Avery Mitchell A, Muraleedharan Kannoth M, Desai Prashant V, Bandyopadhyaya Achintya K, Furtado Marise M, Tekwani Babu L
Department of Medicinal Chemistry, School of Pharmacy, National Center for Natural Products Research, University of Mississippi, Mississippi 38677, USA.
J Med Chem. 2003 Sep 25;46(20):4244-58. doi: 10.1021/jm030181q.
Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.
青蒿素（1）及其类似物因其抗疟活性已得到充分研究。在此，我们展示了一些以青蒿烯为关键中间体合成的新型C-9修饰青蒿素类似物的抗疟活性。此外，首次描述了70多种青蒿素衍生物对杜氏利什曼原虫前鞭毛体的抗利什曼活性。讨论了使用比较分子场分析法（CoMFA）进行的全面构效关系研究。这些类似物在微摩尔浓度下表现出杀利什曼活性，总体活性谱似乎与抗疟活性相似。结果表明，在C-9β位进行取代可提高两种情况下的活性。与相应的内酯相比，10-脱氧衍生物表现出更好的活性。一般来说，与相应的C-9β类似物相比，具有C-9α取代的化合物表现出较低的抗疟和抗利什曼活性。从1-脱氧青蒿素类似物不表现出抗利什曼活性这一事实可以明显看出，过氧化物基团对于这些类似物对利什曼原虫的观察活性至关重要。该研究表明开发青蒿素类似物作为抗疟疾和利什曼病潜在候选药物的可能性。
