title: In Vitro and In Vivo Trypanosomicidal Action of Novel Arylimidamides against Trypanosoma cruzi.
abstract: Arylimidamides (AIAs) have been shown to have considerable biological activity against intracellular pathogens, includingTrypanosoma cruzi, which causes Chagas disease. In the present study, the activities of 12 novel bis-AIAs and 2 mono-AIAs against different strains ofT. cruziin vitroandin vivowere analyzed. The most active wasm-terphenyl bis-AIA (35DAP073), which had a 50% effective concentration (EC50) of 0.5 μM for trypomastigotes (Y strain), which made it 26-fold more effective than benznidazole (Bz; 13 μM). It was also active against the Colombiana strain (EC50= 3.8 μM). Analysis of the activity against intracellular forms of the Tulahuen strain showed that this bis-AIA (EC50= 0.04 μM) was about 100-fold more active than Bz (2 μM). The trypanocidal effect was dissociated from the ability to trigger intracellular lipid bodies within host cells, detected by oil red labeling. Both an active compound (35DAP073) and an inactive compound (26SMB060) displayed similar activation profiles. Due to their high selectivity indexes, two AIAs (35DAP073 and 35DAP081) were moved toin vivostudies, but because of the results of acute toxicity assays, 35DAP081 was excluded from the subsequent tests. The findings obtained with 35DAP073 treatment of infections caused by the Y strain revealed that 2 days of therapy induced a dose-dependent action, leading to 96 to 46% reductions in the level of parasitemia. However, the administration of 10 daily doses in animals infected with the Colombiana strain resulted in toxicity, preventing longer periods of treatment. The activity of the combination of 0.5 mg/kg of body weight/day 35DAP073 with 100 mg/kg/day Bz for 10 consecutive days was then assayed. Treatment with the combination resulted in the suppression of parasitemia, the elimination of neurological toxic effects, and survival of 100% of the animals. Quantitative PCR showed a considerable reduction in the parasite load (60%) compared to that achieved with Bz or the amidine alone. Our results support further investigations of this class with the aim of developing novel alternatives for the treatment of Chagas disease.
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: F H
authors: FH
authors: Guedes-da-Silva
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: D G J
authors: DG
authors: Batista
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: M B
authors: MB
authors: Meuser
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: K C
authors: KC
authors: Demarque
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: T O
authors: TO
authors: Fulco
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: J S
authors: JS
authors: Araújo
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: P B
authors: PB
authors: Da Silva
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: C F
authors: CF
authors: Da Silva
authors: University of North Carolina, Chapel Hill, North Carolina, USA.
authors: D A
authors: DA
authors: Patrick
authors: University of North Carolina, Chapel Hill, North Carolina, USA.
authors: S M
authors: SM
authors: Bakunova
authors: University of North Carolina, Chapel Hill, North Carolina, USA.
authors: S A
authors: SA
authors: Bakunov
authors: University of North Carolina, Chapel Hill, North Carolina, USA.
authors: R R
authors: RR
authors: Tidwell
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: G M
authors: GM
authors: Oliveira
authors: Laboratório de Biologia Molecular e Doenças Endêmicas Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: C
authors: C
authors: Britto
authors: Laboratório de Biologia Molecular e Doenças Endêmicas Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors: O C
authors: OC
authors: Moreira
authors: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil soeiro@ioc.fiocruz.br.
authors: M N C
authors: MN
authors: Soeiro
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology; D059208:Parasite Load; D018512:Parasitemia / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D013730:Terphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000577:Amides; D000578:Amidines; D009593:Nitroimidazoles; D013730:Terphenyl Compounds; D014344:Trypanocidal Agents; C009999:benzonidazole