Philippe Rasoanaivo

Medicinal plants used to treat malaria in Madagascar

Two-hundred thirty-nine Madagascan medicinal plants have been either retrieved from computerized ethnobotany information or identified in our own ethnomedicine work as having antimalarial properties. Such a high rate percent of plants compared to those used empirically to treat other diseases reflects the importance and the complication of this major tropical disease in Madagascar.

A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

Background The global spread of multidrug–resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s. Methods and Findings Using bioassay-guided fractionation based on the parasites hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 μM, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 μM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 μM, TI 46, and IC50 42.4 μM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages. Conclusions A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs.

Modulation of the Multidrug-Resistance Phenotype by New Tropane Alkaloid Aromatic Esters from Erythroxylum pervillei

Nine tropane alkaloid aromatic esters (1-9) were isolated from the roots of Erythroxylum pervillei by following their potential to reverse multidrug-resistance with vinblastine-resistant oral epidermoid carcinoma (KB-V1) cells. All isolates, including seven new structures (3-9), were evaluated against a panel of human cancer cell lines, and it was found that alkaloids 3 and 5-9 showed the greatest activity with KB-V1 cells assessed in the presence of vinblastine, suggesting that these new compounds are potent modulators of P-glycoprotein. Confirmatory results were obtained with human ovarian adenocarcinoma (SKVLB) cells evaluated in the presence of adriamycin and synergistic studies performed with several cell lines from the NCI tumor panel. The structures of the new compounds were determined using spectroscopic techniques. Single-crystal X-ray analysis was performed on the monoester, tropane-3 alpha,6 beta,7 beta-triol 3-phenylacetate (1).

Criblage d’extraits de plantes de Madagascar pour recherche d’activité antipaludique et d’effet potentialisateur de la chloroquine

Cinquante plantes endemiques de Madagascar ont ete soumises a un criblage biologique dans le but de rechercher une activite antiplasmodiale in vitro et une activite modulatrice de la chloroquine sur la souche chloroquinoresistante FCM29. Douze plantes ont montre une activite antiplasmodiale in vitro significative (CI50<5 μg/ml). Sept d’entre elles sont utilisees en medecine traditionnelle pour traiter le paludisme ou la fievre. Le resultat le plus saillant du fractionnement bioguide a ete la mise en evidence d’une activite antiplasmodiale tres marquee (CI50=0.08 μg/ml) d’une dehydroaporphine, la dehydrodicentrine. Sur 34 extraits testes, seul l’extrait alcaloidique de Strychnos sp. (nom vernaculaire Tsivoanino) et ses constituants isoles a l’etat pur ont montre une activite modulatrice de la chloroquine.

Antiplasmodial phenolic compounds from Piptadenia pervillei.

Piptadenia pervillei Vatke (Fabaceae) was selected from a screening programme devoted to the search of naturally-occuring antimalarial compounds from plants of Madagascar. Bioassay-guided fractionation of the ethyl acetate extract of the leaves led to the isolation of four phenolic compounds, (+)-catechin ( 1), (+)-catechin 5-gallate ( 2), (+)-catechin 3-gallate ( 3) and ethyl gallate ( 4). Structures were determined by NMR and mass spectroscopy. Compounds 2 and 3 displayed the highest in vitro activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum with IC (50) values of 1.2 microM and 1.0 microM, respectively, and no significant cytotoxicity against the human embryonic lung cells MRC-5 was measured (IC (50) values > 75 microM). Five analogues ( 5 - 9) of (+)-catechin 5-gallate ( 2) were synthesized and evaluated for their antiplasmodial activity.

Reversal activity of the naturally occurring chemosensitizer malagashanine in Plasmodium malaria

Malagashanine (MG) is the parent compound of a new type of indole alkaloids, the N(b)C(21)-secocuran, isolated so far from the Malagasy Strychnos species traditionally used as chloroquine adjuvants in the treatment of chronic malaria. Previously, it was shown to have weak in vitro intrinsic antiplasmodial activity (IC(50) = 146.5 +/- 0.2 microM), but did display marked in vitro chloroquine-potentiating action against the FcM29 chloroquine-resistant strain of Plasmodium falciparum. The purpose of the present study was to further investigate its reversal activity. Thus, the previous in vitro results were tested in vivo. The interaction of MG with several antimalarials against various strains of P. falciparum was also assessed. As expected, MG enhanced the effect of chloroquine against the resistant strain W2, but had no action on the susceptible strain 3D7 and two sensitive isolates. Interestingly, MG was found to exhibit significant chloroquine-potentiating action against the FcB1 strain formerly described as a resistant strain but one which has since lost its resistance for unknown reasons. One other relevant result that arose from our study was the observation of the selective enhancing action of MG on quinolines (chloroquine, quinine, and mefloquine), aminoacridines (quinacrine and pyronaridine), and a structurally unrelated drug (halofantrine), all of which are believed to exert their antimalarial effect by binding with haematin. MG was finally found to specifically act with chloroquine on the old trophozoite stage of the P. falciparum cycle. Similarities and differences between verapamil and MG reversal activity are briefly presented.

Biological activities of the plant-derived bisindole voacamine with reference to malaria.

The in vivo antiplasmodial activity of voacamine was assessed in a 4‐day test. It was shown to exhibit in vivo activity with 25.4% and 43.4% inhibition of parasitaemia with 2.5 and 10 mg/kg, respectively. In synchronized cultures, it was found to act on trophozoite and schizont stages of Plasmodium falciparum. Using the FMC29 strain of Plasmodium falciparum as parasite and the isobologram curve as a method to assess interaction in drug combination, it was shown to lack any chloroquine‐enhancing activity and its in vitro antiplasmodial effect was not potentiated by the chemosensitizer malagashanine. Copyright

Two prenylated isoflavanones from Millettia pervilleana

Abstract From the root bark of Millettia pervilleana , which showed high cytotoxic activity, two prenylated isoflavanones were isolated. Their structures were determined by means of chemical and spectroscopic properties to be (3 R )-2′,7-dihydroxy-3′,4′-dimethoxy-5′- α , α -dimethylallylisoflavanone, named pervilleanone, and its 3′- O -demethyl derivative.

Goniomedines A and B: Unprecedented Bisindole Alkaloids Formed through Fusion of Two Indole Moieties via a Dihydropyran Unit

Two novel bisindole alkaloids, goniomedines A (1) and B (2), possessing an unprecedented quebrachamine-pleioarpamine-type skeleton, in which indole moieties are fused via a dihydropyran unit, were isolated from the stem bark of Gonioma malagasy. The structures were elucidated by comprehensive analysis of MS and NMR spectroscopic data. Their absolute configurations were deduced following the comparison of experimental and theoretically calculated ECD spectra and through biogenetic considerations. Goniomedine B (2) exhibited moderate activity against Plasmodium falciparum.

Chemical constituents of Anacolosa pervilleana and their antiviral activities.

In an effort to identify novel inhibitors of Chikungunya (CHIKV) and Dengue (DENV) virus replication, a systematic study with 820 ethyl acetate extracts of Madagascan plants was performed in a virus-cell-based assay for CHIKV and a DENV NS5 RNA-dependant RNA polymerase (RdRp) assay. The extract obtained from the leaves of Anacolosa pervilleana was selected for its significant activity in both assays. One new (E)-tridec-2-en-4-ynedioic acid named anacolosine (1), together with three known acetylenic acids, the octadeca-9,11,13-triynoic acid (2), (13E)-octadec-13-en-9,11-diynoic acid (3), (13E)-octadec-13-en-11-ynoic acid (4), two terpenoids, lupenone (5) and β-amyrone (6), and one cyanogenic glycoside, (S)-sambunigrin (7) were isolated. Their structures were elucidated by comprehensive analyses of NMR spectroscopy and mass spectrometry data. The inhibitory potency of these compounds was evaluated on CHIKV, DENV RdRp and West-Nile polymerase virus (WNV RdRp). Both terpenoids showed a moderate activity against CHIKV (EC(50) 77 and 86 μM, respectively) and the acetylenic acids produced IC(50) values around 3 μM in the DENV RdRp assay.