Incorporation of Basic Side Chains into Cryptolepine Scaffold: Structure−Antimalarial Activity Relationships and Mechanistic Studies
| Autor: | Daniel J. V. A. dos Santos, Philip J. Rosenthal, Kenneth T. Douglas, Alexandra Paulo, João Lavrado, Rui Moreira, Jiri Gut, Ghislain G. Cabal, Maria M. Mota, Elena V. Bichenkova, Rita C. Guedes, Cecilia Díaz, Miguel Prudêncio |
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| Rok vydání: | 2011 |
| Předmět: |
Erythrocytes
Stereochemistry Plasmodium falciparum Drug Resistance Oligonucleotides Vacuole Cysteine Proteinase Inhibitors Indole Alkaloids Antimalarials Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Chlorocebus aethiops Drug Discovery Side chain Animals Humans Structure–activity relationship Cytotoxicity Vero Cells biology Chemistry Oligonucleotide Chloroquine DNA biology.organism_classification Mefloquine Cysteine Endopeptidases Pyrimethamine Biochemistry Cryptolepine Quinolines Hemin Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 54:734-750 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm101383f |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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