PLoS ONE (Jan 2012)

In vitro and in vivo investigation of the efficacy of arylimidamide DB1831 and its mesylated salt form--DB1965--against Trypanosoma cruzi infection.

  • Cristiane França da Silva,
  • Denise da Gama Jaen Batista,
  • Gabriel Melo Oliveira,
  • Elen Mello de Souza,
  • Erica Ripoll Hammer,
  • Patricia Bernardino da Silva,
  • Anissa Daliry,
  • Julianna Siciliano Araujo,
  • Constança Britto,
  • Ana Carolina Mondaine Rodrigues,
  • Zongying Liu,
  • Abdelbasset A Farahat,
  • Arvind Kumar,
  • David W Boykin,
  • Maria de Nazaré Correia Soeiro

DOI
https://doi.org/10.1371/journal.pone.0030356
Journal volume & issue
Vol. 7, no. 1
p. e30356

Abstract

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Chagas disease is caused by infection with the intracellular protozoan parasite Trypanosoma cruzi. At present, nifurtimox and benznidazole, both compounds developed empirically over four decades ago, represent the chemotherapeutic arsenal for treating this highly neglected disease. However, both drugs present variable efficacy depending on the geographical area and the occurrence of natural resistance, and are poorly effective against the later chronic stage. As a part of a search for new therapeutic opportunities to treat chagasic patients, pre-clinical studies were performed to characterize the activity of a novel arylimidamide (AIA--DB1831 (hydrochloride salt) and DB1965 (mesylate salt)) against T. cruzi. These AIAs displayed a high trypanocidal effect in vitro against both relevant forms in mammalian hosts, exhibiting a high selectivity index and a very high efficacy (IC(50) value/48 h of 5-40 nM) against intracellular parasites. DB1965 shows high activity in vivo in acute experimental models (mouse) of T. cruzi, showing a similar effect to benznidazole (Bz) when compared under a scheme of 10 daily consecutive doses with 12.5 mg/kg. Although no parasitological cure was observed after treating with 20 daily consecutive doses, a combined dosage of DB1965 (5 mg/kg) with Bz (50 mg/kg) resulted in parasitaemia clearance and 100% animal survival. In summary, our present data confirmed that aryimidamides represent promising new chemical entities against T. cruzi in therapeutic schemes using the AIA alone or in combination with other drugs, like benznidazole.