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Synthesis of amide-type harmiquins

Malaria is the most widespread and deadly parasitic disease, leading to at least 400 000 deaths per year and causing great economic burden. Due to the emergence of resistance to the most commonly used antimalarials, there is an urgent need for development of novel and effective agents. Popular approach in antimalarial drug design involves linking two molecules with individual intrinsic activity into a single, dual-acting chemical entity, i.e. preparing hybrid compounds. Harmiquins are hybrids comprised of harmine, a β-carboline alkaloid with confirmed antimalarial activity, and 7-chloroquinoline moiety, pharmacophore found in chloroquine, a well-known antimalarial.To prepare the target hybrids, we have synthesized 7-chloroquinoline-based amines 1, 2 and carboxylic acid 6, as well as harmine-based carboxylic acid 3 and amines 7-11. 7-chloroquinoline-based intermediates 1, 2 and 6 were prepared by nucleophilic aromatic substitution of 4, 7-dichloroquinoline with: 1) ethylenediamine, 2)1, 4-diaminobutane or 3) glycine, respectively. Harmine-based carboxylic acid 3 was prepared in a two-step procedure. The first step included Michael addition between harmine and methyl acrylate. The obtained ester was subsequently hydrolyzed to the corresponding acid 6. The synthesis of harmine-based amines at positions C-1, C-3, O-6, O-7 and N-9 of the β-carboline core, 7-11, was previously described. Synthesized amines and carboxylic acids were the starting compounds for the coupling reactions that resulted in two types of amides: 4, 5 and 12-16. Harmiquins 4, 5 were prepared using HATU/DIEA in CH2Cl2. On the other hand, due to the better reaction yields and shorter reaction times, T3P/TEA in DMF were used in synthesis of harmiquins 12-16.Structures of novel harmiquins were confirmed by 1H and 13C NMR, IR and MS. Evaluation of their antiplasmodial activity and cytotoxicity is in progress.

malaria, hybrid compound, beta-carboline, chloroquine, amide, coupling reaction

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