Activity of “reversed” diamidines against Trypanosoma cruzi “in vitro”

The biological in vitro effect and selectivity of aromatic dicationic compounds on Trypanosoma cruzi

“…In agreement with our previous studies showing that reversed amidines, also named arylimidamides, exhibited low toxicity to mammalian cells in vitro (Silva et al 2007a), our present data showed that, except for Compounds 1 and 2, only high drug concentrations (> 96 µM) induced alterations in host cell viability.…”

“…Our data showed that although three compounds, Compounds 1, 2 and 3, induced high levels of parasite lysis and dose-dependent effects with low micromolar IC 50 values when assayed at 37°C, all of them showed decreased activity in the presence of blood, possibly due to their association with and/or inactivation by serum components as reported previously (SantaRita et al 2004, 2006, Silva et al 2007a. Therefore, the decreased activity at 4°C in the presence of blood constituents demonstrated that the studied compounds are ineffective for the sterilisation of ex vivo blood batches to control Chagas disease.…”

“…In addition, the pharmaceutical industries have given little attention to the design and development of new antiparasitic compounds aromatic dicationic compounds represent a class of DNA minor-groove binding ligands that exhibit high activity against a variety of pathogens, such as bacteria, fungi and protozoa (Werbovetz 2006, Wilson et al 2008. Recent data showed that diamidines and related compounds, such as the reversed amidines, present considerable efficacy against T. cruzi both in vitro (De Souza et al 2004, Silva et al 2007a) and in vivo (De Souza et al 2006a, da Silva et al 2008) and induce striking alterations on the parasite mitochondrion-kinetoplast complex (De Souza et al 2006b, Silva et al 2007b. In this context, the present study investigated the activity of 10 newly synthesised aromatic dicationic compounds on trypomastigotes and intracellular amastigotes, the clinically relevant forms of T. cruzi and the toxicity of these compounds in cardiac cells.…”

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

“…More recently, new diamidine-related analogues were developed that present improved anti-parasitic activity against T. cruzi and Leishmania [18,19]. In T. cruzi, some of the new compounds (classified as reversed amidines) presented a high level of activity against amastigotes and trypomastigotes both in vivo and in vitro [18][19][20][21][22][23][24][25][26]. Ultrastructural analysis showed that the different aromatic diamines displayed similar effects in T. brucei, T cruzi and Leishmania, characterized by the presence of swollen mitochondria presenting low electron-density structures, fragmentation of the membrane and crista and mitochondrial disruption [12,13,18,20,23,24,[27][28][29][30][31][32].…”

“…Sometimes, the disorganization of the kDNA network, which has mainly been observed in trypomastigotes, seems to be the result of the severe swelling of the mitochondrion and the loss of the inner membrane. In contrast, aromatic diamidines [18,[20][21][22][23], natural and synthetic -carbolines [76], topoisomerase inhibitors [80,82,83], and DAB [68] cause a drastic effect: the destruction or fragmentation of the kDNA network in promastigotes and amastigotes of Leishmania and in trypomastigotes of T. cruzi. These effects were not observed in the kinetoplasts of epimastigote forms of T. cruzi.…”