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Eur J Pharm Sci. 2019 Oct 1;138:105015. doi: 10.1016/j.ejps.2019.105015. Epub 2019 Jul 22.

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.

Author information

1
Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 1715 Augusto de Lima Avenue, Belo Horizonte, MG 30190-009, Brazil.
2
Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João Del-Rei - Campus Centro Oeste, 400 Sebastião Gonçalves Coelho Street, Divinópolis, MG 35501-296, Brazil.
3
Universidade Federal de São João del-Rei, Campus Dom Bosco, 74 Dom Helvécio Square, São João del Rei, MG 36301-160, Brazil.
4
Universidade Federal de São Paulo, Departamento de Biofísica, 669 Pedro de Toledo Street, São Paulo, SP 04039-032, Brazil.
5
Universidade Federal de São Paulo, Departamento de Biofísica, 669 Pedro de Toledo Street, São Paulo, SP 04039-032, Brazil. Electronic address: alexandre.budu@unifesp.br.
6
Núcleo de Pesquisas em Parasitologia, Universidade Federal de Juiz de Fora, José Lourenço Kelmer Street, Juiz de Fora, MG 36036-900, Brazil.
7
Núcleo de Pesquisas em Parasitologia, Universidade Federal de Juiz de Fora, José Lourenço Kelmer Street, Juiz de Fora, MG 36036-900, Brazil. Electronic address: clarice.abramo@ufjf.edu.br.
8
Universidade Federal de São Paulo, Departamento de Biofísica, 669 Pedro de Toledo Street, São Paulo, SP 04039-032, Brazil. Electronic address: ak.carmona@unifesp.br.
9
Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João Del-Rei - Campus Centro Oeste, 400 Sebastião Gonçalves Coelho Street, Divinópolis, MG 35501-296, Brazil. Electronic address: marina@ufsj.edu.br.
10
Universidade Federal de Ouro Preto, Departamento de Farmácia, Campus Morro do Cruzeiro, w/n, Bauxita, Ouro Preto, MG 35400-000, Brazil. Electronic address: giselersilva@ufop.edu.br.
11
Universidade Estadual de Londrina, Departamento de Química, Londrina, PR 86057-970, Brazil.
12
Universidade Estadual de Londrina, Departamento de Química, Londrina, PR 86057-970, Brazil. Electronic address: paolabut@uel.br.
13
Universidade Tecnológica Federal do Paraná, Departamento Acadêmico de Química (DAQUI), Londrina, PR, 6036-370, Brazil. Electronic address: renatoviana@utfpr.edu.br.
14
Universidade Federal de São Paulo, Departamento de Biociências, 136 Silva Jardim Street, Santos, SP 11015-020, Brazil. Electronic address: marcos.gazarini@unifesp.br.
15
Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João Del-Rei - Campus Centro Oeste, 400 Sebastião Gonçalves Coelho Street, Divinópolis, MG 35501-296, Brazil. Electronic address: fabiosantos@ufsj.edu.br.
16
Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João Del-Rei - Campus Centro Oeste, 400 Sebastião Gonçalves Coelho Street, Divinópolis, MG 35501-296, Brazil. Electronic address: whocely@ufsj.edu.br.
17
Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João Del-Rei - Campus Centro Oeste, 400 Sebastião Gonçalves Coelho Street, Divinópolis, MG 35501-296, Brazil. Electronic address: viana@ufsj.edu.br.
18
Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), 1715 Augusto de Lima Avenue, Belo Horizonte, MG 30190-009, Brazil. Electronic address: cristiana.brito@fiocruz.br.
19
Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João Del-Rei - Campus Centro Oeste, 400 Sebastião Gonçalves Coelho Street, Divinópolis, MG 35501-296, Brazil. Electronic address: varotti@ufsj.edu.br.

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.

KEYWORDS:

3-Alkylpyridine marine alkaloid analogs; Antiplasmodial activity; Ferriprotoporphyrin-IX; Malaria; Plasmodium falciparum; Thiazole

PMID:
31344442
DOI:
10.1016/j.ejps.2019.105015
[Indexed for MEDLINE]

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