Dataset Information

In Vitro, In Silico, and In Vivo Analyses of Novel Aromatic Amidines against Trypanosoma cruzi.

ABSTRACT: Five bis-arylimidamides were assayed as anti-Trypanosoma cruzi agents by in vitro, in silico, and in vivo approaches. None were considered to be pan-assay interference compounds. They had a favorable pharmacokinetic landscape and were active against trypomastigotes and intracellular forms, and in combination with benznidazole, they gave no interaction. The most selective agent (28SMB032) tested in vivo led to a 40% reduction in parasitemia (0.1 mg/kg of body weight/5 days intraperitoneally) but without mortality protection. In silico target fishing suggested DNA as the main target, but ultrastructural data did not match.

SUBMITTER: Santos CC

PROVIDER: S-EPMC5786784 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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In Vitro, In Silico, and In Vivo Analyses of Novel Aromatic Amidines against Trypanosoma cruzi.

Santos Camila C CC Lionel Jéssica R JR Peres Raiza B RB Batista Marcos M MM da Silva Patrícia B PB de Oliveira Gabriel M GM da Silva Cristiane F CF Batista Denise G J DGJ Souza Sandra Maria O SMO Andrade Carolina H CH Neves Bruno J BJ Braga Rodolpho C RC Patrick Donald A DA Bakunova Svetlana M SM Tidwell Richard R RR Soeiro Maria de Nazaré C MNC

Antimicrobial agents and chemotherapy 20180125 2

Five bis-arylimidamides were assayed as anti-Trypanosoma cruzi agents by in vitro, in silico, and in vivo approaches. None were considered to be pan-assay interference compounds. They had a favorable pharmacokinetic landscape and were active against trypomastigotes and intracellular forms, and in combination with benznidazole, they gave no interaction. The most selective agent (28SMB032) tested in vivo led to a 40% reduction in parasitemia (0.1 mg/kg of body we ...[more]

PMID: 29203486

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Project description: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.

Dataset Information

In Vitro, In Silico, and In Vivo Analyses of Novel Aromatic Amidines against Trypanosoma cruzi.

Publications

<i>In Vitro</i>, <i>In Silico</i>, and <i>In Vivo</i> Analyses of Novel Aromatic Amidines against Trypanosoma cruzi.

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