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CN-121974812-A - Double-alkylation cationic derivative based on honokiol mother nucleus, and preparation method and antibacterial application thereof

CN121974812ACN 121974812 ACN121974812 ACN 121974812ACN-121974812-A

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a double-alkylation cationic derivative based on honokiol mother nucleus, a preparation method and an antibacterial application thereof. Mixing honokiol, potassium carbonate, dibromoalkane and acetone, carrying out a first reaction to obtain an intermediate product, mixing the intermediate product, a compound R 1 H and acetonitrile, and carrying out a second reaction to obtain the double-alkylation cationic derivative based on honokiol parent nucleus. According to the invention, natural products and magnolol are reasonably modified, and a series of novel amphiphilic derivatives which show effective in-vitro antibacterial activity on gram-positive bacteria are designed and synthesized.

Inventors

  • XIE JIAN
  • PENG CHANGJIN
  • SU DE
  • YANG DEZHI

Assignees

  • 遵义医科大学
  • 黔南民族医学高等专科学校

Dates

Publication Date
20260505
Application Date
20260130

Claims (9)

  1. 1. The double-alkylation cationic derivative based on the honokiol mother nucleus is characterized by having the following structural formula: ; Wherein n is 1, 2 or 3; r 1 is selected from 、 、 One of them.
  2. 2. A process for the preparation of a dialkylated cationic derivative based on a master nucleus of honokiol as claimed in claim 1, comprising the steps of: Mixing honokiol, potassium carbonate, dibromoalkane and acetone, performing a first reaction to obtain an intermediate product, mixing the intermediate product, a compound R 1 H and acetonitrile, and performing a second reaction to obtain a dialkylated cationic derivative based on a honokiol parent nucleus; wherein the dibromoalkane is BrCH 2 (CH 2 ) n CH 2 Br, and n is 1,2 or 3; r 1 in the compound R 1 H is selected from 、 、 One of them.
  3. 3. The method for preparing a dialkylated cationic derivative based on a master nucleus of honokiol as claimed in claim 2, wherein the honokiol has the structural formula of 。
  4. 4. The method for preparing a dialkylated cationic derivative based on a master nucleus of honokiol as claimed in claim 3, wherein the intermediate product has the structural formula Wherein n is 1, 2 or 3.
  5. 5. The preparation method of the double-alkylation cationic derivative based on the honokiol mother nucleus, which is disclosed in claim 2, is characterized in that the dosage ratio of honokiol, potassium carbonate, dibromoalkane and acetone is 2-4 mmol:5-10 mmol:20-40 mmol:20-50 mL.
  6. 6. The method for preparing a double-alkylated cationic derivative based on a honokiol mother nucleus as claimed in claim 5, wherein the temperature of the first reaction is 45-60 ℃, and the time of the first reaction is 6-10 h.
  7. 7. The preparation method of the double-alkylation cationic derivative based on the honokiol mother nucleus according to claim 2, wherein the dosage ratio of the intermediate product, the compound R 1 H and acetonitrile is 0.1-1 mmol:2-10 mmol:10-50 mL.
  8. 8. The method for preparing a double-alkylated cationic derivative based on a honokiol mother nucleus as claimed in claim 7, wherein the temperature of the second reaction is 80-90 ℃, and the time of the second reaction is 12-18 h.
  9. 9. Use of a double alkylated cation derivative based on a honokiol mother nucleus as defined in claim 1 or a double alkylated cation derivative based on a honokiol mother nucleus as defined in any one of claims 2 to 8 in the preparation of an antibacterial agent.

Description

Double-alkylation cationic derivative based on honokiol mother nucleus, and preparation method and antibacterial application thereof Technical Field The invention relates to the technical field of organic synthesis, in particular to a double-alkylation cationic derivative based on honokiol mother nucleus, a preparation method and an antibacterial application thereof. Background The continued growth of antibiotic resistance (AMR) has become one of the most serious challenges facing global public health, and the widespread emergence of multi-drug resistant bacteria (MDR) has greatly reduced the efficacy of traditional antibiotics, resulting in prolonged disease duration, increased healthcare costs and increased mortality in the global world. Of particular concern are ESKAPE pathogens that can significantly evade the action of existing drugs, as well as the primary cause of nosocomial infections. The speed of bacterial evolution is increased and the gap between the development and the stagnation of novel antibiotics is increased, so that the urgent need of developing alternative anti-infection therapies with novel action mechanisms is highlighted. In this context, antibacterial peptides (AMPs), also known as host defensin peptides, are very attractive therapeutic candidates. As an evolutionarily conserved innate immune component, the antibacterial peptide has rapid and broad-spectrum antibacterial activity and can reduce the risk of drug resistance. The structure is generally amphiphilic, cationic sequences can target the surface of anionic bacteria through electrostatic action, hydrophobic structures can penetrate lipid double layers, and physical and chemical interactions can lead to increased permeability of bacterial membranes and loss of cytoplasmic components, and finally cell death. The key advantage of this non-specific mechanism of action is that it possesses inherent selectivity, which stems from the compositional differences between the microorganism and the host cell membrane, thereby effectively limiting cytotoxicity to the host. Besides the direct bactericidal effect, the antibacterial peptide also has the characteristic of an antibacterial film, and the characteristic further consolidates the potential of the antibacterial peptide as a multifunctional anti-infective medicament. Despite its considerable therapeutic potential, its clinical transformation still faces many challenges, including proteolytic instability, significant cytotoxicity (especially hemolysis), unfavorable pharmacokinetic profile, and complex and costly production processes. To address these issues, the research field has been strategically turned to the rational design of antibacterial peptide mimetics. The synthetic antibacterial peptide covers engineering peptide analogues and non-peptide small molecules, the core design thought is to simulate the key amphiphilic topological structure and action mechanism of the natural antibacterial peptide and construct the synthetic antibacterial peptide based on an optimized framework, and the final purpose of the design is to improve the metabolic stability, reduce the toxicity of a host and improve the integral property of the medicament on the premise of not sacrificing the antibacterial efficacy. Currently, the fact that CAS-13, XF-73 and PMX-30063 (structural formulas shown below) await the entry of drug selection into the clinical development stage also confirms that this rational design approach is an effective way to develop novel anti-infective therapies. However, these compounds only exhibit moderate or low antimicrobial activity. Therefore, how to design an antibacterial peptide mimetic with high antibacterial activity is a problem that needs to be solved at present. Disclosure of Invention The invention aims to provide a double-alkylation cationic derivative based on honokiol mother nucleus, a preparation method and an antibacterial application thereof, and solves the problems in the prior art. In order to achieve the above object, the present invention provides the following technical solutions: The invention provides a double-alkylation cationic derivative based on a honokiol mother nucleus, which has the following structural formula: ; Wherein n is 1, 2 or 3; r 1 is selected from 、、One of them. The invention also provides a preparation method of the double-alkylation cationic derivative based on the honokiol mother nucleus, which comprises the following steps: Mixing honokiol, potassium carbonate, dibromoalkane and acetone, performing a first reaction to obtain an intermediate product, mixing the intermediate product, a compound R 1 H and acetonitrile, and performing a second reaction to obtain a dialkylated cationic derivative based on a honokiol parent nucleus; wherein the dibromoalkane is BrCH 2(CH2)nCH2 Br, and n is 1,2 or 3; r 1 in the compound R 1 H is selected from 、、One of them. Preferably, the honokiol has the structural formula of。 Preferably, the intermediate p