Incorporation of Basic Side Chains into Cryptolepine Scaffold: Structure鈭扐ntimalarial Activity Relationships and Mechanistic Studies

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• 作者：Joa虄o Lavrado ; Ghislain G. Cabal ; Miguel Prude虃ncio ; Maria M. Mota ; Jiri Gut ; Philip J. Rosenthal ; Ceci虂lia Di虂az ; Rita C. Guedes ; Daniel J. V. A. dos Santos ; Elena Bichenkova ; Kenneth T. Douglas ; Rui Moreira ; Alexandra Paulo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 10, 2011
• 年：2011
• 卷：54
• 期：3
• 页码：734-750
• 全文大小：1230K
• 年卷期：v.54,no.3(February 10, 2011)
• ISSN：1520-4804

文摘

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.