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

Abstract

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)(ClO4)2], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4-MH)(dmb)(ClO4)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 Kb values in the range of 103–104 M–1, with [Cu(4-MH)(dmb)(ClO4)2] showing the highest Kb value (1.45 × 104 M–1). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO4)2] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond.

Keywords

• Chagas disease
• T. cruzi
• Cu(II) complexes
• DNA binding
• Molecular docking
• Hydrazides