Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi

Abstract

Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affecting about 12-14 million people in endemic areas of Latin America. The chemotherapy of Chagas disease is quite unsatisfactory mainly due to its poor efficacy especially during the later chronic phase and the considerable well-known side effects. These facts emphasize the need to search for find new drugs. Diamidines and related compounds are minor groove binders of DNA at AT-rich sites and present excellent anti-trypanosomal activity. In the present study, six novel aromatic amidine compounds (arylimidamides and diamidines) were tested in vitro to determine activity against the infective and intracellular stages of T. cruzi, which are responsible for sustaining the infection in the mammalian hosts. In addition, their selectivity and toxicity towards primary cultures of cardiomyocyte were evaluated since these cells represent important targets of infection and inflammation in vivo. The aromatic amidines were active against T. cruzi in vitro, the arylimidamide DB1470 was the most effective compound presenting a submicromolar LD(50) values, good selectivity index, and good activity at 4 °C in the presence of blood constituents. Our results further justify trypanocidal screening assays with these classes of compounds both in vitro and in vivo in experimental models of T. cruzi infection.

Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

“…Our team has recently been working on the potential effect of diamidines and congeners against this parasite using both in vitro and in vivo models to compare analogues with different structures, cationic centres, and effective motifs [19]. Our data have clearly shown the promising activity of some of these compounds, which displayed high therapeutic windows [52–56]. …”

“…TEM studies have shown that the organisation of mitochondria and kinetoplasts in T. cruzi is highly altered by several diamidines and related compounds, such as arylimidamides (AIAs), at concentrations that do not affect mammalian host cells [19, 51, 58]. AIAs, previously known as reversed amidines, have extraordinary activity against both Leishmania [71–73] and T. cruzi [52, 53, 55, 56, 74]. They differ from other furan analogues because the amidine is bound to the central aromatic linker via a nitrogen atom rather than a carbon atom [72].…”

“…AIAs have potent in vitro dose-dependent activity against T. cruzi , showing superior trypanocidal activity compared to diguanidino cationic groups and other classical diamidines [52, 56]. Recently, a monoamidine, an arylimidamide, and a guanylhydrazone were evaluated, and the data showed that all compounds exerted, at low micromolar doses, a trypanocidal effect upon both intracellular and bloodstream parasites [74].…”

The Trypanocidal Activity of Amidine Compounds Does Not Correlate with Their Binding Affinity to Trypanosoma cruzi Kinetoplast DNA

“…Aromatic diamidines (ADs) and related compounds, such as arylimidamides (AIAs), are a promising group of heterocyclic compounds with remarkable activity against trypanosomatids both in vitro (9,11,26,31,33,34) and in vivo (3,22,7). Many representatives of this class of compounds, including furamidine (DB75), accumulate in DNA-containing organelles, such as nuclei and, most notably, mitochondria (5,18,21,7).…”

In Vitro and In Vivo Studies of the Biological Activity of Novel Arylimidamides against Trypanosoma cruzi

“…Benznidazole (BZ) and nifurtimox (NF) are used for the treatment of CD, but because of their well-known toxicity and limited efficacy in the later chronic phase of the disease, new drugs are urgently needed (6)(7)(8)(9). We have evaluated several classes of natural and synthetic compounds, including arylimidamides (AIAs), aromatic diamidine (AD) derivatives with extraordinary activity against T. cruzi and other trypanosomatids, both in vitro (10)(11)(12)(13)(14)(15)(16) and in vivo (17,18). In AIAs, the imino group is linked via an anilino nitrogen, while in classical amidines, it is directly attached to an aryl ring, yielding reduced pK values (14).…”