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International audience; Tithonia diversifolia, Cyclea barbata, Tinospora crispa, Arcangelisia flava, Pycnarrhena cauliflora are plants used in Indonesia for the traditional treatment of malaria. In the search for new antiparasitic drugs, the parts traditionally used of these 5 plants were extracted with ethanol and then fractionated with various solvents and evaluated in vitro against Plasmodium falciparum and also against Babesia divergens and Leishmania infantum. Seven crude plant extracts out of 25 tested displayed high antimalarial activities with IC50

Malaria treatment with ACTs (Artemisinin-based Combination Therapies), combining a chemical derivative of artemisinin, and a partner drug has, for more than 15 years, produced a notable decrease in the mortality in tropical and subtropical areas. However, since 2008, a serious threat has emerged in western Cambodia, where the clinical efficacy of artemisinins has significantly declined, with a delayed parasite clearance rate and high recrudescence rates in the following weeks. Resistance of Plasmodium to artemisinins is now reported in several countries in South-East Asia. ACTs remain effective as long as the partner drug retains its activity but more and more clinical failures related to parasite resistance to both resistant parasites in sub-Saharan Africa, the continent most affected by malaria, as was the case in the past with other antimalarial treatments. It is therefore essential to better understand, from phenotypic and genotypic points of view, the mechanisms of resistance developed by the parasite Plasmodium falciparum face artemisinin and its derivatives in order to offer new therapeutic tools.

From a library of compounds of natural sources, a big series of molecules was chosen by random sampling to evaluate their in vitro antimalarial activity against Plasmodium falciparum and their antifungal activity against Candida sp. From 184 molecules tested, no molecules were active against Candida sp. (MIC > 10 μg/ml) whereas 13 clearly showed high antiplasmodial activity in vitro , with an IC 50 less than 1 μg/ml against the chloroquine-resistant strain of P. falciparum FcM29-Cameroon. The molecules with the best antiplasmodial efficacy were 10-hydroxy-ellipticin (IC 50 : 0.08 μg/ml), tchibangensin (IC 50 : 0.13 μg/ml), ellipticin hydrochloride (IC 50 : 0.17 μg/ml), usambarensin (IC 50 : 0.23 μg/ml), 7S,3S-ochropposinine oxindole (IC 50 : 0.25 μg/ml), 3,14-dihydro-ellipticin (IC 50 : 0.25 μg/ml), tetrahydro-4′,5′,6′17-usambarensin 17S (IC 50 : 0.26 μg/ml), ellipticine (IC 50 : 0.28 μg/ml), aricin (IC 50 : 0.3 μg/ml), 10-methoxy-ellipticin (IC 50 : 0.32 μg/ml), aplysinopsin (IC 50 : 0.43 μg/ml), descarbomethoxydihydrogambirtannin (IC 50 : 0.46 μg/ml) and ochrolifuanin A (IC 50 : 0.47 μg/ml). Among these 13 promising molecules, all except descarbomethoxydihydrogambirtannin, ochrolifuanine A and usambarensine presented here novel biological activities since they had never been described in the literature for their antiplasmodial activity. In spite of the large diversity of the molecules which have been tested, it is interesting to note that the ones active against Plasmodium are all indole derivatives (and one is both indolic and aminoimidazolic). To find new antiplasmodial compounds, ethnopharmacological approaches studying traditional medicine treatments for malaria is largely used but random research produced here an interesting yield (7%) of new antiplasmodial hits and appears therefore complementary to the traditional medicine way.

Mature gametocytes, the sexual stage of Plasmodium falciparum, ensure the continued transmission of malaria from the human host to the mosquito vector. Even if gametocytes are not implicated in the malaria physiopathology it is crucial to the spread of malaria. Gametocytes are to be a key target for drugs used against Plasmodium in public health. The expression levels of 4 sexual-stage specific genes, Pfs 16, Pfs 25, Pfg 27 and S 18S rRNA, during gametocytogenesis of various P. falciparum strains were analyzed by a real time PCR assay. The strains showed different capacities to produce mature gametocytes and in parallel different patterns of sexual gene expression. There was a correlation only between Pfs 16 cDNA overexpression in the first 48h of the culture and the production of mature gametocytes. Pfs 16 is an early marker of the development of mature gametocytes in cultures and is therefore a potential target for new antimalarial drugs.

Considerable progress has been made in antimalarial research; however, much more effort is required to develop new antimalarials which overcome plasmodial resistance to clinically available drugs and limit the emergence of resistance. In particular, research must focus on understanding the mechanisms by which Plasmodium falciparum impedes the action of these drugs. In this review, we discuss the different in vitro and in vivo models used to adequately study resistance to antimalarial compounds. For each molecule studied, the best in vitro and/or in vivo model is highlighted with a detailed discussion of its validity in relation to field data on P. falciparum resistance.

Pure natural monoterpenes were evaluated in vitro for their antiplasmodial activities against Plasmodium falciparum. Chemically modified terpenes were also tested to see whether the introduction of an alkyne, a cyclopropane, a diene, or a cyclopentenone moiety had an influence on the biological activity. The IC(50) obtained on a chloroquine-resistant strain of Plasmodium (FcM29-Cameroon) showed moderate activity, but with the alkyne and the cyclopentenone derivatives showing a promising enhancement of activity compared with the parent molecules. On the contrary, no antifungal activity was found in vitro using Candida albicans. Given the observed antiplasmodial activity of some of these modified monoterpenes, new monoterpene derivatives could be the basis for new antimalarial drugs to be researched.

Ethnopharmacology is a very interesting resource in which new therapies may be discovered. In the case of malaria, two major antimalarial drugs widely used today came originally from indigenous medical systems, that is quinine and artemisinin, from Peruvian and Chinese ancestral treatments, respectively. There is an urgent need for the discovery of new drugs due to the critical epidemiological situation of this disease. New inexpensive therapies that are simple to use and that will limit the cost of drug research are good justifications for this ethnopharmacological approach. Therefore, the aim of this review is to empirically analyse plants that are used for antimalarial treatment in West Africa, and to determine those with real promising antimalarial activity. The major leads such as those extracted from Cochlospermum, Cryptolepsis, Guiera and Azadirachta have been highlighted. Indeed, some extracts seem to be promising in future research, but development of new isolation and characterization techniques, for designing new derivatives with improved properties need to be discussed.

Artemisinin is an efficient antimalarial drug containing a 1,2,4-trioxane, which is able to alkylate heme both in vitro and in vivo, giving rise to covalent heme–artemisinin coupling products. The low valent iron(II) protoporphyrin-IX, which is the prosthetic group of hemoglobin, induces the homolysis of the peroxide bond of artemisinin by an inner-sphere electron transfer. The generated alkoxy radical is quickly rearranged to a C-centered radical, which efficiently alkylates the heme macrocycle at meso positions. Heme is therefore both the activating agent and the target of artemisinin. On the basis of this mechanism of action, a new family of peroxide-based antimalarials named trioxaquines ® has been synthesized. Trioxaquines are made by the covalent attachment of a trioxane, having alkylating ability, to a quinoline, known to easily penetrate within infected erythrocytes. Several trioxaquines are active in vitro on chloroquine resistant malaria parasite at nanomolar concentration, and are efficient by oral route to cure infected mice at 20–50 mg/kg.

The aim of this work was to assess the efficacy of oral N'Dribala (tuberous roots decoction of Cochlospermum planchonii Hook) treatment versus chloroquine in non-severe malaria. The study included 85 patients with uncomplicated Plasmodium falciparum infection in Banfora, Burkina Faso. Forty-six patients that received N'Dribala beverage were compared to 21 patients treated with chloroquine. All patients were monitored with clinical examination and a parasitemia control by Giemsa-stained thick films. N'Dribala appeared safe and statistically as efficient as chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria. At day 5 (D5), 57% of chloroquine-treated and 52% of N'Dribala-treated patients were cured with no detectable parasitemia (parasite density (Pd): 0) and more than 90% of whole patients were asymptomatic. N'Dribala is easily available in this country, cheap, without significant side effects and efficient with a clearly demonstrated activity on Plasmodium falciparum blood stages. This study enhances the traditional use of the Cochlospermum planchonii as alternative therapy for treatment of non-severe malaria.

Iridal, a triterpenoidic compound extracted from Iris germanica L., was previously shown to have an interesting activity on two cultured human tumor cell lines (A2780 and K562). In the present work, this same product was tested in vitro on Plasmodium falciparum chloroquine-resistant and -sensitive strains, in vivo on P. vinckei, and on some Candida albicans and C. parapsilosis strains too. The IC(50) obtained in vitro on human malaria strain ranged from 1.8 to 26.0 microg/ml and the ED(50) in vivo is about 85 mg/kg/day by intraperitoneal route. The minimal inhibitory concentrations were higher than to 50 microg/ml, whatever the strain of yeast tested. This product presents an antiplasmodial activity similar to that obtained with extracts from the plant Azadirachta indica classically taken as reference in malaria phytomedicine. Conversely iridal shows no important antifungal activity. The specific activity of iridal on human malaria parasite and on tumor cell lines is discussed.

The preparation and the biological evaluation of a new antimalarial modular drug, named trioxaquine are reported. The trioxane moiety of this trioxaquine is prepared through the halogenocyclisation of a hemiperoxyacetal derived from the allylic hydroperoxide of 2,3-dimethyl-2-butene.