OXIDANTS AS SITE-SPECIFIC ANTIMALARIALS

这项拟议的研究是针对特定地点的 将氧化剂输送到感染疟疾的红细胞。作为疟疾 寄生虫及其宿主红细胞对 氧化应激，额外的氧化剂对寄生虫/宿主的损害 红细胞系统可能导致寄生虫生命中断。 周而复始。由于氯喹和相关喹啉选择性地 集中在红细胞型的消化液泡中 疟疾寄生虫，由于受感染的红细胞具有 L-异亮氨酸、9种过氧化氢的特异性摄取机制 恶氮杂环和氯喹的“氧化还原”类似物，以及六种过氧化氢 L-异亮氨酸的衍生物被认为是定点氧化剂 抗疟疾药。 目标喹啉氧化剂的拟议合成依赖于 两个关键转变。第一种是曼尼什型凝聚 在仲胺、甲醛和过氧化氢之间；以及 第二个是亚胺的过酸氧化为氧杂环烷。L- 异亮氨酸过氧化物化学法合成 适应氨基酸的。建议的特定部位的氧化剂将 在体外进行抗疟活性评估 恶性疟原虫，以及在体内与约翰博士合作的P.Bergh 伊顿在明尼苏达大学和沃尔特里德陆军 研究所。如果抗疟疾活动的增加或 观察到效力与上述假设状态一致， 然后将与伊顿博士一起进行实验，以评估他们的 受感染的红细胞/寄生虫系统的特异性，以及 确定氧化损伤机理(S)。最后，成立公司 将氧化剂官能团转化为有效对抗其他氧化剂的药物 敏感的原虫可能会导致更好的试剂，并延长 氧化剂特定部位输送的概念。

This proposed research is directed toward the site-specific delivery of oxidants to malaria-infected erythrocytes. As malaria parasites and their host erythrocytes are highly susceptible to oxidant stress, additional oxidant damage to the parasite/host erythrocyte system may lead to an interruption of the parasite life cycle. Since chloroquine and related quinoline are selectively concentrated in the digestive vacuoles of the erythrocytic form of the malarial parasite, and since infected erythrocytes possess a specific uptake mechanism for L-isoleucine, nine peroxide, oxazirane and "redox" analogy of chloroquine, and six peroxide derivatives of L-isoleucine are proposed as site-specific oxidant antimalarial. The proposed syntheses of the target quinoline oxidants rely on two key transformations. The first is a Mannish type condensation between secondary amines, formaldehyde, and hydroperoxides; and the second is the peracid oxidation of imines to oxaranes. The L- isoleucine peroxides will be synthesized using proxide chemistry adapted to amino acids. The proposed site-specific oxidants will be evaluated for antimalarial activity against in vitro P falciparum, and in vivo P. bergh in collaboration with Dr. John Eaton at the University of Minnesota and the Walter Reed Army Institute of Research. If an increase in antimalarial activity or potency is observed consistent with the hypothesis states above, then experiments with Dr. Eaton will be conducted to assess their specificity for the infected erythrocyte/parasite system, and to determine mechanism (s) of oxidant damage. Finally, incorporation of oxidant functionality into drugs effective against other oxidant sensitive protozoa may result in superior agents, and extension of the concept of site-specific delivery of oxidants.