OXIDANTS AS SITE-SPECIFIC ANTIMALARIALS

氧化剂作为特定部位的抗疟药

• 批准号: 3436754
• 负责人: Jonathan L Vennerstrom
• 金额: $ 10.08万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3436754
• 关键词: Plasmodium berghei; Plasmodium falciparum; amines; antimalarial agents; chemical condensation; chloroquine; drug delivery systems; drug design /synthesis /production; erythrocytes; formaldehyde; hydrogen peroxide; imides; intracellular parasitism; isoleucine; laboratory mouse; malaria; oxidation; oxidizing agents; peroxides

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.

本研究针对特定地点 将氧化剂输送到感染疟疾的红细胞。 疟疾 寄生虫及其宿主红细胞对 氧化应激，对寄生虫/宿主的额外氧化损伤 红细胞系统可能导致寄生虫生命的中断 周期 由于氯喹和相关的喹啉被选择性地 集中在红细胞形式的消化泡中， 由于感染的红细胞具有 L-异亮氨酸、9种过氧化物 氧氮杂环丙烷和“氧化还原”类似的氯喹，和六个过氧化物 L-异亮氨酸的衍生物被提议作为位点特异性氧化剂 抗疟药 所提出的目标喹啉氧化剂的合成依赖于 两个关键的转变。 第一种是曼尼斯型凝结 仲胺、甲醛和氢过氧化物之间;以及 二是亚胺的过酸氧化为恶烷。 L- 异亮氨酸过氧化物将使用亲氧化物化学合成 适应于氨基酸。 建议的特定地点氧化剂将 评价抗疟活性对体外P 恶性疟原虫，以及体内P. bergh与John博士合作 明尼苏达大学的伊顿和沃尔特里德陆军 研究所。 如果抗疟疾活性的增加或 观察到的效力与上述假设一致， 然后伊顿博士将进行实验，以评估他们的 对感染的红细胞/寄生虫系统的特异性，以及 确定氧化损伤的机制。 最后，合并 将氧化剂功能转化为对其他氧化剂有效的药物 敏感的原生动物可能会导致上级代理商，并扩展 氧化剂定点输送的概念。

项目成果

Inhibition of interleukin 2 driven proliferation of mouse CTLL2 cells, by selected carbamate and organophosphate insecticides and congeners of carbaryl.

• DOI: 10.3109/08923979309025994
• 发表时间: 1993
• 期刊: Immunopharmacology and immunotoxicology
• 影响因子: 3.3
• 作者: G. Casale;J. Vennerstrom;S. Bavari;Tian Lan Wang

Dispiro-1,2,4,5-tetraoxanes: a new class of antimalarial peroxides.

Dispiro-1,2,4,5-四恶烷：一类新型抗疟过氧化物。

• DOI: 10.1021/jm00094a015
• 发表时间: 1992
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Vennerstrom,JL;Fu,HN;Ellis,WY;AgerJr,AL;Wood,JK;Andersen,SL;Gerena,L;Milhous,WK
• 通讯作者: Milhous,WK