CN-121974811-A - Peach toposide derivative, preparation method and antibacterial application thereof

CN121974811ACN 121974811 ACN121974811 ACN 121974811ACN-121974811-A

Abstract

The invention discloses a peach toposide derivative, a preparation method and an antibacterial application thereof. Compared with the peach toposide, the prepared peach toposide derivative has improved water solubility and antibacterial activity, can enhance the chemical stability, has good water solubility and better antibacterial effect, and has the Minimum Inhibitory Concentration (MIC) obviously lower than that of the peach toposide, thus being capable of being used for preparing more antibacterial products. Meanwhile, the synthesis and preparation of the derivative of the totarol are simple and quick, the yield is high, the operation is safe, the derivative of the totarol is suitable for large-scale production and preparation, and more effective methods and products are provided for replacing the raw materials of the totarol.

Inventors

PENG JIANGLING
ZHANG JINSONG
YE JINGYAN
HUANG HUIJING
LI QUANQI

Assignees

广东工业大学

Dates

Publication Date: 20260505
Application Date: 20260407

Claims (10)

1. The derivative of the totarol is characterized in that the derivative of the totarol is a compound shown in a formula (I) and a salt thereof: Formula (I) Wherein R 1 is selected from one of C1-C6 alkylamino and aromatic heterocyclic amino, n=3-12; Or the derivative of the totarol is a compound shown in a formula (II): formula (II) Wherein R 2 is selected from one of C1-C4 alkyl ammonium group, C1-C4 alkyl phosphonium group and aryl phosphonium group, n=3-12, and X - is selected from one of halogen ion, trifluoromethane sulfonate ion ‌ and nitrate ion.
2. The derivative of totarol according to claim 1, wherein said derivative of totarol is selected from any one of the following compounds: 。
3. The derivative of totarol according to claim 2, wherein said derivative of totarol is selected from any one of the following compounds: 。
4. A derivative of totarol according to claim 3, wherein said derivative of totarol is selected from any one of the following compounds: 。
5. The process for preparing a derivative of totarol according to claim 2, comprising the steps of: S1, preparing a peach toposide derivative, namely dissolving the peach toposide compound in an organic solvent, adding a secondary amine compound or thiomorpholine or bis (2-picolyl) amine in an inert atmosphere, stirring for 5-10 hours at 30-70 ℃, quenching the reaction after the reaction is finished, extracting, combining the organic layers, drying and filtering, decompressing and evaporating the solvent, and purifying or obtaining the peach toposide derivative 1-9 and 18; The secondary amine compound is selected from one of dimethylamine, dibutylamine and diethylamine; the peach topological phenol compound is selected from one of the following structural formulas: ; S2, preparing the derivative of the peach toposide, namely dissolving the peach toposide compound in an organic solvent, adding triphenylphosphine or tributylphosphine in an inert atmosphere, reacting at 60-90 ℃, cooling after the reaction is finished, removing the solvent, extracting, drying, and concentrating under reduced pressure to obtain 16-17 and 19-26 of the derivative of the peach toposide; the peach topological phenol compound is selected from one of the following structural formulas: ; S3, preparing the derivative of the peaches, namely dissolving the peaches phenol compound in an organic solvent, adding methyl iodide or MeOTf, stirring to react at normal temperature, removing the organic solvent, extracting, drying and filtering to obtain 10-15 of the derivative of the peaches phenol; the peach topological phenol compound is selected from one of the following structural formulas: 。
6. The process according to claim 5, wherein the molar ratio of the peach-topology phenol compound to the secondary amine compound or thiomorpholine or bis (2-picolyl) amine in step S1 is 1 (3-8).
7. The process according to claim 5, wherein the molar ratio of the peach blossom phenol compound to triphenylphosphine or tributylphosphine in step S2 is 1 (1.5-3).
8. The process according to claim 5, wherein the molar ratio of the peach blossom phenol compound to methyl iodide or MeOTf in step S3 is 1 (70-120).
9. Use of a derivative of totarol according to claim 1 for the preparation of an antibacterial product.
10. An antibacterial product comprising the derivative of totarol according to claim 1.

Description

Peach toposide derivative, preparation method and antibacterial application thereof Technical Field The invention relates to the technical field of compound synthesis and biological medicine, in particular to a derivative of totarol, a preparation method and antibacterial application thereof. Background With the widespread use and abuse of antibiotics, bacterial resistance has evolved into a global public health crisis. Traditional antibiotics (e.g., beta-lactams, quinolones) act primarily by inhibiting specific targets such as bacterial cell wall synthesis, protein synthesis, or nucleic acid replication, which can be easily modified or bypassed by bacteria through genetic mutation or acquired drug resistance genes, resulting in the emergence of multi-drug resistant bacteria and even "superbacteria. Therefore, the development of the antibacterial agent with a brand new action mechanism is an urgent strategic requirement for overcoming the existing drug resistance and guaranteeing the effectiveness of the anti-infective therapy in the future. Antibacterial peptides are a class of natural defenses produced by the innate immune system of an organism. Its core mechanism of action is targeting negatively charged bacterial cell membranes by electrostatic action, disrupting membrane integrity, leading to leakage of cell contents and bacterial death. However, natural antimicrobial peptides have obvious limitations in terms of drug development, such as high production costs, susceptibility to proteolytic hydrolysis in vivo, potential cytotoxicity, and low oral bioavailability. These drawbacks severely limit its immediate clinical use. The tuohol is a natural diterpenoid compound separated from Siraitia plant. The core antibacterial mechanism aims at damaging bacterial cell membranes in a targeted way, remarkably reducing the fluidity of the membranes, and finally leading to perforation of membrane structures and leakage of contents, thereby realizing rapid sterilization. The physical membrane destruction mechanism is highly similar to the action principle of the antibacterial peptide, does not depend on the traditional specific enzyme or receptor target, is not easy to induce bacterial drug resistance, and provides a new thought for solving the increasingly serious problem of antibiotic drug resistance. But at the same time, the inherent defect that the natural product of the totipol is very poor in water solubility, namely, the totipol is a highly lipophilic crystal and is almost insoluble in water, prevents the totipol from being directly developed into medicines or other products. This results in very low oral bioavailability, difficulty in preparing injection, limited in vivo distribution, and greatly affects the patentability. (2) Chemical stability and metabolism, in which the phenolic hydroxyl group is easily oxidized in the air, and the activity and preservation of the phenolic hydroxyl group are affected. (3) The source and cost problems are that the plant extract is mainly extracted from plants, the content is low, the extraction process is complex, the cost is high, and the large-scale production is difficult. Although the chemical total synthesis route is opened, the steps are complicated, the total yield is not high, and the economical efficiency is still not ideal. The prior researches have the step of designing novel peach toposide derivatives (antibacterial peptide mimics) based on a membrane destruction mechanism through structural modification so as to develop antibacterial candidate medicines with higher activity and better pharmacy. If the compound is prepared into a prodrug such as sodium phosphate, the chemical stability of the compound is improved, the water solubility is improved through chemical modification of phenolic hydroxyl groups, and polar groups (amino groups, amide groups, sulfonic groups, glycosyl groups and the like) are introduced to enhance the water solubility. Therefore, there is a need to develop more derivatives of totarol and products thereof for the preparation and development of antibacterial agents. The present application is thus presented. Disclosure of Invention The invention aims to solve the technical problems that the existing peach toposide has poor water solubility and antibacterial activity is to be improved, and provides a peach toposide derivative, a preparation method and antibacterial application thereof. A first object of the present invention is to provide a derivative of totipol or a hydrochloride salt thereof. A second object of the present invention is to provide a process for the preparation of a derivative of totarol or its hydrochloride salt. A third object of the present invention is to provide the use of a derivative of totarol or its hydrochloride salt. The above object of the present invention is achieved by the following technical scheme: The invention provides a derivative of totarol or hydrochloride thereof, wherein the derivative of totarol i