Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon. Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
J Med Chem. 2011 Feb 10;54(3):734-50. doi: 10.1021/jm101383f. Epub 2011 Jan 5.
The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.
报道了含碱性侧链的隐卡林衍生物的合成及其抗疟原虫和细胞毒性评价。与母体化合物相比，丙基、丁基和环烷基二胺侧链显著提高了对耐氯喹恶性疟原虫株的活性，同时降低了细胞毒性。通过荧光显微镜进行的寄生虫血期定位研究表明，这些衍生物在细胞核内积累，表明引入碱性侧链不足以促进在寄生虫酸性消化泡中的选择性积累。该系列中的大多数化合物都显示出与双链 DNA 双链以及单体血红素结合的能力，这表明这些可能是与观察到的抗疟活性相关的潜在靶标。总的来说，这些具有显著改善的抗疟原虫活性和选择性指数的新型隐卡林类似物为开发针对耐药疟原虫的有效且高度选择性药物提供了有希望的起点。
