engleski

Design and synthesis of harmicines, potential antimalarial agents.

Malaria is a deadly mosquito-borne tropical and subtropical disease, caused by parazite of the genus Plasmodium. The most severe form of the disease is caused by P. falciparum. There is neither available vaccine for malaria, nor reliable vector control. In addition, Plasmodium is steadily developing resistance to the existing therapy, which urges the discovery of novel drugs with new mechanisms of action. Alkaloids of β-carboline type are present in the medicinal plants Peganum harmala and Eurycoma longifolia, which have been used in the traditional Oriental medicine for the treatment of cancer and malaria. The active ingredients were identified as harmine, harmaline, harmalol and harman. In vitro and in vivo studies have proven harmine's antimalarial activity. Cinnamic acid and its derivatives are naturally occurring substances found in various plants, and posses diverse pharmacological activities. In addition, N-cinnamoyl chloroquine, primaquine, aminoacridines and 4-aminoquinoline derivatives are reported as dual action antimalarials. The focus of our research was the design and synthesis of a compound library harmicines, comprising harmine and cinnamic acid moiety, which was generated using Cu(I) catalyzed azide-alkyne cycloaddition, resulting in the introduction of 1H-1, 2, 3-triazole scaffold. Harmine was modified at the positions 7 and/or 9 of the β-carboline ring, resulting in 3 classes: O-substituted (1), N-substituted (2) and N, O-substituted (3) harmine derivatives. Evaluation of antimalarial activity is in progress.

harmine, malaria, click chemistry

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