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Synthesis of primaquine semicarbazides and semicarbazones

Primaquine, the 8-aminoquinoline derivative, is known antimalarial drug that is active against various forms of Plasmodium species. A major drawback of primaquine is the occurrencerelatively low therapeutic index and rapid metabolisation to carboxyprimaquine, which is devoid of significant antimalarial activity (1). Many attempts have been made to prepare primaquine derivatives in the search for compounds that would be more effective and stable or less toxic (1). The aim of our research was to prepare semicarbazide primaquine derivatives bearing one or more hydroxyl groups at the one and primaquine moiety at the other end. Recently, we have reported several papers describing the synthesis and biological activity (antitumour, antiviral and antioxidant activity) of various primaquine derivatives (urea, semicarbazide, carbamate). Urea derivatives with one or more hydroxyl groups and semicarbazide derivatives of primaquine have shown significant anticancer and antioxidant activity (2-4). A series of novel 1, 4-substituted semicarbazides 5 with a primaquine moiety bridged by a carbonyl group at position 1 and aminoalcohol (2- hydroxyethanamine, 3-hydroxypropanamine, 5- hydroxypentanamine, tris(hydroxymethyl)aminomethane and diethanolamine). Semicarbazides 5 were prepared by the reaction of primaquine semicarbazide benzotriazolide (4) (not isolated due to its low stability) with corresponding amine RNHR1. Benzotriazolide (2), synthesised by acylation of primaquine with 1-benzotriazole carboxylic acid chloride (1) (4) was used for preparation of primaquine semicarbazide (3). Structures of newly prepared primaquine derivatives were confirmed by IR, 1H and 13C NMR and MS spectroscopy. Evaluation of their biological activity is in progress.

primaquine; semicarbazide; semicarbazone; synthesis

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