Target-Guided Synthesis and Antiplasmodial Evaluation of a New Fluorinated 3-Alkylpyridine Marine Alkaloid Analog

Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil/Universidade Federal de São João del-Rei. Departamento de Ciências Naturais. São João Del Rei, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil/Universidade Federal de São João del-Rei. Departamento de Ciências Naturais. São João Del Rei, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil/Universidade Federal de São João del-Rei. Departamento de Ciências Naturais. São João Del Rei, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil/Universidade Tecnológica Federal do Paraná. Departamento Acadêmico de Química. Londrina, PR, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil
Universidade Federal de São João del-Rei. Núcleo de Pesquisa em Química Biológica. Divinópolis, MG, Brazil

Abstract

The need to develop new alternatives for antimalarial treatment is urgent. Herein, we report the synthesis and antimalarial evaluation of a small library of synthetic 3-alkylpyridine marine alkaloid (3-APA) analogs. First, the compounds were evaluated in vitro against Plasmodium falciparum. The most active compound 5c was selected for optimization of its antimalarial properties. An in silico approach was used based on pure ab initio electronic structure prediction, and the results indicated that a substitution of the hydroxyl group by a fluorine atom could favor a more stable complex with heme at a molecular ratio of 2:1 (heme/3-APA halogenated). A new fluorinated 3-APA analog was synthesized (compound 7), and its antimalarial activity was re-evaluated. Compound 7 exhibited optimized antimalarial properties (P. falciparum IC50 = 2.5 μM), low genotoxicity, capacity to form a more stable heme/3-APA complex at a molecular ratio of 2:1, and conformity to RO5. The new compound, therefore, hás great potential as a new lead antimalarial agent.

Keywords in Portuguese

Malaria
vacina

Keywords

Malaria
vaccine

Publisher

American Chemical Society

Citation

BARBOSA, Camila de Souza et al.Target-Guided Synthesis and Antiplasmodial Evaluation of a New Fluorinated 3-Alkylpyridine Marine Alkaloid Analog. ACS Omega, v. 2, p. 8264-8272, 2017.

DOI

10.1021/acsomega.7b01302

ISSN

2470-1343

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/26982

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Copyright

Restricted access

Embargo date

2080-01-01

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