Application of dihydroxybenzamide derivative in preparation of SerC inhibitor and antituberculous drug

A technology of dihydroxybenzamide and hydroxybenzamide, which is applied in the field of biomedicine, can solve problems such as lack, and achieve the effects of promoting production, inhibiting intracellular survival and in vivo survival, and reducing the amount of bacteria loaded

Active Publication Date: 2021-07-09
SHANGHAI PULMONARY HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is still a lack of relevant research on the effect of interfering with the serine metabolic pathway on the disease process of tuberculosis, especially drug-resistant tuberculosis, and its application in anti-tuberculosis treatment
[0004]The previous inventors found through Mtb aerobic / anaerobic culture proteomics that Mtb significantly up-regulated the synthesis of a serine metabolism-related enzyme (SerC) under anaerobic conditions , and then promote the secretion of D-serine, the product of this metabolic pathway, and D-serine entering the cytoplasm of macrophages can significantly inhibit the production of cytoprotective inflammatory factors, thereby improving the survival of Mtb in cells and infected animals, suggesting that SerC is A virulence factor of Mtb, but the application of using this molecule as a target to screen related inhibitors and prepare anti-tuberculosis drugs has not been reported

Method used

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  • Application of dihydroxybenzamide derivative in preparation of SerC inhibitor and antituberculous drug
  • Application of dihydroxybenzamide derivative in preparation of SerC inhibitor and antituberculous drug
  • Application of dihydroxybenzamide derivative in preparation of SerC inhibitor and antituberculous drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] In this implementation, the in vitro enzyme activity reaction is used to detect the effect of COH29 on its enzyme activity. The specific experimental methods and results are as follows:

[0043] Mix recombinant SerC protein (2 μg) with 10-fold diluted COH29 compound in 100 μL assay buffer (including 50 mM Tris / HCl (pH 8.2), 32 mM ammonium acetate, 2 mM glutamate, 2 mM NADH, 3 units of glutamate Amino acid dehydrogenase), add 2.5mM phosphohydroxypyruvate to trigger the enzymatic reaction, use the BioTek Synergy plate reader to detect the consumption of NADH (OD340) every 30 seconds, and stop the detection after 10 minutes of reaction. By comparing with the control of adding DMSO, calculate the maximum rate (Vmax) of the SerC enzymatic reaction after adding different concentrations of COH29, and draw the curve and calculate IC50, the results are as follows figure 1 shown.

[0044] Depend on figure 1 It can be seen that COH29 can effectively inhibit the enzymatic activit...

Embodiment 2

[0046]In this example, the C57BL / 6 mouse infection model was used to analyze the effect of COH29 on tuberculosis, especially drug-resistant tuberculosis. The specific experimental methods and results are as follows:

[0047] Divide 6-8-week-old female C57BL / 6 mice into 2 groups (control group and experimental group), 6 mice in each group, put them in ABSL-3 for 1 week, and then infect H37Rv or MDR strains by aerosol route, about 200CFU / mouse. After 3 weeks of infection, 1% DMSO was added to the drinking water of the control group, and COH29 (10 mg / kg) was added to the drinking water of the experimental group, and the mice were sacrificed after 4 weeks of administration. Analyze the effect of COH29 on tuberculosis by detecting the following indicators:

[0048] (1) Bacterial load in different organs: collect lungs under sterile conditions, add PBS homogenate, inoculate on 7H10 agar medium after 10-fold dilution, culture at 37°C for 4 weeks, observe the growth of Mtb, and calc...

Embodiment 3

[0052] In this example, the zebrafish infection model was used to analyze the effect of COH29 on mycobacterial diseases, especially the drug-resistant sea branch infection. The specific experimental methods and results are as follows:

[0053] Wild-type zebrafish (strain AB) was obtained from the China Zebrafish Resource Center, raised in a recirculation culture system, and transferred to a toxicology system for infection experiments, while ensuring the standard conditions for zebrafish rearing and infection (water temperature about 28°C, pH about 7.4, conductivity about 1,500μS). After adult healthy fish were anesthetized with 0.1% tricaine, zebrafish were infected with sensitive marinum (M. marinum) or rifampin-resistant mycobacterium marinum (M. The dose was about 400 CFU; after 1 week, the control group was orally administered DMSO, and the experimental group was orally administered COH29 (10 mg / kg). They were sacrificed 1 week after administration, and the effect of COH2...

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PUM

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Abstract

The invention provides an application of a dihydroxybenzamide derivative in preparation of a SerC inhibitor and an antituberculous drug. The SerC inhibitor and the antituberculous drug comprise a dihydroxybenzamide derivative or a pharmacologically acceptable salt thereof, in particular COH29 or a pharmacologically acceptable salt thereof. The SerC small-molecule inhibitor provided by the invention can obviously inhibit the enzyme activity of SerC, reduce the bacterium loading amount of mouse lungs infected by tubercle bacillus, relieve pathological changes, inhibit the deterioration of granuloma, promote the generation of protective inflammatory factors of macrophages, inhibit the intracellular survival and in-vivo survival of tubercle bacillus. Therefore, the SerC small-molecule inhibitor is expected to be used as a new effective prodrug for preparing antituberculosis drugs.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to the application of dihydroxybenzamide derivatives in the preparation of SerC inhibitors and anti-tuberculosis drugs. Background technique [0002] Tuberculosis is an infectious disease controlled by WHO, and it is still a public health problem that seriously endangers people's health. According to relevant statistics, about 1 / 4 of the world's population is infected with tuberculosis. There are about 20 million tuberculosis patients, 8 million to 10 million new cases each year, and about 2 million people die of tuberculosis every year. The total number of deaths. The tuberculosis epidemic in my country is extremely severe. There are currently 500 million people infected with tuberculosis, accounting for 1 / 4 of the world's total. Every year, 130,000 people die from tuberculosis, which is twice the total number of deaths from other infectious and parasitic diseases. The emerge...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/426A61P31/06A61P11/00
CPCA61K31/426A61P31/06A61P11/00
Inventor 戈宝学杨华王菲郭欣娅
Owner SHANGHAI PULMONARY HOSPITAL
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