阅读说明：本技术 一种基于组氨酸的ahl结构类似物及其制备方法 (AHL structural analogue based on histidine and preparation method thereof ) 是由 张丽影 权春善 李容庆 许永斌 肖红艳 范圣第 于 2019-09-30 设计创作，主要内容包括：本发明涉及一种基于组氨酸的AHL结构类似物及其制备方法,属于生物医药领域。主要技术方案如下：一种基于组氨酸的AHL结构类似物的化学结构式如下：<Image he="192" wi="700" file="DDA0002222443070000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中：n为1-13之间的任意整数。本发明提供的基于组氨酸AHL结构类似物,具有制备方法简便,反应条件温和,纯化方法简单,产率高等优点。该结构类似物对粘质沙雷氏菌具有明显的抑菌能力。(The invention relates to an AHL structural analogue based on histidine and a preparation method thereof, belonging to the field of biological medicine. The main technical scheme is as follows: a chemical structure of a histidine-based AHL structural analogue is as follows: Wherein: n is any integer between 1 and 13. The analogue based on the histidine AHL structure provided by the invention has the advantages of simple and convenient preparation method, mild reaction conditions, simple purification method, high yield and the like. The structural analogue has obvious bacteriostatic ability on serratia marcescens.)

1. A histidine-based AHL structural analogue, characterized by the chemical structural formula:

wherein n is any integer between 1 and 13.

2. The method for preparing an AHL analog based on histidine as claimed in claim 1, wherein histidine reacts with fatty aldehyde with different chain length in a solvent mixed with alkaline substance under nitrogen protection for 3-8 hours at 50-90 ℃ to generate the AHL analog based on histidine, and the reaction process is as follows:

Wherein: 1 is an alkaline substance, and 2 is a solvent.

3. The method of claim 2, wherein the alkaline substance is an inorganic base.

4. a method of preparing an AHL structural analog based on histidine as in claim 3, characterised in that said inorganic base is potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate, and said solvent is methanol, ethanol, dichloromethane or diethyl ether.

Technical Field

the invention belongs to the field of biological medicine, and particularly relates to an AHL structural analogue based on histidine and a preparation method thereof.

Background

Quorum Sensing (QS) of bacteria is a particular method of information transfer between bacterial cells. The bacteria can sense the number change of the bacteria and other bacteria in the surrounding environment by utilizing the diffusion of signal molecules among cells, and when the concentration of the signal molecules reaches a certain threshold value, the expression of related genes in the thallus can be started, and related biological functions such as the generation of virulence factors, the synthesis of extracellular polysaccharide, the formation of biofilm and the like can be regulated and controlled. Bacterial resistance has become an increasingly serious global public health problem. The improper use and abuse of broad spectrum antibiotics has led to the overwhelming prevalence of pathogenic bacterial resistance, the result of which has been a dramatic decrease in the efficacy of current antibacterial drugs. Therefore, the search for new antibacterial drugs and the establishment of new antibacterial treatment modalities have become urgent issues in the biomedical field.

Research shows that the bacterial QS system can effectively weaken the biological pathogenicity of pathogenic bacteria, and the bacteria are not directly killed in the process, so that the survival pressure of the bacteria is not generated, and the drug resistance of the bacteria to the bacteria is avoided. Quorum Sensing Inhibitors (QSIs) are expected to be powerful weapons for controlling bacterial infections and the development of drug resistance.

AHLs general structural formula

The Acyl-homoserine lactone (AHLs) -mediated gram-negative bacterial QS system is one of the major types of bacterial QS systems, first found in the marine luminescent bacterium vibrio fischeri. In natural environment, because LuxR protein has special AHL acyl binding frame in different bacteria, each bacteria can recognize, monitor and respond to its own signal molecule. The LuxR/I type QS system is widely found in gram-negative bacteria, including many important human pathogens. For example, the LasR/I system and the RhlR/I system in P.aeruginosa, the YtbR/I system in Yersinia pseudotuberculosis, the Cvir/I system in P.violaceum, etc. all have similar action modes with Vibrio fischeri. Therefore, the discovery of novel QSIs for combating gram-negative bacterial infections and solving the problem of bacterial resistance is of great practical significance.

Schiff base compounds are compounds with imino (> C ═ N-), and are compounds formed by condensation reaction of compounds containing active carbonyl groups, amines, alcohol amines and the like. Schiff base compounds have attracted much attention since their first synthesis in 1864, primarily because the imino groups in the Schiff base compounds impart some special properties to the Schiff base. Currently, Schiff bases and complexes thereof are mainly applied to the aspect of medicines and are used as antibacterial agents, inhibitors, antitumor agents and the like. The Schiff base has mild reaction conditions, simple preparation method and higher synthesis efficiency, and is suitable for large-scale synthesis, and then the corresponding inhibitor is screened from the Schiff base.

Disclosure of Invention

the invention takes histidine as a structural basis, and the histidine is condensed with a series of fatty aldehydes with different carbon chain lengths to generate the AHL structural analogue with imino groups, and the compound has excellent inhibition capability on gram-negative bacteria. The invention provides theoretical support for developing inhibitors of gram-negative bacteria quorum sensing systems.

The technical scheme of the invention is as follows: a structural analogue of AHL based on histidine, the chemical formula is as follows:

Wherein n is any integer between 1 and 13.

The invention also claims a preparation method of the AHL structural analogue based on histidine, under the protection of nitrogen, histidine and fatty aldehyde with different chain lengths react for 3-8 hours at 50-90 ℃ in a solvent mixed with an alkaline substance to generate the AHL structural analogue based on histidine, and the reaction process is as follows:

wherein: 1 is an alkaline substance, and 2 is a solvent.

Further, the alkaline substance is an inorganic base.

further, the inorganic base is potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate, and the solvent is methanol, ethanol, dichloromethane or diethyl ether.

The invention has the following beneficial effects:

(1) The preparation method based on the histidine AHL structural analogue provided by the invention is simple and easy to implement, and has the advantages of mild reaction conditions, simple purification method, high yield and the like.

(2) The histidine-based AHL structural analogue designed by the invention has a structure very similar to that of gram-negative bacteria quorum sensing signal molecules AHLs, has a five-membered aromatic ring and is connected with a long-chain aliphatic tail. It has obvious bacteriostasis capacity to serratia marcescens.

Drawings

FIG. 1 shows n-heptaldehyde histidine Schiff base¹h nuclear magnetic spectrum;

FIG. 2 shows n-octanal histidine Schiff base¹H nuclear magnetic spectrum;

FIG. 3 shows decanal histidine Schiff base¹h nuclear magnetic spectrum;

FIG. 4 shows dodecanal histidine Schiff base¹H nuclear magnetic spectrum;

FIG. 5 is a graph showing the time-dependent change of bacteriostatic effect of 5. mu. mol/mL histidine Schiff base;

FIG. 6 is a graph showing the bacteriostatic effect of 2.5. mu. mol/mL histidine Schiff base as a function of time;

FIG. 7 is a graph showing the time-dependent change of bacteriostatic effect of 1. mu. mol/mL histidine Schiff base;

FIG. 8 is a graph showing the time-dependent effect of histidine Schiff base inhibition at 0.5. mu. mol/mL.

Detailed Description

the present invention will be further described with reference to specific examples, but the starting materials for the present invention are commercially available unless otherwise specified.