Pre-clinical evaluation of LASSBio-1491: From in vitro pharmacokinetic study to in vivo leishmanicidal activity

Author:

de Queiroz Aline CavalcantiORCID,Barbosa GiseleORCID,de Oliveira Victória Regina Thomaz,de Mattos Alves Hélio,Alves Marina Amaral,Carregaro Vanessa,Santana da Silva João,Barreiro Eliezer Jesus,Alexandre-Moreira Magna Suzana,Lima Lidia MoreiraORCID

Abstract

Leishmaniasis is a public health issue. It is among the top five parasitic illnesses worldwide and is one of the most neglected diseases. The current treatment disease includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. LASSBio-1736 was described as antileishmanial drug-candidate to cutaneous leishmaniasis, displaying plasma stability and with no preliminary signals of hepatic or renal toxicity. In this paper, we described thein vitropharmacokinetic study of LASSBio-1491 (a less lipophilic isostere of LASSBio-1736) and it isin vitroandin vivoleishmanicidal activities. Our results demonstrated that LASSBio-1491 has high permeability, satisfactory aqueous solubility, long plasma and microsomal half-lives and lowin vitrosystemic clearance, suggesting a pharmacokinetic profile suitable for its use in a single daily dose. The antileishmanial effect of LASSBio-1491 was confirmedin vitroandin vivo. It exhibited no cytotoxic effect to mammalian cells and displayed goodin –vivoeffect against BALB/c mice infected with Leishmania major LV39 substrain, being 3 times more efficient than glucantime.

Funder

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

Fundação de Amparo à Pesquisa do Estado de Alagoas

Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Publisher

Public Library of Science (PLoS)

Subject

Multidisciplinary

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