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

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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.
Funding Information
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (465.249/2014-0)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E- 26/010.000090/2018 and E-26/202.676/2019)
  • Fundação de Amparo à Pesquisa do Estado de Alagoas
  • Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (465.249/2014-0 and E- 26/010.000090/2018)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (001)

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