engleski

Synthesis of harmisinins, harmine and artemisinin hybrids

Malaria, an infectious disease caused by five species of Plasmodiumparasites, affected 241 million people and claimed 627 000 lives in 2020. The lack of an effective vaccine and the increasing resistance of Plasmodium to approved antimalarial drugs demands the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Harmisinins represent hybrids that combine two moieties with different mechanisms of antiplasmodial activity in one molecule, i.e., artemisinin scaffold, known to destroy the parasite through formation of free radicals, and a ß-carboline ring capable of binding to P. falciparumheat shock protein 90. The synthesis of the targeted compounds was achieved by the coupling reaction between artesunate and ß-carboline amines, using HATU/DIEA, at rt for 5 hours. The required amines were synthesized from harmine, harmole or analogues ß-carboline, bearing phenol at the position 6, by a two-step reaction. In the first step harmine was alkylated at the position N-9, harmole at the position O-7 and ß- carboline at the position O-6 with 2-(Boc-amino)ethyl bromide in the presence of caesium carbonate in DMF, followed by the removal of Boc protecting group in acidic medium (HCl in MeOH). The structures of the newly prepared hybrid compounds were confirmed by IR, 1H and 13C NMR spectroscopy and mass spectrometry.

harmin, artemisinin, hybrid compound, synthesis

nije evidentirano