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CNR RAO Award Lecture
Natural products drug discovery
through a network of Partnerships

Philippe Rasoanaivo
Institut Malgache de Recherches Appliquées
Madagascar

Team
Multi-disciplinary
Natural products
Drug discovery
Inter-disciplinary
Trans-disciplinary

Integrated approach

N
E
T
W
O
R
K

“Eventail” of partnerships
Africa

USA

Sw

ed
en
y
as ts
ag is
al t
M ien
sc

rs
e
l
a
He

n
a
r
F

ce

Italy

IMRA

In 1980’s: Sudden resurgence of malaria in the
Highlands of Madagascar

Malaria programme on medicinal plants

Reversing agents in malaria
Bringing Traditional knowledge into
Useful applications
► Isolation of
active constituents
►Semisynthesis
Integrated
approach

►Source of inspiration for
Medicinal chemistry
►Biochemical tool
►Phytomedicine

Malagasy Strychnos and
Chemosensitizers in malaria
N

CH3

O

H
CO2CH3

N
Ac

N CH3

O

Malagashanine
Active in vitro & in vivo

N
Ac

O

CH3

Strychnobrasiline
Active in vitro but not in vivo

P. Rasoanaivo, S. Ratsimamanga, R. Milijaona, H. Rafatro, C. Galeffi,
M. Nicolleti. Planta Med. 1994, 60, 13-16.

Malagashanine derivatives
N
3

12

R

N
Ac

CH3
N

H
CO2CH3

H

N

19

Ac

O

12-hydroxy-malagashanine
19-epi-malagashanine

CH
3

H
CH2OH

H
O

Malagashanol

N

CH3
H
O

3

N

R2
R1

Ac

H

O

O
Myrtoïdine series

● M.-T. Martin, P. Rasoanaivo, G. Palazzino et al.. Phytochemistry 1999, 51, 479.
● P. Rasoanaivo, G. Palazzino et al. Phytochemistry 2001, 56, 863.

Strychnobrasiline for semisynthesis
O
O

O
N

N

CH3

CH3

N

N

O
Ac

O

O

CH3

CH3

Strychnobrasiline
CH3
N

N
O

O
H3CO

C
O

F. Trigalo, M. T. Martin, A. Blond, B. Rasolondratovo, P. Rasoanaivo, F. Frappier.
Tetrahedron 2002, 58, 4555-58.

Strychnobrasiline for semisynthesis

O

O
N

CH3

N

CH3

H

N

N
Ac

O

CH3

H
H

Strychnobrasiline

O

O

CH3

Fe

D. Razafimahefa, L. Pélinski, M.-T. Martin, D. Ramanitrahasimbola, P. Rasoanaivo,
J. Brocard. Bioorg. Med. Chem. Let. 2005, 15, 1239-1241.

Strychnobrasiline for semisynthesis
N

CH3

O
CH3

N
N

CO2CH3

N

Ac

O

CH3

O

Strychnobrasiline
N

CH3
N

H

CO2CH3

N
O

N

CH3

CO2CH3

O
F. Trigalo, R. Joyeau, V. C. Pham, J. J. Youté, P. Rasoanaivo, F. Frappier.
Tetrahedron 2004, 60, 5471-4.

Malagashanine:
source of inspiration for medicinal chemistry
CH3
N

N
CH3

N
H

N

CO2CH3
N

Desipramine

Ac
O
N

Me

Me

CH3

CH3

N

N

N

H
N
CO2CH3

N

N
Ac

Cl

Ac
O

Chlorpheniramine

Pervilleine series
OCH3
H3CO

OCH3

CH3
N
HO

O

O

OCH3
OCH3
O
OCH3

Erythroxylum pervillei

O

B. Cui, G. L. Silva, D. Chavez, M. You, H.-B. Chai, P. Rasoanaivo, S. M. Lynn, M. O’Neill, J.
A. Lewis, J. M. Besterman, A. Monks, N. R. Farnsworth, G. A. Cordell, J. M. Pezzuto,
A. D. Kinghorn. Journal of Natural Products 2001, 64(12), 1514-19.

Pervilleine series: dissecting the molecule
OCH3
H3CO

OCH3

CH3
N
HO

O

O

OCH3
OCH3
O
OCH3
O

Verapamil

Basic requirements for
Chemosensitizing pharmacophores

S

(C)n

S’

S ~ S’ = N, aromatic

Synthesis ?
P. Rasoanaivo. Proceeding of the 5th Colloquium on Plant Natural Products,
Québec, 7-9 August 2001, pp. 128-140.

Br

X
N

X = N, O
O

N
N
H

F. Chouteau, D. Ramanitrahasimbola, P. Rasoanaivo, K. Chibale.
Bioog. Med. Chem. Lett. 2005, 15, 3024-28.

One relevant result
10 nM
l
a
i
d

o
m
s
a
l
ip
t
n

A
Ch
em

os
en
sit
izi
n

g

Malagashanine as a biochemical tool
N

CH3

CO2CH3

N

HN

Cl

N

Ac

O
N

CH3

N
N
Ac

CO2CH3
H
O

Bi-directional, reversible
Chloroquine transporter in malaria

CQ

D. Ramanitrahasimbola, P. Rasoanaivo, S. Ratsimamanga, H. Vial.
Mol. Biochem. Parasitol. 2006, 146, 58-67.

Standardized Phytomedicine

Placebo controlled,
double blind clinical trial

Aqueous extract
Clinical observational studies
A. Ramialiarisoa, J. Ranaivoravo, P. Rasoanaivo, S. Ratsimamanga.,
Rév. Méd. Pharm. Afr. 1994, 8, 123.

Research Initiative on Traditional
Antimalarial Methods (RITAM)

RITAM inaugural meeting,
Moshi, December 1999

Hepatic stage of malaria parasites
H3CO

10

HO

OH

NH

HO

OCH3
OH

Strychnopsis thouarsii

Tazopsine

M. Carraz, A. Jossang, JF Franetich, A. Siau, L. Ciceron, F. Frappier,
P. Rasoanaivo, G. Snounou, D. Mazier, PLoS Medicine 2006 (in press).

World malaria distribution and
occurrence of antimalarials

Artemisinin
Quinine

?

Chronic degenerative diseases

SA Pharmacology Meeting, 2003

Ageing ~ Resistance
Advanced Glycation End-products
Chronic degenerative diseases

Integrated
approach

►Diabetes

Cardiovascular and
Erectile disorders

► Memory impairment

CNRS-funded bioprospecting
Extract library
Structure diversity

Antimalarial
Cytotoxicity
Antibacterial

Broad screening

Research & Teaching in an
integrated approach

Networking

Acknowledgments
The Government of Brazil
The Academy of Sciences of the Third World
The Brazilian Academy of Sciences
The C.N.R. RAO Prize