Akino Jossang

Isocryptolepine from Cryptolepis sanguinolenta

A new alkaloid, 5-methyl, 5H-indolo-[3,2-c]-quinoline named isocryptolepine, has been isolated from the roots of Cryptolepis sanguinolenta and its structure determined from spectroscopic data, including IR, MS and NMR.

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.

Pentacyclic triterpenes from Combretum nigricans

Abstract From the bark of Combretum nigricans , four pentacyclic triterpenes have been isolated and their structures elucidated from spectral data as the known arjungenin and arjunglucoside, a new pentacyclic triterpene, combregenin (2α,3β,6β,19α,23-pentahydroxyolean-12-en-28-oic acid) and a new saponin, combreglucoside (β- d -glucopyranosyl 2α,3β,6β,19α,23-pentahydroxyolean-12-en-28-oate).

Five new steroids from Solanum nudum

Abstract Five new steroids, the cholest-4-ene-3,22-diones: tumacone A ( 1 ), tumacone B ( 2 ), tumacoside A ( 3 ), tumacoside B ( 4 ), and a furostenone: tumaquenone ( 5 ), besides diosgenone ( 6 ), were isolated from the aerial parts of Solanum nudum . Their structures were determined by 2D NMR, MS analyses and chemical correlations. Steroid 3 and 5 displayed in vitro antimalarial activity against a Plasmodium falciparum chloroquine-resistant FCB-1 strain (IC 50 27 and 16 μM). The observed stereodependent cyclization into spiroketals of two 16-O isomers is discussed.

Structure and total synthesis of (-)-myrionidine and (-)-schoberine, antimalarial alkaloids from Myrioneuron nutans.

Two new alkaloids, (5S,9S,10R)-myrionidine (1) and (5S,9S,10R,13S)-myrionamide (2), along with the known schoberine (3), were isolated from the leaves of Myrioneuron nutans (Rubiaceae), and their structures were determined from spectral analysis, including mass spectrometry and 2D NMR. The total asymmetric syntheses of (-)-myrionidine (1), (-)-schoberine (3), their enantiomers as well as their 9-epimers derivatives were performed, allowing the determination of their absolute configuration together with that of myrionamide (2). (-)-Myrionidine (1) and its synthetic enantiomer (18) showed a significant antimalarial activity on Plasmodium falciparum.

Further studies of the norditerpene (+)-harringtonolide isolated from Cephalotaxus harringtonia var. drupacea: absolute configuration, cytotoxic and antifungal activities.

Harringtonolide (= hainanolide) is a complex polycyclic fused norditerpene isolated from CEPHALOTAXUS HARRINGTONIA var. DRUPACEA. In spite of its appealing biological properties - we measured an IC (50) of 43 nM on KB cells and a significant antifungal activity - its absolute configuration has not yet been firmly established. This was done herein using X-ray anomalous scattering after bromination of the tropone ring, unambiguously giving the stereochemistry 5 R,6 R,7 S,13 S,14 S,15 R,16 R. Detailed IN VITRO biological measurements are provided.

Cytotoxic Acylphenols from Myristica maingayi

Abstract From the cytotoxic AcOEt extract of the fruits of Myristica maingayi, a Myristicaceae, five new acylphenols (promalabaricones B and C, maingayic acids B and C, and maingayone) were isolated, together with the known malabaricones A–C. The structures were determined from spectral analysis, including mass spectrometry and 2D NMR. The cytotoxicity of the new compounds and that of malabaricones was assessed against KB cells. A biosynthetic pathway for malabaricones, via the corresponding promalabaricones as precursors, is suggested.

Asymmetric synthesis of myrioxazines A and B, novel alkaloids of Myrioneuron nutans

Two new epimeric tricyclic alkaloids, myrioxazines A and B were isolated from the leaves of Myrioneuron nutans and their structures elucidated by spectral analysis (mass spectrometry and 2D NMR). Absolute configurations were determined by total asymmetric synthesis.

Antibiotic and Antifungal Pyrrolidine Alkaloids, from Arisarum vulgare

Abstract A new pyrrolidine alkaloid, bgugaine, 1 was isolated along with irniine, 2, from Arisarum vulgare tubers and its structure elucidated by 1H and 13C 2D-COSY NMR techniques. The antibiotic and antifungal properties of both alkaloids were investigated. They exhibited inhibitory effects on the growth of Gram-positive bacteria, yeasts and some filamentous fungi.

Isolation and antimalarial activity of new morphinan alkaloids on Plasmodium yoelii liver stage

Decoction of Strychnopsis thouarsii is used in the Malagasy traditional medicine to combat malaria. We have shown that this traditional remedy prevents malaria infection by targeting Plasmodium at its early liver stage. Bioassay-guided fractionation of S. thouarsii stem barks extracts, using a rodent Plasmodium yoelii liver stage parasites inhibition assay, led to isolate the new morphinan alkaloid tazopsine (1) together with sinococuline (2) and two other new related morphinan analogs, 10-epi-tazopsine (3) and 10-epi-tazoside (4). Structures were characterized by 2D NMR, MS, and CD spectral analysis. Compounds 1-3 were found to fully inhibit the rodent P. yoelii liver stage parasites in vitro.