RASOANAIVO Bioactive constituents to anti malarial plants

PHYTOCHEMICAL SOCIETY OF EUROPE

International Symposium
LEAD COMPOUNDS FROM HIGHER PLANTS

September 12-14, 2001, Lausanne, Switzerland

BIOACTIVE CONSTITUENTS
FROM AN INTEGRATED APPROACH
TO ANTIMALARIAL PLANTS

Philippe Rasoanaivo
Institut Malgache de Recherches Appliquées

WORLD MALARIA SITUATION

Integrated approach to antimalarial plants
- Chemosensitizers
- Prophylactic
- Cytotoxic
- Antiplasmodial

Anticancer agents
True antimalarials

Direct effects on parasite viability

ANTIMALARIAL PLANTS
Effects on host-parasite relationships
- Immunostimulants
- Antipyretic
- Unexpected mechanisms
Rasoanaivo P, Oketch H, Willcox M, Bodeker G. Fitoterapia 2001 (in press)

ANTIPLASMODIAL COMPOUNDS
(vihpal project)
Alkaloids from Isolona ghesquiereina
H3C
H

H3C

N

H

O RO

HO

OCH3

N

O HO

O

OCH3

O
OH

H3CO
H3CO

H
N
CH3

IC50= 0.3-0.9 μM

H
N
CH3

R= H: (-)-Curine
R= CH3: Chondrofoline

Isochondrofoline

Mambu L, Martin MT, Razafimahefa D, Ramanitrahasimbola D,
Rasoanaivo P, Frappier F. Planta Medica 2000, 66, 537.

Quinones and phenolic compounds
from Dalbergia species
OH

O

H3CO

H3CO

O
IC50 = 0.17 μg/ml

OH
IC50 = 0.59 μg/ml

Cl
O
OH
O

Atovaquone

Phenanthrenoid-related compounds
O

Cl

Cl

O

R1

HO

N

CH3
OMe

CHOH
CF3

R2

OMe
Dehydroaporphine
IC50 = 0.08 μg/ml

CH2
N

Halofantrine Bu

HO

MeO

CH2

Bu

Phenanthrenoids
IC50 ~ 1.0 - 1.9 μg/ml

(Domohinea perrieri,
Givotia madagascariensis)

(Ocotea laevis)
MeO
MeO

NO3+
N

OMe
OMe

Burasaine
IC50 = 0.4 μg/ml

(Burasaia madagascariensis)

L. Long, S. K. Lee, M. You, H.-B. Chai, P. Rasoanaivo, N.F. Farnsworth,
G. A. Cordell, J. M. Pezzuto and A. D. Kinghorn.Tetrahedron 1997, 53, 15663.

CYTOTOXIC COMPOUNDS
Sequiterpene lactones of the Asteraceae family
CH2OH
O

O
O

O

O

O

CH2OH
HO

O

O
CH2OH

Onopordopicrin
(Brachylaena ramiflora)

Cynaropicrin
(Vernonia glutinosa)

Rasoanaivo P, Ratsimamanga-Urverg S, Ramanitrahasimbola D, Rafatro H,
Rakoto-Ratsimamanga A. J. Ethnopharmacol. 1999, 64, 117.

Indole alkaloids from Perriera madagascariensis
OCH3

OCH3
N
H3CO

N
H
OCH3
N

N
H3CO

N
H
N

Kirondrine
OCH3

Krebs HC, Rakotoarimanga VJ, Rasoanaivo P, Frappier F, Martin MT.
J. Nat. Prod. 1997, 60, 1183.

CHEMOSENSITIZING AGENTS
(AUF project)

Medicinal plants used to enhance chloroquine action

Strychnos diplotricha
Strychnos myrtoides

Strychnos mostueoides

Hazomalania voyroni

Strychnopsis thouarsii
Spirospermum penduliflorum
Burasaia madagascarienis

Dimer isoquinolines from Hazomalania voyroni
OMe

MeO
N

Me

MeO

7

OR2

N

(CH2)3-NH-CH3

Desipramine

MeO
O
N

MeO
Me
N

MeO

12'

Me

R1O

CN

R1

Herveline A
Herveline B
Herveline C
Herveline D

R2
H
Me
Me H
Me Me
H
H

MeO
OMe

Verapamil

Rasoanaivo P, Ratsimamanga-Urverg S, Galeffi C, Nicoletti M, Frappier F,
Martin MT. Tetrahedron 1995, 51, 1221.

Isobologrammes of interaction
MeO

OMe
N

MeO

OMe

Me

N
7

MeO

OMe

Herveline A
Herveline B
Herveline C
Herveline D

MeO
O
0.80

CH3

12'

7

MeO

1.00

N

Me

OMe

MeO
O
N
CH3

0.60

12'

MeO

HO
0.40

MeO

MeO

OMe
N

OMe

Me

N

0.20

7

MeO

OH

Me
7

MeO

MeO

MeO

0.00

O

O
0.00

N

OH

0.20

0.40

0.60

0.80

1.00

N
CH3

CH3

12'

12'

MeO

HO

P. Rasoanaivo P, Ratsimamanga-Urverg S, Rafatro H, Ramanitrahasimbola D,
Palazzino G, Galeffi C, Nicoletti M. Planta Medica 1998, 64, 58.

Indole alkaloids from Malagasy Strychnos species

N

CH3
H

N
Ac

CO2CH3
H
O

Malagashanine

Rasoanaivo P, Ratsimamanga-Urverg S, Milijaona R, Rafatro H,
Galeffi C, Nicoletti M. Planta Medica 1994, 60, 13.

Minor alkaloids of Strychnos species
N
3

N

12

R

Ac

CH3
N

H

CH3
H

CO2CH3
H

CH2OH

N

19

Ac

O

12-hydroxy-malagashanine
19-epi-malagashanine

H
O

Malagashanol

N

CH3
H

3

O
R2

N
R1 Ac

O

H
O

Myrtoïdine series

Martin MT, Rasoanaivo P, Palazzino G, Galeffi C, Nicoletti M,
Trigalo F, Frappier F. Phytochemistry 1999, 51, 479.
P. Rasoanaivo, G. Palazzino, C. Galeffi, M. Nicoletti.
Phytochemistry 2001, 56, 863.

The 1,4-diamino unit hypothesis
Me
N

O

N
N
H

O

CH3

N

CH3

O

Strychnobrasiline

CH3

Spermostrychnine

HN
Me

N
H

N
H

CO2Me
O

Malagashanine

N
N

Me

Cl

N

N
N

Chloroquine

N
Cl

Chlorpheniramine

MeO
MeO

CN Me
N

Verapamil

R
OMe
OMe

synthetic chemosensitiser

Choroquine resistance and MDR
1.00

N

CH3

N
H

OCH3
CO2CH3
HN

Fractional IC5O of test alkaloids as chemosensitizers

H3CO2C

0.80

0.60

0.40

0.20

0.00

N

0.00

Voacamine

0.20

0.40

0.60

0.80

Fractional IC50 of test alkaloids as antimalarials

Ramanitrahasimbola D, Rasoanaivo P, Ratsimamanga-Urverg S,
Federici E, Palazzino G, Galeffi C, Nicoletti M. Phytoter. Res. 2001, 15, 30.

1.00

Chloroquine resistance and MDR
H3CO

OCH3

OCH3

O

CH3

N
O

O
OCH3
O
OCH3
OCH3

Silva GL, Cui B, Chavez D, You M, Chai HB, Rasoanaivo P, Lynn SM, O’Neill
MJ, Lewis JA, Besterman JM, Monks A, Farnsworth NR, Cordell GA, Pezzuto
JM, Kinghorn AD. J. Nat Prod. 2001 (in press).

CONCLUSION
Natural products
Leads
Biochemical tools
Messages
Drug discovery
Mechanisms of action