Artemisone -: A highly active antimalarial drug of the artemisinin class
Artemisone -: A highly active antimalarial drug of the artemisinin class
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DOI：
10.1002/anie.200503071
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Römer, A
中科院分区：
文献类型：
--
作者：
Haynes, RK;Fugmann, B;Römer, A
青蒿素是最有效和最迅速的抗疟疾药物。为了应对耐多药疟疾的全球威胁，它们现在被广泛用于与半衰期较长的药物联合治疗亲本青蒿素(1)通过还原转化为二氢青蒿素（DHA, 2）[3]，然后转化为半青蒿素（ATS, 3； DHA产率65%）[3]以DHA、甲醇和酸性催化剂为原料，经分离结晶去除α-外聚体，收率约为60%，得到蒿醚(4)[4]和蒿醚(5)[5]。因此，最容易获得的衍生物是ATS(3)。尽管青蒿素表现出可变的药代动力学和低生物利用度，但这些特性会被寄生红细胞选择性摄取它们诱导I期酶，主要是CYP3A4和CYP2B6，导致疗效的时间依赖性下降此外，青蒿琥酯和醚代谢DHA(2)是容易的。[8,9]根据动物模型bbb的体内实验和神经细胞培养的体外研究，青蒿素，特别是DHA，具有神经毒性。[11-13]虽然在动物实验中，神经毒性取决于给药途径，但尚未确定对人类也会产生问题然而，从监管的角度来看，这是一个有争议的问题，开发新的青蒿素疗法必须考虑到这一点。尽管付出了巨大的努力，但没有新的青蒿素衍生物达到开发状态。10-烷基氨基青蒿素6 （R ' = H，烷基；R " =烷基；R ', R " =环烷基）是一类青蒿素，其制备所涉及的化学性质与产生其他衍生物的化学性质不同，其功效范围超出了已知的青蒿素。[16,17]任何这类化合物要开发成新药，其生产成本必须与ATS相当(3)，除非在允许相应增加成本的情况下获得更大的疗效。由于青蒿素与其可能的靶点PfATP6 Ca2+泵的相互作用尚不清楚[19,20]，“合理设计”方法是不可能的，必须强调改善全身行为。虽然这取决于许多因素，但通过logP参数（P =）评估，[21]的水溶性增强到一个极限值，而亲脂性衰减
The artemisinins are the most potent and rapidly acting antimalarial drugs. In response to the global threat of multidrug-resistant malaria, they are now widely used in combination therapies with drugs that have a longer half life.[1] The parent, artemisinin (1), is converted by reduction into dihydroartemisinin (DHA, 2)[2] and then into the hemiester artesunate (ATS, 3; 65% yield from DHA).[3] Artemether (4)[4] and arteether (5)[5] are obtained from DHA, methanol, and an acid catalyst in about 60% yield after fractional crystallization to remove the α-epimers. Therefore, the most accessible derivative is ATS (3). Although artemisinins display variable pharmacokinetics and low bioavailability,[6] such properties are countered by selective uptake into parasitized erythrocytes.[7] Their induction of phase I enzymes, primarily CYP3A4 and CYP2B6, leads to a timedependent decrease in efficacy.[8] Additionally, metabolism of artesunate and the ethers to DHA (2) is facile.[8, 9] The artemisinins, especially DHA, are neurotoxic according to in vivo assays with animal models [10] and in vitro studies with neuronal cell cultures.[11–13] Although neurotoxicity is dependent upon the route of administration in animal screens,[14] it has not yet been definitively established to be a problem in humans.[15] From a regulatory viewpoint, however, it is a contentious issue, and the development of new artemisinin therapies must be conducted with this in mind. Despite an immense effort, no new artemisinin derivative has reached development status. 10-Alkylaminoartemisinins 6 (R’= H, alkyl; R’’= alkyl; R’, R’’= cycloalkyl) are an artemisinin class whose preparation entails chemistry distinct to that leading to other derivatives and which extends the efficacy limit beyond those of the known artemisinins.[16, 17] For any such compound to be developed into a new drug, the production cost must be comparable to that of ATS (3),[18] unless a greater efficacy is obtained when a commensurate increase in cost is permitted. As the interaction of artemisinins with their likely target, the PfATP6 Ca2+ pump, is still unclear,[19, 20] a “rational design” approach is not possible and emphasis must be placed on improving systemic behavior. Whilst this depends upon a number of factors,[21] an enhancement of aqueous solubility to a limiting value and attenuation of lipophilicity as assessed through the logP parameter (P is