application of imidazopyridine compound in preparation of anti-flavivirus virus infection agent or drug
阅读说明：本技术 咪唑并吡啶类化合物在制备抗黄病毒属病毒感染试剂或药物中的应用 (application of imidazopyridine compound in preparation of anti-flavivirus virus infection agent or drug ) 是由 刘超 马小草 张萍 于 2019-09-09 设计创作，主要内容包括：本发明涉及咪唑并吡啶类化合物在制备抗黄病毒属病毒感染试剂或药物中的应用。所述咪唑并吡啶类化合物的结构如式(Ⅰ)所示,其中,R选自卤素。式(Ⅰ)所示的咪唑并吡啶类化合物可以有效地减低病毒粒子的产生和病毒包膜蛋白的表达,具有显著地抑制黄病毒属病毒复制的效果,且对正常细胞的生长增殖无明显影响,毒性较低、安全性好。将其应用于制备抗黄病毒属病毒感染的药物,可以有效预防和治疗黄病毒属病毒感染引起的疾病,包括：新生儿小头畸形、吉兰巴雷综合症。<Image he="276" wi="700" file="DDA0002196331700000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to application of imidazopyridine compounds in preparation of an agent or a medicine for resisting flavivirus infection. The structure of the imidazopyridine compound is shown as a formula (I), wherein R is selected from halogen. The imidazopyridine compound shown in the formula (I) can effectively reduce the generation of virus particles and the expression of virus envelope protein, has the effect of obviously inhibiting the replication of flavivirus viruses, has no obvious influence on the growth and proliferation of normal cells, and has low toxicity and good safety. The compound can be applied to preparing anti-flavivirus virus infection drugs, can effectively prevent and treat diseases caused by flavivirus virus infection, and comprises the following components: malformation of newborn head,Guillain-Barre syndrome.)
1. the application of imidazopyridine compounds or isomers thereof or pharmaceutically acceptable salts or prodrug molecules thereof in preparing anti-flavivirus virus infection agents or drugs is disclosed, wherein the imidazopyridine compounds have a structure shown in a formula (I):
Wherein R is selected from halogen.
2. Use according to claim 1, wherein R is Cl.
3. Use according to claim 2, characterized in that the imidazopyridine-like compound has the structure:
4. The use according to any one of claims 1 to 3, wherein the flavivirus is Zika virus.
5. The use according to any one of claims 1 to 3, wherein the agent or medicament is for the prevention or treatment of a disease caused by a flavivirus infection, comprising: neonatal microcephaly or gillyram syndrome.
6. Use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of the imidazopyridine compound of formula (I) is: the imidazopyridine compound forms a salt with an inorganic acid or an organic acid.
7. Use according to claim 6, wherein the organic acid is methanesulfonic acid, p-toluenesulfonic acid, succinic acid, lactic acid, tartaric acid, ascorbic acid, maleic acid, salicylic acid, trifluoroacetic acid, oxalic acid or acetic acid.
8. Use according to claim 6, characterized in that the inorganic acid is hydrochloric acid, nitric acid, sulfuric acid, sulfurous acid, sulfamic acid, hydrobromic acid or phosphoric acid.
9. A method for inhibiting replication of a flavivirus virus in a cell in vitro and not for therapeutic purposes, comprising the steps of:
Adding imidazopyridine compounds shown in formula (I) or isomers or pharmaceutically acceptable salts or prodrug molecules thereof into a cell culture solution,
Wherein R is selected from halogen.
10. The method of claim 9, wherein the imidazopyridine compound of formula (i) or the isomer or the pharmaceutically acceptable salt or prodrug molecule thereof is added in an amount of 0.1 μ M to 200 μ M; and/or, the cell comprises: huh7 cells or Huh7.5 cells.
Technical Field
The invention relates to the field of medicines, in particular to application of imidazopyridine compounds in preparation of an anti-flavivirus infection agent or a medicament.
Background
Flaviviruses (flaviviruses) are a large group of single positive stranded RNA viruses with an envelope. Zika virus (ZIKV) is one of its representative viruses.
Zika virus is a mosquito-borne flavivirus that was first discovered in Wuganda monkeys in 1947. It was later confirmed in 1952 among humans in the united republic of udhura and tanzania. Zika virus causes Zika virus disease after infecting the body, and mild symptoms include fever, rash, conjunctivitis, muscle and joint pain, malaise or headache. Infection of adults and children with less immune system by Zika virus may cause serious neurological complications, Guillain-Barre syndrome (GBS) being one of its representative complications. Infection of pregnant women with Zika virus may also cause the born infant to have microcephaly.
zika virus spread rapidly, and to date, a total of 86 countries and regions report evidence of Zika virus infection transmitted via mosquitoes, and to date there is no effective antiviral drug against Zika virus. Since infection with Zika virus poses a great threat to human health, the development of drugs that can efficiently and safely inhibit the replication of Zika virus is one of the problems to be solved at present.
Disclosure of Invention
Based on the above, one of the objects of the present invention is to provide an imidazopyridine compound or an isomer thereof or a pharmaceutically acceptable salt thereof or a prodrug molecule thereof for use in the preparation of an agent or a medicament for resisting flavivirus infection.
the specific technical scheme is as follows:
The application of imidazopyridine compounds or isomers thereof or pharmaceutically acceptable salts or prodrug molecules thereof in preparing an agent or a medicine for resisting flavivirus infection is disclosed, wherein the imidazopyridine compounds have a structure shown in a formula (I):
wherein R is selected from halogen.
It is another object of the present invention to provide a method for inhibiting replication of a flavivirus virus in a cell in vitro for a non-therapeutic purpose, comprising the steps of:
Adding an imidazopyridine compound shown in formula (I) or an isomer or a pharmaceutically acceptable salt or a prodrug molecule thereof into a culture solution of the cell,
wherein R is selected from halogen.
Compared with the prior art, the invention has the following beneficial effects:
The inventor of the invention unexpectedly finds that the imidazopyridine compound shown in the formula (I) can effectively reduce the generation of virus particles and the expression of virus envelope protein, has the effect of obviously inhibiting the replication of flavivirus viruses, has no obvious influence on the growth and proliferation of normal cells, and has low toxicity and good safety. The compound can be applied to preparing anti-flavivirus virus infection drugs, can effectively prevent and treat diseases caused by flavivirus virus infection, and comprises the following components: microcephaly of newborn, gillyram syndrome.
drawings
FIG. 1 shows the construction of the model of Huh7 cell infection Zika and the compound C22H26ClN7O·CH3SO3H inhibitory Effect on Zika Virus replication in this System;
FIG. 2 shows the construction of the model of Huh7.5 cell infection Zika and Compound C22H26ClN7O·CH3SO3h inhibitory Effect on Zika Virus replication in this System;
FIG. 3 shows MTT assay for Compound C22H26ClN7O·CH3SO3h toxicity to cell growth;
FIG. 4 shows a common flavivirus replication inhibitor and Compound C22H26ClN7O·CH3SO3H inhibitory effect on zika virus replication in Huh7 and Huh7.5 cell lines.
Detailed Description
In order that the invention may be more readily understood, reference will now be made to the following more particular description of the invention, examples of which are set forth below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. These embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The application of imidazopyridine compounds or isomers thereof or pharmaceutically acceptable salts or prodrug molecules thereof in preparing an agent or a medicine for resisting flavivirus infection is disclosed, wherein the imidazopyridine compounds have a structure shown in a formula (I):
Wherein R is selected from halogen.
In some of these embodiments, R is Cl.
In some of these embodiments, the imidazopyridines are of the structure:
In some of these embodiments, the flavivirus is Zika virus.
In some embodiments, the agent or medicament for preventing or treating a disease caused by a flavivirus infection comprises: neonatal microcephaly or gillyram syndrome.
In some of these embodiments, the pharmaceutically acceptable salts of the imidazopyridines of formula (I) are: salts of imidazopyridines with inorganic or organic acids.
In some of these embodiments, the organic acid is methanesulfonic acid, p-toluenesulfonic acid, succinic acid, lactic acid, tartaric acid, ascorbic acid, maleic acid, salicylic acid, trifluoroacetic acid, oxalic acid, or acetic acid.
In some of these embodiments, the inorganic acid is hydrochloric acid, nitric acid, sulfuric acid, sulfurous acid, sulfamic acid, hydrobromic acid, or phosphoric acid.
in some of these embodiments, the salt of the imidazopyridine with methanesulfonic acid is:(C22H26ClN7O·CH3SO3h; CAS number: 1469284-79-4), which has high solubility in water and good safety.
a method for inhibiting replication of a flavivirus virus in a cell in vitro and not for therapeutic purposes, comprising the steps of:
Adding an imidazopyridine compound shown in formula (I) or an isomer or a pharmaceutically acceptable salt or a prodrug molecule thereof into a culture solution of the cell,
wherein R is selected from halogen.
In some embodiments, the imidazopyridine compound of formula (I) or its isomer or its pharmaceutically acceptable salt or prodrug molecule is added in an amount of 0.1-200. mu.M.
in some of these embodiments, the cell comprises: huh7 cells or Huh7.5 cells.
The present invention will be described in further detail with reference to specific examples.
The following examples relate to the following starting materials:
Human hepatoma cell lines Huh7 and Huh7.5 cells: huh7 cells were provided by the national academy of sciences (academy of sciences) cell bank; huh7.5 cells were supplied by Apath, l.l.c.
Zika virus: provided by the Guangzhou disease control center.
Compound (I)(C22H26ClN7O·CH3SO3H) The method comprises the following steps Purchased from Sigma-Aldrich.