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Tri-substituted phenyl-1, 2, 4-triazole derivative as well as preparation and application thereof in treatment of neuron injury

A derivative and tri-substituted technology, applied in the field of medicinal chemistry, can solve the problems of difficult to cross the blood-brain barrier, poor clinical effect, influence effect, etc., and achieve the effects of excellent blood-brain barrier penetration, simple preparation method and novel structure

Pending Publication Date: 2022-04-05
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there are still no specific drugs for many neurodegenerative diseases. The main problem in this field is that although many drugs have good results in animal experiments during the development process, their clinical effects are poor, such as 3,5-diaryl Substituted oxadiazole, due to its high polarity, it is difficult to cross the blood-brain barrier, which affects its effect

Method used

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  • Tri-substituted phenyl-1, 2, 4-triazole derivative as well as preparation and application thereof in treatment of neuron injury
  • Tri-substituted phenyl-1, 2, 4-triazole derivative as well as preparation and application thereof in treatment of neuron injury
  • Tri-substituted phenyl-1, 2, 4-triazole derivative as well as preparation and application thereof in treatment of neuron injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 3

[0047] Example 1 Preparation of trisubstituted phenyl-1,2,4-triazole derivatives

[0048] The structure of the trisubstituted phenyl-1,2,4-triazole derivative provided by the present invention is shown in formula I:

[0049]

[0050] In formula I: R 1 Respectively -H, -OH, -CH 2 OH,R(C 1 -C 4 ),-OR(C 1 -C 4 ),-X(F,Cl,Br),-CX 3 (F,Cl),-NO 2 ,-NH 2 ,-NR 2 (C 1 -C 4 ),-COOH,-COR(C 1 -C 4 ),-COOR(C 1 -C 4 ); 2 Respectively -H, -OH, -CH 2 OH,R(C 1 -C 4 ),-OR(C 1 -C 4 ),-X(F,Cl,Br),-CX 3 (F,Cl),-NO 2 ,-NH 2 ,-NR 2 (C 1 -C 4 ),-COOH,-COR(C 1 -C 4 ),-COOR(C 1 -C 4 ); m are 0,1,2,3 respectively; R 3 Respectively -OH, -CH 2 OH,R(C 1 -C 4 ),-OR(C 1 -C 4 ),-X(F,Cl,Br),-CX 3 (F,Cl),-NO 2 ,-NH 2 .

[0051] The present invention also includes precursors or pharmaceutically acceptable salts having the above structures. The precursors include prodrug forms such as esters and ethers, and the pharmaceutically acceptable salts include salts formed with ...

Embodiment 2

[0149] The lipophilicity calculation of embodiment 2 compound 1 to 12

[0150] SwissADME is a tool for calculating ADME parameters, pharmacokinetic properties and druggability properties of small molecules (Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of smallmolecules[J].Scientific Reports.2017,7:42717.) Import the structural formulas of compounds 1-12 on SwissADME, calculate the oil-water partition coefficient Log P of each compound, molecular polar surface area and rotatable bonds and other parameters, the results are shown in the following table 1.

[0151]Compounds with good blood-brain barrier permeability generally have the following chemical properties: molecular weight less than 450, LogP between 2 and 5; molecular polar surface area less than The number of hydrogen bond donors is less than 3, the number of rotatable bonds is less than 8, calculated by software, and the blo...

Embodiment 3

[0154] Example 3 Study on the protective effect of compound 1-12 on PC12 cell injury induced by sodium nitroprusside

[0155] (1) Establishment of injury model of PC12 cells induced by nitroprusside (SNP)

[0156] Rat adrenal pheochromocytoma cells (PC12 cells) were placed in DMEM medium containing 5% fetal bovine serum and 5% horse serum at 37°C, 5% CO 2 cultivated in an environment. After the cells adhered to the wall for a period of time, they were digested with trypsin, diluted with medium, and counted with a cell counting plate. Then, PC12 cells were inoculated in a 96-well plate at a density of 5000 cells / well, culture medium was added for 24 hours, the old medium was discarded, new medium was added to the control group to continue the culture, and the experimental group was added with different SNP concentrations ( 200, 300, 400, 500, 600 μM) culture medium. After 12h, the cell survival rate was measured by MTT method, cell survival rate=OD 各浓度 / OD control *100%, t...

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Abstract

The invention belongs to the technical field of medical chemistry, particularly relates to a trisubstituted phenyl-1, 2, 4-triazole derivative as well as preparation and application of the trisubstituted phenyl-1, 2, 4-triazole derivative in treatment of neuron injury, and discloses the trisubstituted phenyl-1, 2, 4-triazole derivative, the structure of the compound is shown as a formula I, the compound is prepared by taking an o-hydroxybenzoic acid derivative, an o-hydroxybenzamide derivative and a phenylhydrazine derivative as raw materials, and is novel in structure and simple in preparation method. The compound can significantly resist oxidative stress reaction, protect nerve cells against oxidative stress damage caused by sodium nitroprusside, and improve the survival rate of the cells and the morphology of the nerve cells; meanwhile, the compound has a good neuroprotective effect on ischemia-reperfusion injury, and can be applied to preparation of drugs for preventing and treating neurodegenerative diseases such as cerebral apoplexy, cerebral injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis and the like.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a trisubstituted phenyl-1,2,4-triazole derivative and its preparation and application for treating neuron damage. Background technique [0002] Neurodegenerative diseases are a type of neuron injury disease in which nerve cells undergo degenerative changes, including stroke, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. A large number of studies have shown that when the nervous system is damaged and stimulated, the oxidative stress pathway of nerve cells will be abnormal, resulting in excessively high levels of reactive oxygen species (ROS) or reactive nitrogen species (NOS) in the cells, which in turn have a negative impact on the nervous system. Biomacromolecules such as DNA, RNA, proteins and lipids in cells cause damage, eventually leading to the death of nerve cells. Among them, the free radicals produced by oxidative st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08A61K31/4196A61P25/00A61P39/06A61P43/00A61P25/16A61P25/28
Inventor 张静夏劳尧强王杨
Owner SUN YAT SEN UNIV
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