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Title: | 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. |
Authors: | Guimarães, Daniel Silqueira Martins Luz, Letícia Silveira de Sousa Nascimento, Sara Batista do Silva, Lorena Rabelo Martins, Natália Rezende de Miranda Almeida, Heloísa Gonçalves de Reis, Vitória de Souza Maluf, Sarah El Chamy Budu, Alexandre Marinho, Juliane Aparecida Abramo, Clarice Carmona, Adriana Karaoglanovic Silva, Marina Goulart da Silva, Gisele Rodrigues da Kemmer, Victor Matheus Butera, Anna Paola Viana, Renato Márcio Ribeiro Gazarini, Marcos Leoni Nascimento Júnior, Clébio Soares Guimarães, Luciana Santos, Fabio Vieira dos Castro, Whocely Victor de Ribeiro, Gustavo Henrique Brito, Cristiana Ferreira Alves de Varotti, Fernando de Pilla |
Keywords: | Plasmodium falciparum Antiplasmodial activity Ferriprotoporphyrin-IX |
Issue Date: | 2019 |
Citation: | GUIMARÃES, 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. |
Abstract: | The 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. |
URI: | http://www.repositorio.ufop.br/handle/123456789/12217 |
metadata.dc.identifier.uri2: | https://www.sciencedirect.com/science/article/pii/S0928098719302799?via%3Dihub |
metadata.dc.identifier.doi: | https://doi.org/10.1016/j.ejps.2019.105015 |
ISSN: | 0928-0987 |
Appears in Collections: | DEFAR - Artigos publicados em periódicos |
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File | Description | Size | Format | |
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ARTIGO_ImprovementAntimalarialctivity.pdf Restricted Access | 1,11 MB | Adobe PDF | View/Open |
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