Tetradentate polyamines as efficient metallodrugs for Chagas disease treatment in murine model

Abstract

A series of tetraamine-based compounds was prepared, and their trypanocidal effects against Trypanosoma cruzi and cytotoxicity were determined through the determination of IC₅₀ values. In vivo assays were performed in mice, where parasitaemia levels were quantified by fresh blood examination and the assignment of a cure was determined by polymerase chain reaction and reactivation of blood parasitaemia levels after immunosuppression. The mechanisms of action were elucidated at metabolic and ultra-structural levels, by ¹H NMR, Fe-SOD inhibition and TEM studies. The high-selectivity indexes observed in vitro were the basis of promoting one of the tested compounds to in vivo assays. Compound 6 induced a remarkable decrease in the reactivation of parasitaemia after immunosuppression and curative rates of 33%. The experiments allowed us to select compound 6 as a promising candidate for treating Chagas disease, but a further high-level study should be considered to obtain an improved efficiency.

Keywords:

• American trypanosomiasis
• Chemotherapy
• Tetradentate polyamines
• Murine model

Acknowledgments

We acknowledge Generalitat de Catalunya for an ICREA Academia Award (X.R. and M.C.). Financial support from the Spanish Ministry of Economy and Competitiveness (MINECO), CONSOLIDER-INGENIO 2010 CSD2010-00065. F.O. is grateful for a FPU Grant (AP2010-3562) from the Ministry of Education of Spain.