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CN-122011022-A - Honokiol phosphine salt derivative and preparation method and application thereof

CN122011022ACN 122011022 ACN122011022 ACN 122011022ACN-122011022-A

Abstract

The invention belongs to the technical field of organic synthesis, and provides a honokiol phosphine salt derivative, a preparation method and application thereof. The compound shows strong activity (MIC=1-4 mug/mL) on a series of gram-positive bacteria, meanwhile, the hemolytic activity is extremely low (HC 50 =106.9 mug/mL), and the cytotoxicity is also low (CC 50 =19.25 mug/mL). In addition, the derivative has the advantages of rapid sterilization, low drug resistance, good plasma stability, and the capability of inhibiting the formation of biological films and damaging mature biological films. The antibacterial effect is more excellent in vivo, and compared with vancomycin, the antibacterial effect can remarkably reduce the bacterial load.

Inventors

  • XIE JIAN
  • ZHANG LINSU
  • WU JUNLIN
  • YANG DEZHI

Assignees

  • 遵义医科大学
  • 黔南民族医学高等专科学校

Dates

Publication Date
20260512
Application Date
20260130

Claims (8)

  1. 1. A honokiol phosphine salt derivative is characterized in that, the structure of the honokiol phosphine salt derivative is shown as follows: ; wherein R 2 is independently 、 、 、 、 、 、 Or (b) 。
  2. 2. A process for the preparation of honokiol phosphonium salt derivatives according to claim 1, characterized in that it comprises the following steps: (1) Reacting an amino compound, dichloromethane, 4-bromobutyl acetate and triethylamine to obtain a compound 1; (2) Mixing the compound 1, the compound 2, the organic base, a coupling reagent and acetonitrile, and performing an amide coupling reaction to obtain a compound 3; (3) Mixing the compound 3, alkali and a solvent, performing hydrolysis reaction, and then acidizing to obtain a compound 4; (4) Brominating the compound 4, carbon tetrabromide, triphenylphosphine and methylene dichloride to obtain a compound 5; (5) And (3) reacting the compound 5, triphenylphosphine and acetonitrile to obtain the honokiol phosphine salt derivative.
  3. 3. The process for preparing a honokiol phosphine salt derivative as claimed in claim 2, wherein R 2 -NH 2 ,R 2 is an amino compound in the step (1) 、 、 、 、 、 、 Or (b) ; In the step (1), the dosage ratio of the amino compound to the dichloromethane to the 4-bromobutyl acetate to the triethylamine is 13-14 mmol to 10-30 mL to 13-14 mmol to 14.5-15.5 mmol; the reaction temperature in the step (1) is 20-30 ℃ and the reaction time is 2-4 hours; The structural formula of the compound 1 is ; Wherein R 2 in the compound 1 is 、 、 、 、 、 、 Or (b) 。
  4. 4. The process for preparing a honokiol phosphine salt derivative as claimed in claim 3, wherein the compound 2 in the step (2) has the structural formula ; The organic base in the step (2) is one or more of N, N-diisopropylethylamine, triethylamine and pyridine; the coupling reagent in the step (2) is one or more of HATU, TBTU and BOP; in the step (2), the molar ratio of the compound 1 to the compound 2 to the organic base to the coupling reagent is 5-6:2-3:7.5-8.5:5-6; the temperature of the amide coupling reaction in the step (2) is 20-30 ℃, and the time is 6-8 hours; the structural formula of the compound 3 in the step (2) is ; R 2 in Compound 3 is independently 、 、 、 、 、 、 Or (b) 。
  5. 5. The method for preparing a honokiol phosphine salt derivative as defined in claim 4, wherein the alkali in the step (3) is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; The solvent in the step (3) comprises methanol and water, wherein the volume ratio of the methanol to the water is 1-10:1-10; in the step (3), the dosage ratio of the compound 3, the alkali and the solvent is 1-3 mmol:8-12 mmol:10-30 mL; the temperature of the hydrolysis reaction in the step (3) is 50-70 ℃ and the time is 5-10 h; the acidified target pH value in the step (3) is less than or equal to 3; the structural formula of the compound 4 in the step (3) is ; R 2 in Compound 4 is independently 、 、 、 、 、 、 Or (b) 。
  6. 6. The method for preparing a honokiol phosphine salt derivative according to claim 5, wherein the dosage ratio of the compound 4, carbon tetrabromide, triphenylphosphine and methylene dichloride in the step (4) is 1-2 mmol:2-4 mmol:10-30 mL; the bromination reaction in the step (4) is carried out at a temperature of 20-30 ℃ for 4-6 hours; The structural formula of the compound 5 in the step (4) is ; R 2 in Compound 5 is independently 、 、 、 、 、 、 Or (b) 。
  7. 7. The method for preparing a honokiol phosphine salt derivative according to claim 6, wherein the dosage ratio of the compound 5, triphenylphosphine and acetonitrile in the step (5) is 0.1-1 mmol:4-6 mmol:5-20 mL; the temperature of the reaction in the step (5) is 70-90 ℃ and the time is 12-24 hours.
  8. 8. Use of a honokiol phosphine salt derivative according to claim 1 in the preparation of an antibacterial agent.

Description

Honokiol phosphine salt derivative and preparation method and application thereof Technical Field The invention relates to the technical field of organic synthesis, in particular to a honokiol phosphine salt derivative, a preparation method and application thereof. Background The continued exacerbation of antibiotic resistance (AMR) has become one of the most serious challenges in the world public health field. The widespread emergence and spread of multi-drug resistant bacteria (MDR) has severely impaired the clinical efficacy of traditional antibiotics, directly resulting in prolonged disease course and increasing medical burden of infectious diseases, and promoting a significant increase in mortality worldwide. According to the existing statistics, the number of deaths caused by drug-resistant bacteria infection exceeds 70 ten thousand per year, and if an effective intervention measure is lacking, the number is estimated to break through 1000 ten thousand in 2050, and the number forms a profound threat to human health. Of particular concern are ESKAPE pathogens, which are not only effective against the antibacterial effects of current commonly used drugs, but are also a major source of infection in medical institutions, where the difficulty of treatment is great, often leading to severe and even death. At the same time, the global antibiotic research and development pipeline is in a state of stagnation for a long time, and new antibiotics with brand new structures or action mechanisms are hardly marketed in recent decades, which further aggravates the AMR crisis. Currently, an increasingly expanding "development gap" is formed between the continual increase in the rate of bacterial evolution and the slow arrest of new antibiotic discovery processes. The difference between the line of the risk stands out the weak links of human beings when facing drug resistance challenges, and the urgent call is to accelerate the development of alternative therapies with brand-new action mechanisms so as to cope with the continuously-upgraded global health crisis. Disclosure of Invention The invention aims to overcome the defects in the prior art and provides a honokiol phosphine salt derivative, a preparation method and application thereof. In order to achieve the above object, the present invention provides the following technical solutions: the invention provides a honokiol phosphine salt derivative, which has the structure shown as follows: ; wherein R 2 is independently 、、、、、、Or (b)。 The invention also provides a preparation method of the honokiol phosphine salt derivative, which comprises the following steps: (1) Reacting an amino compound, dichloromethane, 4-bromobutyl acetate and triethylamine to obtain a compound 1; (2) Mixing the compound 1, the compound 2, the organic base, a coupling reagent and acetonitrile, and performing an amide coupling reaction to obtain a compound 3; (3) Mixing the compound 3, alkali and a solvent, performing hydrolysis reaction, and then acidizing to obtain a compound 4; (4) Brominating the compound 4, carbon tetrabromide, triphenylphosphine and methylene dichloride to obtain a compound 5; (5) And (3) reacting the compound 5, triphenylphosphine and acetonitrile to obtain the honokiol phosphine salt derivative. Preferably, the amino compound in step (1) is R 2-NH2,R2 is、、、、、、Or (b); In the step (1), the dosage ratio of the amino compound to the dichloromethane to the 4-bromobutyl acetate to the triethylamine is 13-14 mmol to 10-30 mL to 13-14 mmol to 14.5-15.5 mmol; the reaction temperature in the step (1) is 20-30 ℃ and the reaction time is 2-4 hours; The structural formula of the compound 1 is ; Wherein R 2 in the compound 1 is、、、、、、Or (b)。 Preferably, compound 2 in step (2) has the formula; The organic base in the step (2) is one or more of N, N-diisopropylethylamine, triethylamine and pyridine; the coupling reagent in the step (2) is one or more of HATU, TBTU and BOP; in the step (2), the molar ratio of the compound 1 to the compound 2 to the organic base to the coupling reagent is 5-6:2-3:7.5-8.5:5-6; the temperature of the amide coupling reaction in the step (2) is 20-30 ℃, and the time is 6-8 hours; the structural formula of the compound 3 in the step (2) is ; R 2 in Compound 3 is independently、、、、、、Or (b)。 Preferably, in the step (3), the alkali is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; The solvent in the step (3) comprises methanol and water, wherein the volume ratio of the methanol to the water is 1-10:1-10; in the step (3), the dosage ratio of the compound 3, the alkali and the solvent is 1-3 mmol:8-12 mmol:10-30 mL; the temperature of the hydrolysis reaction in the step (3) is 50-70 ℃ and the time is 5-10 h; the acidified target pH value in the step (3) is less than or equal to 3; the structural formula of the compound 4 in the step (3) is ; R 2 in Compound 4 is independently、、、、、、Or (b)。 Preferably, in the step (4), the dosage ratio of