Pyridoindole derivative and antibacterial application thereof

A technology of indole derivatives, which is applied in the field of pyridoindole derivatives and their antibacterial applications, achieving the effects of mild reaction conditions, easy availability of raw materials, and abundant raw materials

Inactive Publication Date: 2012-07-18
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 p...

Method used

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  • Pyridoindole derivative and antibacterial application thereof
  • Pyridoindole derivative and antibacterial application thereof
  • Pyridoindole derivative and antibacterial application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Active compounds were screened by computer-aided virtual screening method. Using the three-dimensional structure of the complex of the first extreme thermophilic bacterial RNA polymerase and the inhibitor acting on the active site of the "switch area" published on Cell in 2008, the active site of the "switch area" was selected. Use Surflex to conduct a three-dimensional database search to conduct a rough screening of 50,000 compounds and derivatives in the natural product library, and then select the compounds with a score of 7 or more in the docking results, and then use Gold and Autodock to perform detailed screening respectively, and obtain 20 compounds Molecules with higher scoring and binding energy were combined with drug-like analysis and visual observation to remove obviously unreasonable ones, and finally 6 compounds were selected to enter the next step of the experiment. The scoring values ​​of these six compounds are shown in Table 1.

[0051] Table 1: Scori...

Embodiment 2

[0054] N-((4-fluorobenzyloxy)methyl)-O-methyl-N-(6-(trifluoromethyl)-2,3,4,9-tetrahydropyridoindole)hydroxylamine, etc. In vitro inhibition experiment of 6 compounds on bacterial RNA polymerase. For N-((4-fluorobenzyloxy)methyl)-O-methyl-N-(6-(trifluoromethyl)-2,3,4,9-tetrahydropyridoindole)hydroxylamine Molecules, by detecting the reduction of substrate ATP——Kool? NC-45? RNAP Activity & Inhibitor Screening Kit (Epicentre Company): 2 μg of E. 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? NC- 50 μL of 45? Reagent per well was left standing at room temperature for 10 minutes, and the chemiluminescence value was read to indicate the amount of ATP remaining in the reaction. The experiment without compound was set as the control group. Finally calculate N-((4-fluorobenzyloxy)methy...

Embodiment 3

[0061] N-(4-(5-(6-(Benzyloxy)-2,3,4,9-tetrahydropyridindole)-2-methoxybenzyloxy)phenyl)acetamide etc.6 In vitro inhibition experiments of compounds on the growth of standard bacteria

[0062] Use the standard tube dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI):

[0063] 1. Inoculate the bacteria in fresh MH liquid medium and culture overnight at 37°C;

[0064] 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;

[0065] 3. Take out the tube with the lowest concentration of bacteria that does not g...

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Abstract

The invention relates to the fields of medicine design science, medicinal chemistry and medicine science. A molecule capable of inhibiting the activity of bacterial ribonucleic acid (RNA) polymerase is searched by computer virtual screening on the basis of a crystal three-dimensional structure of the bacterial RNA polymerase, and the screened compound is derived, so that a pyridoindole derivative which can inhibit the activity of the bacterial RNA polymerase and has a structure shown as a formula (I) and pharmaceutically acceptable salt of the derivative are provided. The invention also relates to a medicinal composition of the pyridoindole derivative with the structure shown as the formula (I) and application of the composition. The compound can be used as an inhibitor for the bacterial RNA polymerase and selectively inhibits bacterial growth and propagation by inhibiting the activity of the bacterial RNA polymerase, so the compound and the medicinal composition can be used as an active substance for effectively treating and/or preventing bacterial infectious diseases.

Description

technical field [0001] The present invention relates to the fields of drug design and medicinal chemistry. More specifically, the present invention uses computer virtual screening based on the three-dimensional structure of bacterial RNA polymerase crystals to seek molecules that can inhibit the activity of bacterial RNA polymerase, and the screened compounds Molecules are derivatized, thereby providing novel pyridoindole derivatives with bacterial RNA polymerase inhibitory activity, and the present invention also relates to the use of pyridoindole derivatives, salts thereof and pharmaceutical combinations. 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...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P31/04C40B30/02
Inventor 周鲁蔡鑫
Owner SICHUAN UNIV
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