DEFAR - Departamento de Farmácia

URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530

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    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.
    (2019) 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
    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.