BIS(BENZYL)POLYAMINE ANALOGS INHIBIT THE GROWTH OF CHLOROQUINE-RESISTANT HUMAN MALARIA PARASITES (PLASMODIUM-FALCIPARUM) INVITRO AND IN COMBINATION WITH ALPHA-DIFLUOROMETHYLORNITHINE CURE MURINE MALARIA
BIS(BENZYL)POLYAMINE ANALOGS INHIBIT THE GROWTH OF CHLOROQUINE-RESISTANT HUMAN MALARIA PARASITES (PLASMODIUM-FALCIPARUM) INVITRO AND IN COMBINATION WITH ALPHA-DIFLUOROMETHYLORNITHINE CURE MURINE MALARIA
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DOI：
10.1073/pnas.86.2.651
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发表时间：
1989-01-01
影响因子：
11.1
通讯作者：
SJOERDSMA, A
中科院分区：
文献类型：
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作者：
BITONTI, AJ;DUMONT, JA;SJOERDSMA, A
发现许多双(苄基)多胺类似物在体外是人疟疾寄生虫恶性疟原虫的氯喹抗性菌株和氯喹敏感性菌株的有效抑制剂(IC 50 值＝0.2-14μM)。以10-15 mg/kg i.p.施用化合物之一MDL 27695，其为N,N''-双{3-[(苯基甲基)氨基]丙基}-1,7-二氨基庚烷(C6H5CH2NH(CH2)73NH(CH2)3NH(CH2)3NHCH2C6H5)。每天三次，持续3天，与饮用水中的2％α-二氟甲基鸟氨酸(DFMO；依氟鸟氨酸)组合，对47/54只感染伯氏疟原虫的小鼠进行了治愈。在初次感染和药物诱导治愈后 4 个月，用相同的伯氏疟原虫菌株再次攻击时，发现治愈的小鼠具有免疫力。 MDL 27695 迅速抑制[3H]次黄嘌呤掺入恶性疟原虫RNA和DNA中，而[3H]异亮氨酸的掺入直到很久以后才受到影响。因此，我们得出结论，主要的细胞毒性事件可能是 MDL 27695 与 DNA 直接结合，随后破坏大分子生物合成和细胞死亡。这些化合物为寻找新的疟疾化疗药物提供了先导。
A number of bis(benzyl)polyamine analogs were found to be potent inhibitors of both chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodium falciparum in vitro (IC50 values = 0.2-14 .mu.M). Administration of one of the compounds, MDL 27695, which is N,N''-bis{3-[(phenylmethyl)amino]propyl}-1,7-diaminoheptane (C6H5CH2NH(CH2)73NH(CH2)3NH(CH2)3NHCH2C6H5), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% .alpha.-difluoromethylornithine (DFMO; eflornithine) in drinking water effected cures of 47/54 mice infected with Plasmodium berghei. Cured mice were found to be immune upon rechallenge with the same P. berghei strain 4 months after the initial infection and drug-induced cure. MDL 27695 rapidly inhibited the incorporation of [3H]hypoxanthine into P. falciparum RNA and DNA, whereas the incorporation of [3H]isoleucine was not affected until much later. We conclude, therefore, that the major cytotoxic event may be direct binding of MDL 27695 to DNA with subsequent disruption of macromolecular biosynthesis and cell death. These compounds offer a lead in the search for new agents for chemotherapy of malaria.