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

  • PLoS One. 2022 Jun 6;17(6):e0269447. doi: 10.1371/journal.pone.0269447.
Aline Cavalcanti de Queiroz  1  2  3 ,  Gisele Barbosa  1 ,  Victória Regina Thomaz de Oliveira  1 ,  Hélio de Mattos Alves  1 ,  Marina Amaral Alves  1 ,  Vanessa Carregaro  4 ,  João Santana da Silva  4 ,  Eliezer Jesus Barreiro  1 ,  Magna Suzana Alexandre-Moreira  1  2 ,  Lidia Moreira Lima  1
Affiliations
  • 1. National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio®, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil.
  • 2. Laboratory of Pharmacology and Immunity (LaFI), Sector of Physiology and Pharmacology, ICBS, UFAL, Maceió, Alagoas, Brazil.
  • 3. Laboratory of Microbiology, Immunology and Parasitology, Center for Medical Sciences, Campus Arapiraca, Federal University of Alagoas, Arapiraca, Alagoas, Brazil.
  • 4. Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
PMID: 35666748 DOI: 10.1371/journal.pone.0269447
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 the in vitro pharmacokinetic study of LASSBio-1491 (a less lipophilic isostere of LASSBio-1736) and it is in vitro and in vivo leishmanicidal activities. Our results demonstrated that LASSBio-1491 has high permeability, satisfactory aqueous solubility, long plasma and microsomal half-lives and low in vitro systemic clearance, suggesting a pharmacokinetic profile suitable for its use in a single daily dose. The antileishmanial effect of LASSBio-1491 was confirmed in vitro and in vivo. It exhibited no cytotoxic effect to mammalian cells and displayed good in -vivo effect against BALB/c mice infected with Leishmania major LV39 substrain, being 3 times more efficient than glucantime.

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