ABSTRACT. Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity and with a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7 and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high anti-parasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent.
Chagas disease (CD)
is a parasitic, systemic, chronic, and often
fatal illness caused by infection with the protozoan
Trypanosoma
cruzi
. The World Health Organization classifies CD as the
most prevalent of poverty-promoting neglected tropical diseases, the
most important parasitic one, and the third most infectious disease
in Latin America. Currently, CD is a global public health issue that
affects 6–8 million people. However, the current approved treatments
are limited to two nitroheterocyclic drugs developed more than 50
years ago. Many efforts have been made in recent decades to find new
therapies, but our limited understanding of the infection process,
pathology development, and long-term nature of this disease has made
it impossible to develop new drugs, effective treatment, or vaccines.
This Review aims to provide a comprehensive update on our understanding
of the current life cycle, new morphological forms, and genetic diversity
of
T. cruzi
, as well as identify intervention points
in the life cycle where new drugs and treatments could achieve a parasitic
cure.
Anti-proliferative effects are described for newly synthesised copper (II) complexes of two triazolo-pyrimidine derivatives (1,2,4-triazolo-[1,5-a]pyrimidine, tp, and 5,7-dimethyl 1,2,4-triazolo-[1,5-a]pyrimidine, dmtp) against to Trypanosoma cruzi and Leishmania (Viannia) peruviana. Of the compounds assayed, those that presented the ligand tp and auxiliary ligand 1,10-phenanthroline (C24b, C49) were most highly active against to T. cruzi with IC(50) within the range of the reference drug benznidazole. These compounds, together with C35 were the most effective against L. (V.) peruviana with an IC(50) greater than that presented by reference drugs (Pentostam and Glucantim). These compounds were not toxic to the host cell. IC(25) diminished the infection capacity and severely reduced the multiplication of intracellular forms of T. cruzi, and L. (V.) peruviana. In the case of T. Cruzi, the transformation to trypomastigote was seriously depressed. Copper (II) complexes C24b, C49 and C35, acted on the energy metabolism of the parasites at the level of the NAD(+)/NADH balance and at the level of the organelle membranes, causing degradation and cell death.
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