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Studies on molecular mechanism of action and synthesis of new derivatives of the antimalarial drug artemisinin.

机译：研究抗疟药物青蒿素的分子作用机理和新衍生物的合成。

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摘要

The thesis commences with an overview of the history and development of the Chinese peroxidic sesquiterpene qinghaosu or artemisinin, and its conversion into the current derivatives artemether and artesunate which are used in the chemotherapy of malaria. Whilst the efficacy of these compounds for treatment of malaria are not in doubt, an enormous amount of research has been conducted on the chemical basis for the mode of action of these compounds for killing the malaria parasite. Because of the necessity of the presence of the peroxide as the active pharmacophore, a large amount of ad hoc experimentation has led to the growth of the carbon-centred radical theory for parasiticidal activity, in which a Fenton-type reaction generates O-centred, and then C-centred radicals by abstraction of hydrogen atoms from the periphery of the molecule by the O-centred radical. Two agents have been held responsible for generating these species from the artemisinin derivative, namely the free ferrous iron, or ferrous iron complexed in haem.; In this thesis, we examine the effect of these agents, and of thiols both on known and new artemisinin derivatives which were prepared as part of a programme under support from Bayer AG for the development of new antimalarials. The new derivatives, which have been shown in other work to be extremely active against the malaria parasite both in vitro and in vivo, were therefore screened against thiols, and ferrous iron, both in the free state, and in ferrous haem. Thiols were also tested in the presence of ferrous iron. Several reactions involving the oxophilic Lewis acid trimethylsilyl trifluoromethane sulfonate in the presence of thiols were also carried out. In addition, a UV-VIS spectrophotometric examination of the behaviour of the artemisinin derivatives against desferrioxamine and ferrioxamine was also carried out, in order to establish how these reagents inhibit the activity of artemisinin in vitro.; Whilst many of the results obtained are relatively inconclusive, they do indicate that the new artemisinin derivatives react sluggishly with ferrous sulfate in aqueous acetonitrile at room temperature. In addition, whereas the known derivative 10-deoxoartemisinin is relatively easily decomposed under the foregoing conditions, it is unaffected by ferrous haem in aqueous acetonitrile.; In the second part of the thesis, a new straightforward phase transfer method is disclosed which enables new and known aminoaryl and O-aryl derivatives of dihydroartemisinin to be prepared in an extremely straightforward fashion. (Abstract shortened by UMI.)
机译：本文首先概述了中国过氧化物倍半萜清蒿素或青蒿素的历史和发展，并将其转化为目前用于疟疾化学治疗的蒿甲醚和青蒿琥酯衍生物。尽管毫无疑问这些化合物治疗疟疾的功效，但是已经在化学基础上对这些化合物杀死疟原虫的作用方式进行了大量研究。由于必须使用过氧化物作为活性药效基团，因此大量的临时实验导致了以碳为中心的自由基理论对杀虫活性的发展，在该理论中，芬顿型反应产生了以O为中心的活性，然后通过以O为中心的自由基从分子的外围提取氢原子，以C为中心的自由基。两种试剂被认为是由青蒿素衍生物产生这些物质的原因，即游离亚铁或在血红素中络合的亚铁。在本文中，我们研究了这些试剂以及硫醇对已知和新青蒿素衍生物的影响，这些衍生物是在拜耳公司支持下开发新抗疟药的计划的一部分。因此，在其他工作中显示出的新衍生物在体外和体内对疟疾寄生虫都具有极高的活性，因此，在游离状态和亚铁血红素中都筛选了针对硫醇和亚铁的筛选。还在亚铁存在下测试了硫醇。在硫醇的存在下，还进行了一些涉及亲氧路易斯酸三甲基甲硅烷基三氟甲烷磺酸盐的反应。另外，还进行了紫外-可见分光光度法检查青蒿素衍生物对去铁胺和亚铁胺的行为，以确定这些试剂如何在体外抑制青蒿素的活性。尽管获得的许多结果相对不确定，但它们确实表明新的青蒿素衍生物在室温下与乙二酸在亚乙基水溶液中反应缓慢。另外，虽然已知的衍生物10-脱氧青蒿素在上述条件下相对容易分解，但不受乙腈水溶液中亚铁血红素的影响。在论文的第二部分中，公开了一种新的直接相转移方法，该方法能够以极其简单的方式制备新的和已知的二氢青蒿素的氨基芳基和O-芳基衍生物。 （摘要由UMI缩短。）

著录项

  • 作者

    Ho, Wing Yan.;

  • 作者单位

    Hong Kong University of Science and Technology (People's Republic of China).;

  • 授予单位 Hong Kong University of Science and Technology (People's Republic of China).;
  • 学科 Chemistry Pharmaceutical.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 348 p.
  • 总页数 348
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药物化学;药理学;
  • 关键词

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