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Anti-drug-resistance antibacterial amidine oligomer as well as preparation method and application thereof

A production method and oligomerization-like technology, which can be used in medical preparations containing active ingredients, antibacterial drugs, pharmaceutical formulations, etc., can solve problems such as high toxicity, and achieve low toxicity, broad-spectrum antibacterial activity, and high therapeutic index. Effect

Pending Publication Date: 2022-07-22
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the problem of high toxicity of traditional high-molecular-weight antibacterial polymers, the invention discloses an antibacterial amidine oligomer with anti-drug resistance and its preparation method and application

Method used

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  • Anti-drug-resistance antibacterial amidine oligomer as well as preparation method and application thereof
  • Anti-drug-resistance antibacterial amidine oligomer as well as preparation method and application thereof
  • Anti-drug-resistance antibacterial amidine oligomer as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] After testing, an antibacterial amidine oligomer with broad-spectrum antibacterial properties has the following chemical formula:

[0032]

[0033] Here, 5≤n≤8, and R1 and R2 have the structures described above. It can be seen from the above structural formula that 81 compounds can be obtained by different combinations of R1 and R2. In order to facilitate the analysis and description of these compounds, 60 compounds are labeled in Table 1 below. It should be noted that, For those skilled in the art, unlabeled compounds can also be synthesized. The properties and synthesis methods of these unlabeled compounds are similar to those of the labeled 60 compounds, so they are not further analyzed and explained in the present invention.

[0034] The structural formulas of the 60 compounds, their antibacterial activities, and biocompatibility lists are shown in Table 1 and Table 2. From Table 2, it can be seen that the therapeutic indices of P1, P2, P3, P4, P6, and P7 are rel...

Embodiment 2

[0041] As shown in Figure 1, the present invention also discloses a method for synthesizing an antibacterial amidine oligomer with drug resistance, comprising the following steps:

[0042] S1: prepare a compound monomer having the following molecular formula:

[0043]

[0044] S2: react the compound monomer with H2N-R2-NH2, anhydrous N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIPEA) to obtain the amidines Oligomers, R1 and R2 have the structures described above.

[0045] Wherein, the above-mentioned step S1 includes the following steps:

[0046] S11: Weigh 5-cyanoindole or 6-cyanoindole and di-tert-butyl dicarbonate, then add dichloromethane and mix evenly, add a catalytic amount of 4-dimethylaminopyridine (DMAP) at 2-6 After stirring at ℃ for half an hour, it was returned to room temperature of 20-25 ℃ and stirred overnight, the mixture was filtered and washed, and then spin-dried with a rotary evaporator to obtain a solid product, and then the product wa...

experiment example 1

[0053] This experimental example is described in detail with the P2 compound:

[0054] Materials and methods: All reagents were provided by TCI (USA), Sigma-Aldrich, McLean, Adamas and other organic reagent companies and Biyuntian Biotechnology Company, and were used directly without further purification (unless otherwise noted). The ultrapure water used in the experiment was obtained from the Milli-Q purification instrument. The inert gas is nitrogen.

[0055] The synthesis steps of P2 are shown in Figure 1. First, the synthesis of 4',6-diamidino-2-phenylindole hydrochloride monomer was carried out. Weigh 6-cyanoindole (10 g, 70.3 mmol) and di-tert-butyl dicarbonate (BOC) (35.36 g, 162 mmol), then add 100 mL of dichloromethane and mix well, then add a catalytic amount of 4-dimethylamino Pyridine (DMAP) (0.86 g, 7.03 mmol) was stirred at room temperature for 12-24 h to obtain a mixture. The mixture was extracted and spin-dried to obtain a solid mixture. The solid mixture wa...

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Abstract

The invention discloses an antibacterial amidine oligomer with resistance to drug resistance, a preparation method, application and an antibacterial mechanism of the antibacterial amidine oligomer, and application of the antibacterial amidine oligomer in sterilization in an intracellular infection model and a zebra fish model infected by accidental mycobacteria. The antibacterial types of the amidine oligomer comprise escherichia coli, enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, mycobacterium smegmatis, mycobacterium fortuitum and the like. The structure disclosed by the invention has double antibacterial mechanisms of destroying bacterial cell membranes and combining chromosome DNA, has the characteristics of rapid sterilization and drug resistance, and shows antibacterial broad spectrum. In addition, the structure has low toxicity to blood cells, and has high safety in blood. Meanwhile, the structure can be applied to a Raw264.7 cell model infected by mycobacterium smegmatis and mycobacterium fortuitum, and the structure also has a good treatment effect on a zebra fish model infected by MRSA and mycobacterium fortuitum.

Description

technical field [0001] The invention relates to the field of pharmaceutical and chemical materials, in particular to an antibacterial amidine oligomer with drug resistance and a preparation method and application thereof. Background technique [0002] The abuse of antibiotics in the field of antibacterial has accelerated the emergence of drug-resistant strains and multi-drug-resistant strains. Bacterial drug resistance has become a common and serious problem that endangers human health. Therefore, it is urgent to develop new antibacterial agents that can quickly kill drug-resistant bacteria without causing bacterial resistance. Recently, the concept of anti-drug-resistant antibacterial agents has been established, aiming to solve the problem of bacterial drug resistance by designing a cationic amidine-based antibacterial oligomer with dual antibacterial mechanisms. [0003] Amidine anti-drug-resistant antibacterial agents with dual antibacterial mechanisms should have the f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/18C07D209/20C07D295/13C07C257/22C07C257/08C07C319/20C07C323/25A61P31/04A61P31/06A61K31/496A61K31/404A61K31/155
CPCC07D209/18A61P31/04C07D295/13C07C323/25C07C257/18Y02A50/30
Inventor 冯欣欣白玉罡王建雪陈先会陈亚杰
Owner HUNAN UNIV
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