Biological evaluation of hydroxynaphthoquinones as anti-malarials

Malaria Journal

Research

Miriam S Moraes¹  Desiree C Schuck¹  Myna Nakabashi¹  Laura N Cruz¹  Celia RS Garcia²  David R da Rocha³  Vitor F Ferreira³  Sabrina B Ferreira⁴  Philip J Rosenthal⁵ 

[1] Departamento de Fisiologia, Universidade de São Paulo, 05508-900, São Paulo, Brazil;Departamento de Fisiologia, Universidade de São Paulo, 05508-900, São Paulo, Brazil;Instituto de Biociências, Rua do Matão, Universidade de São Paulo, travessa 14, n.321 Cidade Universitária, CEP 05508-900, São Paulo, SP, Brazil;Departamento de Química Orgânica, Universidade Federal Fluminense, 24020-141, Niterói, Brazil;Departamento de Química Orgânica, Universidade Federal Fluminense, 24020-141, Niterói, Brazil;Departamento de Química Orgânica, Universidade Federal do Rio de Janeiro, 27930-560, Macaé, Brazil;Department of Medicine, University of California, 94143, San Francisco, CA, USA;

关键词: Plasmodium falciparum;    Hydroxynaphthoquinone;    2-hydroxy-1,4-naphthoquinone;    Mitochondria;    Malaria;    Plasmodium berghei;   

DOI  :  10.1186/1475-2875-12-234

 received in 2012-12-14, accepted in 2013-06-12,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe hydroxynaphthoquinones have been extensively investigated over the past 50 years for their anti-malarial activity. One member of this class, atovaquone, is combined with proguanil in Malarone®, an important drug for the treatment and prevention of malaria.MethodsAnti-malarial activity was assessed in vitro for a series of 3-alkyl-2-hydroxy-1,4-naphthoquinones (N1-N5) evaluating the parasitaemia after 48 hours of incubation. Potential cytotoxicity in HEK293T cells was assessed using the MTT assay. Changes in mitochondrial membrane potential of Plasmodium were measured using the fluorescent dye Mitrotracker Red CMXROS.ResultsFour compounds demonstrated IC50s in the mid-micromolar range, and the most active compound, N3, had an IC50 of 443 nM. N3 disrupted mitochondrial membrane potential, and after 1 hour presented an IC50ΔΨmit of 16 μM. In an in vitro cytotoxicity assay using HEK 293T cells N3 demonstrated no cytotoxicity at concentrations up to 16 μM.ConclusionsN3 was a potent inhibitor of mitochondrial electron transport, had nanomolar activity against cultured Plasmodium falciparum and showed minimal cytotoxicity. N3 may serve as a starting point for the design of new hydroxynaphthoquinone anti-malarials.

【 授权许可】

Unknown   
© Schuck et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.