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Indole derivative with 1, 2, 4-oxadiazole structure, preparation method thereof and application thereof in preparation of antibacterial medicines

A technology of indole derivatives and oxadiazoles, applied in the field of drug synthesis, can solve the problems of death of patients and uncontrollable antibiotics

Inactive Publication Date: 2017-05-31
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Infections due to resistant bacteria that cannot be controlled by antibiotics and ultimately lead to patient death

Method used

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  • Indole derivative with 1, 2, 4-oxadiazole structure, preparation method thereof and application thereof in preparation of antibacterial medicines
  • Indole derivative with 1, 2, 4-oxadiazole structure, preparation method thereof and application thereof in preparation of antibacterial medicines
  • Indole derivative with 1, 2, 4-oxadiazole structure, preparation method thereof and application thereof in preparation of antibacterial medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation of formula 2 compound

[0028]

[0029] Dissolve 1.42 g of powdered p-cyanindole (Formula 1) in 50 ml of absolute ethanol, cool in ice to 0° C., add 4.04 g of triethylamine and 1.67 g of hydroxylamine hydrochloride, stir for 0.5 h, then heat to reflux (80 °C) overnight. TLC detected that the reaction was complete, and the reaction solution was concentrated. Extracted with ethyl acetate (50ml*3), the combined organic layers were washed 3 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 1.44 g of yellow viscous N'-hydroxy-1H-indole-5-carboxamidine (Formula 2), with a yield of 82.3%. 1 H NMR (DMSO-d 6 ,300MHz)δ11.15(s,1H),9.36(s,1H),7.85(m,1H),7.45(dd,J=1.59Hz,J=8.45Hz,1H),7.36-7.33(m,2H ),6.44(m,1H),5.69(s,2H).ESI-MS m / z:176.1[M+H] +

Embodiment 2

[0031] The preparation of general formula I compound

[0032]

[0033] Dissolve 2mmol of the compound of formula 3 in 10ml of dichloromethane, add 2.2mmol of N,N-diisopropylethylamine and 2.2mmol of 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (HATU) , stirred at room temperature for 3 h, and TLC detected that the reaction was complete. 2 mmol of N'-hydroxy-1H-indole-5-carboxamidine (Formula 2) dissolved in dichloromethane was added to the above reaction liquid, stirred at room temperature for three hours, TLC detected that the reaction was complete, and the reaction liquid was concentrated. Extracted with ethyl acetate (25ml*3), the combined organic layer was washed 3 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The above residue was dissolved in 10 ml of ethanol, 4 mmol of anhydrous sodium acetate was added, and heated to reflux (80° C.) overnight, TLC dete...

Embodiment 3

[0108] Bacteriostatic activity test

[0109] In this study, the half-inhibitory concentration (MIC) of the compound against methicillin-resistant Staphylococcus aureus (MRSA) was determined by the microbroth dilution method. 50 ): First, the compounds were diluted to different concentrations with dimethyl sulfoxide (DMSO), and 5 μL of each concentration of the drug solution was added to 195 μL of bacterial suspension (10 5 CFU / mL), the final concentration of the compound in the medium was 125 μg / mL, 62.5 μg / mL, 31.25 μg / mL, 15.625 μg / mL, 7.8125 μg / mL, 3.9063 μg / mL, 1.95315 μg / mL, 0.976575 μg / mL, 0.4882875 μg / mL, 0.24414375 μg / mL, 0.122071875 μg / mL, 0.061035938 μg / mL. Incubate at 37°C for 24 hours to observe the results, and calculate the half inhibitory concentration MIC of the compounds 50 value.

[0110] The antibacterial activities of some compounds such as compounds 4, 20, 23, 25, 28, 29, 31 and 34 in the examples are shown in the table below:

[0111] compoun...

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Abstract

The invention discloses an indole derivative with a 1, 2, 4-oxadiazole structure, which has antibacterial activity, a preparation method thereof and application thereof in preparation of antibacterial medicines, belonging to the technical field of medicine synthesis. The compound has the structure as shown in the general formula I, wherein when an A ring is an aromatic ring, R1 and R2 are ortho-positions, meta-positions and para-substituted groups on the aromatic ring; and when the an A ring is a non-aromatic ring, both the R1 and R2 are hydrogen. The compound disclosed by the invention is a novel alkaloid compound which is synthesized for the first time; and the compound has certain inhibitory activity on methicillin-resistant staphylococcus aureus (MRSA), which is found for the first time in synthetic compound in vitro model testing experiments, and therefore, the compound has potential application prospects in preparation of antibacterial medicines and treatment of bacterial infection.

Description

technical field [0001] The invention relates to a 1,2,4-oxadiazole-structured indole derivative with antibacterial activity, a preparation method and an application in the preparation of antibacterial drugs, belonging to the technical field of drug synthesis. Background technique [0002] Infectious diseases are a class of common clinical diseases caused by pathogenic microorganisms (such as bacteria, viruses, parasites or fungi), and are also one of the most common causes of patient death. [0003] Due to the antibiotic resistance caused by the abuse of antibiotics, the international medical community has paid great attention to it. About 50% of the antibiotics are misused every year in the world, especially in China, the proportion is even close to 80%. According to the data of my country's Bacterial Drug Resistance Detection Network in 2009 (Lv Yuan, Zheng Bo, Li Yun, etc. National Bacterial Resistance Surveillance (Basic Network) Report of the Ministry of Health. Procee...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D413/14A61K31/4245A61K31/4709A61K31/4439A61P31/04
CPCC07D413/04C07D413/14
Inventor 江成世李家诚谷劲松张华单秋丽韩甜
Owner UNIV OF JINAN
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