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Aromatic heterocycle substituted acridine quaternary ammonium salt derivative as well as preparation method and application thereof

A technology of aromatic heterocycles and quaternary ammonium salts, applied in the field of pharmaceutical compounds, can solve the problems of high side effects and antibacterial activity to be further improved, and achieve good bactericidal effect and significant interference effect

Active Publication Date: 2021-09-28
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the current compounds all have high side effects, and the antibacterial activity needs to be further improved

Method used

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  • Aromatic heterocycle substituted acridine quaternary ammonium salt derivative as well as preparation method and application thereof
  • Aromatic heterocycle substituted acridine quaternary ammonium salt derivative as well as preparation method and application thereof
  • Aromatic heterocycle substituted acridine quaternary ammonium salt derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0043] The preparation method of the acridine quaternary ammonium salt derivatives substituted by the aromatic heterocycle comprises the following reaction scheme:

[0044]

[0045] Among them, R 1 , X are all as above.

[0046] Specifically, the preparation method: first carry out Ullmann reaction to obtain followed by intramolecular cyclization to obtain followed by a nucleophilic substitution reaction to obtain followed by a nucleophilic substitution reaction to obtain Finally, the compound shown in formula (I) is obtained through nucleophilic substitution and rearrangement.

[0047] with R 1 for As an example, the preparation route looks like this:

[0048]

[0049] Operation steps: o-bromobenzoic acid and aniline undergo Ullman condensation, intramolecular ring closure, nucleophilic substitution reaction with methyl iodide, and then chlorination to obtain intermediate 5. The aromatic heterocyclic substituent is prepared by nucleophilic substitution, and...

Embodiment 1

[0068] Preparation of 2-(phenylamino)benzoic acid (2)

[0069]

[0070] Weigh raw material 2-bromobenzoic acid (2.0g, 10mmol), aniline (1.85g, 20mmol), potassium carbonate (1.37g, 10mmol) and catalytic amount of copper powder (0.2-0.3 microns, 4.97mmol) and dissolve in 80mL in ethanol. The reaction solution was heated under reflux for 12 hours. After the reaction was monitored by TLC, the cooled reaction solution was poured into hot water, filtered through diatomaceous earth to remove insoluble matter, and then the filtrate was acidified with diluted hydrochloric acid solution to adjust the pH to 5-6, a large amount of precipitates were separated out, and the resulting precipitated product was purified by ethanol recrystallization to obtain 1.65 g of pure gray solid product, namely intermediate 2, with a yield of 78%.

Embodiment 2

[0072] Preparation of 9(10H)-acridone (3)

[0073]

[0074] The intermediate 2-(anilino)benzoic acid (2.0 g, 9.4 mmol) prepared in Example 1 above was put into a 100 mL round bottom flask, and 10 mL of concentrated sulfuric acid was added thereto. Stir the mixture under nitrogen protection at 100°C for 6 hours. After monitoring the complete reaction by TLC, cool to room temperature, and then pour the cooled reaction solution into a large amount of ice water and stir. After the solid precipitates, it is collected by suction filtration under reduced pressure. The solid was washed several times with sodium bicarbonate solution, and dried in vacuo to obtain 1.5 g of a yellow solid product, ie Intermediate 3, with a yield of 82%.

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Abstract

The invention belongs to the technical field of pharmaceutical compounds, and relates to an aromatic heterocycle substituted acridine quaternary ammonium salt derivative and a preparation method and application thereof, the aromatic heterocycle substituted acridine quaternary ammonium salt derivative has a structure as shown in a formula (I): wherein R1 is selected from aromatic heterocycle and substituted aromatic heterocycle ; and X is halogen or benzenesulfonic acid anion. The invention provides the aromatic heterocycle substituted acridine quaternary ammonium salt derivatives and the preparation method and application thereof, the aromatic heterocycle substituted acridine quaternary ammonium salt derivatives are designed and synthesized by simplifying the structure, intercepting effective fragments in sanguinarine and berberine, and splicing the effective fragments with aromatic heterocycle pharmacophores. The unique antibacterial effect is expected to be exerted through a dual antibacterial mechanism of inhibiting bacterial FtsZ and bacterial biofilm.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical compounds, and relates to acridinium quaternary ammonium salt derivatives substituted by aromatic heterocycles, a preparation method and application. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] The discovery of antibiotics is hailed as one of the greatest achievements in the history of human medicine. Its wide application not only significantly improves the quality of human life, but also effectively prolongs the overall life span of human beings. At present, more than 200 kinds of antibiotics have been used clinically, and diseases caused by various bacterial infections have also be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06C07D401/06A61K31/438A61P31/04
CPCC07D417/06C07D401/06A61P31/04Y02A50/30
Inventor 马淑涛宋迪张楠
Owner SHANDONG UNIV
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