Printer Friendly

Indole and aminoimidazole moieties antiplasmodial molecules appear as key structural units in antiplasmodial molecules.

ARTICLE INFO

Keywords: Antiplasmodial activity Antifungal activity Random screening Plant and marine products Indole- and Aminoimidazole derivatives

ABSTRACT

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 [micro]g/m1) whereas 13 clearly showed high antiplasmodial activity in vitro, with an [IC.sub.50] less than 1 [micro]g/ml against the chloroquine-resistant strain of P. falciparum FcM29-Cameroon. The molecules with the best antiplasmodial efficacy were 10-hydroxy-ellipticin ([IC.sub.50]: 0.08 [micro]g/ml), tchibangensin ([IC.sub.50]: 0.13 [micro]g/ml), ellipticin hydrochloride ([IC.sub.50]: 0.17 [micro]g/ml), usambarensin ([IC.sub.50]:0.23[micro]g/m1), 7S, 3S-ochropposinine oxindole [[IC.sub.50]: 0.25 [micro]g/m1), 3,14-dihydro-ellipticin ([IC.sub.50]:0.25 [micro]g/ml), tetrahydro-4'5',617-usambarensin 17S ([IC.sub.50]: 0.26 [micro]g/ml), ellipticine ([IC.sub.50]: 0.28 [micro]g/ml), aricin ([IC.sub.50]: 0.3 [micro]g/ml), 10-methoxy-ellipticin ([IC.sub.50]: 0.32 [micro]g/m1), aplysinopsin ([IC.sub.50]: 0.43 [micro]g/m1), descarbomethoxydihydrogambirtannin ([IC.sub.50]: 0.46 [micro]g/ml) and ochrolifuanin A ([IC.sub.50]: 0.47 [micro]g/m1). 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. [c] 2011 Elsevier GmbH. All rights reserved.

Introduction

Malaria is an endemic parasitic disease and one of the most common scourges of the XXI (e) century worldwide, next to HIV and tuberculosis. Every year, more than two billion people are exposed to malaria, with about 1 million deaths (Hay et al- 2010) Fungal infections are another alarming problem with in particular the development of opportunistic pathogens such as Candida albicans that causes serious infections in immunologically compromised people (Calderone 2002).

Since the XIX century and the discovery of the pathogenic parasite and fungi, a considerable number of drugs have been developed. A new treatment should be discovered every five years to avoid the resurgence of this infectious disease, particularly due the development of drug resistance by the pathogen. In this work, nature is a major source of pharmacological drugs and the most efficient antimalarial drugs such as quinine and artemisinin are natural products. According to the WHO, only 4 products (benflumetol, proguanil, pyrimethamine, sulfadoxine) out of 15 current antiplasmodial molecules are totally synthetic. In fact, more than thirty percent of the current pharmaceutical market is composed of natural molecules (Harvey 2004; Phillipson 2001).

We have here carried out an extensive survey from a large catalogue of 184 randomly selected molecules from natural sources, and evaluated their antiplasmodial and antifungal activity.

Since the large 1947 survey of about 600 species of higher plants extracts (Spencer et al. 1947), this present work is particularly representative to report in vitro antiplasmodial activity against P. falciparum with a so big sampling of molecules with various chemical structures in the search for new antimaterial drugs.

Materials and methods

Origin of the molecules tested

The molecules tested have been extracted either from plants or from marine organisms or prepared as intermediates during the synthesis or semi-synthesis of the isolated products (Tables 1 and 2).

Plasmodium falciparum strain and in vitro culture

The both chloroquine-resistant strains of P. falciparum FcM29-Cameroon strain ([IC.sub.50] values for chloroquine of 400 nM) and W2-Indochina ([IC.sub.50] values for chloroquine of 300 nM) were continuously cultured according to Trager and Jensen (1976) with modifications (Benoit-Vical et al. 1998). The parasite culture was carried out at 37[degrees]C with an hematocrit of 2-4% and in an atmosphere of 5% C02. The parasites were maintained in vitro in 0[+ or -] human red blood cells (French Blood Bank). The culture medium was RPMI 1640 (Gibco Invitrogen, USA) supplemented with 5% human serum (French Blood Bank) and containing 25 mM HEPES and 2mM L-glutamine. The sensitivity to chloroquine and artemisinin, taken as controls, was regularly tested on these strains.

Evaluation of antiplasmodial activity

The radioisotopic micromethod described by Desjardins et al. (1979) was used to evaluate the activity of the tested molecules against P. falciparum. All the molecules were first tested against the strain FcM29; however for molecules with the best pharmacological interest, they were secondly tested against W2, another P. falciparum strain. Tests of the drug activity were performed in 96 well-culture plates (TPP, Switzerland) with cultures at 1% para-sitaemia and 2% hematocrit. The asexual erythrocytic stages were cultured in the plates for 48 h. For each test, the parasite culture was incubated with the drugs at various concentrations (from 0.1 to 50 ug/m1). For molecules having [IC.sub.50] values lower than 1 lagfml, another concentrations range (0.01 [micro]g/ml from to 1 p1g/m1) was tested. Parasite growth was estimated by [3H] hypoxanthine incorporation (Perkin Elmer, USA) and compared with that incorporated by parasites without any test compounds. using this method, the [IC.sub.50] (50% inhibitory concentration) values were determined graphically by plotting concentrations versus percentage inhibition. The [IC.sub.50] values reported are the mean of 2-4 independent experiments.

Testing the antifungal activity with Candida sp.

The Candida albicans American Type Culture Collection 90028 (ATCC 90028) was used to evaluate the antifungal activity of the 184 molecules. A micro-dilution method adapted from the Clinical and Laboratory Standards Institute (CLS1, formerly NCCLS-M27A) (NCCLS 1997) was used. The 13 molecules selected because of their antiplasmodial activity (Table 1) were also tested on Candida parapsilopsis (ATCC 22019) and C glabrata (#0500024220). These 3 Candida were chosen because even if C. albicans remained predominant in the Candida bloodstreams infections found in Europe, C parapsilosis and C. glabrata are the most frequent nonalbicans isolates. The culture medium used was RPMI 1640 (Sigma, France) with 2mM L-glutamine and 0.165 M morpholinopropanesulfonic acid (MOPS) buffer (Sigma, France). Prior to testing, the isolate was sub-cultured on Sabouraud dextrose agar (Bio-Merieux, France) and was incubated at 35 CC during 48 h. Inoculates were prepared by suspending the yeast in 1.0 ml of a sterile saline solution and adjusting to a final concentration of 2.5 x 106 yeast cells/ml. 100 RI of this suspension was added to each well of 96-well plates and 100[micro]llOOji.1 of various concentrations of drugs added (with the maximum concentration at 10 [micro]g/ml), and the plates incubated for 48 h at 35 nC. The results were determined using a spectrophotometer (Elx 808, Vetra Microplate Reader, Avantec) tit a wavelength of 550 nm. Two readings were necessary at 24 h and 48 h growth to interpret the results and determinate the MIC (Minimal Inhibitory Concentration). These MIC were determined graphically by plotting concentrations of tested drugs versus percentage inhibition. For comparison, the control 5-fluorocytosine was routinely used as a reference in this test and gave an MIC of 0.7511g/m1 for the 48 h incubation time, similar to the ATCC reference values for this ATCC 90028 strain that range from 0.5 to 2 [micro]g/ml with this molecule.
Table. 1

List of the 13 molecules from the 184 tested showing promising in
vitro antiplasmodial activity (1[C.sub.50] less than 1 [micro]g/mL)
against FcM29-Came roon. a high chloroquine-resistant stra in of
Plasmodium falciparum

Molecules                                  I[C.sub.50] [mu]g/ml
                                           on FcM29

1 = Descarbomethoxydihydmbirtannine          0.46 [+ or -] 0.07 (a)
(MW: 274 g/mol) (Ahond et al. 1981)           (4) (b) 1.68 [micro]M (c)

2 = aricin (MW: 436 g/mol) (Ahond et            0.3 (2) 0.69 [micro] M
al. 1981; Robert et al. 1983b)

3 = 7s. 3S ochropposinine oxindole           0.25 [+ or -] 0.14 (2)
(MW: 374 g/mol)(Ahond et al. 1981)                       0.67 [micro]M

4 = usambarensin (MW: 432 g/mol)             0.23 [+ or -] 0.06 (3)
(Robert et al. 198 3a)                                   0.53 [micro]M

4A = tchibangensin = 5', 6'                  0.13 [+ or -] 0.03 (3)
dihydro-usambarensin                                     0.29 [micro]M
(Robert et al. 1983b)
(MW: 436 g/mol)

4B = teerahydre-4', 5', 6', 17-              0.26 [+ or -] 0.15 (2)
usambarensin 17S (Robert et al.                          0.59 [micro]M
1983b) (MW: 436 g/mol)

4C = ochrolifuanin A = heahydro-             0.47 [+ or -] 0.18 (4)
4', 5', 6', 17, 19, 20-                                  1.09 [micro]M
usambarensin (MW: 436 g/mol)
(Robert et al. 1983a)

5 = ellipticine (MW: 246 g/mol)              0.28 [+ or -] 0.12 (3)
(Ahond et al. 1981)                                      1.13 [micro]M

5A = elipticine, HCI = 5, hci                0.17 [+ or -] 0.07 (2)
(Ahond et al. 1981)                                      0.06 [micro]M
(MW: 282/284 g/mol)

5B = 3.14-dilpydro-ellipticin                 0.25 [+ or -] 0.2 (2)
(Ahond et al. 1981)                                      1.01 [micro]M
(MW: 248 g/mol)

5C = 10-hydroxy-ellipticin                   0.08 [+ or -] 0.02 (4)
(semisynthesis from 5D)                                   0.3 [micro]M
(MW: 294 g/mol)

5D = 10-hydroxy-ellipticin                   0.32 [+ or -] 0.15 (3)
(Ahond et al. 1981)                                      1.15 [micro]M
(MW: 278 g/mol)

6 = aplysinopsin (MW: 254 g/mol)              0.43 [+ or -] 0.1 (2)
(Ahond et al. 1982)                                      1.69 [micro]M

Chloroquine                                              400 nM (d)

Artemisinin                                               12 nM (d)

(a) I[C.sub.50] values in [mu]M/ml [+ or -] sd (standard deviation).
(b) Number of experiments, in brackets.
(c) I[C.sub.50] values in [mu]M.
(d) Routinely tested.


Results and discussion

From a vast natural compounds library, 184 molecules were randomly chosen and proposed by chemists from the "Institut de Chimie des Substances Naturelles" of the French National Center of the Scientific Research (CNRS) to be tested in vitro against Plasmodium and against Candida. The major interest of this random research was the large chemical structure diversity of the selected molecules and thus their different potential targets in these eukaryotic pathogens. The screening of these selected molecules randomly chosen produced no antifungal activity pharmacologically relevant whatever the species of Candida used (C albicans, C parapsilosis and C glabrata with MIC values systematically higher than 10(jLg/ml (data not shown) whereas the drug control 5-fluorocytosine gave an MIC of 0.75 [micro]g/ml.

On the contrary, 13 of these molecules (corresponding to 7% of the molecules tested) clearly showed a real and specific antimatarial activity against the strain FcM29, with [IC.sub.50] values largely less than 1 [micro]g/m1(ranging from 0.08 to 0.47 fig/m1). The cut-off for this preliminary screening was fixed at 1 [micro]g/ml for the antiplasmodial activity because above this value, the molecules would not present any real pharmacological interest for future drug development. In these conditions, none of the 13 selected molecules showed hemolytic properties to the concentrations used in pharmacological doses ranging between 0.1 and 50 [micro] g/ml. The lack of activity against Candida sp. heightens the specific activity of these 13 molecules against Plasmodium.

Moreover, the 171 molecules without any antiplasmodial activity (and no antifungal properties) can also be interesting for scientific community because these "non-active" compounds give useful information on the structure/activity relationships, nearly at least as much as molecules with positive results (Table 2).
Table 2

List of 171 molecules (from 184 tested) showing no in vitro
antiplasmodial activity (IC5o superior to 1 (xg/mL) on
Plasmodium falciparum.

Molecules                        Plant origin       References

N, N-Dimethyltryptamine         Acacia              Poupat et al.
                              simplicifolia       (1976)

N-2-Methyl                    Acacia              Poupat et al.
tryptamine                    simplicifolia       (1976)
hydrochloride

N-Methyl for                  Acacia              Poupat et al.
myltryptamine                simplicifolia       (1976)

N-Methyl                      Acacia              Poupatetal.
tetrahydro                    simplicifolia       (1976)
[beta] carboline

Hordenine                     Acacio              Poupat and
                              spirorbis           Sevenet
                                                  (1975)

N-Cinnamo                     Acacia              Poupat
yhistamine                    spirorbis           and Sevenet
                                                  (1975)

Deplancheine                  Alstonia            Besselievre
                              deplanchei          etal.(1980)

Androcymbine                  Androcy             Simanek
                              mbium sp.

Reticuline                    Anona sp.           Poupat
perchlorate

Dihydrocorynantheol           Aspidosperma        Robert
                              marcgravianum       etal. (1983b)

Haplocidine                   Aspidosperma        Robert.
                              marcgravianum       etal (1983b)

Rhazinilam                    Aspidosperma        Robert
                              marcgravianum       etal. (1983b)

16-Epi                        Aspidosperma        Robert
isositsirikine                marcgravianum       etal. (1983b)

yohimbine                     Aspidosperma        Robert etal.
                              marcgravianum       (1983b)

17-Epi                        Aspidosperma        Robert etal.
alloyohimbine                 oblongum            (1983a)

18,19-Dihydro                 Aspidosperma        Robert etal.
sitsirikine 16(R)             oblongum            (1983a)

3 Yohimbine                   Aspidosperma        Robert etal.
                              oblongum            (1983a)

Corynanthine                  Aspidosperma        Robert etal.
                              oblongum            (1983a)

2'-Desacetyl                  Austrotaxus         Ettouati etal.
austrospicatine               spicata             (1989)

Spicataxine                   Austrotaxus         Ettouati
                              spicata             etal. (1989)

2'-Desacetoxy                 Austrotaxus         Ettouati etal.
-autrospicatine               spicata             (1989)

Anemonine                     Austrotaxus         Ettouati
                              spicata             etal. (1988)

Coronaridine                  Bonafousia          Makani etal.
                              speciosa

N-Dimethyl epi                Bonafousia          Makani
-16 accedine                  speciosa            et al.

Capitavine                    Buchenavia          Ahond
                              capitata            etal. (1984)

Buchenavianine                Buchenavia          Ahond etal.
                              macrophylla         (1984)

O-demethyl                    Buchenavia          Ahond etal.
buchenavianine                macrophylla         (1984)

14-0-Desacetyl-O-             Cavernulina         Clastres
propionyl cavernuline         grandiflora         etal. (1984b)

                              Cavernulina         Clastres
                                                  etal.(1984b)

Cavernuline                   grandiflora
24-EthylchoIesterol           Clathria            Clastres et al.
                              astroderma

Codonocarpine                 Codonocarpus        Poupat
                              attenuatus

N-Methyl-                     Codonocarpus        Poupat
codonocarpine                 attenuatus

Nor-sinoacutine               Croton sp.          Sanchez

Allantome                     Cymbastela          AIMourabit etal
                              cantharella         (1997)

Taurine                       Cymbastela          Al
                              cantharello         Mourabitetal.
                                                  (1997)

15p-Hydroxy-                  Didymeles cf.       Sanchez
irhediamine H                 madagascariensis    etal. (1984)

3,18-Dioxo-20(S)-             Didymeles cf.       Sanchez etal.
dimethylamino                 madagascariensis    (1984)

pregna-l,4-diene 3            Didymeles cf.       Sanchez etal.
-Hydroxy-l9-nor-cona-l,       madagascariensis    (1984)
3,5,14-tetraene

Holadienine                   Didymeles cf.       Sanchez etal.
                              madagascariensis    (1984)

N-Acetyl                      Didymeles cf.       Sanchez etal.
irhediamine F                 madagascariensis    (1984)

3,18-Dioxo                    Didymeles           Sanchez etal.
-cona-l,4,14-triene           penieri             (1987)

3-IVlethyl-16a,               Didymeles           Sanchez etal.
18-dihydroxy-20(S             perrieri            (1987)
)- dimethy Iaminop
regn-5-ene3-Oxo-l

8a-hydroxy-cona               Didymeles sp.       Sanchez etal.
-1, 4,14-triene                                   (1987)

O-Acetyl isori                Geijera             Ahond etal.
balinine                      balansae            (1979)

Skimmianine                   Geijera             Ahond etal.
                              balansae            (1979)

Gentianine                    Hugonia             Mahamane
                              oreogena            and
                              and                 Poupat
                              H.penicillanthemum

Absouline                     Hugonia oreogena    Ikhiri etal.
                              and H.              (1987a)
                              penicillanthemum

Absouline N-oxide             Hugonia             Ikhiri etal.
                              oreogena and H.     (1987a)
                              penicillanthemum

Ipalbidine                    Ipomea              Ikhiri etal.
                              albQ                (1987b)

Ipalbine                      Ipomea              Ikhiri etal.
                              alba                (1987b)

Cytisine                      Laburnum sp.        Poupat

Laburnamine LI                Laburnum sp.        Poupat

Laburnamine L2                Laburnum sp.        Poupat

Limeolide                     Limeum              Ikhiri
                              pterocarpum         etal. (1995)

Dehydro                       Limeum              Ahond and
limeolide                     pterocarpum         Abdouiaye

Isolunarinol I                Lunaria             Poupat etal.
                              biennis             (1972b)

Isolunarinol 11               Lunaria             Poupatetal.
                              biennis             (1972b)

LBX                           Lunaria             Poupatetal.
                              biennis             (1972b)

LBY                           Lunaria             Poupat etal.
                              biennis             (1972b)

LBZ                           Lunaria             Poupat etal.
                              biennis             (1972b)

Lunarine                      Lunaria             Poupat etal.
                              biennis             (1972b)

Lunarinol I                   Lunaria             Poupat etal.
                              biennis             (1972b)

Luiwinol                      Lunaria             Poupat etal.
                              biennis             (1972b)

White                         Lunaria             Poupatetal.

numismine                     biennis             (1972b)

Yellow                        Lunaria             Poupat etal.
numismine                     biennis             (1972b)

Isolunaridine                 Lunaria             Poupat etal.
                              biennis             (1972a)

Lunaridine                    Lunaria             Poupat etal.
                              biennis             (1972a)

Melicopidine                  Melicope            Ahond etal.
                              leratii             (1978a)

N-methyl trime                Melicope            Ahond etal.
thoxy acridone                leratii             (1978a)

Xanthevodine                  Melicope            Ahond etal.
                              leratii             (1978a)

Neothyonidioside              Neothyonidium       Bedoya-Zurita.
                              magnum              et al (1986)

10,11-Dimethoxy-              Ochrosia            Ahond etal.
18,19-dihydro sitsi           moorei              (1981)
rikine-16(S),20( R)

1O-Methoxydihydr              Ochrosia            Ahond etal.
ocorynantheol                 moorei              (1981)

Dimethoxypicr                 Ochrosia            Ahond etal.
aphylline                     moorei              (1981)

Isoreserpiline                Ochrosia            Ahond etal.
                              moorei              (1981)

Rauvoxine                     Ochrosia            Ahondetal.
                              moorei              (1981)

Reserpiline                   Ochrosia            Ahondetal.
                              moorei              (1981)

Heyneanine                    Pandaca retusa      Picot and
Latrunculine                  Podospongia         Ahond
                              aff.                Delaun
                              lovenii             eux et al.

Debromohy                     Pseudaxinyssa       deNanteuiletal.
menialclisine                 canthareila         (1985)

Oxidized                      Pseudaxinyssa       deNanteuiletal.
debromohymenialdisine         canthareila         (1985)

Dibromophakelline             Pseudaxinyssa       deNanteuil
                              canthareila         etal.
                                                  (1985)

12-0-desacetyl-12-0-          Ptero'ides          Clastres et al.
benzoyl pteroTdine            laboutei            (1984a)

Labouteine                    Ptero'ides          Clastresetal.
                              laboutei            (1984a)

PteroYdine                    Ptero'ides          Clastres etal.
                              laboutei            (1984a)

Lochnerine                    Rauvolfia           Abauletal.
                              biauriculata        (1986)

Desaceryl                     Taxus               Poupat etal.
taxine A                      baccata             (1994)

Taxine B                      Taxus               Ettouati etal.
                              baccata             (1991b)
evoxanthine                   Vepris sp.          Kan

4'-5,-Dihydroxy-3',           Zygogynum           Ahondetal.
7-dimethoxy flavone           pauciflorum         (1990)

4'-Hydroxy-5,7f3'-            Zygogynum           Ahondetal.
trimethoxy flavone            pauciflorum         (1990)

5,7,3',4'-Tetramethoxy        Zygogynum           Ahondetal.
flavone                       pauciflorum         (1990)

5,7-Dimethoxy-3'.             Zygogynum           Ahondetal.
4'-methylenedioxy fla         pauciflomm          (1990)

vone5-Hydroxy-7-3',           Zygogynum           Ahond etal.
4'-trimethoxy flavone         pauciflorum         (1990)

5-Hydroxy-7-methoxy-3',       Zygogynum           Ahond etal.
4'-mechylendioxy flavone      pauciflomm          (1990)

Bubbialidine                  Zygogynum           Ahondetal.
                              pauciflorum         (1990)

Bubbialine                    Zygogynum           Ahond etal.
                              pauciflorum         (1990)

Irhediamine                   Semisy              Goutarel etal.
                              nthesis             (1967)

1,2,9J0-Diaceto               Semisy              Ettouati etal.
nide-5,20-dihydroxy-13-       nthesis             (1991a)

oxo-taxllene 1,2,9,10-        Semisy              Ettouati etal.
Tetr ahydroxy-5-cinnam        nthesis             (1991a)
oyl -13-oxo-tax-11-ene

2,9,10-Triacetyl-5-c:         Semisy              Ettouati etal.
innamoyl taxicine I           nthesis             (1991a)

l,2,9,10-Diacetonide-         Semisy              Ettouati etal.
5-hydroxy-5,20-o              nthesis             (1991a)
xido-13-cinnamoyl-tax-11-ene

3,17-Dihydroxy                Semisy              Langlois etal.
androstane                    nthesis             (1970)

3-Chloro-l 7-aziridino        Semisy              Langlois etal.
androst-5-ene                 nthesis             (1970)

3-Hydroxy-17-                 Semisy              Langlois etal.
iminoethanof and              nthesis             (1970)

rost-5-ene3,17-Dihy           Semisy              Langlois et al.
droxy androst-4-ene           nthesis

3-Epoxymethylene-17           Semisy              Langlois et al.
-hydroxy androstane           nthesis

Androst-2ene                  Semisy              Langlois etal.
                              nthesis

Ribalinine                    Semisy              Ahond etal.
                              nthesis             (1979)

Maytenine                     Semisy              Husson etal.
                              nthesis             (1973b)

Hexahydro lunarine            Semisy              Poupat etal.

                              nthesis             (1972b)

N.O-Diacetyl                  Semisy              Poupat etal.
tetrahydroiunarinol I         nthesis             (1972b)

N-Acetyl tetrahy              Semisy              Poupat etal.
droiunarinol I                nthesis             (1972b)

N-Methyl tetrahy              Semisy              Poupat etal.
droiunarinol I                nthesis             (1972b)

Tetrahydrolunarine            Semisy              Poupat etal.
                              nthesis             (1972b)

Tetrahy                       Semisy              Poupat etal.
droiunarinol                  nthesis             (1972b)

Tetrahydr                     Semisy              Poupat etal.
oiunarinol II                 nthesis             (1972b)

Hexahydro                     Semisy              Poupat etal.
lunaridine                    nthesis             (1972a)

Tetrahy                       Semisy              Poupat etal.
drolunaridine                 nthesis             (1972a)

N.O-Diacetyl                  Semisy              Poupat
lunarinol 1                   nthesis             (1971)

N-Acetyl                      Semisy              Poupat
isolunarinol 1                nthesis             (1971)

N-Acetyl                      Semisy              Poupat
lunarine                      nthesis             (1971)

N-Acetyl                      Semisy              Poupat
lunarinol 1                   nthesis             (1971)

618,9-Trimethoxy              Synthesis           Moron
l3r5-trioxa
-cyclopenta[ban
thracen-10-one

3-(4-[5-(2-car                Synthesis           Poupat
boxyethyl)                                        (1976)
-2-hydroxy phen
oxy)]-3-methoxyph

enyl) propionic acid

N-methyl                      Synthesis           Poupat
4-methoxy
-cinnamamide
tetrahydro                    Synthesis           Husson etal.
maytenine                                         (1973b)

3-(4-benzyloxyp               Synthesis           Poupat
henyl)-N-(3-)4-                                   (1971)
(3-(4-benzylo
xyphenyl)-
propionyl aminol-
butylamino)-propyl)
propionamide

3-(4-hydr                     Synthesis           Poupat
oxy phenyl                                        (1971)
)N-(3-(4-hy
droxyphenyl)
-propionyl
aminol-butyl
amino)-propyl)
-propionamide

Methyl 4-benzy                Synthesis           Poupat
loxy propionate                                   (1971)

N-[3-(-4-amino                Synthesis           Poupat
butylamino)                                       (1971)
propyl-]3-4-b
enzyloxyphenyI)

-propionamide

N-Acetyl tetrahy              Synthesis           Poupat
drolunarine                                       (1971)

N-Acety                       Synthesis           Poupat
lnumismine                                        (1971)

Tetrahy                       Synthesis           Poupat
drolunaridinol                                    (1971)

N-(3-(-4-amino                Synthesis           Poupat
propylamino)                                      (1971)
propyI-]3-
(4-benzy loxy
phenyl)
-propionamide

9,9b-Dimethyl                 Synthesis           Husson
-l,4,4a,9b-tetrahy                                etal.
dro-2H-diben                                      (1971)
zofuran-3-one

Dihydroferulic                Synthesis           Husson etal.
acid                                              (1971)

Methy/3(2-(-carb              Synthesis           Husson etal.
oxyethyl)-7-ox                                    (1971)
o-6,7,8.9-tetr
ahydro-5aH-
dibenzofuran
-9a-yl]
propionate

3[2-(-carboxy                 Synthesis           Rodriguez and
ethyl)-7-oxo-                                     Poupat
6,7,8,9
-tetrahydro-
5aH-dibenzo
furan-9a-yl]
propionic acid

9,9b-Dimethyl-                Synthesis           Rodriguez
2H-dibenzofuran                                   and
-3-one                                            Poupat

Methyl                        Synthesis           Poupat
bromo ferulate                                    (1976)

Tetrahydroco                  Synthesis           Poupat
donocarpine                                       (1976)

l-Iodo-2,3                    Synthesis           Ahond
-methylenedioxy                                   and
benzene                                           Poupat

1 -Methoxy-2,3                Synthesis           Ahond
-methylenedioxy                                   and
- benzene                                         Poupat

1 -Methoxy-2,3                Synthesis           Ahond and
-methylenedioxy                                   Poupat
-4,5,6-trinitro
benzene

l-Methoxy-2,3                 Synthesis           Ahond and
-methylenedioxy-                                  Poupat
5-amino benzene

l-Methoxy-2,3-                Synthesis           Ahond and
methylenedioxy-                                   Poupat
5-nitro benzene

2,3,4,9-                      Synthesis           Ahond and
Tetrahydro-l                                      Poupat
H-(3-carboli
n-1yI-acetic acid

Methyl 2,3.4,9                Synthesis           Ahond and
-tetrahydro-                                      Poupat
lH-P-carbolin-l
-yl-acetate

l,4-Dimethyl-7                Synthesis           Ahond etal.
-hydroxy                                          (1978b)
carbazole

1,4-Dime                      Synthesis           Ahond etal.
thyl-7-meth                                       (1978b)
oxy carbazole

2-(l,3-Benzo                  Synthesis           Ahond etal.
dioxol-5-                                         (1978b)
yiamino)
benzoic acid

2,3-Methy                     Synthesis           Ahond etal.
lenedioxy-                                        (1978b)
5-methyla
cridan-9-one

4-Methoxy-7,8,                Synthesis           Ahond etaL
91I0-tetrahydro                                   (1978b)

-5H-benzo[b]
carbazole
l,2,3,4,7-Penta               Synthesis           Moron
methoxy-9
H-xanthen
-9-one

Methyl 6-                     Synthesis           Moron
hydroxy-l,3
benzodioxol-5
-carboxylate

Methyl 6-met                  Synthesis           Moron
hoxy-benzo-1,
3'dioxole-5
-carboxylate

Methyl benzo-l                Synthesis           Moron
, 3-dioxole-
5-carboxylate

Desmethyl                     Synthesis           Robert
aplysinopsine                                     (1982)

3-(4-benzyloxy                Synthesis           Husson etal.
phenyl)-N-(3-                                     (1973a)
(3-[3-(4-benz
yloxyphenyl)-
propionylamino
]-propylamino
-propyl)
-propionamide

N-[3-(acetyl-                 Synthesis           Husson etal.
(3-[3(4                                           (1973a)
-benzyloxy
phenyl)
propionylamino]
-propyl)-amino
)-propyI]-3-
[(4-benzyloxy
phenyl)-
propionamide

Nacetyl-3-(4-                 Synthesis           Husson etal.
hydroxy phenyl)                                   (1973a)
-N- (4-(3- [(4-
benzy loxyphe
nyl)-propionyla
mino]-propylam
ino)-propyl)
-propionamide

Nacetyl-3-(4-hydroxy          Synthesis           Husson etal.
pheny)-N-(4-(3-K4-                                (1973a)
hydroxyphenyl)-
propionyl amino]-
propylamino)-pro
pyl)-propionamide

1 l-Methoxy-5H-[l,3]          Commercial
dioxolo-I4,5-b]               product
acridinin-10-one

4-Methoxy cinnamic acid       Commercial
                              product

Chiysine                      Commercial
                              product

Colchicine                    Commercial
                              product

Digitaline                    Commercial
                              product

Ouabaine                      Commercial
                              product

Spermidine                    Commercial
hydrochloride                 product

Tectochrysine                 Commercial
                              product


This large and randomly screening enabled us thus to select new molecules with promising antiplasmodial activity. Indeed, among these 13 selected molecules, only 3 (descarbomethoxy-dihydrogambirtannin (Frederich et al. 2002), ochrolifuanine A (Frederich et al. 2002) and usambarensine (Frederich et al. 2002)) had already been described in the literature for their antiplasmodial activity with values close to ours.

These 13 selected molecules (Table 1) were extracted from 3 different plants (or synthesized derivatives) and from an Australian reef sponge. Ellipticine 5 ([IC.sub.50]: 1.13 |iM), ellipticin hydrochloride 5A ([IC.sub.50]: 0.60 [micro]M% 3,14-dihydro-ellipticin 5B ([IC.sub.50] = 1.01 [micro]M), 10-hydroxy-ellipticin 5C ([IC.sub.50]: 0.3011M), 10-methoxy-ellipticin 5D ([IC.sub.50]: 1.15 [micro]M), descarbomethoxydihydrogambirtannin 1 ([IC.sub.50] = 1.68 p.M), usambarensin 4 ([IC.sub.50]:0.53 [micro]M) and 7S,3S ochrop-posine oxindole 3 ([IC.sub.50]: 0.67 [micro]M) were extracted from Ochrosia moorei or prepared as intermediates compounds (Ahond et al. 1981). Tetrahydro-usambarensin 17S 4B ([IC.sub.50]: 0.5911M) was extracted from Aspidosperma marcgravianum (Robert 1982; Robert et al. 1983a,b) (and cited references) and tchibangensin 4A ([IC.sub.50]: 0.29 [micro]M) was extracted from Strychnos tchibangensis. Ochrolifuanin A 4C ([IC.sub.50]: 1.0911M) and aricin 2 ([IC.sub.50]: 0.69 [micro]M) were extracted from both Ochrosia moorei (Ahond et al. 1981) and Aspidosperma marcgravianum (Robert 1982; Robert et al. 1983a, b). Aplysinopsin 6 (IC50: 1.69 p.M) came from the marine sponge Dendrophyllia nigrescens (Robert 1982; Robert et al. 1983a,b) but was also found in Thorecta aplysinopsis (Bialonska and Zjawiony 2009).

In spite of the large diversity of the 184 molecules that have been tested (Tables 1 and 2), it is interesting to note that the ones active against Plasmodium are all indole or aminoimidazole derivatives. The chemical structure of aplysinopsin is even more representative because it has both indole and aminoimidazole moieties.

In the literature, indole derivatives are already known to their antiplasmodial activity by acidifying the parasite cytosol (van Schalkwyk et al. 2010). Furthermore, oxindole-based compounds are reported to selectively inhibit P. falciparum cyclin dependent protein kinases (Woodard et al. 2003) that could explain the interesting antiplasmodial activity of ochropposine oxindole. On the contrary, to our knowledge, only one aminoimidazole, girolline, a marine drug product was reported for its antiplasmodial properties (Benoit-Vical et al. 2008).

However, the presence of these two indole and aminoimidazole moieties does not guarantee that they will have antiplasmodial activity. Indeed, some molecules like those extracted from Pseu-daxinyssa cantharella contain aminoimidazole structures, and alkaloids from Pandaca sp. or Bonafousia sp. or Rauvoffia sp., for example, contain indole structures, and none are active against Plasmodium (Table 2).

The structure-activity relationship here conducted showed that for molecules like ellipticine 5 and its derivatives, we can observe that hydroxylation of the molecule (5C) increases significantly the activity in comparison with the parent 5, and the hydrogenated 5B and methoxylated 5D derivatives. The antiplasmodial activity of ellipticin hydrochloride 5A can be explained by a higher solubility of this form in the parasite culture medium than the basic form 5.

Ellipticine and its derivatives were essentially studied for their anticancer properties with multiple mechanisms of action (for review, see Paoletti et al. 1981; Auclair 1987). The planar poly-cyclic structure of ellipticine was found to interact with DNA with a high binding affinity, through intercalation. Ellipticine also demonstrated strong inhibition of DNA topoisomerase II activity. More recently, formation of covalent DNA adducts mediated by ellipticine oxidation with cytochromes P450 and peroxidases was proposed as well as one of its mode of action. All these pharmacological properties could explain the antiplasmodial activities reported in the present work. The cytotoxicity of ellipticine family was often reported (DeMarini et al. 1983) with implication of their antioxidant properties (Rousseau-Richard et al. 1990) or by production of an oxidation stress (Meunier et al. 1983). The IC50 values for the cytotoxicity of ellipticine varied from 0.34 [micro]M on HL-60 cells to 4.7 [micro]M on CCRF-CEM cells leading to a very weak security index value (Poljakova et al. 2007). However, the cytotoxicity of these compounds is largely structure dependent with for example hydroxy-ellipticine 10 fold more toxic than methoxy-ellipticine on HeLa cells (Oustrin and Pieraggi 1974). Unfortunately the antiplasmodial activity of this compounds family seems also correlated with their toxicity. Indeed, from a screening of 19 analogs of ellipticine, 10-hydroxy-ellipticine appeared as the most immunosuppressive agent (Hayat et al. 1974). So, instead of its very promising [IC.sub.50] value against Plasmodium (300 [micro]M), it is to be feared that this compound could be not adapted as antimalarial drug.

In other respects, according to the literature, ochrolifuanine A and dihydrousambarensine (tchibangensine) have shown cytotoxicity values on Human Colon Cancer Cell Line HCT-116of 16.1 [micro]M (given a security index value of 15 corresponding to the ratio of the cytotoxicity value on the antiplasmodial activity) and 12.01.1M (Security index: 41), respectively (Frederich et al. 2002). In parallel, on HeLa cells line, usambarensine and dihydrousambarensine had cyototoxic effect with 10 [micro]g/m1 (Leclercq et al. 1986) leading to security index of 19 and 35, respectively. That is why, given the best IC50 values from all the molecules that we tested on the strain FcM29 of P. falciparum, and in view of its weak cytotoxicity, we have decided to continue the pharmacological investigations with tchibangensin (dihydrousambarensine). First assays against another P. falciparum strain, W2-Indochina (isolated from another endemic malaria area with also high chloroquine resistance level) confirmed the interest of this compound with IC50 values (data not shown) close to those obtained against FcM29 and lower than 300 [micro]M. A pharmaco-modulation strategy is also envisaged with the aim of still improve its antiplasmodial activity and limiting the toxicity.

In conclusion, no molecule from the 184 tested in this study had antifungal activity whereas 7% of the molecules showed potential antimalarial activity but unfortunately often linked to their cytotoxicity. A recent large screening from 2 million compounds in GlaxoSmithKline's chemical library, 0.4% of the compounds (which 15% of those displayed some cytotoxicity) were selected for their antiplasmodial activity and proved new potential targets and very diversified chemical structures from current antimalarials (Gamo et al. 2010). For example, the present work reveals that in spite of the large chemical diversity of all these molecules tested, the ones active against Plasmodium own systematically indole or aminoim-idazole moieties. This information could be useful for research of new antiplasmodial drug-candidates by synthetic approaches. On the contrary, compounds extracted via a bio-guided fractionation from plants used in traditional medicine give a better yield of molecules with antimalarial activity, to date between 10 and 30% of the examples studied (Benoit-Vical 2005; Soh and Benoit-Vical 2007) and because of their ancestral use, showing in general a very weak toxicity.

To find new antimalarial hits from natural sources, research on traditional medicine appears thus more convincing thanrandom methods but both ways seem complementary to supply the drugs pipeline in order to find new chemical structures for the treatment of infectious diseases.

Acknowledgments

The authors thank Professors J.Y. Lallemand (Institut de Chimie des Substances Naturelles, CNRS UPR8241, Gif-sur-Yvette, France), A. Berry and J.F. Magnaval (Centre Hospitalier Universitaire, Toulouse, France) for many fruitful discussions and Dr John Woodley for the editing of the English. The authors gratefully acknowledge financial support from the ICSN (CNRS, UPR2301).

doi:10.1016/j.phymed.2011.03.010

0944-7113/$--see front matter [c] 2011 Elsevier GmbH. All rights reserved, doi: 10.1016/j.phymed.2011.03.010

References

Abaul, j., Philogene, E., Bourgeois, P., Merault, G., 1986. Alcaldides indoliques de Rauvolfia biauriculata. J. Nat. Prod. 49, 829-832.

Ahond, A., Abdoulaye, A., unpublished results.

Ahond, A., Fernandez, H.Julia-Moore, M., Poupat, C., Sanchez, V., Potier, P., Kan, S.K., Sevenet, T., 1981. Contribution a l'etude des Ochrosiinees: Alcaldides de Ochrosia moorei.J. Nat. Prod. 44, 193-199.

Ahond, A.. Fournet, A., Moretti, C, Philogene, E., Thoison, 0., Potier, P., 1984. Premiers alcaloides vrais isoles de Combretacees, Buchenavia macrophylla Eichl. et Buchenavia capitata. Eichl. Bull. Soc. Chim. II 41-45.

Ahond, A., Guilhem.J., Hamon.J., Hurtado, C, Poupat, C, Pusset, J., Pusset, M., Sevenet, T., Potier, P., 1990. Blubbialine et Bubbialidine, Alcaldides nouveauxextraits de Zygogynum pauciflorurn. J. Nat. Prod. 53, 875-881.

Ahond, A., Picot, F, Poupat, C, Sevenet, T., 1978a. Alcaloides de Melicope leratii. Phytochemistry 17, 166-167.

Ahond, A., Poupat, C. unpublished results.

Ahond, A., Poupat, C, Potier, P., 1978b. Etude par RMN13C d'alcaloides a squelette acridanone 9 (10H) et pyrido (H,3-b) carbazole (6H). Tetrahedron 34, 2385-2388.

Ahond, A., Poupat, C, Pusset, J., 1979. Geibalansine et O-methyl geibalansine, nou-veaux alcaloides ioles de Geijera balansae. Phytochemistry 28,1415-1416.

Al Mourabit, A., Pusset, M., Chtourou, M., Gaigne, C, Ahond, A., Poupat, C, Potier, P., 1997. Pyraxinine: a novel nitrogenous compound from the marine sponge Cymbastela cantharella. J. Nat. Prod. 60, 290-291.

Auclair, C, 1987. Multimodal action of antitumor agents on DNA: the ellipticine series. Arch. Biochem. Biophys. 259, 1-14.

Bedoya-Zurita, M., Ahond, A., Poupat, C-, Potier, P., 1986. Invertebres marins du Lagon Neo-Caledonien, VII, etude structurale d'un nouveau saponoside sulfate extrait de I'holothurie, Neothyodium magnum. J. Nat. Prod. 49, 809-813.

Benoit-Vical, F., 2005. Ethnomedicine in malaria treatment I. Drugs 8,45-52.

Benoit-Vical. F., Salery, M.r Soh, P.N., Ahond, A., Poupat, C, 2008. Girolline: a potential lead structure for antiplasmodial drug research. Pianta Med. 74,438-444.

Benoit-Vical, R, Valentin, A., Cournac, V., Pelissier, Y., Mallie, M., Bastide, J.M.. 1998. In vitro antiplasmodial activity of stem and root extracts of Nauclea latifolia S.M. (Rubiaceae).J. Ethnopharmacol. 61, 173-178.

Bcsselievre, R., Cosson, J., Das, B., Husson, H., 1980. Structure and total synthesis of deplancheine.a novel indoloquinolizidine alkaloid. Tetrahedron Lett., 21-63.

Bialonska, D., Zjawiony, J.K., 2009. Aplysinopsins-marine indole alkaloids: chemistry, bioactivity and ecological significance. Mar. Drugs 7, 166-183.

Calderone, R.A.e., 2002. Candida and Candidiasis. ASM Press, Washington, DC.

Clastres, A., Ahond, A., Poupat, C, unpublished results.

Clastres, A., Ahond, A., Poupat, C, Potier, P., Kan, S.K., 1984a. Invertebres Marins du Lagon Neo-Caledonien, II etude structurale de trois nouveaux diterpenes isoles du pennatuiaire Pteroides laboutei.j. Nat. Prod. 47, 155-161.

Clastres, A., Laboute, P., Ahond, A., Poupat, C, Potier, P., 1984b. Invertebres Marins du Lagon Neo-Caledonien, III. Etude structurale de trois nouveaux Diterpenes isoles du pennatuiaire, Cavernutina grandiflora. J. Nat. Prod. 47,162-166.

deNanteuil.G., Ahond, A., GuilhemJ., Poupat, C. TranHuu Dau, E., Potier, P., Pusset, M., Pusset, J., Laboute, P., 1985. Invertebres marins du lagon neo-caledonien-V: Isolement et identification des metabolites d'une nouvelle espece de Spongiaire, Pseudaxinyssa cantharella. Tetrahedron 41, 6019-6033.

Delauneux, J.M., Pusset, M., Ahond, A., Poupat, C, unpublished results.

DeMarini, D.M., Cros. S., Paoletti, C, Lecointe, P., Hsie, A.W., 1983. Mutagenicity and cytotoxicity of antitumor ellipticines in mammalian cells and their structure-activity relationships in Salmonella. Cancer Res. 43, 3544-3552.

Desjardins, R.E., Canfield, C.J., Haynes, J.D., Chuiay, J.D., 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob. Agents Chemother. 16, 710-718.

Ettouati, L, Ahond, A., Convert, O., Laurent, D., Poupat, C, Potier, P., 1988. Plantes de Nouvelle-Caledonie. 124. Taxanes isoles des feuilles d'Austrotaxus spicata Compton (Taxacees). Bull. Soc. Chim. France, 749-755.

Ettouati, L, Ahond, A., Convert, O., Poupat, C, Potier, P., 1989. Plantes de Nouvelle-Caledonie. 124. Taxanes isoles des ecorces de tronc d'Austrotaxus spicata Compton (Taxacees). Bull. Soc. Chim. France, 687-694.

Ettouati, L., Ahond, A., Poupat, C, Potier, P., 1991 a. Premiere hemisynthese d'un compose de type taxane porteur d'un groupement oxetane en 4(20), 5. Tetrahedron 47,9823-9838.

Ettouati, L, Ahond, A., Poupat, C, Potier, P., 1991 b. Revision structurale de la Taxine B, Alcalo'ide majoritaire des feuilles de Plf d'Europe, Taxus baccata.J. Nat. Prod. 54, 1455-1458.

Frederich, M.Jacquier, M J., Thepenier, P., De Mol, P., Tits, M., Philippe, G., Delaude, C, Angenot, L., Zeches-Hanrot, M., 2002. Antiplasmodial activity of alkaloids from various Strychnos species. J. Nat. Prod. 65,1381-1386.

Gamo, F.J., Sanz, L.M., Vidal.J., de Cozar, C, Alvarez, E., Lavandera, J.L., Vanderwall, D.E., Green, D.V., Kumar, V., Hasan, S., Brown, J.R., Peishoff, C.E.. Cardon, L.R., Garcia-Bustos.J.F., 2010. Thousands of chemical starting points for antimalarial lead identification. Nature 465, 305-310.

Goutarel, R., R, M.H., Green, G., Khuong-Hu, Q., Cave, A., Conreur, C, Jarreau, F.X., Hannart, J., 1967. Steroidal alkaloids.LXXI. Synthesis of the four 3,20-diaminopreg-5-ene (irhediamine A and stereoisomers). Comparison of their interactions with the DNA from E. coil Bull. Soc. Chim. France, 4575-4582.

Harvey, A., 2004. The place of natural products in drug discovery. Drug Plus Int. 3, 6-8.

Hay, S.I., Okiro, E.A., Gething, P.W., Patil, A.P., Tatem, A.J., Guerra, C.A., Snow, R.W., 2010. Estimating the global clinical burden of Plasmodium falciparum Malaria in 2007. PLoS Med. 7, el000290.

Hayat, M., Mathe, G., Janot, M.M., Potier, P., Dat-Xuong, N., Cave, A., Sevenet, T., Kan-Fan, C, Poisson, J., Miet, J., Le Men, J., Le Goffic, F., Gouyette, A., Ahond, A., Dalton, L.K., Connors, T.A., 1974. Experimental screening of 3 forms and 19 derivatives or analogs of ellipticine: oncostatic effect on 11210 leukaemia and immunosuppressive effect of 4 of them. Biomedicine [publiee pour l'A.A.I.C.I.G. 21, 101-106].

Husson, H., Poupat, C, Rodriguez, B., Potier, P., 1971. Alcaloides de Lunaria biennis Moench (Cruciferes): Synthesede la ([+ or -])tetrahydro!unaridine.Tetrahedron Lett., 2697-2700.

Husson, H., Poupat, C, Rodriguez, B., Potier, P., 1973a. Syntheses biomfmetiques dans laseriede la lunarine. Tetrahedron, 1405-1411.

Husson, H.P., Poupat, C, Potier, P., 1973b. Synthese de la maytenine, alcalo'ide derive de la spermidine. C. R. Acad. Sci. Paris 276,1039-1040.

Ikhiri, K., Ahond, A., Poupat, C, Potier, P., Pusset, J., Sevenet, T., 1987a. Plantes de Nouvelle-Caledonie. 109. Absouline, alcaloide pyrrolizidinique nouveau isole de Hugonia oreogena et Hugonia penicillanthemum. J. Nat. Prod. 50, 626-630.

Ikhiri, K, Dan Koulodo, D.D., Garba, M., Mamane, S., Ahond, A., Poupat, C, Potier, P., 1987b. Nouveaux alcaldides indoliziniques isoles de Ipomoea alba. J. Nat. Prod. 50,152-156.

Ikhiri, K., Mahaman, I., Ahond, A., Chiaroni, A., Poupat, C, Riche, C, Potier, P., 1995. Le limeolide, nouveau sesquiterpene de type drimane isole de Limeum pterocarpum. J. Nat. Prod. 58,1136-1138.

Kan, C, personal communication.

Langlois, Y., Husson, P., Poupat, C unpublished results.

Langiois, Y., Poupat, C, Husson, P., Potier, P., 1970. Preparation de derives aziridino en serie sterdide. Tetrahedron 26,1967-1976.

LeclercqJ., De Pauw-Gillet, M.C, Bassleer, R., Angenot, L., 1986. Screening of cytotoxic activities of Strychnos alkaloids (methods and results). J. Ethnopharmacol. 15,305-316.

Mahamane, I., Poupat, C, unpublished results.

Makani, S., Ahond, A., Poupat, C. unpublished results.

Meunier, B., Auclair, C, Bernardou, J., Meunier, G., Maftouh, M., Cros, S., Monsarrat, B., Paoietti, C., 1983. In vitro oxidative activation: a model for the cytotoxic action of 9-hydroxy ellipticine derivatives. Structure activity relationships of anti tumour agents. Dev. Pharmacol, 149-181.

Moron, J., unpublished results.

NCCLS, 1997. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard M27-A Na. Com. LS, Wayne, PA.

Oustrin, M.L, Pieraggi, M.T., 1974. Action of hydroxy-9- and methoxy-9-elIipticines on HeLa S3 cells in culture in vitro. C. R. Acad. Sci. Paris 278,1967-1970.

Paoletti, C., Auclair, C., Lesca, R.Tocanne, J.F., Malvy, C, Pinto, M., 1981. Ellipticine, 9-hydroxyellipticine, and 9-hydroxyellipiticinum: some biochemical properties of possible pharmacologic significance. Cancer Treat. Rep. 65 (Suppl. 3), 107-118.

Phillipson, J.D., 2001. Phytochemistry and medicinal plants. Phytochemistry 56, 237-243.

Picot, E., Ahond, A., unpublished results.

Poljakova, J., Frei, E., Gomez, J.E., Aimova, D., Eckschlager, T., Hrabeta, J., Stiborova, M., 2007. DNA adduct formation by the anticancer drug ellipticine in human leukemia HL-60 and CCRF-CEM cells. Cancer Lett. 252, 270-279.

Poupat, C., unpublished results.

Poupat, C., 1971. Contribution a I'etude chimique et biogenetique des alcaloi'des de la Monnaie du Pape, lunaria biennis Moench, Cruciferes These de Doctorat es-Sciences Physiques, Paris-Sud.

Poupat, C., 1976. Synthese totale de la tetrahydrocodonocarpine. Tetrahedron Lett., 1669-1672.

Poupat, C., Ahond, A., Potier, P., 1994. Nouveau Taxoide Basique isole des feuilles d'lf Taxus baccata: LA 2-Desacetyltaxine A. J. Nat. Prod. 57,1468-1469.

Poupat, C., Ahond, A., Sevenet, T., 1976. Alcaloides de Acocia simplicifolia. Phytochemistry 15, 2019-2020.

Poupat, C., Husson, H., Das, B., Bladon, P., Potier, P., 1972a. Etudes recentes des alcaloides de Lunaria biennis Moench (Cruciferes) II. Structure de la lunaridine. Tetrahedron 28,3103-3111.

Poupat, C., Husson, H., Rodriguez, B., Husson, A., Potier, P.Janot, M., 1972b. Etudes recentes des alcaloides de Lunaria biennis Moench (Cruciferes) I, Lunarine et derives: structure dequatre alcaloides secondaires. Tetrahedron 28,3087-3101.

Poupat, C., Sevenet, T., 1975. Cinnamoylhistamine et hordenine, alcaloides d'Acacia spirorbis. Phytochemistry 14,1881-1882.

Robert, G.M. T., 1982. Analyse structural d'alcaloides isoles de deux especes guyanaises de Aspidosperma: A. margravianum, A. oblongum (Apocynacees). Syn

these d'aplysinopsine, substance naturelle d'origine marine, biologiquement active, et de quelques composes structuralement lies. These de Doctorat es-Sciences Physiques, Paris-Sud.

Robert, G.M.T., Ahond, A., Poupat, C, Potier, P.Jacquemin, H., Kan, S.K., 1983a. Aspidosperma de Guyane: Alcaloides des Graines de Aspidosperma oblongum. Nat. Prod. 46, 708-722.

Robert, G.M.T., Ahond, A., Poupat, C, Potier, P., Jolles, C, Jousselin, A., Jacquemin, H., 1983b. Aspidosperma de Guyane: Alcaloides de Aspidosperma marcgravianum. J. Nat. Prod. 46, 694-707.

Rodriguez, B., Poupat, C, unpublished results.

Rousseau-Richard, CM Auclair, C.r Richard, C., Martin, R., 1990. Free radical scavenging and cytotoxic properties in the ellipticine series. Free Radic. Biol. Med. 8, 223-230.

Sanchez, V.t unpublished results.

Sanchez, V., Ahond, A., Debray, M.M., Picot, Poupat, C, 1984. Alcaloides des ecorces de tronc de Didymeles cf. madagascariensis (Didymelacees). Bull. Soc. Chim. France, 71-75.

Sanchez, V., Ahond, A., Guilhem J., Poupat, C, Potier, P., 1987. Alcaloides des feuilles de Didymeles madagascariensis Willd., des feuilles et des ecorces de racines de Didymeles perrieri Leandri (Didymelacees). Bull. Soc. Chim. France II, 887-884.

Simanek, V., personal communication.

Soh, P.N., Benoit-Vical, F., 2007. Are West African plants a source of future antimalarial drugs? J. Ethnopharmacol. 114, 130-140.

Spencer, C.F., Koniuszy, F.R., Rogers, E.F., ShavelJ., Easton, N.R., Kaczka, E.A., Kuehl, FA, Phillips, R.F., Walti, A., Folker, K., 1947. Survey of plants for antimalarial activity. Lloydia 10-3,145-147.

Trager, W.Jensen J.B., 1976. Human malaria parasites in continuous culture. Science 193,673-675.

van Schalkwyk, D.A., Chan, X.W., Misiano, P., Gagliardi, S., Farina, C, Saliba, K.J., 2010. Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death. Biochem. Pharmacol. 79, 1291-1299.

Woodard, C.L, Li, Z., Kathcart, A.K., Terrell, J., Gerena, L., Lopez-Sanchez, M., Kyle, D.E., Bhattacharjee, A.K., Nichols, D.A., Ellis, W., Prigge, S.T., Geyer, J.A., Waters, N.C., 2003. Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases. J. Med. Chem. 46, 3877-3882.

Charlotte Passemar (a), (b), (c), Mariette Salery (a), (b), (c), Patrice Njomnang Soh (a), (b), (c), Marie-Denise Linasc, Alain Ahond (d), Christiane Poupatd, Francoise Benoit-Vical (a), (b), (c), *

(a) CNRS, ICC (Laboratoire de Chimie de Coordination) UPR8241,205, route de Narbonne, F-31077 Toulouse, France

(h) Universite de Toulouse III, UPS, LCC, 118, route de Narbonne, F-31077 Toulouse, France

(c) Service de Parasitologie-Mycologie, Centre Hospitaller Universitaire de Rangueil, Universite de Toulouse et Faculte de Medecine de Rangueil, Universite de Toulouse III, UPS, TSA 50032, 31059 Toulouse cedex 9, France

(d) Institut de Chimie des Substances Naturelles du CNRS, UPR2301,91198 Gif-sur-Yvette cedex, France

* Corresponding author at: Service de Parasitologic CHU Toulouse-Rangueil, 1 av Poulhes, TSA50032, 31059 Toulouse cedex 9, France. Tel.: +33 561323446; fax: +33 561322096.

E-mail address: Francoise.Vical@inserm.fr (F. Benoit-Vical).
COPYRIGHT 2011 Urban & Fischer Verlag
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2011 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Passemar, Charlotte; Salery, Mariette; Soh, Patrice Njomnang; Linas, Marie-Denise; Ahond, Alain; Pou
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:4EUFR
Date:Oct 15, 2011
Words:6584
Previous Article:American ginseng (Panax quinquefolius) prevents glucose-induced oxidative stress and associated endothelial abnormalities.
Next Article:Effect of honokiol on activity of [GAD.sub.65] and of mice [GAD.sub.67] in the cortex and hippocampus.
Topics:

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters