Aryl or heteroaryl substituted thiadiazole compound and antibacterial application thereof

A compound, heteroaryl technology, applied in the field of antibacterial drugs, can solve serious problems such as the slowdown of antibacterial drug research and development, and antibiotic resistance

Active Publication Date: 2021-01-29
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, the research and development of antibacterial drugs has slowed down, and few antibacterial drugs have been marketed, making the problem of antibiotic resistance more and more serious

Method used

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  • Aryl or heteroaryl substituted thiadiazole compound and antibacterial application thereof
  • Aryl or heteroaryl substituted thiadiazole compound and antibacterial application thereof
  • Aryl or heteroaryl substituted thiadiazole compound and antibacterial application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Embodiment 1: Preparation and detection of compound J1

[0096]

[0097] Add benzonitrile (1.03g, 10mmol) to a 100mL eggplant-shaped bottle, dissolve it with 10mL trifluoroacetic acid (TFA) and stir for 5 minutes, then add thiosemicarbazide (1.00g, 11mmol) in batches, and then add trifluoroacetic acid (TFA) 10 mL of acetic acid, and the mixed solution was reacted at 70° C. for 8 hours. The reaction was monitored by thin-layer chromatography, and when the benzonitrile was consumed, the heating was stopped and allowed to cool naturally. Then, the reaction solution was poured into ice water, and the pH was adjusted to 11-12 with 1 normality of sodium hydroxide solution, and a large amount of yellow precipitates could be seen. Suction filtration, the filter cake was washed with water (150mL) and suction filtration to obtain the crude product. Recrystallization was performed with 95% ethanol to obtain 1.21 g of the target product (yield: 67.9%).

[0098] 12.8 mL (73.6 ...

Embodiment 2

[0104] Embodiment 2: Preparation and detection of compound J2

[0105] Taking 4-chlorobenzonitrile as the starting raw material, the synthesis method is the same as the preparation of the intermediate 5-phenyl-1,3,4-thiadiazol-2-amine mentioned in Example 1 to obtain the intermediate 5-( 4-Chlorophenyl)-1,3,4-thiadiazol-2-amine (yield: 77.2%).

[0106] Using 5-(4-chlorophenyl)-1,3,4-thiadiazol-2-amine and 1-ethyl-4-hydroxyl-2-quinolone-3-carboxylic acid as starting materials, the synthesis method is the same as the implementation The preparation of the final product J1 mentioned in Example 1 gave N-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-4-hydroxy- 2-Quinolone-3-carboxamide (J2).

[0107]

[0108] Pale yellow solid, yield 31.5%. ESI-MS(m / z):428.12[M+H] + . 1 H NMR (500MHz, DMSO-d 6)δ7.80(d, J=8.2Hz, 2H), 7.55(d, J=8.3Hz, 3H), 7.50(s, 3H), 4.27(dd, J=19.5, 12.3Hz, 2H), 1.22( t,J=7.1Hz,3H).

Embodiment 3

[0109] Embodiment 3: Preparation and detection of compound J3

[0110] Taking 4-bromoxynil as the starting material, the synthesis method is the same as the preparation of the intermediate 5-phenyl-1,3,4-thiadiazol-2-amine mentioned in Example 1 to obtain the intermediate 5-( 4-bromophenyl)-1,3,4-thiadiazol-2-amine (yield: 55.3%).

[0111] Using 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine and 1-ethyl-4-hydroxyl-2-quinolone-3-carboxylic acid as starting materials, the synthesis method is the same as the implementation The preparation of the final product J1 mentioned in Example 1 gave N-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-4-hydroxy- 2-Quinolone-3-carboxamide (J3).

[0112]

[0113] Off-white solid, yield 19.2%. ESI-MS(m / z):472.31[M+H] + . 1 H NMR (500MHz, DMSO-d 6 )δ7.73(d, J=8.5Hz, 2H), 7.69(d, J=8.4Hz, 3H), 7.51(s, 3H), 4.30(p, J=6.8Hz, 2H), 1.23(t, J=7.1Hz,3H).

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an aryl or heteroaryl substituted thiadiazole compound, a preparation method and application thereof as an antibacterial drug. The compound is represented by formula (1), wherein Ar represents a substituted or unsubstituted aryl group or heteroaryl group. The aryl or heteroaryl substituted thiadiazole compound provided by the invention is a compound with a new structure, and the series of compounds have a relatively strong inhibition effect on gram-positive bacteria and mycoplasma like staphylococcus aureus,staphylococcus epidermidis, enterococcus and clostridium difficile, especially drug-resistant gram-positive bacteria (MRSA, MRSE and VRE); certain inhibition is achieved on macrolide drug-resistant mycoplasma pneumoniae, intragastric administration has a good protection effect on systemic infection mice caused by MRSA intraperitoneal injection, and the compound is worthy of further research and development.

Description

technical field [0001] The invention belongs to the technical field of antibacterial drugs, and specifically relates to thiadiazole compounds substituted by aryl or heteroaryl groups, a preparation method and an application as antibacterial drugs. Background technique [0002] The abuse or irrational use of antibiotics promotes the continuous emergence of pathogenic microorganisms such as drug-resistant bacteria or mycoplasma, resulting in the loss of efficacy of currently available antibacterial drugs. The World Health Organization identified antibiotic resistance as one of the threats to global health in 2001. In recent years, the research and development of antibacterial drugs has slowed down, and very few antibacterial drugs have been marketed, making the problem of antibiotic resistance more serious. Therefore, the development of antibacterial drugs with new structure types or new mechanisms of action has important clinical significance and application value for solvin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D417/14A61P31/04A61P31/10A61K31/4709
CPCC07D417/12C07D417/14A61P31/04A61P31/10Y02A50/30
Inventor 吴松夏杰薛文杰张驰
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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