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Five-membered dihydroheterocyclic ketone derivatives and applications as Dhodh inhibitors

A technology of heterocyclic group, dihydroorotic acid, applied in the direction of anti-inflammatory agent, drug combination, non-central analgesic agent, etc., can solve the problems of mucositis side effect, narrow therapeutic window, limited wide application and the like

Active Publication Date: 2015-11-25
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Brequinar is used for anti-tumor and host immune response caused by organ transplantation, but the therapeutic window of Brequinar is narrow, and when administered orally in combination with cisplatin or cyclosporin A, it is easy to cause side effects of thrombocytopenia and mucositis, which limits its clinical application Wide application in

Method used

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  • Five-membered dihydroheterocyclic ketone derivatives and applications as Dhodh inhibitors
  • Five-membered dihydroheterocyclic ketone derivatives and applications as Dhodh inhibitors
  • Five-membered dihydroheterocyclic ketone derivatives and applications as Dhodh inhibitors

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Experimental program
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Embodiment 1

[0269] The in vitro inhibitory effect of compound provided by the invention on dihydroorotate dehydrogenase (DHODH) activity:

[0270] The catalytic region 159-565 of PfDHODH (Plasmodium falciparum dihydroorotatedehydrogenase) was cloned into the vector pET101 / D (The Journal of Biological Chemistry, 2008, 283, 35078-35085), and transferred into the expression strain E.coliBL21, and 1.5ml of pET101 / D-PfDHODH containing liquid was inoculated for 5 In 2×YT medium with 250 μM ampicillin, culture on a shaker at 37° C. at 230 rpm for about 4 hours. When the OD value of the bacteria reached 0.8-1, IPTG was added to the culture medium so that the final concentration of IPTG was 0.5 mM, and induced at 25°C for 4-6 hours. Centrifuge at 4000rpm for 20min at 4°C to collect the induced cells, resuspend the cells in 15ml of deionized water, and centrifuge at 10,000rpm for 30min to collect the cell pellet. 40mMimidazole, 0.1% TritonX-100 resuspended, sonicated to lyse the bacteria. After e...

Embodiment 2

[0274] The inhibitory effect of the compound of the present invention on the in vitro activity of two kinds of Plasmodium falciparum cell lines:

[0275]Chloroquine is purchased from Sigma Company, and SYBRGreen is purchased from Invitrogen Company, and the Plasmodium falciparum Dd2 cell line of chloroquine-sensitive Plasmodium falciparum Dd2 cell line is used for testing antimalarial activity in vitro, replaces human with 0.5%AlbumaxII (Invitrogen Company) Serum, others were cultured according to the culture method of Trager and Jensen. Both Plasmodium falciparum strains were from MR4 (Malaria Research and Reference Reagent Resource Center) in the United States.

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Abstract

The present invention relates to the synthesis and use of a pentabasic dihydrogen heterocyclic ketone derivative of general formula (I) used as a DHODH inhibitor for Plasmodium falciparum, and the compound related to the present invention can be used for the treatment and prevention of diseases related to DHODH, comprising treatment for parasitic diseases, such as malaria, etc., caused by malaria parasites.

Description

technical field [0001] The invention belongs to the field of malaria treatment, and specifically relates to the synthesis and application of dihydrothiophene derivatives as DHODH inhibitors. Background technique [0002] Malaria (Malaria) is a vector-borne infectious disease caused by the infection of Plasmodium through mosquito bites, and it is still one of the global problems affecting human health. At present, typical drugs for treating malaria include chloroquine, artemisinin, pyrimethamine, etc., which have been marketed. In recent decades, more and more drug resistance problems have arisen in many once very effective drugs, such as quinine, chloroquine, and melquinoline, etc.; Plasmodium is affected by chloroquine, and the nuclear fragmentation of Plasmodium, Vacuoles appeared in the cytoplasm, and malarin aggregated into clumps. Chloroquine does not directly kill the malaria parasite, but it interferes with its reproduction. It has a strong binding force with nucle...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/58C07D333/32A61K31/381A61K31/341A61P33/06A61P37/06A61P37/02A61P19/02A61P17/06A61P29/00A61P13/12
CPCC07D333/38A61K31/341A61K31/381C07D307/68C07D333/76C07D405/12C07D409/12A61P1/00A61P13/12A61P17/06A61P19/02A61P29/00A61P33/06A61P35/00A61P37/00A61P37/02A61P37/06Y02A50/30
Inventor 李洪林赵振江黄瑾徐玉芳许鸣豪刁妍妍周洪昌金黄涛高瑞朱俊生
Owner EAST CHINA UNIV OF SCI & TECH