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Design, synthesis and biological activity of novel β-carboline hybrids

Malaria is a life-threatening tropical disease caused by the parasite of the genus Plasmodium, which causes over 400 000 deaths annually, mostly pregnant women and children under 5 years old [1]. Due to the spread of a multidrug- resistant malaria parasite, the development of novel, more efficacious antimalarials is necessary. One of the possible approaches is the preparation of hybrid drugs, i.e. two drugs covalently linked in one molecule. Here we present the design and synthesis of hybrids based on β-carboline alkaloid harmine (Figure 1.), a natural product with significant antimalarial activity [2]. Cinnamic acid and its derivatives, due to their broad spectrum of biological and pharmacological properties including antimalarial activity, as well as chloroquine, a well-known antimalarial drug, were chosen as harmine’s partners [3]. Harmicines, β- carboline-cinnamic acid hybrids, were prepared by “click” reaction, i.e. copper(I)-catalyzed alkyne-azide cycloaddition, in t-BuOH/H2O, using sodium ascorbate and CuSO4 x 5 H2O as a source of Cu(I) ions. Harmiquines, β-carboline- chloroquine hybrids, were synthesized using both “click” and coupling reactions. “Click” reaction proceeded in MeOH, using Cu(II) acetate, while coupling reactions were performed in the presence of T3P/TEA in DMF. To determine structure-activity relationship, hybrids were prepared at five different positions of the β-carboline core. The proposed structures of the synthesized hybrids 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 stages of the Plasmodium life cycle, as well as cytotoxicity against human cell lines.

armine, chloroquine, cinnamic acid derivatives,

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