Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle : mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

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dc.contributor.authorGuimarães, Daniel Silqueira Martins
dc.contributor.authorLuz, Letícia Silveira de Sousa
dc.contributor.authorNascimento, Sara Batista do
dc.contributor.authorSilva, Lorena Rabelo
dc.contributor.authorMartins, Natália Rezende de Miranda
dc.contributor.authorAlmeida, Heloísa Gonçalves de
dc.contributor.authorReis, Vitória de Souza
dc.contributor.authorMaluf, Sarah El Chamy
dc.contributor.authorBudu, Alexandre
dc.contributor.authorMarinho, Juliane Aparecida
dc.contributor.authorAbramo, Clarice
dc.contributor.authorCarmona, Adriana Karaoglanovic
dc.contributor.authorSilva, Marina Goulart da
dc.contributor.authorSilva, Gisele Rodrigues da
dc.contributor.authorKemmer, Victor Matheus
dc.contributor.authorButera, Anna Paola
dc.contributor.authorViana, Renato Márcio Ribeiro
dc.contributor.authorGazarini, Marcos Leoni
dc.contributor.authorNascimento Júnior, Clébio Soares
dc.contributor.authorGuimarães, Luciana
dc.contributor.authorSantos, Fabio Vieira dos
dc.contributor.authorCastro, Whocely Victor de
dc.contributor.authorRibeiro, Gustavo Henrique
dc.contributor.authorBrito, Cristiana Ferreira Alves de
dc.contributor.authorVarotti, Fernando de Pilla
dc.date.accessioned2020-05-18T20:55:32Z
dc.date.available2020-05-18T20:55:32Z
dc.date.issued2019
dc.description.abstractThe development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to‑lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 μM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV–vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.pt_BR
dc.identifier.citationGUIMARÃES, D. S. M. et al. Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: mode of action, mutagenicity profile, and Caco-2 cell-based permeability. European Journal of Pharmaceutical Sciences, v. 138, p. 105015-105025, out. 2019. Disponível em: <https://www.sciencedirect.com/science/article/pii/S0928098719302799?via%3Dihub>. Acesso em: 10 fev. 2020.pt_BR
dc.identifier.doihttps://doi.org/10.1016/j.ejps.2019.105015pt_BR
dc.identifier.issn0928-0987
dc.identifier.urihttp://www.repositorio.ufop.br/handle/123456789/12217
dc.identifier.uri2https://www.sciencedirect.com/science/article/pii/S0928098719302799?via%3Dihubpt_BR
dc.language.isoen_USpt_BR
dc.rightsrestritopt_BR
dc.subjectPlasmodium falciparumpt_BR
dc.subjectAntiplasmodial activitypt_BR
dc.subjectFerriprotoporphyrin-IXpt_BR
dc.titleImprovement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle : mode of action, mutagenicity profile, and Caco-2 cell-based permeability.pt_BR
dc.typeArtigo publicado em periodicopt_BR
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