Chemical Investigation of Antimalarial Compounds from Marine Organisms

海洋生物抗疟化合物的化学研究

基本信息

批准号：
11672107
负责人：
HIGA Tatsuo
金额：
$ 2.3万
依托单位：
University of the Ryukyus
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672107/
关键词：
Antimalarial drugs Marine Natural Products Manzamines マンザミンA マラリア海綿

项目摘要

Malaria is one of the most important infectious diseases. It is estimated to inflict more than 300 million people and to kill some two million people a year in the world. Chemotherapy is still the most effective method of treatment of the disease. However, because of the emergence of resistant parasites against the most frequently used drugs such as chloroquine, it is necessary to develop new effective and safe drugs. In this project we have screened in collaboration with Dr. A.U.Kara more than 100 compounds isolated from marine organisms. The screening was an in vivo test using mice infected with the rodent malaria parasite Plasmodiun berghei. Drugs of the doses ranging from 50 to 1000 μM/kg were injected to the mice on day 2 of postinfection and recorded the days and numbers of surviving mice. As a result manzamine A, a complex alkaloid from a sponge, was shown to be most effective antimalarial. Efficacy of manzamine A was compared with artemisinin and chloroquine. Manzamine A at a single dose of 100 μM/kg gave the best result with 40% recovery, survival of two out of five mice for 60 days postinfection. Artemisinin gave 20% recovery at a dose of 1000 μM/kg, while the treatment with chloroquine gave no recovery, all mice died by day 10. In order to examine structure activity relationship of the manzamine alkaloids, we have prepared Several derivatives of manzamine A.They were similarly tested together with 8-hydroxymanzamine A and manzamine F which have also been isolated from sponges. Only 8-hydroxymanzamine A showed some efficacy, but all others were not active. The result suggested that the complex framework of manzamine A would be important for the activity. Further work is needed to clarify the structure activity relationship and mechanism of the action of manzamine A.

疟疾是最重要的传染病之一，据估计，全世界每年有超过 3 亿人罹患疟疾，并导致约 200 万人死亡。然而，化疗仍然是治疗该疾病的最有效方法。由于出现了对氯喹等最常用药物产生抗药性的寄生虫，因此有必要开发新的有效且安全的药物。在该项目中，我们与 A.U.Kara 博士合作筛选了从其中分离出的 100 多种化合物。筛选是使用感染啮齿动物疟原虫伯氏疟原虫的小鼠进行的体内试验，在感染后第2天向小鼠注射50至1000μM/kg的药物，并记录感染的天数和数量。结果表明，曼扎明 A（一种来自海绵的复杂生物碱）是最有效的抗疟药。青蒿素和氯喹 A 单剂量 100 μM/kg 的恢复率最高，为 40%；感染后 60 天，五分之二的小鼠存活率为 1000 μM/kg。而氯喹治疗没有恢复，所有小鼠在第 10 天就死亡。为了检查曼扎明的结构活性关系我们制备了几种曼扎明A的衍生物。它们通常与也从海绵中分离出来的8-羟基曼扎明A和曼扎明F一起进行测试，结果只有8-羟基曼扎明A表现出一定的功效，但其他的都没有活性。表明曼扎明 A 的复杂框架对该活性很重要，需要进一步的工作来阐明曼扎明 A 的结构活性关系和作用机制。