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Antimicrobial Agents and Chemotherapy, November 2008, p. 3868-3874, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00510-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Synthesis, Antimalarial Activity, and Intracellular Targets of MEFAS, a New Hybrid Compound Derived from Mefloquine and Artesunate{triangledown}

Fernando de Pilla Varotti,1,2 Ana Cristina C. Botelho,3 Anderson Assunção Andrade,1 Renata C. de Paula,1 Elaine M. S. Fagundes,4 Alessandra Valverde,4 Lúcia M. U. Mayer,5 Jorge Souza Mendonça,5 Marcus V. N. de Souza,5 Núbia Boechat,5 and Antoniana Ursine Krettli1,2*

Laboratório de Malária, Instituto de Pesquisas René Rachou-Fundação Oswaldo Cruz, Av. Augusto de Lima 1715, 30190-002 Belo Horizonte, MG, Brasil,1 Programa de Farmacologia Bioquímica e Molecular, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901 Belo Horizonte, MG, Brasil,2 Laboratório de Entomologia Médica, Instituto de Pesquisas René Rachou-Fundação Oswaldo Cruz, Av. Augusto de Lima 1715, 30190-002 Belo Horizonte, MG, Brasil,3 Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, 31270-901 Belo Horizonte, MG, Brasil,4 Instituto de Tecnologia em Fármacos-FarManguinhos-Fundação Oswaldo Cruz, R. Sizenando Nabuco 100, 21041-250 Rio de Janeiro, RJ, Brasil5

Received 18 April 2008/ Returned for modification 18 July 2008/ Accepted 10 August 2008

A new synthetic antimalarial drug, a salt derived from two antimalarial molecules, mefloquine (MQ) and artesunate (AS), here named MEFAS, has been tested for its pharmacological activity. Combinations of AS plus MQ hydrochloride are currently being used in areas with drug-resistant Plasmodium falciparum parasites; although AS clears parasitemia in shorter time periods than any other antimalarial drug, it does not cure infected patients; in addition, MQ causes side effects and is rather expensive, important problems considering that malaria affects mostly populations in poor countries. Here, we show that MEFAS is more effective than the combination of AS and MQ, tested in parallel at different mass proportions, against P. falciparum (chloroquine-resistant clone W2 and chloroquine-sensitive clone 3D7) in vitro and in mice infected with Plasmodium berghei, promoting cure of this infection. MEFAS tested against HepG2 hepatoma cells exhibited lower toxicity than the antimalarials AS and MQ alone or combined. Possible targets of MEFAS have been studied by confocal microscopy using fluorescent probes (Fluo-4 AM and BCECF-AM) in P. falciparum synchronous culture of W2-infected red blood cells. Dynamic images show that MEFAS exhibited intracellular action increasing cytoplasmic Ca2+ at 1.0 ng/ml. This effect was also observed in the presence of tapsigargin, an inhibitor of SERCA, suggesting an intracellular target distinct from the endoplasmic reticulum. Trophozoites loaded with BCECF-AM, when treated with MEFAS, were still able to mobilize protons from the digestive vacuole (DV), altering the pH gradient. However, in the presence of bafilomycin A1, an inhibitor of the H+ pump from acidic compartments of eukaryotic cells, MEFAS had no action on the DV. In conclusion, the endoplasmic reticulum and DV are intracellular targets for MEFAS in Plasmodium sp., suggesting two modes of action of this new salt. Our data support MEFAS as a candidate for treating human malaria.

* Corresponding author. Mailing address: Laboratório de Malária, Instituto de Pesquisas René Rachou—Fundação Oswaldo Cruz, Av. Augusto de Lima 1715, 30190-002 Belo Horizonte, MG, Brasil. Phone: 55 31 3349 7770. Fax: 55 31 3295 3115. E-mail: akrettli{at}cpqrr.fiocruz.br

{triangledown} Published ahead of print on 18 August 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 3868-3874, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00510-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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