Phenol hydroxamic acid urease inhibitors and preparation method and application thereof

A technology of phenol hydroxime and aniline hydroxamic acid, which is applied in the fields of urinary system diseases, digestive system, organic chemistry, etc., and can solve problems such as poor results

Inactive Publication Date: 2018-05-18
JISHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These studies reveal that simple isosteric substitution is like targeting with eyes closed, and the effect is not good. Good results can only be obtained based on the complementary combination of drug molecules and targets.
However, designing a suitable R group to act on a specific region of urease is a challenging and creative work

Method used

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  • Phenol hydroxamic acid urease inhibitors and preparation method and application thereof
  • Phenol hydroxamic acid urease inhibitors and preparation method and application thereof
  • Phenol hydroxamic acid urease inhibitors and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: 2-phenoxyacetohydroxamic acid (1)

[0039] Dissolve 470mg of phenol into 15mL of anhydrous tetrahydrofuran, stir for 10min, add 1.7mL of ethyl bromoacetate and anhydrous K 2 CO 3 2.76g, stirred at 60°C for 12h, cooled, evaporated THF, added water, extracted three times with ethyl acetate, combined organic phases, washed with water, anhydrous MgSO 4 After drying, the solvent was evaporated, and purified by silica gel column chromatography, eluent volume ratio: AcOEt:petroleum ether=1:7, to obtain 846 mg of ethyl 2-phenoxyacetate as a white solid, with a yield of 94%. Dissolve 180 mg of ethyl 2-phenoxyacetate in 5 mL of anhydrous methanol, and add NH 2 OH·HCl 278mg, CH 3 ONa 432mg, stirred at room temperature for 17h, evaporated methanol, added 8mL deionized water, extracted with AcOEt, combined organic layers, washed with water, anhydrous MgSO 4 After drying, the solvent was evaporated and purified by silica gel column chromatography, eluent volume ratio: ...

Embodiment 2

[0043] The phenolic hydroxamic acid series compounds 1-60 listed in Table 1 and Table 2 were synthesized in the same manner as in Example 1, using different substituted phenols as raw materials.

[0044] Each R group of the phenolic hydroxamic acid series compound when n=1 in the general formula I of table 1

[0045]

[0046]

[0047]

[0048] Each R group of the phenolic hydroxamic acid series compound when n=2 in the general formula I of table 2

[0049]

[0050]

[0051] Note: The initial raw materials were purchased from aldrich company

Embodiment 3

[0052] Embodiment 3: the inhibitory enzyme activity of compound

[0053] Add 25 μL of Jack bean urease (4U) and 25 μL (1 mM) of the test compound solution to the 96-well plate, incubate at 37°C for 2 hours, then add 55 μL of phosphate buffer solution containing 100 mM urea and 100 mM, at 30 Incubate at ℃ for 15 min, add 45 μL of phenol reagent (mixed solution containing 1% phenol and 0.005% sodium nitroprusside) and 70 μL alkali reagent (mixed solution of NaOCl containing 0.5% NaOH and 0.1% active chlorine), at room temperature After standing for 50 minutes, measure the OD value at 630nm with a microplate reader, and the percentage inhibition rate is calculated according to the following formula:

[0054]

[0055] All experiments were carried out in solutions at pH 8.2 (0.01M K 2 HPO 4 , 1mM EDTA, 0.01M LiCl), the level of activity is measured by the half-inhibition rate IC 50 to indicate that the IC 50 The smaller the value, the higher the activity of the compound. The...

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PUM

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Abstract

The invention provides a kind of phenol hydroxamic acid compounds. The general formula of the compounds is shown in the description. The compounds have a good inhibition function on urease and can beused for preparing medicine resisting gastritis, gastric ulcer, urinary calculi and the like. The invention discloses a preparation method of the phenol hydroxamic acid compounds.

Description

technical field [0001] The invention relates to a preparation method of a class of phenolic urease inhibitors and their application in the preparation of anti-gastritis, anti-gastric ulcer and anti-urolithiasis drugs. technical background [0002] Helicobacter pylari can cause gastritis, gastric ulcer, duodenal ulcer, gastric atrophy, intestinal metaplasia, gastric cancer, gastric lymphoma and other diseases. In 1994, the World Health Organization and the International Cancer Research Center listed H. pylori as the first type of carcinogen. According to statistics, about half of the world's population is infected with H. pylori, and the infection rate is as high as 80-90% in developing countries. The infection rate in our country is about 60%. The detection rate of H.pylori in patients with gastritis is 80-90%, and it is higher in patients with peptic ulcer, reaching more than 95%. More than 90% of duodenal ulcers and about 80% of gastric ulcers are caused by H. pylori. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/06A61P1/04A61P1/00A61P13/04
CPCC07C259/06
Inventor 肖竹平刘琦袁静刘佩曹芃
Owner JISHOU UNIVERSITY
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