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Gram-positive bacterium resistant quaternary ammonium salt glycopeptides and medicinal applications thereof

A technology of antibacterial drugs and quaternary ammonium salt cations, applied in the direction of antibacterial drugs, glycopeptide components, peptides, etc., can solve problems such as irrational use of antibiotics, reduction of affinity between drugs and targets, and accelerated

Inactive Publication Date: 2019-03-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Relevant studies have shown that the emergence of bacterial resistance is the result of natural selection, and the irrational use of antibiotics has greatly accelerated this process
Resistance to glycopeptide antibiotics is due to genetic recoding leading to the change of the peptidoglycan terminal residues of the bacterial cell wall from D-Ala-D-Ala to D-Ala-D-Lac, i.e. D at the C-terminal site. -Alanine is replaced by D-lactic acid, this change (NH→O) causes the drug to lose a molecule of hydrogen bonding with the target, thus greatly reducing the affinity of the drug to the target

Method used

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  • Gram-positive bacterium resistant quaternary ammonium salt glycopeptides and medicinal applications thereof
  • Gram-positive bacterium resistant quaternary ammonium salt glycopeptides and medicinal applications thereof
  • Gram-positive bacterium resistant quaternary ammonium salt glycopeptides and medicinal applications thereof

Examples

Experimental program
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preparation example Construction

[0029] The invention provides a method for synthesizing the above-mentioned vancomycin quaternary ammonium salt derivatives, comprising: R 2 Nitrogen-containing groups and bromovaleric acid (bromoheptanoic acid, bromononanoic acid and bromodecanoic acid) are substituted to generate quaternary ammonium hydrochloride, and then condensed with NHS to generate active intermediates, and finally in alkaline

[0030] Under the conditions, the active intermediate is replaced by the sugar amino group of vancomycin to generate the above target compound. As shown in the reaction formula (1).

[0031]

[0032] Table of Target Compound Numbers

[0033]

[0034]

Embodiment 1

[0035] Embodiment 1: the synthesis of quaternary ammonium salt modified vancomycin derivative 1a

[0036] Dissolve 180mg (1.00mmol) of 5-bromovaleric acid in 5ml of pyridine, and reflux for 7h. TLC DCM:MEOH=1:1 monitored the disappearance of the starting material, and stopped heating. The reaction solution was rotary evaporated to a small volume, cooled, a solid precipitated, filtered, and the solid was washed with DCM several times to obtain 173 mg of a white powdery solid, with a yield of 96.1%. Weigh 100 mg (0.56 mmol) of the obtained solid compound, dissolve 96.7 mg (0.84 mmol) of NHS in DMF, add 141.3 mg (1.12 mmol) of DIC, and react at room temperature for 4 h. TLC monitored the completion of the raw material reaction, added 3-5 times the volume of diethyl ether to the reaction solution, discarded the solution to obtain an oil, purified by column chromatography to obtain 114.9 mg of the side chain compound, and the yield was 74%. Take a dry 10mL eggplant-shaped bottle,...

Embodiment 2

[0037] Example 2: For the synthesis of quaternary ammonium salt modified vancomycin derivative 1b, refer to the synthesis of 1a in Example 1.

[0038] White solid, yield 17%. 1 H NMR(400MHz,DMSO)δ:9.05(s,1H),8.61(s,1H),8.55(m,2H),,8.33(m,2H),8.24(s,1H),8.10(m,4H ),7.83(s,1H),7.54(s,1H),7.44(m,3H),7.29(m,2H),7.25(s,1H),7.20(d,J=7.4Hz,1H),7.12 (s,1H),6.75(s,1H),6.68(s,1H),6.65(s,1H),6.59(s,1H),6.41(s,1H),6.23(s,1H),5.97( s,1H),5.74(s,1H),5.57(s,1H),5.19(m,2H),5.14(s,2H),4.88(s,1H),4.69(s,1H),4.61(m ,2H),4.40(s,2H),4.24(s,1H),4.16(s,1H),3.22–3.55(m,6H),3.01(m,1H),2.83(s,2H),2.70( d,J=6.7Hz,2H),2.58(m,4H),2.20–2.00(m,6H),1.97(m,4H),1.80(m,3H),1.40(m,3H),1.50-1.30 (m,4H),1.02(m,2H),0.89(m,4H),0.78(m,9H).

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Abstract

The invention belongs to the technical fields of pharmaceutical chemistry and medicine, and relates to gram-positive bacterium resistant quaternary ammonium salt glycopeptides and medicinal applications thereof. The invention provides quaternary ammonium salt vancomycin derivatives represented by the formula (1). Cation segments in ionic liquid and amino residues of polysaccharide and protein molecules form hydrogen bonds, the structure of cell walls of bacteria is broken, vancomycin is taken as the primary raw material, micromolecules of cations of quaternary ammonium salt are used to modifythe amino group of vancomycin to design and synthesize the novel gram-positive bacterium resistant quaternary ammonium salt vancomycin derivatives; and the test results show that the prepared quaternary ammonium salt compounds have better antibacterial activity, compared with that of vancomycin. The novel glycopeptides vancomycin derivatives can be further made into various preparations that contain an effective and safe amount of novel glycopeptides vancomycin derivatives and a pharmaceutical carrier.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and medicine, and in particular relates to a novel anti-gram-positive bacterium quaternary ammonium salt glycopeptide compound and its medicinal application. Background technique [0002] Currently, the glycopeptide drug vancomycin is the drug of choice for clinical treatment of severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Studies have shown that the common structure of glycopeptide antibiotics is a highly modified heptapeptide skeleton, and the target is D-alanyl-D-alanine, which is a component of the bacterial cell wall; it can be divided according to the amino acid content. There are four families: vancomycin family, ristocetin family, avoparcin family, and symmonicin family. The current vancomycin group of drugs includes vancomycin (Vancomycin), norvancomycin (Demethylvancomycin), teicoplanin (Teicoplanin), telavansu (Telavancin), oritavancin dip...

Claims

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Application Information

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IPC IPC(8): C07K9/00A61K38/14A61P31/04
CPCA61K38/00C07K9/008
Inventor 孙逊江永伟唐美麟俞立挺孟志
Owner FUDAN UNIV