Antimalarial activities and therapeutic properties of febrifugine analogs
Antimalarial activities and therapeutic properties of febrifugine analogs
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DOI：
10.1128/aac.49.3.1169-1176.2005
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发表时间：
2005-03-01
影响因子：
4.9
通讯作者：
Fang, DH
中科院分区：
文献类型：
--
作者：
Jiang, SP;Zeng, Q;Fang, DH
常山碱（Febrifugine）是50年前从中药常山（Dichroafebrifuga Lour）中分离出的有效成分，在中国传统医学中作为抗疟药已有2,000多年的历史。然而，由于其副作用，对febrifugine性质的深入研究已经阻碍了几十年。我们报道了新的发现，与从D.退烧药提取的常山碱的性质与我们的合作者提供的标准常山碱的性质相当。沃尔特里德化学信息系统的基于febrifugine结构的计算机搜索确定了10种体外抑制寄生虫生长的类似物，50%抑制浓度范围为0.141至290 ng/ml。宿主巨噬细胞（J744细胞）对常山碱类似物的敏感性比寄生虫低50至100倍。神经元（NG 108）细胞对这些药物甚至更不敏感（选择性指数，> 1，000），表明可以建立用于人类的可行治疗指数。类似物，特别是常山酮，显着减少寄生虫血症到无法检测的水平，并显示在疟原虫感染的小鼠的疗效。在用常山碱类似物治疗后，寄生虫的复发是导致接受有效剂量的组中的大多数小鼠死亡的关键因素。当用抗疟剂量范围内的剂量处理动物时，用类似物进行皮下处理不会引起胃肠道刺激。总之，这些类似物似乎是有前途的先导抗疟化合物，需要深入研究以优化进一步的向下选择和开发。
Febrifugine is the active principal isolated 50 years ago from the Chinese herb chang shan (Dichroa febrifuga Lour), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side effects. We report new findings on the effects of febrifugine analogs compared with those of febrifugine extracted from the dry roots of D. febrifuga. The properties of the extracted febrifugine were comparable to those obtained from the standard febrifugine provided by our collaborators. A febrifugine structure-based computer search of the Walter Reed Chemical Information System identified 10 analogs that inhibited parasite growth in vitro, with 50% inhibitory concentrations ranging from 0.141 to 290 ng/ml. The host macrophages (J744 cells) were 50 to 100 times less sensitive to the febrifugine analogs than the parasites. Neuronal (NG108) cells were even more insensitive to these drugs (selectivity indices, >1,000), indicating that a feasible therapeutic index for humans could be established. The analogs, particularly halofuginone, notably reduced parasitemias to undetectable levels and displayed curative effects in Plasmodium berghei-infected mice. Recrudescence of the parasites after treatment with the febrifugine analogs was the key factor that caused the death of most of the mice in groups receiving an effective dose. Subcutaneous treatments with the analogs did not cause irritation of the gastrointestinal tract when the animals were treated with doses within the antimalarial dose range. In summary, these analogs appear to be promising lead antimalarial compounds that require intensive study for optimization for further down-selection and development.