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Synthesis of triazole-type harmicenes

Malaria, a life-threatening infectious disease, affects more than 100 countries, putting half of the world's population in danger.[1] As resistance of the malaria parasite to the known antimalarial drugs rises, there is a crucial need for new and effective antimalarial agents.[2] To this end, we employed molecular hybridization of two bioactive scaffolds, [3] a popular approach in the discovery of molecules with improved properties, in the synthesis of harmicenes. Harmicenes represent hybrids comprised of harmine, a β-carboline alkaloid with confirmed antimalarial activity, and ferrocene, an organometallic compound that enhances antimalarial properties. Cu(I) catalyzed azide- alkyne cycloaddition, i.e. “click” chemistry, was selected as a method of choice for the preparation of two series of harmicenes, 1a-e and 2a-e, in the positions C-1, C-3, O-6, O-7 and N-9 of the β-carboline ring. Compounds 1 were obtained by reacting β-carboline-based alkyne with ferrocene-based azide, while harmicenes 2 were synthesized in the reaction of β-carboline- based azides and ethynylferrocene (Figure 1.). “Click” reactions proceeded smoothly with Na ascorbate and CuSO4 × 5H2O as a source of Cu(I) ions, in DMF/H2O mixture (1:1), giving hybrids in good to excellent yields. References 1) https://www.who.int/news-room/fact sheets/detail/malaria 2) J. A. Naughton, et al. Biochem Pharmacol. 2008 ; 5:1580-7. 3) Shaveta et al. Eur J Med Chem. 2016 ; 124:500- 536.

malaria, hybrid compounds, harmine, ferrocene, triazole, "click" chemistry, amide, coupling reactions

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