Laboratory of Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
Bioorg Med Chem. 2009 Oct 15;17(20):7209-17. doi: 10.1016/j.bmc.2009.08.057. Epub 2009 Sep 3.
Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.
基于作为新型抗疟药物先导化合物的 indoloquinoline 生物碱 cryptolepine（1）、neocryptolepine（2）、isocryptolepine（3）和 isoneocryptolepine（4），我们合成了一系列三环和双环类似物，包括咔啉、氮杂吲哚、吡咯并喹啉和吡咯并异喹啉，并对它们进行了生物评价。与三环衍生物相比，双环化合物对氯喹抗性疟原虫 Plasmodium falciparum K1 没有明显的活性。三环化合物 2-甲基-2H-吡啶并[3,4-b]吲哚（9）或 2-甲基-β-咔啉表现出最好的体外活性，对 P. falciparum K1 的 IC50 值为 0.45μM，对 L6 细胞没有明显的细胞毒性（SI>1000）。然而，该化合物在伯氏疟原虫小鼠模型中没有活性。讨论了构效关系，并与相关的天然存在的化合物进行了比较。
