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Benzofuran and benzofuran coumarin derivatives and preparation method and application thereof

A technology for benzofuran and derivatives, which is applied in the field of preparation of benzofuran and Coumestans derivatives, can solve the problems of aggravating the burden of patients, reducing the curative effect of tuberculosis, prolonging the treatment period, etc., and achieves good bacteriostatic activity and good bioavailability. degree of effect

Active Publication Date: 2019-06-28
EAST CHINA NORMAL UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many anti-tuberculosis drugs are not easy to penetrate the cell wall structure, which greatly reduces the efficacy of tuberculosis treatment, prolongs the treatment cycle, and increases the burden on patients

Method used

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  • Benzofuran and benzofuran coumarin derivatives and preparation method and application thereof
  • Benzofuran and benzofuran coumarin derivatives and preparation method and application thereof
  • Benzofuran and benzofuran coumarin derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1 Preparation of 5-hydroxyl-(4-(1-(4-methylpiperazinyl))methylene)-2-phenylbenzofuran-3-carboxylic acid ethyl ester (compound S1)

[0089]1.1 Add 3.45g of diethyl carbonate and 0.87g of sodium hydride to 15mL of toluene, then slowly add 2.19g of acetophenone dropwise to the system under the protection of nitrogen, stir at 110°C for 30min, after the reaction is completed, cool to room temperature and add ice water , add glacial acetic acid until the system is neutral, extract with ethyl acetate (50mL×3), separate the organic layer, wash with saturated brine 100ml, dry over anhydrous sodium sulfate, evaporate the solvent ethyl acetate, and the crude product is subjected to flash column chromatography ( Petroleum ether: ethyl acetate = 15:1) to obtain ethyl benzoyl acetate (compound 1‐1);

[0090] 1.2 Dissolve 1.38g of ethyl benzoyl acetate and 86.37mg of copper trifluoromethanesulfonate in 20mL of toluene, slowly add 0.52g of 1,4‐benzoquinone dropwise under nitrog...

Embodiment 2

[0093] Example 2 Preparation of 4-(dipropylamino)methylene-5-hydroxyl-2-phenylbenzofuran-3-carboxylic acid ethyl ester (compound S2)

[0094] Prepared by a method similar to Example 1, the difference is that N-methylpiperazine is replaced by dipropylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the final product. 1 H NMR (400MHz, CDCl 3 )δ7.78–7.72(m,2H),7.48–7.40(m,3H),7.31(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.35(q,J =7.1Hz, 2H), 4.06(s, 2H), 2.54(t, J=7.5Hz, 4H), 1.70– 1.51(m, 4H), 1.29(t, J=7.2Hz, 3H), 0.91(t ,J=7.4Hz,6H). 13 C NMR (101MHz, CDCl 3 )δ166.4, 156.6, 155.6, 148.1, 130.0, 129.5, 128.3, 127.8, 125.3, 115.2, 112.9, 110.6, 110.0, 61.4, 55.7, 54.2, 19.6, 13.9, 11.8. M+H) + 396.2169; Found 396.2168.

Embodiment 3

[0095] Example 3 5-hydroxyl-(4-(1-(4-(4-(hydroxymethyl) piperidinyl)) methylene)-2-phenylbenzofuran-3-carboxylate ethyl ester (compound S3) preparation

[0096] Prepared by a method similar to Example 1, except that 4-hydroxymethylpiperidine is used instead of N-methylpiperazine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the final product. 1 H NMR (400MHz,MeOD)δ7.73–7.67(m,2H),7.51–7.45(m,3H),7.39(d,J=8.9Hz,1H),6.88(d,J=8.9Hz,1H) ,4.33(q,J=7.1Hz,2H),4.16(s,2H),3.43(d,J=6.3Hz,2H),3.33–3.30(m,1H),3.19(d,J=11.9Hz, 2H), 2.45(t, J=11.3Hz, 2H), 1.84(d, J=13.0Hz, 2H), 1.70–1.56(m, 1H), 1.45–1.30(m, 2H), 1.23(t,J =7.1Hz, 3H). 13 C NMR (101MHz, MeOD) δ167.6, 159.3, 156.1, 149.7, 131.2, 130.9, 129.5, 129.2, 127.2, 115.8, 112.7, 112.5, 111.4, 67.3, 64.3, 62.7, 56.5, 53.8, 38.9, 249.2, MS (ESI)m / z: Calcd for C24H28NO5(M+H) + 410.1962; Found 410.1980.

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Abstract

The invention discloses benzofuran and coumestans derivatives as shown in formulae (I|), (II) and (III) and a preparation method and an application thereof in treating multidrug-resistant tuberculosis. The benzofuran and coumestans derivatives are anti-mycobacterium tuberculosis compounds which are novel in structure and obvious in antibacterial effect. The compounds taking polyketone synthase coded by a mycobacterium tuberculosis pks13 gene fragment as an acting target spot inhibits growth and reproduction of microorganisms, in particular synthesis of mycolic acid in mycobacterium tuberculosis cell walls. The derivatives have a potential application prospect in the medical field.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method and application of a class of benzofurans and Coumestans derivatives. Background technique [0002] Tuberculosis is one of the infectious diseases that still maintain high morbidity and mortality worldwide so far. According to the survey report of the World Health Organization, about 8 million people are infected with tuberculosis every year, and more than 1.6 million people die from the disease. At the same time, due to the widespread use of first-line drugs, such as isoniazid, rifampicin, ethambutol, etc., the cases of drug-resistant and extensively drug-resistant tuberculosis are on the rise, and the co-infection of tuberculosis and AIDS is also spreading rapidly. An anti-tuberculosis drug with a new structure and a new target to curb the spread of tuberculosis. [0003] Mycobacterium tuberculosis is the pathogen that causes tuberculosis, belonging to t...

Claims

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Application Information

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IPC IPC(8): C07D307/84C07D405/06C07D405/04C07D498/04C07D498/14C07D493/04C07D491/048C07D491/052C07D495/04A61P31/06A61P35/00A61P31/12A61P31/10A61P29/00A61P1/16A61P9/12A61P7/04A61K31/496A61K31/4525A61K31/343A61K31/454A61K31/5377A61K31/4025A61K31/4545A61K31/538A61K31/55
CPCA61K31/343A61K31/4025A61K31/4164A61K31/4525A61K31/454A61K31/4545A61K31/496A61K31/505A61K31/5377A61K31/538A61K31/55A61P1/16A61P7/04A61P9/12A61P29/00A61P31/06A61P31/10A61P31/12A61P35/00C07D307/84C07D311/36C07D405/04C07D405/06C07D491/048C07D491/052C07D493/04C07D495/04C07D498/04C07D498/14Y02A50/30
Inventor 于丽芳汪澍环沈岽皓张维刘玲玲杨帆汤杰威廉·比夏论世春吴宣良阿比盖尔·L·曼森艾希莉·M·厄尔
Owner EAST CHINA NORMAL UNIV
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