engleski

Synthesis of novel amide type harmicines

Malaria, one of the most dangerous parasitic diseases, causes almost half a million deaths each year (1). In an effort to reduce the growing resistance of the parasite to the available drugs, the approach of molecular hybridization has been used to produce amide type (AT) harmicines, i.e. hybrids composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs) linked via amide bond. In our previous work we showed that AT harmicines prepared at O-7 and N-9 of the β-carboline core exert increased antimalarial activity compared to harmine (2). Encouraged by those results we decided to prepare novel AT harmicines at the positions C-1, C-3 and C-6 of the β-carboline core (4a-h, 5a-h, 6a-h). Synthesis of harmicines (4a-h, 5a-h, 6a-h) involves preparation of harmine-based primary amines 1-3 and coupling reactions between amines and different CADs (Scheme). Synthesis of amines 1-3 included several reaction steps. C-1, C-3 and O-6 substituted β-carbolines were generated by Pictet-Spengler reaction between tryptamine (C- 1), L-tryptophan methyl ester (C-3) or 5- methoxytryptamine (O-6) and the corresponding aldehyde (2, 2-dimethoxyacetaldehyde/acetaldehyde dimethyl acetal) in TFA, followed by their aromatisation at rt using KMnO4 in DMF (C-1) or in the microwave reactor using 10% Pd/C in EtOH (C-3 and O-6). Reduction of aldehyde (C-1) or ester (C-3) with LiAlH4 yielded alcohols, which were transformed to azides using ADMP/DBU. Subsequent catalytic hydrogenation of azides generated amines 1 and 2. On the other hand, ether at O-6 was hydrolysed in AcOH/HBr and the obtained phenol alkylated with 2-(Boc-amino)ethyl bromide. The removal of the Boc-protecting group under acidic conditions resulted in the preparation of amine 3. Finally, the targeted harmicines (4a-h, 5a-h, 6a-h) were prepared by coupling reactions between CADs and harmine-based amines (1-3) in the presence of HATU/DIEA in dichloromethane. Structures of newly prepared harmicines were confirmed by spectroscopic and spectrometric methods (IR, MS, 1H and 13C NMR). Evaluation of their antimalarial activity and cytotoxicity is in progress.

malaria ; hybrids ; harmine ; amide type

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