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CN-121990940-A - Antibacterial biphenol derivative and preparation method thereof

CN121990940ACN 121990940 ACN121990940 ACN 121990940ACN-121990940-A

Abstract

The invention provides an antibacterial biphenol derivative and a preparation method thereof, belonging to the technical field of organic synthesis. According to the invention, through carrying out structural modification on a biphenol core skeleton, introducing an amide bond at a phenolic hydroxyl site, connecting an amino group and a guanidyl cationic group, and simultaneously introducing a biphenyl methyl or n-hexyl hydrophobic side chain, the amphiphilic target compound with high antibacterial activity is obtained. The derivative has obvious inhibition effect on gram-positive bacteria, gram-negative bacteria and multi-drug resistant strains. The compound can be widely applied to the preparation of antibacterial drugs, medical disinfection preparations and antibacterial functional materials, and has important clinical conversion value in the fields of infectious disease treatment and medical protection.

Inventors

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

Assignees

  • 遵义医科大学

Dates

Publication Date
20260508
Application Date
20260130

Claims (10)

  1. 1. An antibacterial biphenol derivative is characterized by having the following structural formula: A Or (b) B; Wherein n is 1, 2 or 3.
  2. 2. The method for producing an antibacterial biphenol derivative according to claim 1, wherein when the antibacterial derivative is a compound a, comprising the steps of: step 1), mixing a compound 1, a compound 2 and acetonitrile, and reacting under the action of potassium carbonate to obtain a compound 3; step 2), mixing the compound 4, potassium carbonate and ethyl bromoacetate in a solvent, and carrying out O-alkylation reaction to obtain an intermediate 5; Step 3), hydrolyzing the intermediate 5 under alkaline conditions to obtain a compound 6, sequentially acidifying, filtering and drying the obtained compound 6, mixing the compound 6 with DIPEA, HATU, the compound 3 and acetonitrile, and performing amide coupling to obtain an intermediate 7; step 4), mixing the intermediate 7, trifluoroacetic acid and dichloromethane, and removing the protecting group to obtain a compound 8, namely the antibacterial biphenol derivative; In step 1), the structural formula of the compound 1 is ; The structural formula of the compound 2 is N is 1, 2 or 3; in the step 2), the compound 4 is honokiol, and the structural formula is 。
  3. 3. The method for preparing an antibacterial biphenol derivative according to claim 2, wherein in step 1), the molar ratio of the compound 1 to the compound 2 to the potassium carbonate is 0.5-1.5:0.5-1.5:1-2; the reaction temperature is 40-60 ℃, and the reaction time is 6-10 hours; in the step 2), the temperature of the O-alkylation reaction is 60-70 ℃ and the time is 7-9 h; the molar ratio of the compound 4 to the potassium carbonate is 1:1-4, and the adding amount of the ethyl bromoacetate is excessive relative to the compound 4.
  4. 4. The method for preparing the antibacterial biphenol derivative according to claim 2, wherein in the step 3), the hydrolysis is performed after the compound 5 and sodium hydroxide are mixed in a methanol/water solution, the hydrolysis temperature is 50-70 ℃ and the hydrolysis time is 4-6 hours; The molar ratio of the intermediate 5 to the sodium hydroxide is 1:8-15; the molar ratio of the compound 6 to the compound 3 to the DIPEA to the HATU is 1-2:2-4:4-6:2-5, and the dosage ratio of the compound 6 to the acetonitrile is 2-3 mmol:25-40 mL; the reaction temperature of the amide coupling is 23-35 ℃, and the reaction time is 6-8 hours.
  5. 5. The method for preparing an antibacterial biphenol derivative according to claim 2, wherein in step 4), the reaction temperature for removing the protecting group is 23-35 ℃, and the reaction time is 4-6 hours; The dosage ratio of the intermediate 7 to the trifluoroacetic acid to the dichloromethane is 0.3-1.2 mmol, 1-3 mL and 4-7 mL.
  6. 6. The method for producing an antibacterial biphenol derivative according to claim 1, wherein when the antibacterial derivative is compound B, comprising the steps of: Step S1), mixing a compound C, tert-butyl (4-aminobutyl) carbamate, DIPEA, HATU and acetonitrile, and performing a coupling reaction to obtain a compound 9; Step S2), mixing the compound 9 with CF 3 COOH and dichloromethane, and performing acidic deprotection to obtain a compound 10; Step S3), in an inert atmosphere, mixing the compound 10, N' -bis-Boc-1-guanidyl pyrazole, DIPEA and dichloromethane for reaction, diluting and washing to obtain a compound 11, mixing the compound 11, CF 3 COOH and dichloromethane, and deprotecting to obtain a compound 12, namely an antibacterial biphenol derivative; the structural formula of the compound C is 。
  7. 7. The method for preparing an antibacterial biphenol derivative according to claim 6, wherein in step S1), the compound C, t-butyl (4-aminobutyl) carbamate, DIPEA and HATU are used in a ratio of 1 to 2:2 to 4:4 to 6:2 to 5; The dosage ratio of the compound C to the acetonitrile is 1-2 mmol:15-30 mL; The temperature of the coupling reaction is 20-32 ℃ and the time is 6-10 h.
  8. 8. The method for producing an antibacterial biphenol derivative according to claim 6 or 7, wherein in step S2), the reaction temperature for the acidic deprotection is 23 to 35 ℃ for 5 to 7 hours; The dosage ratio of the compound 9 to CF 3 COOH is 1-2:2-6, and the dosage ratio of the compound 9 to dichloromethane is 1-2 mmol:5-20 mL.
  9. 9. The method for preparing an antibacterial biphenol derivative according to claim 8, wherein in step S3), the molar ratio of the compound 10, N' -bis-Boc-1-guanidinopyrazoles to DIPEA is 1-2:2-4:2-5, the reaction temperature is 23-35 ℃, and the reaction time is 10-14 hours.
  10. 10. The method for preparing an antibacterial biphenol derivative according to claim 6 or 9, wherein in step S3), the dosage ratio of the compound 11, CF 3 COOH and dichloromethane is 0.3-0.8 mmol:1-4 ml:4-8 ml, the deprotection temperature is 23-35 ℃ and the time is 5-8 h.

Description

Antibacterial biphenol derivative and preparation method thereof Technical Field The invention relates to the technical field of organic synthesis, in particular to an antibacterial biphenol derivative and a preparation method thereof. Background Bacterial infections continue to pose serious challenges to global public health, significantly increasing global morbidity and mortality. The abuse and overprescription of traditional antibiotics, together with the natural adaptation and evolution ability of bacteria, drive the generation of multi-drug resistant strains and weaken the curative effect of a plurality of existing therapeutic drugs. The lancet report states that the severe burden of antimicrobial resistance (AMR) results in about 495 tens of thousands of deaths annually, 127 of which are directly attributable to drug-resistant infections. This death has exceeded the sum of AIDS (HIV/AIDS) and malaria. So-called "superbacteria" such as methicillin-resistant staphylococcus aureus (MRSA), carbapenem-resistant pseudomonas aeruginosa, vancomycin-resistant enterococci, multi-drug resistant acinetobacter baumannii are now ubiquitous in medical institutions and community environments, and pose a serious threat to immunocompromised and critically ill patients. For this reason, the world health organization has prioritised the development of new therapeutic strategies for these critical priority pathogens. Thus, there is an urgent need to continually explore innovative therapeutic strategies and novel chemical entities to combat these refractory infections. In face of this pressing challenge, antimicrobial peptides (AMPs) are increasingly being viewed as a promising class of alternative antimicrobial agents. AMPs are usually short-chain, cationic, amphiphilic peptides consisting of 20-50 amino acids as key effector molecules of the innate immune system in a variety of organisms. Its mechanism of action is mostly through targeting the microbial cell membrane, leading to membrane structural disruption and cell death. The membrane targeting property, together with its broad-spectrum activity against bacteria, fungi and even viruses, makes AMPs an ideal candidate for breaking through the traditional drug resistance mechanism. Unlike conventional antibiotics which act on specific intracellular targets, AMPs generally act by physically disrupting membrane integrity, a mode of action which is not prone to eliciting rapid bacterial resistance. Despite its great potential, its clinical transformation is still subject to inherent drawbacks such as proteolytic instability, high production costs, systemic toxicity, and large scale synthesis difficulties. To break through these limitations, researchers have begun to design antibacterial peptide mimics aimed at replicating the core physicochemical and biological properties of AMPs, while optimizing pharmacological properties. Among the many mimics, small molecule amphiphiles and cationic salts exhibit significant potential. By changing the length of the linker, introducing an aromatic core structure, and controlling structural modifications such as hydrophobic tails, researchers optimize the antibacterial efficacy while reducing cytotoxicity. Notably, the use of the obtained drug lot or natural product as a molecular scaffold has strategic advantages in that it can integrate known safety and bioavailability into new designs. Small molecule mimics such as CSA-13, XF-73 and PMX-30063 have entered the clinical trial phase, highlighting the feasibility of this strategy in the development of next generation anti-infective agents. Disclosure of Invention The invention aims to provide an antibacterial biphenol derivative and a preparation method thereof, which are used for solving the technical problems. In order to achieve the above object, the present invention provides the following technical solutions: the invention provides an antibacterial biphenol derivative, which has the following structural formula: A Or (b) B; Wherein n is 1, 2 or 3. The invention provides a preparation method of the antibacterial biphenol derivative, which comprises the following steps when the antibacterial derivative is a compound A: step 1), mixing a compound 1, a compound 2 and acetonitrile, and reacting under the action of potassium carbonate to obtain a compound 3; step 2), mixing the compound 4, potassium carbonate and ethyl bromoacetate in a solvent, and carrying out O-alkylation reaction to obtain an intermediate 5; Step 3), hydrolyzing the intermediate 5 under alkaline conditions to obtain a compound 6, sequentially acidifying, filtering and drying the obtained compound 6, mixing the compound 6 with DIPEA, HATU, the compound 3 and acetonitrile, and performing amide coupling to obtain an intermediate 7; step 4), mixing the intermediate 7, trifluoroacetic acid and dichloromethane, and removing the protecting group to obtain a compound 8, namely the antibacterial biphenol derivative; In step 1),