Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether
Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether
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DOI：
10.1021/jm9903545
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发表时间：
1999-12-30
影响因子：
7.3
通讯作者：
Park, BK
中科院分区：
文献类型：
--
作者：
O'Neill, PM;Searle, NL;Park, BK
设计和合成了10种新型的第二代氟醚和酯类似物，它们是第一代强效类似物蒿甲醚（4a）和蒿甲醚（4b）。所有化合物在体外对氯喹敏感的HB3和耐药的恶性疟原虫K1株显示出很高的抗疟效力。最有效的衍生物8对恶性疟原虫HB3株的效力是青蒿素(2)的15倍。在体内，与小鼠体内的伯氏疟原虫相比，所选衍生物的效力通常低于双氢青蒿素，ED50值在5至8 mg/kg之间。从体外仿生Fe（II）介导的8分解得到的产物来看，该系列生物活性的自由基介质可能不同于母体药物青蒿素(2)。
Ten novel, second-generation, fluorinated ether and ester analogues of the potent first-generation analogues artemether (4a) and arteether (4b) have been designed and synthesized. All of the compounds demonstrate high antimalarial potency in vitro against the chloroquine-sensitive HB3 and -resistant K1 strains of Plasmodium falciparum. The most potent derivative 8 was 15 times more potent than artemisinin (2) against the HB3 strain of P. falciparum. In vivo, versus Plasmodium berghei in the mouse, selected derivatives were generally less potent than dihydroartemisinin with ED50 values of between 5 and 8 mg/kg. On the basis of the products obtained from the in vitro biomimetic Fe(II)-mediated decomposition of 8, the radical mediator of biological activity of this series may be different from that of the parent drug, artemisinin (2).