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Synthesis and structural characterization of novel β-carboline-CADs conjugates as potential antiplasmodial agents

Malaria is one of the most prevalent parasitic diseases. According to the World Health Organisation, approximately 3.3 billion people are living at risk of catching the disease. Human malaria is caused by five species of the genus Plasmodium (P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi) and it is transmitted by female Anopheles mosquitoes [1]. The lack of specific vaccines and the emergence of resistant Plasmodium strains, even to the most recent combinations of antimalarial drugs, urge the development of structurally novel and effective antiplasmodial agents [2]. A potent antimalarial activity of a number of natural β- carboline alkaloids (harmaline, harmine, harmalol, harmol, and tetrahydroharmine), isolated from Peganum harmala, has been reported [1]. On the other hand, cinnamic acid derivatives (CADs) received much attention in medicinal chemistry research as valuable scaffolds in synthetic bioactive agents. Moreover, CADs inhibit the growth of intraerythrocytic life stage of P. falciparum [3]. Taken together, such facts prompted us to combine both agents, -carboline derivative and CAD, in a single molecule, i.e. to prepare their hybrid drugs. To obtain structural diversity and establish a relevant structure- activity relationship, we decided to modify β- carboline scaffold at 4 different positions (3, 6, 7 and 9). Amino groups were chosen and introduced as a convenient entry point in the preparation of amides with various CADs, by the means of standard coupling conditions (HATU, DIEA). The proposed structures of the synthesized β-carboline-CADs conjugates were confirmed by the standard methods (IR, MS, 1H- NMR and 13C-NMR). Antimalarial activity of the prepared compounds will be evaluated in vitro on both erythrocytic and hepatic stage of the Plasmodium, as well as cytotoxicity against human cell lines.

Malaria, β-carboline, antiplasmodial, synthesis, CADs, conjugates

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