engleski

Synthesis of C-1- and C-3-tethered triazole type harmicines

As malaria remains a global health threat, there is a great need for new and effective antimalarials. Novel and emerging approach in the development of antimalarial agents is molecular hybridization, i.e. preparation of hybrid compounds. Harmicines are hybrids consisting of two moieties with antimalarial properties, namely harmine, a β-carboline alkaloid and cinnamic acid derivatives (CADs), linked via triazole ring or amide bond. In our previous work, we have shown that triazole type (TT) harmicines prepared at O- 7 and N-9 positions of the β-carboline core exert significant antiplasmodial activities. To broaden our knowledge on their structure-activity relationship, we decided to expand the series of TT harmicines by preparing new generation of hybrids tethered at C-1 and C-3 positions of the β-carboline ring, 4a-e and 5a-e. Novel harmicines were prepared via “click” reaction of CAD-based alkynes (1a-e) and β- carboline azides (2 and 3), resulting in a triazole type linker. “Click” reaction proceeded smoothly with Na ascorbate and CuSO4 × 5H2O as a source of Cu(I), in a t-BuOH/water mixture (1:1). Synthesis of CAD-based alkynes (1a-e) was straightforward and it was accomplished by the reaction of a corresponding CAD with propargyl bromide in presence of K2CO3. On the other hand, synthesis of azides 2 and 3 involved several steps. Pictet-Spengler condensation of tryptamine and 2, 2-dimethoxyacetaldehyde (C-1) or tryptophan methyl ester and acetaldehyde dimethyl acetal (C- 3), followed by the oxidation with KMnO4 at rt or Pd/C under microwave irradiation yielded substituted β-carbolines. Their reduction with LiAlH4, i.e. reduction of aldehyde (C-1) or ester (C-3), resulted in the synthesis of the corresponding alcohols, which were efficiently transformed to azides using ADMP/DBU. Structures of novel harmicines were confirmed by IR, 1H and 13C NMR and MS. Evaluation of their antiplasmodial activity and cytotoxicity is in progress.

malaria, hybrid compounds, harmine, cinnamic acid derivatives, "click" chemistry

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