1,4-Bis(alkylamino)benzo[ g]phthalazines able to form dinuclear complexes of Cu(II) which as free ligands behave as SOD inhibitors and show efficient in vitro activity against Trypanosoma cruzi

• Published in: Bioorganic & medicinal chemistry 2007-03, Vol.15 (5), p.2081-2091
• Main Authors: Rodríguez-Ciria, Marinela, Sanz, Ana M., Yunta, María J.R., Gómez-Contreras, Fernando, Navarro, Pilar, Sánchez-Moreno, Manuel, Boutaleb-Charki, Samira, Osuna, Antonio, Castiñeiras, Alfonso, Pardo, Mercedes, Cano, Carmen, Campayo, Lucrecia
• Format: Article
• Language: English
• Subjects: 1,4-Bis(alkylamino)benzo[ g]phthalazines; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic activity; Antiparasitic agents; Biological and medical sciences; Cercopithecus aethiops; Copper - chemistry; Dinuclear copper complexes; Enzyme Inhibitors - pharmacology; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; OH endogenous bridges; Pharmacology. Drug treatments; Phthalazines - chemistry; Phthalazines - metabolism; Phthalazines - pharmacology; Spectrometry, Mass, Fast Atom Bombardment; Spectrophotometry, Infrared; Superoxide Dismutase - antagonists & inhibitors; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi SOD inhibitors; Vero Cells
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.12.033

The synthesis of a new series of benzo[ g]phtalazine derivatives is reported, and the complexating ability of these compounds towards Cu(II) might be connected with their SOD inhibitory activity in Tripanosoma cruzi. The synthesis of a new series of 1,4-bis(alkylamino)benzo[ g]phthalazines 1– 3 is reported, and their ability to form dinuclear complexes with Cu(II) assayed. The geometry of the complexes is dependent on the nature of the electron-donor sites at the sidechains. Compounds 1 and 2, that contain sp 3 or sp 2 nitrogens at the end of the alkylamino groups, originate monopodal dinuclear complexes which seem to include endogenous OH bridges, and the sidechains seem to actively participate in complexation. However, the substitution of nitrogen by oxygen in 3 leads to a tripodal dinuclear complex in which the sidechains are not involved. The in vitro antiparasitic activity on Trypanosoma cruzi epimastigotes and amastigotes and the SOD activity inhibition have been evaluated for compounds 1– 3, and, as expected, 1 and 2 show in all cases relevant results, whereas 3 is always the less active among the three substrates tested.