Phenyl substitution of furamidine markedly potentiates its anti-parasitic activity against Trypanosoma cruzi and Leishmania amazonensis

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

“…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

“…They have been described as DNA binders but also inhibit multiple classes of enzymes such as proteases, topoisomerases, polymerases, and others [15]. 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].…”

“…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.…”

“…Furamidine (DB75), its N-phenyl-substituted analogue (DB569) [18], and reversed [22,23] and aromatic diamidines [26,85] induce severe alterations in nuclear morphology. After DB75 and DB569 treatment, T. cruzi trypomastigotes presented characteristics of type I PCD [20,21].…”