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Pharmaceutical application of N-(thiophene-2)amide derivatives in pyrazinamide-resistant tuberculosis and tuberculosis therapy

A technology resistant to pyrazinamide and amide compounds, applied in the field of medicine, can solve the problems of inability to inhibit the trans-translation process, inability to interact, and inactivation, etc.

Inactive Publication Date: 2016-11-16
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, the PZA-resistant Mycobacterium tuberculosis produced clinically is partly due to the lack of pyrazinamidase (PZase), which prevents PZA from being hydrolyzed into the active form POA, and cannot bind to RpsA, resulting in the inability to inhibit the trans-translation process; Mainly due to the mutation of the RpsA structure, POA cannot combine with RpsA and cannot interact, resulting in inactivation

Method used

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  • Pharmaceutical application of N-(thiophene-2)amide derivatives in pyrazinamide-resistant tuberculosis and tuberculosis therapy
  • Pharmaceutical application of N-(thiophene-2)amide derivatives in pyrazinamide-resistant tuberculosis and tuberculosis therapy
  • Pharmaceutical application of N-(thiophene-2)amide derivatives in pyrazinamide-resistant tuberculosis and tuberculosis therapy

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Embodiment Construction

[0013] The present invention mainly relates to the discovery process of compounds containing N-(thiophene-2) amides, as well as the study of the interaction between compounds and proteins at the molecular level (fluorescence quenching titration method), as well as the in vitro anti-Mycobacterium tuberculosis and PZA resistance at the cellular level Antibacterial experiment of Mycobacterium tuberculosis.

[0014] Medicines and reagents

[0015] sample

[0016]

[0017] Reagents: control POA and PZA and compounds to be determined ZRL07 and 08; expressed and purified protein samples: MtRpsA (285-476), MtRpsAd438A (285-476) and MsRpsA (285-474); Mycobacterium tuberculosis strain: wild type The all-sensitive strain (H37Ra) and 3 clinically found resistant strains of PZA (PZA069, PZA080 and PZA073); other conventional chemical reagents: DMSO, D 2 O, phosphate buffered saline (PBS), etc.

[0018] Instruments: Fluorescence spectrophotometer (F-7000, Hitachi, Japan), Roche medium, constant te...

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Abstract

The present invention discloses ribosomal protein S1(RpsA) with structural N-(thiophene-2)amide derivatives (formula (1)) antagonistic ribosome 30S small subunits, and the protein can effectively inhibit the growth of Mycobacterium tuberculosis and pyrazinamide-resistant Mycobacterium tuberculosis and can be used to prepare drugs for treating pyrazinamide-resistant tuberculosis and tuberculosis.

Description

Technical field [0001] The invention relates to the field of medicine, in particular to the medical use of N-(thiophen-2) amide derivatives in the treatment of pyrazinamide-resistant tuberculosis and tuberculosis. Background technique [0002] Tuberculosis is one of the most widespread diseases in the world caused by Mycobacterium tuberculosis infection. Pyrazinamide (PZA) is a first-line anti-tuberculosis drug. It has obvious bacteriostatic effect on Mycobacterium tuberculosis that grows slowly in the acidic environment of phagocytes, and can effectively shorten the treatment period. It is the current first-line anti-tuberculosis drug. The emergence of PZA-resistant Mycobacterium tuberculosis poses a severe challenge to existing treatment options. Science research results in 2011 proposed the mechanism by which PZA is hydrolyzed to pyrazinic acid (POA) by pyrazinamidase (PZase) in vivo to inhibit the trans-translation of ribosomal protein S1 (RpsA) of the small 30S subunit of r...

Claims

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Application Information

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IPC IPC(8): C07D285/135C07D277/46A61K31/426A61K31/433A61P31/06
CPCC07D277/46C07D285/135
Inventor 林克江支运宝陈萍萍
Owner CHINA PHARM UNIV
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