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Anti-drug resistant tuberculosis compound targeting bacteria RNA polymerase

An RNA polymerase, compound technology, used in antibacterial drugs, pharmaceutical formulations, resistance to vector-borne diseases, etc.

Inactive Publication Date: 2014-04-09
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the frequent use of the above-mentioned drugs and the abuse of antibiotics, rifamycin-resistant and multidrug-resistant bacteria have emerged, leading to increasingly serious problems of tuberculosis or drug-resistant infections, and public health is being threatened by drug-resistant bacteria , so it is imminent to develop a new type of bacterial RNA polymerase inhibitor

Method used

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  • Anti-drug resistant tuberculosis compound targeting bacteria RNA polymerase
  • Anti-drug resistant tuberculosis compound targeting bacteria RNA polymerase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] In vitro inhibition experiment of compound RNAP-005 (purchased from IBScreen Company) on bacterial RNA polymerase. For the compound RNAP-005 molecule, by detecting the reduction of the substrate ATP——Kool NC-45 RNAP Activity & Inhibitor Screening Kit (Epicentre Company): 2 μg of Escherichia coli, Staphylococcus aureus, and mycobacterium-binding RNA polymerase were mixed with The gradient diluted pyridoindole derivatives were reacted at 25°C for 20 minutes, and then 1002 μM ATP (total reaction volume 50 μL) was added. After acting at 25°C for 20 minutes, the reaction mixture was added to a 96-well microtiter plate, 50 μL per well, and Kool 50 μL of NC-45Reagent per well was allowed to stand at room temperature for 10 minutes, and the chemiluminescence value was read to indicate the amount of ATP remaining in the reaction. In the experiment, the group without compound was set as the control group. Finally, calculate the inhibitory rate of compound RNAP-005 on the activity...

Embodiment 2

[0023] In vitro inhibition experiment of compound RNAP-005 on the growth of standard bacteria. Use the standard tube dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI):

[0024] 1. Inoculate the bacteria in fresh MH liquid medium and culture overnight at 37°C;

[0025] 2. Correct the bacterial solution to the 0.5 McFarland turbidity standard with fresh MH liquid medium, then dilute it with MH liquid medium at 1:200, add 1 mL to each test tube, and add 1 mL of N-( (4-fluorobenzyloxy)methyl)-O-methyl-N-(6-(trifluoromethyl)-2,3,4,9-tetrahydropyridoindole)hydroxylamine and other 6 compounds (The final concentration of solvent DMSO is maintained at 1%), cultured at 37°C for 18 hours, with 1% DMSO + bacteria as the control, and sterile medium as the blank control;

[0026] 3. Take out the tube with the lowest concentration of no bacteria growth compared with the blank control, which is the minimum inhibitory concentration of the compound RNAP-005...

Embodiment 3

[0031] In vitro inhibition experiment of compound RNAP-005 on drug-resistant Mycobacterium tuberculosis. Using the experimental method described in Example 3, the compound RNAP-005 was used to carry out antibacterial experiments on three strains of drug-resistant Mycobacterium tuberculosis collected clinically. At the same time, the commonly used clinical anti-binding drugs streptomycin (SM), ethambutol (EMB), kanamycin (KM), isoniazid (INH), rifampicin (RFP), levofloxacin (LVFX), Ofloxacin (OFLX), moxifloxacin (MOX), capreomycin (CPM), and amikacin (AMK) were used as controls.

[0032] The results showed that the compound RNAP-005 had obvious inhibitory effect on the growth of drug-resistant Mycobacterium tuberculosis collected in clinic, and its MIC9 0 The values ​​are shown in Table 3.

[0033] Strain number RNAP-005 SM RFP EMB INH CPM KM AMK OFLX LVFX MOX 1 0.3 64 64 16 1 4 2 1 0.5 0.25 0.06 2 0.5 64 64 4 8 1 1 0....

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Abstract

The invention belongs to the field of pharmacy and relates to an application of a small-molecule inhibitor for mycobacterium tuberculosis, escherichia coli and staphylococcus aureus RNA polymerase and shown by the formula (I) and an application of the compound in preparing a medicine for preventing or treating related bacterial infection diseases. The results of biochemical and biological experiments indicate that the inhibitor shown by the formula (I) has strong adhesion with the target protein, namely, the mycobacterium tuberculosis, escherichia coli and staphylococcus aureus RNA polymerase, and can obviously inhibit the activity of the polymerase and remarkably inhibit the growth of the mycobacterium tuberculosis (including drug-resistant mycobacterium tuberculosis), escherichia coli and staphylococcus aureus. The inhibitor provided by the invention also can be prepared into a disinfectant.

Description

technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to the application of the small molecular compound of formula I to inhibit the RNA polymerase of Mycobacterium tuberculosis, Escherichia coli and Staphylococcus aureus and the application of the compound in the preparation of prevention and treatment of related bacterial infectious diseases. Background technique [0002] Bacterial RNA polymerase (RNAP) is a well-defined target protein for the development of broad-spectrum antibacterial drugs. It is a key enzyme in the process of bacterial DNA transcription. Inhibiting the activity of this polymerase can terminate the transcription of bacterial DNA, thereby effectively blocking bacterial protein synthesis. At present, there are some drugs that inhibit bacterial RNAP, such as rifamycin antibiotics (such as rifampicin, rifapentine and rifabutin, etc.), which are excellent inhibitors of bacterial RNA polymerase. They have played a ve...

Claims

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Application Information

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IPC IPC(8): A61K31/4985A61P31/06A61P31/04
CPCY02A50/30
Inventor 周鲁蔡鑫
Owner SICHUAN UNIV
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