title: In vitro and in vivo biological effects of novel arylimidamide derivatives against Trypanosoma cruzi.
abstract: Chagas disease (CD), a neglected tropical disease caused by Trypanosoma cruzi, remains a serious public health problem in several Latin American countries. The available chemotherapies for CD have limited efficacy and exhibit undesirable side effects. Aromatic diamidines and arylimidamides (AIAs) have shown broad-spectrum activity against intracellular parasites, including T. cruzi. Therefore, our aim was to evaluate the biological activity of eight novel AIAs (16DAP002, 16SAB079, 18SAB075, 23SMB022, 23SMB026, 23SMB054, 26SMB070, and 27SMB009) against experimental models of T. cruzi infection in vitro and in vivo. Our data show that none of the compounds induced a loss of cellular viability up to 32 μM. Two AIAs, 18SAB075 and 16DAP002, exhibited good in vitro activity against different parasite strains (Y and Tulahuen) and against the two relevant forms of the parasite for mammalian hosts. Due to the excellent selective indexes of 18SAB075, this AIA was moved to in vivo tests for acute toxicity and parasite efficacy; nontoxic doses (no-observed-adverse-effect level [NOAEL], 50 mg/kg) were employed in the tests for parasite efficacy. In experimental models of acute T. cruzi infection, 18SAB075 reduced parasitemia levels only up to 50% and led to 40% protection against mortality (at 5 mg/kg of body weight), being less effective than the reference drug, benznidazole.
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Bruno Lisboa
authors.initials: BL
authors.lastname: Timm
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Patrícia Bernadino
authors.initials: PB
authors.lastname: da Silva
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Marcos Meuser
authors.initials: MM
authors.lastname: Batista
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Francisca Hildemagna Guedes
authors.initials: FH
authors.lastname: da Silva
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.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Patrick
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Susan Kilgore
authors.initials: SK
authors.lastname: Jones
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Stanislav A
authors.initials: SA
authors.lastname: Bakunov
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Bakunova
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil soeiro@ioc.fiocruz.br.
authors.forename: Maria de Nazaré C
authors.initials: Mde N
authors.lastname: Soeiro
mesh_terms: D000578:Amidines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D002470:Cell Survival; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D005696:Galactosidases / Q000378:metabolism; D008297:Male; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology; D019055:No-Observed-Adverse-Effect Level; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D061251:Primary Cell Culture; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000578:Amidines; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D005696:Galactosidases; C009999:benzonidazole
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