title: Synthesis, antimalarial activity, and intracellular targets of MEFAS, a new hybrid compound derived from mefloquine and artesunate.
abstract: 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 Ca(2+) 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.
authors: Laboratório de Malária, Instituto de Pesquisas René Rachou-Fundação Oswaldo Cruz, Belo Horizonte, MG, Brasil.
authors: Fernando
authors: F
authors: de Pilla Varotti
authors: Ana Cristina C
authors: AC
authors: Botelho
authors: Anderson Assunção
authors: AA
authors: Andrade
authors: Renata C
authors: RC
authors: de Paula
authors: Elaine M S
authors: EM
authors: Fagundes
authors: Alessandra
authors: A
authors: Valverde
authors: Lúcia M U
authors: LM
authors: Mayer
authors: Jorge Souza
authors: JS
authors: Mendonça
authors: Marcus V N
authors: MV
authors: de Souza
authors: Núbia
authors: N
authors: Boechat
authors: Antoniana Ursine
authors: AU
authors: Krettli
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D037621:Artemisinins / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000077332:Artesunate; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008288:Malaria / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy; D015767:Mefloquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; D015767:Mefloquine