A kind of 4-thiazolidinone carboxylic acid derivative and its preparation method and application

A technology of thiazolidinone carboxylic acid and derivatives, which is applied in the field of medicinal chemistry and combinatorial chemistry, can solve the problems of few synthesis reports, and achieve good anti-biofilm activity, good inhibitory effect, and good antibacterial activity

Inactive Publication Date: 2011-12-21
NANJING UNIV OF TECH
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Problems solved by technology

[0003] The research on anti-biofilm compounds has received extensive attention. Melander's research group has been committed to the research of marine alkaloids Bromoageliferin and oroidin derivatives, and synthesized a series of aminoimidazole derivatives, which have good biofilm inhibition activity ( J.Am.Chem.Soc.2009, 131, 9868-9869); Guanylic acid is a naturally occurring small molecular compound and is an important regulator of bacterial signaling systems, and its analogs can effectively inhibit the formation of biofilms by Staphylococcus aureus ( Antimicrob.Agents.Chemother.2005, 49(8):3109-13); Schillaci et al. reported that modified pyrazole derivatives have potential anti-biofilm activity (Chemotherapy 2008, 54, 456-462); Chinese Patent CN1875955A and CN1875974A reported that small molecules of pyrimidothiazoles, 2,4-thiazolidinediones, and 4-thiazolidinones inhibit the formation of biofilm by inhibiting the growth of Gram coccus, but there are few related synthesis reports

Method used

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  • A kind of 4-thiazolidinone carboxylic acid derivative and its preparation method and application
  • A kind of 4-thiazolidinone carboxylic acid derivative and its preparation method and application
  • A kind of 4-thiazolidinone carboxylic acid derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-5-[4-(4-vinylphenoxymethyl)]benzoic acid-4-thiazolidinone

[0031] Preparation of 1,3-bis(4-chlorophenyl)thiourea

[0032] 4-Chloroaniline (20mmol), CS 2 (10mmol) and 6mol / L aqueous NaOH solution (20ml) were placed in a 100ml flask and heated to 55°C, and the reaction was detected by TLC. After reacting for 8 hours, the system was cooled to room temperature, poured into 100ml of ice-water mixture, stirred, and filtered. The filter cake was washed with water several times, and recrystallized from methanol to obtain a white powder, which was 1,3-bis(4-chlorophenyl)thiourea.

[0033] Preparation of 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-4-thiazolidinone

[0034] 1,3-bis(4-chlorophenyl)thiourea (3mmol), ethyl bromoacetate (3.6mmol), anhydrous sodium acetate (3mmol) and ethanol (20ml) were added to a 50ml flask and refluxed for 1 hour. After the reaction, the solvent was evaporated to dryness under reduced pre...

Embodiment 2

[0041] Preparation of 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-5-[3-(5-vinylfuryl)]benzoic acid-4-thiazolidinone

[0042] Acetic acid 2ml, alanine 0.03g, 3-(5-formyl-2-furyl)-benzoic acid (0.41mmol) and 2-(4-chlorophenylimino)-3-(4-chlorophenyl )-4-thiazolidinone (0.41mmol) (preparation method is the same as the preparation of 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-4-thiazolidinone in Example 1) The flask was refluxed for 0.5 hours. Cool to room temperature, add ice water and let stand, filter with suction, recrystallize with methanol to obtain a yellow powder, which is 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-5-[ 3-(5-Vinylfuryl)]benzoic acid-4-thiazolidinone.

[0043] Yellow powder, yield 81%; 1 H NMR (300MHz, DMSO): δ (ppm) = 12.79 (s, 1H), 8.28 (s, 1H), 7.93 (d, J = 7.8Hz, 1H), 7.82 (d, J = 7.9Hz, 1H) , 7.67(s, 1H), 7.61(d, J=2.9Hz, 4H), 7.49(d, J=8.8Hz, 3H), 7.35(d, J=3.7Hz, 1H), 7.18(d, J= 3.7Hz, 1H), 7.06(d, J=8.6Hz, 2H).

[0044] ESI-MS: m / z 535.1 (M+1) ...

Embodiment 3

[0046] Preparation of 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-5-(4-vinylphenoxyacetic acid)-4-thiazolidinone

[0047] 2ml of ethanol, 0.03g of proline, 2-(4-formyl)phenoxyacetic acid (0.37mmol) and 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-4-thiazole Alkanone (0.37mmol) (preparation method is the same as the preparation of 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-4-thiazolidinone in Example 1) was added to a 25ml flask, and reflux reaction 1.5 hours. Cool to room temperature, add ice water and let it stand, suction filter, recrystallize with methanol to obtain a white powder, which is 2-(4-chlorophenylimino)-3-(4-chlorophenyl)-5-( 4-vinylphenoxyacetic acid)-4-thiazolidinone.

[0048] White powder, yield 39%; 1 H NMR (300MHz, DMSO): δ (ppm) = 13.11 (s, 1H), 7.79 (s, 1H), 7.61 (d, J = 1.2Hz, 4H), 7.54 (d, J = 8.8Hz, 2H) , 7.44(d, J=8.6Hz, 2H), 7.03(dd, J=14.0, 8.7Hz, 4H), 4.74(s, 2H).

[0049] ESI-MS: m / z 498.9 (M+1) +

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Abstract

The present invention relates to a kind of 4-thiazolidinone carboxylic acid derivative and its preparation method and application. Its general chemical structure formula is: wherein: R1 is hydrogen, halogen, methyl, ethyl, methoxy, amino, nitro , cyano, carbamoyl, aminosulfonyl, hydroxyl, N-(C1-C3) amino, N, N-(C1-C3) diamino, trifluoromethyl, trifluoromethoxy, mercapto, carboxyl or Ester group; R2 is this type of compound as an inhibitor of Staphylococcus epidermidis YycG histidine kinase, which can selectively kill Staphylococcus and inhibit the formation of Staphylococcus biofilm.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and combinatorial chemistry, in particular to a 4-thiazolidinone carboxylic acid derivative and its preparation method and application, especially to the preparation of the derivative as an inhibitor of Staphylococcus epidermidis YycG histidine kinase Use in medicines for preventing and treating biofilm infection. Background technique [0002] Staphylococcus epidermidis is one of the normal flora colonizing human skin and mucous membranes, and its pathogenicity is usually low. In recent years, with the widespread use of medical implants and biomedical materials such as catheters, artificial catheters, heart valves, and artificial organs, the infection caused by Staphylococcus epidermidis has become more and more serious, and it has become an important pathogenic bacteria of hospital infection. Staphylococcus epidermidis will stubbornly stay on the surface of medical indwelling objects ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/54C07D417/06A61K31/426A61K31/427A61P31/04
Inventor 韩世清郑礼康金明张敬先赵丹何国珍
Owner NANJING UNIV OF TECH
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