliquinoline derivative.
The activity of the indoloquinoline derivatives is tested by a standard virus activity test method, and the results are as follows: the maximum inhibition rate of RD cytopathic effect caused by EV71 is 60.83% when JL-70 is at 25. Mu.M; the maximum inhibition rate of RD cytopathic effect caused by EV71 is 72.5% when JL-72 is at 12.5. Mu.M; the maximum inhibition of EV 71-induced RD cytopathic effect was 87.67% at JL-86 at 12.5. Mu.M.
The application of the indole quinoline derivative or the pharmaceutically acceptable salt thereof as an enterovirus EV71 inhibitor or the application in preparing medicines for resisting enterovirus EV 71.
An anti-enterovirus EV71 medicament comprises the indole quinoline derivative or pharmaceutically acceptable salt thereof, and can further comprise pharmaceutically acceptable auxiliary materials and/or carriers. Further, the pharmaceutical preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.
The invention has the advantages and beneficial effects as follows: through a large number of biological experiments, the novel indoquinoline derivative has the activity of resisting EV71 virus. The specific expression is that the method can inhibit cytopathic effect caused by EV71 virus, enhance the survival rate of infected cells, inhibit the replication and proliferation of EV71 virus in cells and reduce the yield of progeny virus. Therefore, the compound has potential to prepare specific therapeutic drugs for resisting EV71 infection, and has great clinical application prospect.
Drawings
FIG. 1 is the effect of novel indoloquinoline derivatives JL-70, JL-72 and JL-86 on RD cell viability with EV71 action.
FIG. 2 shows the inhibitory effect of novel indoloquinoline derivatives JL-70, JL-72 and JL-86 on EV 71-induced RD cell CPE.
FIG. 3 is the inhibitory effect of novel indoloquinoline derivatives JL-70, JL-72 and JL-86 on EV71 progeny virus production.
FIG. 4 is the chemical structural formula of novel indoloquinoline derivatives JL-70, JL-72 and JL-86.
Detailed Description
The technical scheme of the invention is further elaborated in the following in connection with specific embodiments. It will be appreciated by those skilled in the art that these specific embodiments are provided to illustrate the invention and not to limit the invention.
Hereinafter, the materials and methods of operation used in the present invention are well known in the art, unless specifically indicated.
The novel indoloquinoline derivative can be prepared by referring to the method recorded in the patent 'preparation method of indoloquinoline compound' of publication number CN113336749A filed by the applicant.
Example 1
The invention carries out the research experiment of the anti-EV 71 activity on the compound, and the experimental condition is as follows.
1. The test contents are as follows:
Compound anti-EV 71 activity assay: the invention combines cytopathic effect analysis and MTT (methyl thiazolyl tetrazolium) assay cell viability detection methods to evaluate the anti-EV 71 activity of novel indoquinoline derivatives.
2. The test method comprises the following steps:
2.1.1 toxicity of Compounds to host RD cells
RD cells are respectively plated into 96-well plates, after the RD cells are cultured in a culture box with 5% CO 2 at 37 ℃ to grow into a single layer, cell culture solution is discarded, cell maintenance solutions containing test compounds with different concentrations are respectively added for continuous culture, after 48 hours, the cell viability is measured by microscopic observation and recording of cytotoxicity of the RD cells respectively by an MTT method. SPSS 11.5 software calculated the median toxic concentration of drug to cells (Median cyctoxic concentration, CC 50). Cell viability= (mean OD 492 value of drug group/mean OD 492 value of cell control group) ×100%.
2.1.2 Inhibitory Activity of Compounds on EV71
RD cells were plated in 96-well plates, after confluence with a monolayer in a 5% CO 2 incubator at 37℃and the culture was discarded, and cells were infected with EV71 virus solution of 100TCID 50 for 1.5h, and incubated with different concentrations of test compound (ribavirin as a positive control). When about 90% of CPE lesions appear in the virus control wells after further incubation for about 48 hours, cytopathic effects (CPE) are observed under a microscope. Observation and recording method of CPE: no cytopathy is marked as-, less than 25% of cytopathy is marked as +25% -50% of cytopathy is marked as++, 50% -75% of cytopathy is marked as++, and more than 75% of cytopathy is marked as++.
After the CPE is observed, the MTT method is used for detecting the inhibition rate of the drug to EV 71. The method comprises the following specific steps: MTT was added at 30. Mu.L (5 mg. ML -1) per well, the supernatant was removed after 3-4h incubation, and 50. Mu.L DMSO was added to dissolve the pellet. The corresponding absorbance (OD 492 value) was read at 492nm using a microplate reader. The inhibition ratio of the drug to EV71 and CVB3 was calculated using the following formula. The half-effective concentration of the drug was calculated using SPSS 11.5 software (Concentration for 50%of maximal effect,EC 50).
2.1.3 Therapeutic Index (TI) of the medicament
Ti=cc 50/EC50. The higher the therapeutic index, the greater the antiviral potential.
3. Experimental results
TABLE 1 novel Indoloquinoline derivatives cytotoxicity and anti-EV 71 Activity
The cytotoxicity and anti-EV 71 activity test results of the compounds are shown in Table 1. The effect of compounds on EV 71-acting RD cell viability is shown in figure 1. The maximum inhibition rate of RD cytopathic effect caused by EV71 is 60.83% when JL-70 is at 25. Mu.M; the maximum inhibition rate of RD cytopathic effect caused by EV71 is 72.5% when JL-72 is at 12.5. Mu.M; the maximum inhibition of EV 71-induced RD cytopathic effect was 87.67% at JL-86 at 12.5. Mu.M.
The inhibition of EV 71-induced cytopathic effect (CPE) by the compounds is shown in figure 2. The untreated RD cells have good growth state, compact adherence, full shape and clear edges. While the EV71 infected virus control cells almost all apoptosis or die, become round, and fall off the cell plate wall. The compounds JL-70, JL-72 and JL-86 can well protect cytopathic effect caused by viruses, and are close to a cell control group without infected viruses. Thus demonstrating the good antiviral effect of the compounds.
Example 2
The invention carries out intensive research on anti-EV 71 activity on novel indole quinoline derivatives, and carries out an inhibition test of compounds on EV71 progeny virus yield, wherein the test conditions are as follows:
1. Test content
Inhibition of EV71 progeny virus production by compounds after EV71 infection of RD cells, respectively, was examined.
2. Test method
RD cells in the logarithmic growth phase are plated in 24-well plates respectively, 100TCID 50 EV71 infected cells after growing a monolayer, the virus solution is removed after incubation for 1.5h at 37 ℃, washed three times with PBS, and cell maintenance solutions containing compounds at different concentrations are added. After 48h, cells and supernatant medium were collected and after three freeze-thaw lysates at-20℃and 37℃the EV71 virus titer was determined by the TCID 50 method.
3. Test results
As shown in FIG. 3, the RD cells treated with the compounds have significantly decreased viral titers relative to the viral control group, by 5.02log, 5.52log, and 5.52log, respectively, relative to the viral control group.
In conclusion, the novel indoquinoline derivative has strong EV71 inhibition activity, can inhibit RD cell death caused by EV71 virus, and has potential to be prepared into medicaments for effectively resisting EV71 infection clinically.
Claims (1)
1. An application of an indoquinoline derivative or a pharmaceutically acceptable salt thereof in preparing a medicine for resisting enterovirus EV71, which is characterized in that: the indole quinoline derivatives are JL-70, JL-72 and JL-86 with the following chemical structural formulas:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310737143.XA CN116617226B (en) | 2023-06-21 | Application of novel indole quinoline derivative as enterovirus 71 inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310737143.XA CN116617226B (en) | 2023-06-21 | Application of novel indole quinoline derivative as enterovirus 71 inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116617226A CN116617226A (en) | 2023-08-22 |
| CN116617226B true CN116617226B (en) | 2024-06-25 |
Family
ID=
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL267823A1 (en) * | 1985-06-17 | 1988-04-28 | A method of obtaining derivatives of 6h-indolo-/2,3-b/-quinoline |
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL267823A1 (en) * | 1985-06-17 | 1988-04-28 | A method of obtaining derivatives of 6h-indolo-/2,3-b/-quinoline |
Non-Patent Citations (1)
| Title |
|---|
| Kaczmarek, Lukasz et al.Synthesis of 6-substituted 6H-indolo[2,3-b]quinolines as novel cytotoxic agents and topoisomerase II inhibitors.Acta poloniae pharmaceutica.2002,199-207. * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113332279A (en) | Application of Ganetespib compound in preparation of anti-EV 71 virus drugs | |
| CN111110669B (en) | Application of polyiodinated iodocarboxylic acid in resisting EV71 virus | |
| CN110960520B (en) | Application of mono-iodo benzoic acid in resisting EV71 virus | |
| CN108578399B (en) | Application of amino acid ester compound in preparation of anti-CVB 3 virus medicine | |
| CN116617226B (en) | Application of novel indole quinoline derivative as enterovirus 71 inhibitor | |
| CN113274393B (en) | Application of Linsitinib compound in preparation of anti-EV 71 virus drugs | |
| CN110898046A (en) | Application of monoiodo aromatic acid as CVB3 virus inhibitor | |
| CN113332286A (en) | Application of Onalesipb compound in preparation of anti-EV 71 virus medicine | |
| CN111053763B (en) | Application of bifunctional iodine-containing aromatic acid in resisting EV71 virus | |
| CN113181152B (en) | Application of Tiratricol compound in preparation of anti-EV 71 virus drugs | |
| CN116617226A (en) | Application of novel indole quinoline derivative as enterovirus 71 inhibitor | |
| CN113332289A (en) | Application of Pazopanib HCl compound in preparation of anti-EV 71 virus drugs | |
| CN115381816A (en) | Application of VER50589 in preparing medicine for resisting enterovirus 71 | |
| CN111012770B (en) | Monoiodobenzoic acid compound and application thereof in resisting ADV7 virus | |
| CN106668012A (en) | Application of nitrogenous heterocycle containing aromatic ester compounds to preparation of medicament for resisting Coxsaekievirus B3 type | |
| CN111116404B (en) | Multi-iodo aromatic acid modified Anderson polyacid organic derivative and application thereof as CVB3 virus inhibitor | |
| CN113143923B (en) | Application of Retapamulin compound in preparation of anti-EV 71 virus drugs | |
| CN113332290B (en) | Application of Voxtalisib compound in preparation of anti-EV 71 virus drugs | |
| CN115737646B (en) | Use of Mefloquine Hydrochloride in preparation of anti-enterovirus medicine | |
| CN114306298B (en) | Application of 2,3, 5-triiodo-benzoyl hydrazine in preparing anti-EV 71 virus medicament | |
| CN110898070A (en) | Application of multi-iodo benzoic acid as CVB3 virus inhibitor | |
| CN115381828B (en) | Application of pilalaisib in preparation of anti-enterovirus 71 type medicine | |
| CN115869324B (en) | Application of Efavirennz in preparation of anti-enterovirus drugs | |
| CN110974816A (en) | Application of bifunctional iodocarboxylic acid as coxsackie virus inhibitor | |
| CN114452273B (en) | Application of iodized hydrazide and iodized hydrazide polyacid derivative in preparation of CVB3 virus resistant drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |