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

Abstract

dMost antimalarial drugs target asexual parasites without reducing gametocyte formation or development. Drugs with dual roles, i.e., those that can target both asexual parasites and gametocytes, would improve the control of malaria. In the current study, MEFAS, a hybrid drug derived from mefloquine and artesunate that has been shown to be an active blood schizonticidal drug, was assessed to determine its ability to block the infectivity of Plasmodium falciparum gametocytes. MEFAS was 280 and 15 times more effective than mefloquine alone and artesunate alone, respectively. D espite significant recent advances in the treatment of malaria, the eradication of this disease, which is a goal of the World Health Organization, has not yet been achieved. An ideal drug should have dual effects, i.e., it should cure the disease and should reduce the infectivity of gametocytes in mosquitoes, thereby limiting transmission (1). Reports of delayed parasite clearance rates in patients treated with artemisinin derivatives have triggered the development of novel antimalarials that target multiple stages of the parasite life cycle, thus blocking infection and transmission (2). Gametocytes, the sexual forms of the parasite that are responsible for parasite development in mosquito vectors, are affected by a few drugs, such as primaquine (PQ), that prevent parasite transmission. This is especially important in Plasmodium falciparum, because the gametocytes of this species survive longer than the asexual forms (3). Although the initial gametocyte stages (stages I to III) are sensitive to most schizonticidal antimalarials, the mature stages (stages IV and V) are sensitive only to PQ (4-6).Single-dose PQ is used as a P. falciparum transmission-blocking drug; long-term PQ treatments (14 days) are used for Plasmodium vivax. In this case, PQ blocks transmission and prevents late relapse (7). However, prolonged use of PQ requires medical supervision, because this drug may cause gastrointestinal problems and severe hemolytic anemia in patients who lack the glucose-6-phosphate dehydrogenase (G6PD) enzyme (8, 9).New antimalarial drugs with different biological functions and distinct pharmacophores include hybrids that are covalently linked to single compounds (10). MEFAS, a hybrid salt derived from artesunate (AS) and mefloquine (MQ), was synthesized on a large scale and evaluated for chemical purity (N. Boechat, M. V. N. de Souza, A. L. Valverde, and A. U. Krettli, international patent application WO 2005/100370 A1). 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.Two gametocyte-producing P. falciparum strains, 3D7...

Commercial drugs containing flavonoids are active in mice with malaria and in vitro against chloroquine-resistant Plasmodium falciparum

“…Discovering and developing new drugs, active against the sexual and asexual forms of the parasite, 6 and increasing new available antimalarial options, should reduce the dilemma of malaria control, which has few therapeutic alternatives.…”

Antimalarial and antioxidant activities of novel artesunate-ellagic acid hybrid compound in vitro and in vivo

“…Reports so far indicate that hybrid molecules are effective against all Plasmodium species including resistant strains ( Lödige and Hiersch, 2015 ). Notably, MEFAS, a hybrid compound of mefloquine and artesunate, was highly effective against chloroquine-resistant strains and also exhibited low cytotoxicity ( Varotti et al, 2008 ; Penna-Coutinho et al, 2016 ). Peptide-quinine hybrid compounds have also been synthesized.…”

The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines

“…The combined fixed dose of ASMQ (artesunate + mefloquine) was 3-fold more toxic than MEFAS [42]. MEFAS has been demonstrated to be an active blood schizonticidal and can also block the infectivity of P. falciparum gametocytes, 280- and 15-fold more effectively than mefloquine and artesunate alone, respectively [43]. These results make this compound very promising to target both the asexual parasites and gametocytes, improving the antimalarial effects.…”