OXIDANTS AS SITE-SPECIFIC ANTIMALARIALS

氧化剂作为特定部位的抗疟药

基本信息

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
项目类别：
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

项目摘要

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.

这项拟议的研究针对特定地点向感染疟疾的红细胞输送氧化剂。作为疟疾寄生虫及其宿主红细胞对感染高度敏感氧化应激，对寄生虫/宿主的额外氧化损伤红细胞系统可能会导致寄生虫生命的中断循环。由于氯喹和相关喹啉具有选择性集中在红细胞形式的消化液泡中疟疾寄生虫，并且由于受感染的红细胞具有 L-异亮氨酸、九过氧化物、氧氮杂环和氯喹的“氧化还原”类比，以及六过氧化物 L-异亮氨酸衍生物被提议作为位点特异性氧化剂抗疟药。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结仲胺、甲醛和氢过氧化物之间；和第二个是亚胺过酸氧化为氧杂环己烷。 L- 异亮氨酸过氧化物将使用丙氧化物化学合成适应氨基酸。所提出的位点特异性氧化剂将评估体外抗疟活性恶性疟原虫，以及体内 P. bergh 与 John 博士合作明尼苏达大学伊顿分校和沃尔特里德陆军研究所。如果抗疟活性增加或观察到的效力与上述假设一致，然后将与伊顿博士进行实验来评估他们的受感染的红细胞/寄生虫系统的特异性，并确定氧化损伤的机制。最后，合并将氧化剂功能转化为有效对抗其他氧化剂的药物敏感的原生动物可能会产生更好的药物，并延长氧化剂位点特异性递送的概念。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria.

双喹啉类。

DOI：
10.1021/jm00089a025
发表时间：
1992-05-01
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
J. Vennerstrom;W. Ellis;W. Ellis;W. Ellis;A. Ager;A. Ager;A. Ager;Steven L. Andersen;Steven L. Andersen;Steven L. Andersen;L. Gerena;L. Gerena;L. Gerena;W. Milhous;W. Milhous;W. Milhous
通讯作者：
W. Milhous

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

通过选定的氨基甲酸酯和有机磷酸酯杀虫剂以及西维因同系物，抑制白细胞介素 2 驱动的小鼠 CTLL2 细胞增殖。

DOI：
10.3109/08923979309025994
发表时间：
1993-09-14
期刊：
Immunopharmacology and immunotoxicology
影响因子：
3.3
作者：
G. Casale;J. Vennerstrom;S. Bavari;Tian Lan Wang
通讯作者：
Tian Lan Wang

Bisquinolines. 2. Antimalarial N,N-bis(7-chloroquinolin-4-yl)heteroalkanediamines.

双喹啉类。

DOI：
10.1021/jm9803828
发表时间：
1998-09-25
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
J. Vennerstrom;A. Ager;A. Dorn;S. L. Andersen;L. Gerena;R. Ridley;W. Milhous
通讯作者：
W. Milhous

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。