Title
In vitro anti-Trypanosoma cruzi activity of ternary copper(II) complexes and in vivo evaluation of the most promising complex
Author
Drielly A. Paixão, Carla D. Lopes, Zumira A. Carneiro, Luana M. Sousa, Leticia P. de Oliveira, Norberto P. Lopes, Marcos Pivatto, Joana Darc S. Chaves, Mauro V. de Almeida, Javier Ellena, Mariete B. Moreira, Adelino V. G. Netto, Ronaldo J. de Oliveira, Silvana Guilardi, Sérgiode Albuquerque, Wendell Guerra
Year
2019
Journal
Biomedicine & Pharmacotherapy
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 Kbvalues 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.
Instrument
J-815
Keywords
Circular dichroism, DNA binding, DNA structure, Chemical stability, Inorganic chemistry, Biochemistry, Pharmaceutical