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Synthesis, structure and biological activity of novel 4,5-dihydro-1H-imidazol-2-yl-phthalazine derivatives and their copper(II) complexes
* 1 , 1 , 1 , 2 , 2 , 3 , 1
1  Department of Chemical Technology of Drugs, Medical University of Gdańsk
2  Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki
3  Faculty of Chemistry, A. Mickiewicz University, Poznań
Academic Editor: Alfredo Berzal-Herranz


As a continuation of our previous investigations aimed at the synthesis of novel nitrogen-containing heterocycles and their metal complexes, we have now prepared two series of compounds incorporating a phthalazine ring at the position C2 of 4,5-dihydro-1H-imidazole.

The starting phthalazine (I) in the reaction with 2-chloroimidazoline (II) gives rise to the formation of pseudobase III. Then, compound III upon treatment with HOSA yields betaine which under basic conditions gives 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (IV). In turn, the reactions of compound IV with variety of acyl and sulfonyl chlorides lead to the formation of benzamides (V) and benzenesulfonamides (VI). Moreover, compounds V and VI can be transformed into corresponding 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one derivatives VII and VIII.

Such ligands are susceptible to the reaction with CuCl2 giving rise to the formation of corresponding copper(II) complexes: dichloro[2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine]copper(II) (1), dichloro[2-(1-benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]copper(II) (2) and dichloro{bis-[2-(1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]}copper(II) (3).

The most promising results of biological studies were obtained for complex 1 towards the HeLa cell line (IC50 = 2.13 μM) without a toxic effect against fibroblasts BALB/3T3 (IC50 = 135.30 μM), which pointed towards its selectivity as a potential antitumor agent. It should be pointed out, that corresponding free ligand 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (IV) was less active than its metal complex (IC50 = 87.74 μM).

Keywords: phthalazine, imidazoline, copper(II) complexes, synthesis, structure, X-ray, cytotoxic activity