In vitro anti-Trypanosoma cruzi activity of ternary copper(II) complexes and in vivo evaluation of the most promising complex

• Autor(a) principal: Paixão, Drielly A.
• Data de Publicação: 2019
• Outros Autores: Lopes, Carla D., Carneiro, Zumira A., Sousa, Luana M., de Oliveira, Leticia P., Lopes, Norberto P., Pivatto, Marcos, Chaves, Joana Darc S., de Almeida, Mauro V., Ellena, Javier, Moreira, Mariete B. [UNESP], Netto, Adelino V.G. [UNESP], de Oliveira, Ronaldo J., Guilardi, Silvana, de Albuquerque, Sérgio, Guerra, Wendell
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNESP
• Texto Completo: http://dx.doi.org/10.1016/j.biopha.2018.10.057; http://hdl.handle.net/11449/189671
• topic: Chagas disease; Cu(II) complexes; DNA binding; Hydrazides; Molecular docking; T. cruzi

In order to improve the previously observed antichagasic activity of Cu(II) complexes containing 2-chlorobenzhydrazide (2-CH), we report herein the synthesis and anti-Trypanosoma cruzi activity of novel copper complexes containing 2-methoxybenzhydrazide (2-MH), 4-methoxybenzhydrazide (4-MH) and three α-diimine ligands, namely, 1,10-phenanthroline (phen), 2,2-bipyridine (bipy) and 4-4′-dimethoxy-2-2′-bipyridine (dmb). Two of these complexes showed higher in vitro anti-Trypanosoma cruzi activity when compared to benznidazole, the main drug used in Chagas disease treatment. One of them, the copper complex with 4-MH and dmb, [Cu(4-MH)(dmb)(ClO 4 ) 2 ], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4-MH)(dmb)(ClO 4 ) 2 ] was selected for preliminary in vivo assays, which verified that this compound was able to reduce parasitemia by 64% at the peak of infection. Further investigations were performed on all compounds. The Cu(II) complexes bind to ct-DNA with K b values in the range of 10 3 –10 4 M –1 , with [Cu(4-MH)(dmb)(ClO 4 ) 2 ] showing the highest K b value (1.45 × 10 4 M –1 ). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO 4 ) 2 ] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond.