MALARIA CHEMOTHERAPY AND CHEMOPREVENTION

在传染病中，疟疾在世界许多地区很常见。 奎宁和氯喹等标准生物碱越来越少， 效果较差，因为疟疾寄生虫正在对这种 毒品。因此，迫切需要发展 用于治疗的抗疟疾疫苗和新的抗疟疾非生物碱药物 这一日益普遍的国际卫生问题。使用有限的 现在已经用完了约翰·霍普金斯大学的资金，我们设计，准备， 并测试了临床上使用的各种简单的结构类似物 中药1，2，4-三氧六环青蒿素(青蒿素)我们的两个轻而易举 制备的三氧六环已在体外和最近也在体内被证明 (啮齿动物和猿猴)在清除寄生虫血症方面比乙醚更快。 并对其作用的分子机制进行了探讨。 相对较新的一类抗疟疾三氧六环药物；这种机制 研究使我们能够发现以碳为中心的自由基 中间体可能是这类三氧六环抗疟疾活性的中间体。 我们建议在这里使用这种对分子机制的新理解 对结构修改进行设计、准备和评估的行动 以碳为中心的自由基中间体将是三氧六环 病情稳定，导致更高的抗疟疾活性。我们还提议 在我们最好的三氧六环的基础上制备第二代药物 (即苄基醚和磷酸酯) 药用有益的氟原子或碱性氮原子，其 可以季节化形成一种水溶性的，因此作用更快 铵盐。研究还将包括放射性标记的三氧六环以及 氯化血红素-三氧六环加合物。这项研究计划很可能会产生 用于有效化疗的有意义和实用的三氧六环新药 疟疾。这更具投机性，因此也更具风险 该提案通过打破疟疾化学预防的循环 疟疾通过预期的疟原虫配子体杀伤力传播 我们的三氧六环的活性，类似于青蒿素。 作为药物化学家，我们处于一个独特的地位，可以做出基本的 分子寄生虫学的研究进展，特别是关于其机制的研究 易于制备和相对较好的药物的作用和改善的治疗方面 廉价的三氧杂环类新药。

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.