Halogenated Xanthones as Antimalarial Agents

作为抗疟剂的卤代氧杂蒽酮

• 批准号: 6983451
• 负责人: Michael Kevin RISCOE
• 金额: $ 34.67万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983451
• 关键词: Halogenated; Xanthones; Antimalarial; Agents

DESCRIPTION (provided by the applicant): We have already published our discovery that xanthones exhibit potent antimalarial activity, even against multi-drug resistant strains of Plasmodium falciparum. Based on our understanding of xanthone mode of action, we have developed a 2nd generation xanthone, 3,6-bis-omega-diethylaminoamyloxyxanthone (C5). C5 is approximately as potent as chloroquine, yet with equal activity against a panel of drug resistant strains. Herein, we propose to develop the 3 rd generation of xanthone anti-malarials, with a long-term view toward clinical trials. The steps toward this goal are: . Evaluate the in vivo efficacy of existing xanthone analogs. This will be investigated in the P. v. vinckei murine model of malaria. The possibility for acute toxicity of xanthones will be investigated in uninfected mice. . Evaluate the in vitro metabolism of C5 by microsomes. This will be investigated with both human and murine derived microsomes. . Optimize the drug structure beginning with C5 for both safety and antimalarial potency. This will be done in a process iterative between in vitro and in vivo testing, molecular modeling, pharmacokinetics, and spectroscopic evidence. . Synthesis and evaluation of 3rd generation compounds. The hallmark of these 3 rd generation xanthones will be improved safety and antimalarial potency. The 3 rd generation compounds will be inexpensive to produce, chemically and metabolically stable, and orally bioavailable. The mode of action of these xanthone-based antimalarial agents is inhibition of hemozoin formation via complexation of heme. Since heme is an immutable biomolecule, it is difficult to envision any simple mutation that could lead to resistance.

描述（由申请人提供）：我们已经发表了我们的发现，即山酮类药物具有有效的抗疟疾活性，甚至可以对抗多重耐药的恶性疟原虫菌株。基于我们对口山酮作用方式的了解，我们开发了第二代口山酮，3,6-双- - - - -二乙基氨基淀粉基口山酮（C5）。C5的效力与氯喹大致相当，但对一组耐药菌株具有相同的活性。为此，我们拟开发第三代克山酮类抗疟疾药物，并以临床试验为长期目标。实现这一目标的步骤是：

项目成果

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye.

通过苄基噻唑鎓染料选择性杀死人类疟原虫恶性疟原虫。

• DOI: 10.1016/j.exppara.2006.12.001
• 发表时间: 2007
• 期刊: Experimental parasitology
• 影响因子: 2.1
• 作者: Kelly,JaneX;Winter,RolfW;Braun,TheodoreP;Osei-Agyemang,Myralyn;Hinrichs,DavidJ;Riscoe,MichaelK
• 通讯作者: Riscoe,MichaelK