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.

New approaches in antimalarial drug discovery and development: a review

“…The hybrid molecule MEFAS, which is derived from MQ and AS, is more effective and less toxic than the combination of MQ and AS, as shown using an experimental in vitro test with P. falciparum and in animal models (de Pilla Varotti et al 2008). The hybrid compound comprises dual functions and, as in acridone hybrid molecules, the drug is based on the aminoquinoline ring.…”

Influence of Amodiaquine on the Antimalarial Activity of Ellagic Acid: Crystallographic and Biological Studies

“…A hybrid molecular complex (MEFAS), containing mefloquine and artesunate, was obtained earlier . Antimalarial activity of MEFAS is higher than that of one of its component (mefloquine) and comparable with that of the second (artesunate).…”

Transmission-Blocking Potential of MEFAS, a Hybrid Compound Derived from Artesunate and Mefloquine

“…Knowledge about this combination provides a starting point from which to evaluate the possible dual effects of MEFAS, a potent schizonticidal drug (11). In the current study, the ability of MEFAS to interfere with the final critical steps of P. falciparum gametocyte maturation and gamete formation was demonstrated in vitro.…”

“…MEFAS was less toxic and more effective than AS and MQ applied separately against chloroquine-resistant (clone W2) and chloroquine-sensitive (3D7 strain) P. falciparum in vitro. Additionally, MEFAS was able to cure Plasmodium berghei malaria in experimentally infected mice (11). In this work, the ability of MEFAS to interfere with gametocyte infectivity, male gamete exflagellation, and female gamete activation was evaluated using mature P. falciparum gametocytes cultured in vitro.…”