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CN-122010764-A - Honokiol derivative with cationic group, preparation method thereof and application thereof in preparation of anti-infective medicament

CN122010764ACN 122010764 ACN122010764 ACN 122010764ACN-122010764-A

Abstract

The invention belongs to the technical field of honokiol derivatives, and particularly discloses a honokiol derivative with a cationic group, a preparation method thereof and application thereof in preparation of anti-infective drugs. The invention carries out amide coupling reaction on a compound 1 and a compound 2 to obtain a compound 3, then carries out hydrolysis reaction on the compound 3 to obtain a compound 4, carries out bromination reaction on the compound 4 to obtain a compound 5, and carries out nucleophilic substitution reaction on the compound 5 and H-R 2 to obtain honokiol derivatives with cationic groups . The small molecular mimics prepared by the invention can replicate the core physicochemical and biological characteristics of the antibacterial peptide, can optimize the pharmacological characteristics, and solves a plurality of problems existing in the antibacterial peptide as an anti-infective drug.

Inventors

  • XIE JIAN
  • WANG WEI
  • YE PENG
  • 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 (10)

  1. 1. A honokiol derivative with cationic groups is characterized in that, the structural formula of the honokiol derivative with the cationic group is as follows: ; wherein R 1 is selected from 、 、 、 、 、 Or (b) ; Said R 2 is selected from 、 Or (b) 。
  2. 2. The method for preparing the honokiol derivative with the cationic group as claimed in claim 1, comprising the following steps: 1) Performing amide coupling reaction on the compound 1 and the compound 2 to obtain a compound 3; 2) Carrying out hydrolysis reaction on the compound 3 to obtain a compound 4; 3) Brominating the compound 4 to obtain a compound 5; 4) Carrying out nucleophilic substitution reaction on the compound 5 and H-R 2 to obtain honokiol derivatives with cationic groups; Wherein the structural formula of the compound 1 is ; The structural formula of the compound 2 is Wherein R 1 is selected from 、 、 、 、 、 、 Or (b) ; The structural formula of the compound 3 is ; The structural formula of the compound 4 is ; The structural formula of the compound 5 is ; R 2 in the H-R 2 is selected from 、 Or (b) 。
  3. 3. The method for preparing honokiol derivative with cationic group according to claim 2, wherein the amide coupling reaction in step 1) is to mix compound 1, compound 2, organic base, peptide coupling reagent and solvent for amide coupling reaction.
  4. 4. The method for preparing honokiol derivatives with cationic groups according to claim 3, wherein the molar ratio of the compound 1 to the compound 2 to the organic base to the peptide coupling reagent is 1:2-2.6:3-6:2-2.6; The time of the amide coupling reaction is 6-8 hours; The organic base comprises one or more of N, N-diisopropylethylamine, triethylamine and pyridine; The peptide coupling reagent comprises one or more of HATU, TBTU and BOP.
  5. 5. The method for preparing honokiol derivative with cationic group as claimed in claim 4, wherein the hydrolysis reaction in step 2) is to mix compound 3 with alkaline solvent, perform hydrolysis reaction, and then acidify to obtain compound 4; The temperature of the hydrolysis reaction is 60-80 ℃ and the time is 5-10 h.
  6. 6. The method for preparing a honokiol derivative with a cationic group as claimed in claim 5, wherein the bromination reaction in the step 3) is an apael bromination reaction.
  7. 7. The method for preparing a honokiol derivative with a cationic group according to claim 6, wherein the molar ratio of the compound 5 to H-R 2 in the step 4) is 1:8-10; The temperature of the nucleophilic substitution reaction is 80-100 ℃, and the reaction time is 12-24 hours.
  8. 8. The method for preparing a honokiol derivative with a cationic group according to any one of claims 2 to 7, wherein the method for preparing the compound 2 comprises the following steps: R 1 -NH 2 and 4-bromobutyl acetate are subjected to substitution reaction to obtain the product.
  9. 9. The method for preparing a honokiol derivative with a cationic group according to claim 8, wherein the molar ratio of R 1 -NH 2 to 4-bromobutyl acetate is 1:0.8-1.2; The time of the substitution reaction is 2-4 hours.
  10. 10. The application of the honokiol derivative with the cationic group prepared by the preparation method of any one of claims 2-9 in preparation of anti-infective drugs.

Description

Honokiol derivative with cationic group, preparation method thereof and application thereof in preparation of anti-infective medicament Technical Field The invention relates to the technical field of honokiol derivatives, in particular to a honokiol derivative with a cationic group, a preparation method thereof and application thereof in preparing anti-infective drugs. Background Bacterial infections continue to pose serious challenges to public health, significantly increasing 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 worldwide each year, 127 tens of thousands 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. 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 anti-infective 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. Therefore, how to prepare a class of small molecule mimics, copy the core physicochemical and biological characteristics of AMPs, optimize pharmacological characteristics, and develop next-generation anti-infective drugs is a challenge to be solved in the field. Disclosure of Invention In view of the above, the invention provides a honokiol derivative with a cationic group, a preparation method thereof and application thereof in preparing anti-infective drugs, and solves a plurality of defects of the antibacterial peptide as the anti-infective drugs. In order to achieve the above purpose, the invention adopts the following technical scheme: a honokiol derivative with a cationic group, the honokiol derivative with a cationic group having the structural formula: ; wherein R 1 is selected from 、、、、、、Or (b); Said R 2 is selected from、Or (b)。 Another object of the present invention is to provide a method for preparing honokiol derivatives with cationic groups, comprising the steps of: 1) Performing amide coupling reaction on the compound 1 and the compound 2 to obtain a compound 3; 2) Carrying out hydrolysis reaction on the compound 3 to obtain a compound 4; 3) Brominating the compound 4 to obtain a compound 5; 4) Carrying out nucleophilic substitution reaction on the compound 5 and H-R 2 to obtain honokiol derivatives with cationic groups; Wherein the structural formula of the compound 1 is ; The structural formula of the compound 2 isWherein R 1 is selected from、、、、、、Or (b); The structural formula of the compound 3 is; The structural formula of the compound 4 is; The structural formula of the compound 5 is; R 2 in the H-R 2 is selected from、Or (b)。 Preferably, the amide coupling reaction in step 1) is performed by mixing the compound 1, the compound 2, the organic base, the peptide coupling reagent and the solvent. Preferably, the molar ratio of the compound 1 to the compound 2 to the organic base to the peptide coupling reagent is 1:2-2.6:3-6:2-2.6; The time of the amide coupling reaction is 6-8 hours; The organic base comprises one or more of N, N-diisopropylethylamine, triethylamine and pyridine; The peptide coupling reagent comprises one or more of HATU, TBTU and BOP. Preferably, in the step 2), the hydrolysis reaction is to mix the compound 3 with an alkaline solvent