Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/10184
Title: Oral effectiveness of PMIC4, a novel hydroxyethylpiperazine analogue, in Leishmania amazonensis
Authors: Vasconcelos, Mariela Ferreira de
Cunha Júnior, Edézio Ferreira da
Andrade Neto, Valter Viana de
Siqueira, Larissa Moreira
Levy, Cláudia Masini D`Avila
Moreth, Marcele
Cunico, Wilson
Souza, Marcus Vinicius Nora de
Gomes, Cláudia Regina Brandão
Santos, Eduardo Caio Torres
Affilliation: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Síntese de Fármacos. Rio de Janeiro, RJ, Brasil.
Universidade Federal de Pelotas. Centro de Ciências Químicas, Farmacêuticas e de Alimentos. Laboratório de Química Aplicada à Bioativos. Pelotas, RS, Brasil.
Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Síntese de Fármacos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Farmanguinhos. Departamento de Síntese de Fármacos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ, Brasil.
Abstract: Pentavalent antimonials have saved the lives of thousands of Leishmania-infected patients more than seventy years but, unfortunately, they are highly toxic and require parenteral delivery. Therefore, the search for safer and orally delivered alternative is a need. This paper describes the antileishmanial properties of PMIC4, a novel hydroxyethylpiperazine analogue. PMIC4 showed potent activity against intracellular amastigotes of Leishmania amazonensis, with IC50 of 1.8 lM and selectivity index higher than 100-fold, calculated in relation to the toxicity on the host cell. Following laboratory animal welfare policies, we analyzed the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and calculated the Lipinski’s rule of five of PMIC4 before proceeding to in vivo tests. PMIC4 satisfied Lipinski’s rule of five and presented high probability of human intestinal absorption, suggesting a good chance of druglikeness and oral bioavailability. For in vivo studies, PMIC4 was administered via intralesional injection (3.4 mg/kg/day, three times a week) or orally (34.0 mg/kg/day, five times a week) to L. amazonensisinfected BALB/c mice throughout the 98 day experiments. At the end of the treatment period, serum markers of toxicity were measured. When administered orally, PMIC4 controlled the lesions in L. amazonensis- infected BALB/c mice without altering serological markers of toxicity. These results demonstrate that PMIC4 is a promising molecular scaffold, orally effective against experimental leishmaniasis.
Keywords: Leishmaniasis chemotherapy
Hydroxyethylamines
Oral bioavailability
In silico ADMET
Keywords in spanish: Leishmania
keywords: Leishmania
DeCS: Ciências Biológicas
Issue Date: 2014
Publisher: ScienceDirect
Citation: VASCONCELOS, Mariela Ferreira de et al. Oral effectiveness of PMIC4, a novel hydroxyethylpiperazine analogue, in Leishmania amazonensis. International Journal for Parasitology: Drugs and Drug Resistance, v.4, n,3, p.210-213, 2014.
DOI: 10.1016/j.ijpddr.2014.10.005
ISSN: 2211-3207
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos

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