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N
A
P
R
E
C
A
11th NAPRECA Symposium
Natural Products and Drug Discovery
through a Network of Partnerships
Philippe Rasoanaivo
Chairman, Organising committee
“Eventail” of partnerships
Fr
e
c
n
a
Italy
South Africa
US
A
y
as s
ag st
al ti
M ien
sc
s
r
e
l
a
He
Ca
na
da
Malaria Lab
Contents
► Malaria programme
► Semisynthesis/Synthesis programme
► Anti-inflammatory---antiviral pathway
In 1985’s: Sudden resurgence of malaria in the
Highlands of Madagascar
Malaria programme
Integrated approach to
antimalarial plants
Chemosensitising
True antiplasmodial
Antimalarial
plants
Cytotoxic
Prophylactic
A chemosensitizing and prophylactic plant
OCH3
H3CO
N
H3C
N
OCH3
H
CH3
O
H
O
OCH3
Fangchinolin
Strychnopsis thouarsii
(Menispermaceae)
S. Ratsimamanga, P. Rasoanaivo, D. Ramanitrahasimbola, et al.
Planta Med. 1992; 58:540-543.
Research Initiative on Traditional
Antimalarial Methods
RITAM inaugural meeting,
Moshi, December 1999
S
S
S
Strychnopsis thouarsii
N-R
OCH3
H3CO
N
H3C
N
OCH3
H
CH3
O
S
S
H
O
OCH3
Fangchinolin
S
Morphinan alkaloid
Active in vitro & in vivo
Patent N° 04291055.4, 22 April 2004.
Control mice (red), treated mice (green)
and dead mice (black dot)
60
% parasitémie
50
40
30
20
10
0
J3
J4
J5
J6
J7
J8
J9
J10 J12 J14 J16 J19 J21
Post-infection days
M. Carraz, PhD, 2005
Chemosensitizing indole alkaloids
Malagasy Strychnos: S. myrtoides, S. mostueoides, and
S. diplotricha
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
N
N
CH3
CH3
N
CO2CH3
N
O
O
H3CO
C
O
O
F. Trigalo, M. T. Martin, A. Blond, B. Rasolondratovo, P. Rasoanaivo, F. Frappier.
Tetrahedron 2002, 58, 4555-58.
F. Trigalo, R. Joyeau, V. C. Pham, J. J. Youté, P. Rasoanaivo, F. Frappier.
Tetrahedron 2004, 60, 5471-4.
Strychnobrasiline derivative
O
O
N
N
CH3
H
N
H
H
N
O
Ac
CH3
O
CH3
O
CH3
Fe
D. Razafimahefa, L. Pélinski, M.-T. Martin, D. Ramanitrahasimbola, P. Rasoanaivo,
J. Brocard. Bioorg. Med. Chem. Let. 2005, 15, 1239-1241.
Naturally-occurring chemosensitizers:
source of inspiration for medicinal chemistry
CH3
CH
3
NN
N
N
H
CO2CH3
N
N
Desipramine
Ac
O
Me
Me
CH3
CH
3
N
N
N
H
N
CO2CH3
NN
Cl
Ac
Ac
O
Chlorpheniramine
Pervilleine series
OCH3
H3CO
OCH3
CH3
N
HO
O
O
OCH3
OCH3
O
OCH3
Erythroxylum pervillei
O
Collaboration with the University of Illinois at Chicago
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.
OCH3
H3CO
OCH3
OCH3
H3CO
OCH3
CH3
CH3
N
N
O
HO
O
O
O
OCH3
OCH3
O
H3CO
OCH3
H3
CO
NC
O
CH3
N
CH3
N
Verapamil
OCH3
OCH3
OCH3
OCH3
O
OCH3
O
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.
Chemosensitizing pharmacophore and polyamines
NH2
H2N
Putrescine
H2N
N
H
NH2
Spermidine
CH3
NC
H3CO
N
OCH3
Verapamil
H3CO
OCH3
CH3
OCH3
OCH33
OCH
N
OCH33
OCH
H
H33CO
O
H
H33CO
O
O
Pervilleine C
H2N
OCH
OCH33
O
H
N
Spermine
N
H
NH2
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
MeO
Herveline series
OMe
N
MeO
OMe
Me
N
7
MeO
OMe
Me
7
MeO
1.00
MeO
N
CH3
MeO
Herveline A
Herveline B
Herveline C
Herveline D
O
0.80
O
N
CH3
12'
12'
MeO
0.60
MeO
HO
0.40
OMe
N
OMe
MeO
OMe
Me
N
7
MeO
OH
Me
7
MeO
0.20
MeO
OH
MeO
O
O
0.00
N
CH3
N
0.00
0.20
0.40
0.60
0.80
CH3
1.00
12'
12'
MeO
HO
P. Rasoanaivo, S. Rasimamanga-Urverg, C. Galeffi, M. Nicoletti, F. Frappier,
M-T. Martin. Tetrahedron 1995, 51, 1221-8.
P. Rasoanaivo P, Ratsimamanga-Urverg S, Rafatro H, Ramanitrahasimbola D,
Palazzino G, Galeffi C, Nicoletti M. Planta Med. 1998, 64, 58-62.
Malagashanine as a biochemical tool
N
CH3
CO2CH3
N
HN
Cl
N
Ac
O
N
CH3
N
N
Ac
CO2CH3
H
O
D. Ramanitrahasimbola, P. Rasoanaivo, S. Ratsimamanga, H. Vial.
Mol. Biochem. Parasitol. 2005 (revised).
Chloroquine with modified side chains
OH
N
N
N
HN
HN
HN
Fe
Cl
Cl
N
Chloroquine
N
Cl
Amodiaquine
O
HN
N
R1
N
Ferroquine
R2
R3
N
R4
Cl
N
Cape Town and IMRA partnership, work in progress
World malaria distribution and
occurrence of antimalarials
Artemisinin
Quinine
?
Anti-inflammatory---antiviral pathway
Baobab
Strong antiviral activities
Anti-inflammatory activities
J. B. Hudson, M. K. Lee, P. Rasoanaivo.
Pharm. Biol. 2000, 38, 36-39.
Helichrysum
Inhibition of NF-κB
Strong anti-HIV actitivities
Integrated approach for the screening of plants
used in the treatment of vascular or pulmonary disorders
Plants
Anti-inflammatory
Vaso-relaxing
Broncho-relaxing
+
NFκB
+
Anti-HIV
Mechanism of action
Integrative approach
Partnerships