title: Oral effectiveness of PMIC4, a novel hydroxyethylpiperazine analogue, in Leishmania amazonensis.
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 μM 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. amazonensis-infected 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.
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Mariela Ferreira de
authors.initials: MF
authors.lastname: Vasconcelos
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Edézio Ferreira da
authors.initials: EF
authors.lastname: Cunha-Júnior
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Valter Viana de
authors.initials: VV
authors.lastname: Andrade-Neto
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Larissa Moreira
authors.initials: LM
authors.lastname: Siqueira
authors.affiliation: Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Cláudia Masini
authors.initials: CM
authors.lastname: d'Avila-Levy
authors.affiliation: Departamento de Síntese de Fármacos, Farmanguinhos, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Marcele
authors.initials: M
authors.lastname: Moreth
authors.affiliation: Laboratório de Química Aplicada à Bioativos, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, Brazil.
authors.forename: Wilson
authors.initials: W
authors.lastname: Cunico
authors.affiliation: Departamento de Síntese de Fármacos, Farmanguinhos, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Marcus Vinícius Nora de
authors.initials: MV
authors.lastname: Souza
authors.affiliation: Departamento de Síntese de Fármacos, Farmanguinhos, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Cláudia Regina Brandão
authors.initials: CR
authors.lastname: Gomes
authors.affiliation: Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Eduardo Caio
authors.initials: EC
authors.lastname: Torres-Santos
keywords: Hydroxyethylamines; In silico ADMET; Leishmaniasis chemotherapy; Oral bioavailability