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Benzothiazole compounds and application thereof in preparation of bacterial biofilm inhibitors

A technology of bacterial biofilm and benzothiazole, which is applied in the field of medicine, achieves the effects of good induction activity, high safety, and small toxic and side effects

Active Publication Date: 2019-06-21
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, after nearly 20 years of hard work, no bacterial quorum sensing inhibitor has been successfully used in clinical practice.

Method used

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  • Benzothiazole compounds and application thereof in preparation of bacterial biofilm inhibitors
  • Benzothiazole compounds and application thereof in preparation of bacterial biofilm inhibitors
  • Benzothiazole compounds and application thereof in preparation of bacterial biofilm inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Synthesis of 2,3-dimethylbenzo[d]thiazole-3-iodide (synthesis of compound 2)

[0051] Dissolve 0.76ml (6mmol) of 2-methylbenzothiazole in 10ml of acetonitrile solution, add 0.94ml (15mmol) of methyl iodide, and heat the mixture to reflux for 24h under a nitrogen atmosphere, cool to room temperature, filter with suction, and use a small amount of acetonitrile and After washing with ether, 1.42 g of white solid was obtained. The yield was 83%. 1 H NMR (400 MHz, DMSO) δ8.49(d, J=8.1Hz, 1H), 8.28(d, J=8.4Hz, 1H), 7.85(t, J=7.8 Hz, 1H), 7.77(t, J=7.7Hz, 1H), 4.23(s, 3H), 3.23(s, 3H); 13 C NMR(101MHz, DMSO)δ177.45,141.98,129.70,129.07,128.45,125.02,117.26,37.29,18.40. ESI-MS(m / z):164[M-I] + .

Embodiment 2

[0052] Example 2: (E)-2-(4-aminostyryl)-3-methylbenzo[d]thiazole-3-iodide (compound A1)

[0053]

[0054] Dissolve 150mg (0.52mmol) of compound 2 and 75mg (0.62mmol) of 4-aminobenzaldehyde in methanol, add dropwise 21μl (0.26mmol) of pyridine, heat to reflux for 12h, cool to room temperature, filter with suction, wash with methanol and After washing with a small amount of ether, 178 mg of a purple solid was obtained. The yield is 87%. 1 H NMR (400MHz, DMSO) δ8.29(d, J=8.0Hz, 1H), 8.08(d, J=8.4Hz, 1H), 7.99(d, J=15.3Hz, 1H), 7.81-7.75(m ,3H),7.67(t,J=7.6Hz,1H),7.55(d,J=15.3Hz,1H),6.68(d,J=8.7Hz,4H),4.21(s,3H); 13 C NMR(101MHz,DMSO)δ171.85,155.20, 150.95,142.39,133.92,129.29,127.84,127.17,124.25,122.03,116.35,114.32, 106.04,36.02. ESI-MS(m / z):267. + .

Embodiment 3

[0055] Example 3: (E)-2-(4-(dimethylamino)styryl)-3-methylbenzo[d]thiazole-3-iodide (Compound A2)

[0056]

[0057] Using compound 2 as raw material, the preparation method is the same as in Example 2, the only difference being that 75mg (0.62mmol) of 4-aminobenzaldehyde is replaced by 92mg (0.62mmol) of 4-(dimethylamino)benzaldehyde to obtain purple Solid A2 in 83% yield. 1 H NMR (400MHz, DMSO) δ8.30(d, J=8.0Hz, 1H), 8.08(dd, J=14.5, 12.0Hz, 2H), 7.91(d, J=8.9Hz, 2H), 7.79(t ,J=7.8Hz,1H),7.68(t,J=7.6Hz,1H),7.62(d,J=15.3Hz,1H),6.83(d,J=8.9Hz,2H),4.23(s,3H ),3.11(s,6H); 13 C NMR (101MHz, DMSO) δ171.80, 153.96, 150.57, 142.41, 133.29, 129.32, 127.89, 127.27, 124.27, 121.93, 116.40, 112.42, 106.73, 100.00, 36.07. ESI-MS (m / z) + .

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Abstract

The invention belongs to the medical field and discloses benzothiazole compounds as well as a preparation method and an application thereof. The benzothiazole compounds have the structural formula shown in formula I, wherein Ar is substituted benzene ring five-member nitrogen heterocyclic ring, six-member nitrogen heterocyclic ring, indolyl or substituted indole group; R is -H,-F, -Br, -NO2, -NH2,-N(CH3)2, 4-methylpiperazine-1-yl, 4-morpholinyl, -OH or -OCH3. 2-methyl benzothiazole is used as a lead compound and modified and transformed, a series of benzothiazole compounds are designed and synthesized, the obtained compounds have better bacterial signal molecule c-di-GMP aggregation induction activity, smaller toxic and side effects and higher safety and can be applied to preparation of bacterial biofilm inhibitors, particularly pseudomonas aeruginosa biofilm inhibitors, when Ar is 3-position substituted indole, the induction activity is obviously superior to a positive control compound.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a benzothiazole compound and a preparation method thereof and the preparation method based on inducing 3',5'-cyclic diguanosine (c-di-GMP) to form a function-deficient G-quadruplex Application of Strategies for Bacterial Biofilm Inhibitors. Background technique [0002] The problem of bacterial drug resistance has become increasingly prominent, and about 16 million patients die directly from bacterial infections every year. Studies have found that more than 70% of malignant infections are related to the formation of biofilm resistance by bacteria. Bacterial biofilm refers to the highly structured encapsulation complex formed by bacteria after attaching to a solid surface by secreting a sticky extracellular matrix and growing and multiplying in it. After the bacteria form a biofilm, they can prevent the drug from reaching an effective inhibitory concentration in the biofilm b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/64C07D417/06A61P31/04A61K31/428A61K31/496A61K31/5377A61K31/4439A61K31/497
Inventor 林静陈卫民宣腾飞汪自强刘君
Owner JINAN UNIVERSITY
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