engleski

Harmicines as novel antiplasmodial leads

Malaria, caused by the protozoal parasite Plasmodium, is a neglected tropical disease responsible for over 400000 deaths in 2017.1 The emergence of the multi-drug resistant Plasmodium strains has rendered the existing therapy ineffective. Harmine is an alkaloid of the -carboline type, with confirmed in vitro and in vivo antimalarial properties, while cinnamic acids have been shown to enhance antimalarial activity when linked to the known antimalarial drug.2 Such findings prompted us to design cinnamic acid-harmine conjugates, i.e. harmicines (Fig. 1). Three synthetic routes were developed. The first employed 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 three classes: O-substituted (1), N- substituted (2) and N, O-disubstituted (3) harmine derivatives. The pathway to amides 4 included O-alkylation of harmole with 2-(Boc- amino)ethyl bromide, deprotection and coupling with cinnamic acids, respectively. Finally, acylhydrazides 5 were obtained by Michael reaction between harmine and methyl acrylate, substitution with hydrazine and subsequent coupling reaction with various cinnamic acids. Evaluation of antiplasmodial activity revealed some of the compounds as interesting antiplasmodial leads.

malaria, harmine, cinnamic acid, antiplasmodial, synthesis

nije evidentirano