title: In vitro and in vivo investigation of the efficacy of arylimidamide DB1831 and its mesylated salt form--DB1965--against Trypanosoma cruzi infection.
abstract: 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.
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Cristiane França
authors.initials: CF
authors.lastname: da Silva
authors.forename: Denise da Gama Jaen
authors.initials: Dda G
authors.lastname: Batista
authors.forename: Gabriel Melo
authors.initials: GM
authors.lastname: Oliveira
authors.forename: Elen Mello
authors.initials: EM
authors.lastname: de Souza
authors.forename: Erica Ripoll
authors.initials: ER
authors.lastname: Hammer
authors.forename: Patricia Bernardino
authors.initials: PB
authors.lastname: da Silva
authors.forename: Anissa
authors.initials: A
authors.lastname: Daliry
authors.forename: Julianna Siciliano
authors.initials: JS
authors.lastname: Araujo
authors.forename: Constança
authors.initials: C
authors.lastname: Britto
authors.forename: Ana Carolina Mondaine
authors.initials: AC
authors.lastname: Rodrigues
authors.forename: Zongying
authors.initials: Z
authors.lastname: Liu
authors.forename: Abdelbasset A
authors.initials: AA
authors.lastname: Farahat
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Maria de Nazaré Correia
authors.initials: Mde N
authors.lastname: Soeiro
mesh_terms: D000577:Amides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000578:Amidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000981:Antiprotozoal Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D008698:Mesylates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology
chemical_list: D000577:Amides; D000578:Amidines; D000981:Antiprotozoal Agents; C572442:DB1831; D008698:Mesylates; D011743:Pyrimidines