MALARIA CHEMOTHERAPY AND CHEMOPREVENTION

在传染病中，疟疾在世界许多地方很常见。 标准生物碱如奎宁和氯喹越来越少， 因为疟疾寄生虫正在产生抗药性， 毒品因此，迫切需要发展 抗疟疫苗和新的抗疟非杀疟药物， 这一日益普遍的国际健康问题。有限的 现在已经用完了来自约翰霍普金斯的资金，我们已经设计，准备， 并测试了临床上使用的各种简单的结构类似物， 中国1，2，4-三恶烷药物青蒿素。我们的两个容易 制备的三恶烷已经在体外和最近也在体内显示 （啮齿动物和猿猴）在清除寄生虫血症方面比蒿乙醚更快。 本文还探讨了其作用的分子机制 相对较新的一类抗疟疾三恶烷药物;这种机制 研究使我们能够发现碳中心的自由基 中间体可能是这类三恶烷的抗疟活性。 我们建议在这里使用这种新的理解的分子机制， 采取行动，设计、准备和评估结构修改 三恶烷，其中碳中心的自由基中间体将 稳定，导致更高的抗疟疾活性。我们还建议， 制备第二代药物，改进我们最好的三恶烷 (i.e.苄基醚和磷酸酯醚）， 有利的氟原子或碱性氮原子， 可以季铵化形成水溶性的， 铵盐研究还将包括放射性标记的三恶烷以及 氯化血红素-三恶烷加合物。这项研究计划可能会产生 具有重要意义和实用价值的三恶烷类新药 疟疾一个更具投机性，因此风险更大的方面， 建议通过打破恶性循环来解决疟疾化学预防问题， 疟疾通过预期的杀疟原虫配子体传播 我们的三恶烷的活性，与青蒿素类似。 作为药物化学家，我们处于独特的地位，可以使基础 分子寄生虫学进展，特别是关于 作用和改善的治疗方面， 廉价的三恶烷新药

Among infectious diseases, malaria is common in many parts of the world. Standard alkaloids such as quinine and chloroquine are becoming less and less effective because malaria parasites are developing resistance to such drugs. There is a critical and urgent need, therefore, for development of antimalarial vaccines and new antimalarial non-alkaloidal drugs to treat this increasingly widespread international health problem. With limited and now used-up funding from Johns Hopkins, we have designed, prepared, and had tested various simple structural analogs of the clinically used Chinese 1,2,4-trioxane drug artemisinin (qinghaosu). Two of our easily prepared trioxanes have been shown in vitro and very recently also in vivo (rodents and simians) to be faster than arteether in clearing parasitemia. We have also probed into the molecular mechanism of action of this relatively new class of antimalarial trioxane drugs; such mechanistic studies have enabled us to discover that carbon-centered radical intermediates are likely for the antimalarial activity of such trioxanes. We propose here to use this new understanding of molecular mechanism of action to design, prepare and have evaluated structurally modified trioxanes in which carbon-centered radical intermediates will be stabilized, leading to higher antimalarial activity. We propose also to prepare second-generation drugs improving on the best of our trioxanes (i.e. benzyl ethers and phosphate ethers) by incorporating a pharmacologically beneficial fluorine atom or a basic nitrogen atom that can be quaternized to form a water-soluble and therefore faster acting ammonium salt. Studies will include also radiolabeled trioxanes as well as hemin-trioxane adducts. This research program is likely to produce significant and practical new trioxane drugs for effective chemotherapy of malaria. A more speculative and therefore more risky aspect of this proposal addresses malaria chemoprevention by breaking the cycle of malaria transmission via the anticipated Plasmodium gametocytocidal activity of our trioxanes, in analogy with artemisinin. As medicinal chemists, we are in a unique position to make fundamental advances in molecular parasitology specifically concerning mechanism of action and improved therapeutic aspects of easily prepared and relatively inexpensive new trioxane drugs.