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New antibiotics for treatment of drug-resistant gram-positive bacteria and tuberculosis

A halogen and carbon number technology, applied in the field of new antibiotics, can solve the problems of high toxicity and limited clinical use

Active Publication Date: 2018-12-07
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These life-saving drugs are often limited in clinical use due to their high toxicity

Method used

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  • New antibiotics for treatment of drug-resistant gram-positive bacteria and tuberculosis
  • New antibiotics for treatment of drug-resistant gram-positive bacteria and tuberculosis
  • New antibiotics for treatment of drug-resistant gram-positive bacteria and tuberculosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Preparation of compounds shown in embodiment 1, formula I-1, formula I-2 and formula I-3

[0097] (1) Preparation of compound shown in formula 3

[0098] The reaction equation is as follows:

[0099]

[0100] Put N-Boc-O-tert-butyl-L-serine (11mmol) in a round bottom flask, add dichloromethane and N,N-dimethylformamide as a mixed solvent 50ml, HCTU (6-chlorobenzo Triazole-1,1,3,3-tetramethyluronium hexafluorophosphate) (11mmol) and DIEA (N,N-diisopropylethylamine) (11mmol) were added to the reaction solution, and then the formula The compound shown in 1-1 (10 mmol) was stirred at room temperature for 3 hours, and the reaction was quenched by adding dilute hydrochloric acid. Add 100ml of dichloromethane to dilute the reaction solution, wash with sodium bicarbonate and saturated aqueous solution of sodium chloride respectively, distill off the dichloromethane under reduced pressure, and separate the obtained product on a silica gel column (petroleum ether: ethyl acet...

Embodiment 2

[0159] The active test of the compound shown in embodiment 2, formula I-1, formula I-2 and formula I-3

[0160] Compounds were tested for MIC according to CLSI guidelines.

[0161] THY medium was selected for bacterial cultivation, and MHB medium was selected for testing. The medium used was supplemented with 0.002% Tween 80 to inhibit drug attachment. Cell concentration adjusted to 5 x 10 5 per milliliter. The concentration of the compound from high to low is 8 μg / ml, 4 μg / ml, 2 μg / ml, 1 μg / ml, 0.5 μg / ml and 0.25 μg / ml. The drug concentration is the minimum inhibitory concentration.

[0162] The test results are shown in Table 1.

[0163] MIC (μg / ml) of each compound in Table 1

[0164]

[0165]

[0166] It can be seen from the data in Table 1 that the antibacterial activity of the compound prepared by the present invention is equivalent to that of teixobactin, and the molecular structure and synthesis cost are lower.

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Abstract

The invention discloses new antibiotics for treatment of drug-resistant gram-positive bacteria and tuberculosis. The new antibiotics have a structural formula shown in a formula I, wherein the group R1 is hydrogen, an alkyl group with 1-15 carbon atoms, a vinyl group with 2-15 carbon atoms and an alkynyl group, aryl group or acyl group with 2-15 carbon atoms, and the group R2 is hydrogen, halogen,an alkyl group with 1-15 carbon atoms, a vinyl group with 2-15 carbon atoms and an alkynyl group, aryl group, substituted aryl group or acyl group with 2-15 carbon atoms; and R4 is an alkyl group with 1-15 carbon atoms, a vinyl group with 2-15 carbon atoms and an alkynyl group or aryl group with 2-15 carbon atoms, and the group R5 is an amino group, a guanidyl group or a ureido group; and m is anatural number between 1 and 4, and X is O, S or NH. A series of the teixobactin analogues are synthesized by using a solid phase-liquid phase combination method for the first time, and synthesis of awide variety of compounds is facilitated by adopting a convergent synthesis strategy; and the compounds with activity equivalent to the activity of teixobactin are obtained.

Description

technical field [0001] The invention relates to a novel antibiotic used for the treatment of drug-resistant Gram-positive bacteria and tuberculosis. Background technique [0002] Gram-positive bacterial infection is a common and frequently-occurring disease that endangers human health. In recent years, Gram-positive cocci infections have increased day by day, the detection rate of methicillin-resistant Staphylococcus aureus (MRSA) has increased, penicillin-resistant Streptococcus pneumoniae (PRSP) has spread in many countries and regions, glycopeptide-resistant and other Antibiotic-resistant vancomycin-resistant enterococci (VRE) have emerged, and multidrug-resistant tuberculosis has continued unabated. In order to effectively control the antibiotic-resistant and antibacterial drug-resistant bacterial infections, the research and development of drugs for the treatment of Gram-positive drug-resistant bacterial infections has become a worldwide concern. [0003] At present, ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06A61K38/08A61P31/04
CPCA61K38/00C07K7/06A61K38/08A61P31/04A61P31/10C07K1/06C07K11/02Y02A50/30
Inventor 饶燏宗昱
Owner TSINGHUA UNIV
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