engleski

Synthesis of novel carbamate-type harmicines

The development of drug resistance remains one of the greatest threats to malaria control. In search of an effective and versatile compound that could overcome resistance, a series of harmicines - hybrid compounds of harmine and cinnamic acid derivatives were synthesized and tested for their antimalarial activity. The most promising compounds were harmicines at the N-9 position of the β-carboline core in which harmine and cinnamic acid derivatives were linked via an amide bond. As a continuation of our research we decided to replace the amide linker with bioisosteres. Therefore, five novel carbamate-type harmicines were synthesized at the N-9 position of the β-carboline core (Scheme 1). Amine 1 was synthesized from harmine by a two-step reaction: 1) alkylation of harmine at the N-9 position with 2-(Boc-amino)ethyl bromide in the presence of caesium carbonate in DMF and 2) removal of Boc protecting group in acidic medium (HCl in MeOH). Alcohols 2a-e were prepared from the corresponding cinnamic acids, which were first converted to acid chlorides with thionyl chloride, and then simply reduced with sodium borohydride in tetrahydrofuran with dropwise addition of methanol. The synthesis of the targeted carbamates 3a-e was carried out using 1, 1'-carbonyldiimidazole (CDI) reagent and NaH as a base. CDI is known to react with amines to give N-substituted 1H-imidazole-1-carbonyl (carbonylimidazolide), which can be converted to urea, carbamate, or thiocarbamate. The carbonylimidazolide derived from primary amine 1 reacts in situ with the corresponding cinnamyl alcohol as a nucleophile to give carbamates 3a-e. The structures of the newly prepared carbamates 3a-e and alcohols 2a-e were determined by IR, 1H and 13C NMR spectroscopy and mass spectrometry.

malaria, resistance, harmicines, carbamate-type

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