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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; Elsevier BV; Volume: 138; Linguagem: Inglês

10.1016/j.ejps.2019.105015

1879-0720

Daniel Silqueira Martins Guimarães, Letícia Silveira de Sousa Luz, Sara Batista do Nascimento, Lorena Rabelo Silva, Natália Rezende de Miranda Martins, Heloísa Gonçalves de Almeida, Vitória de Souza Reis, Sarah El Chamy Maluf, Alexandre Budu, Juliane Aparecida Marinho, Clarice Abramo, Adriana K. Carmona, Marina Goulart da Silva, Gisele Rodrigues da Silva, Victor Matheus Kemmer, Anna Paola Butera, Renato Ribeiro-Viana, Marcos L. Gazarini, Clébio Soares Nascimento Júnior, Luciana Guimarães, Fábio Vieira dos Santos, Whocely Victor de Castro, Gustavo Henrique Ribeiro Viana, Cristiana Ferreira Alves de Brito, Fernando de Pilla Varotti,

Synthesis and biological activity

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.