engleski

Synthesis of novel primaquine ureas and semicarbazide

Primaquine is a well known antimalarial drug and an interesting molecule for derivatization in the search of potential biologically active agents (1). Its usefulness is offset by inherent toxicity, and rapid metabolism in mammals to carboxyprimaquine, which is devoid of significant antimalarial activity (2). Recently, we have reported several papers describing the synthesis and biological activity (antitumour, antiviral and antioxidant activity) of various primaquine derivatives (urea, semicarbazide, carbamate) (1, 3) which have shown the importance of benzhydryl group in the molecule. On the other hand, semicarbazides are important pharmacophores in the search of new drugs with exerted antitumour activity (3). Based on these findings we found it worth to prepare new primaquine ureas with modified benzhydryl substituents and semicarbazide according to the following scheme. Scheme outlines the general preparative route. The sequence leading from 1 to 3 was identical with the one described earlier (4). Urea primaquine derivatives 3a-d and semicarbazide 4 (Table 1.) were prepared by the reaction of benzotriazolide 2 with corresponding amine and hydrazine, respectively. The new urea derivatives were prepared in a microwave reactor (P = 150 W, t = 65 C). Microwave assisted synthesis significantly shortened the reaction times (1h compared to 4 days at r.t.). The synthesis of semicarbazide 4 was performed in dioxane at room temperature for 4 days. Benzotriazolide 2 was synthesised by acylation of primaquine with 1-benzotriazole carboxylic acid chloride 1 (4). 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. 1. Šimunović, M. ; Perković, I. ; Zorc, B. ; Ester, K. ; Kralj, M. ; Hadjipavlou-Litina, D. ; Pontiki, E. Urea and carbamate derivatives of primaquine: synthesis, cytostatic and antioxidant activities. Bioorg. Med. Chem. 2009, 17, 56055613. 2. Vale, N. ; Moreira, R. ; Gomes, P. Primaquine revisited six decades after its discovery. Eur. J. Med. Chem. 2009, 44, 937–953. 3. Perković, I. ; Tršinar, S. ; Žanetić, J. ; Kralj, M. ; Martin-Kleiner, I. ; Balzarini, J. ; Hadjipavlou-Litina, D. ; Katsori, A.M. ; Zorc, B. Novel 1-acyl-4- substituted semicarbazide derivatives of primaquine  synthesis, cytostatic, antiviral and antioxidative studies. J. Enzyme Inhib. Med. Chem. 2013, 28, 601–610. 4. Džimbeg, G. ; Zorc, B. ; Kralj, M. ; Ester, K. ; Pavelić, K. ; Balzarini, J. ; De Clercq, E. ; Mintas, M. The novel primaquine derivatives of N-alkyl, cycloalkyl or aryl urea: synthesis, cytostatic and antiviral activity evaluations. Eur. J. Med. Chem. 2008, 43, 1180– 1187.

primaquine; urea; semicarbazide; benzotriazole

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