RASOANAIVO Substances Naturelles d’Intérêt Biologique

Substances Naturelles d’Intérêt Biologique

Université de Maurice à Reduit
30 Septembre à 3 Octobre 2003

Natural Products:
Source of inspiration for medicinal chemists

Philippe Rasoanaivo
Institut Malgache de Recherches Appliquées
Antananarivo, Madagascar

DRUG DISCOVERY PROCESS AND DEVELOPMENT
Extracts/chemical library
Biological screening

HITS
Message

LEAD COMPOUND
Lead optimisation

QSAR
Combinatorial chemistry
Rational drug design

Clinical candidate
Pre-clinical & clinical studies

LIVING ORGANISMS
Reproductive system
BIRTH

DEATH

LIVING ORGANISMS
Reproductive system
BIRTH

DEATH

RESISTANCE

Plasmodium food vacuole:
HEMOGLOBINE
Proteases

AMINOACIDS

HAEM
Biocrystallization

Detoxification

O22H2O

HEMOZOINE

One mechanism of chloroquine resistance
CQ

Chemosensitizers

CQ
CQ

Strychnos of Madagascar

The 1,4-diamino hypothesis
N

CH3
3

Nb

O
N

CO2CH3

N
Ac

H

21
N

N

H

O

Ac

O

Spermostrychnine

Malagashanine

N
N

O

CH3

N
H

CO2CH3

N

O

CH3
N

N
H

O

CH3

Strychnobrasiline

CH3

N
H

CH3

CH3

Synthetic chemosensitizers: the 1-phenyl,4-amino hypothesis

CN
MeO

Me

Me

N

N Me
Cl

N

MeO
MeO
Verapamil

N Me
H
Desipramine

S

OMe

N

Chloropromazine

N

Cl
HO

F

N

N Me
Me
Amitriptyline

N
Me
Cyproheptadine

CF3

F
Penfluridol

Unifying pharmacophore for
chloroquine reversal
N
N
N

S

(C)n
S = N, Phenyl
n>2

S

MeO

OMe
N

Me
7

MeO

OMe

MeO
O
N
CH3

12'

MeO

Herveline series isolated from
Hernandia voyroni

Erythroxylum of Madagascar

The pervilleine series
H3CO

OCH3
OCH3
CH3
N

O
O
OCH3
OCH3

O
O

OCH3

Chemosensitizers and polyamines
CH3
OCH3

OCH3

N

OCH3

H3CO

O
O

H3CO
O

OCH3
O

Pervilleine C
CH3

NC
H3CO

N

OCH3

Verapamil

H3CO
H2N

OCH3

N
H

NH2

Spermidine
H2N

H
N
N
H

Spermine

NH2

Hypothesis for CQ reversal
HN
HN
Cl

N

N

Chloroquine
CQ CQ CQ

CS

CQ

CONCLUSION
Traditional knowledge

Pharmacophore
Chemical structures

Synthesis
Biochemical tools

World malaria distribution and
occurrence of antimalarials

Artemisinin
Quinine

?

« Nature has created diseases and also cure for the
diseases ». Svoboda

Thank you for your attention