Antimalarial
Moustafa K. Soltan
Antimalarial drugs.
Malaria has two hosts: 1) vertebral host (human). 2) Vector (mosquito).
Classification of antimalarial drugs: according to chemical structure.
1) Cinchona alkaloids: quinine (-),while quinidine its isomer (+) is used as
antiarrythmic.
2) 8-aminoquinolines: pamaquine, primaquine.
3) 4-aminoquinolines: chloroquine, hydroxychloroquine, Santoquine and
amodiaquine.
4) Aminoacridine: quinacrine.
5) Biguanides: proguanil, chloroguanil, bromoguanil, and cycloguanil.
6) pyrimidines: pyrimethamine.
7) sulfonoes: sulfadoxine.
8-aminoquinoline
pamaquine
-[ -(N,N-diethylamino)
- -methylbutyl]amino
- - methoxy quinoline
primaquine
N,N-diethylamino is
replaced by amino group
only to give
-[ -amino- -methylbutyl]amino
- -methoxy quinoline
Curative Exoerythrocytic schizonticides, but primaquine is 4-6 times as active as
pamaquine and ½ toxicity, this is because of terminal 1ry amino gp in
primaquine.
SAR.
1)quinoline ring is important for activity, if reduced or changed
into isoquinoline activity is lost.
2) 6-methoxy group is not essential for activity
If changed into 6-hydroxy, activity increase
if to 6-ethoxy or 6- methyl ,activity is lost.
3)the side chain in 8 show optimum activity if alkyl group C4-C6,
if less than 4 or more than 6, activity decrease.
4) 2ry amino group at position 8 is active than 1ry or 3ry.
5) Terminal amino group show increase in activity from 3ry to 2ry
to 1ry, so primaquine is 4-6 more active and ½ toxic than
pamaquine .
1)skraup synthesis of quinoline ring:
( glycerol + H2SO4 = acrolein react with aniline dv).
1)glycerol
2)H2SO4 H3CO
H3CO
NH2
NO2
3) FeSO4
4)nitrobenzene
H3CO
N
NO2
Sn / HCl
reduction
N
(I) NH2
2)preparation of side chain:
EtONa
base
-HI
COCH 3
COCH 3
N
I+
COOEt
COOEt
diethylamino ethylacetoacetae
1)hyd of ester
ethyliodide
2)decarboxylation
1)reduction of C=O
Br
O
to
2ry
alc
(II) N
CH3 2)halogenation by PBr3 N
CH
N
3
3)condensation of (I) + (II) to give pamaquine.
**synthesis can be modified to give primaquine
4-aminoquinoline
chloroquine
-[ -(N,N-diethylamino)
- -methylbutyl]amino
- -chloroquinoline
R=
Hydroxychloroquine
-[ -(N-ethyl-N-( -hydroxyethyl)
amino)- -methylbutyl]
amino- -chloroquinoline
R=
amodiaquine
R=
-[( -hydroxy- -(N,Ndiethylamino)methyl)phenyl]amino
- -chloroquinoline
Chloroquine:
1) Suppressive erythrocytic schizonticide: inhibit development of schizonts
during erythrocytic stage.2) concentrate in liver so used in hepatic amoebiasis.
Hydroxychloroquine, Amodiaquine are also suppressive erythrocytic
schizonticides
SAR.
1)quinoline ring is important for activity, if reduced or changed into
isoquinoline activity is lost.
2) introduction of 3-methyl group on quinoline ring of hydroxychloroquine
give santoquine which is less active.
3) halogenation is restricted in 7- position if changed, lose activity,
Chloride is the best halogen.
4)any substitution in 8- position like methyl, cancels activity.
5) introduction of hydroxyl group in the ethyl group of terminal amino group
reduce toxicity and produce higher blood levels, increase activity.
So hydroxychloroquine is more active, less toxic than chloroquine
.
6) p-aminophenol derivatives in the side chain as in amodiaquine decrease
activity and also decrease toxicity than chloroquine.
(Hydroxychloroquine> Chloroquine>Amodiquine>Santoquine)
in activity due to SAR.
9-aminoacridine
derivatives
H3C
HN
8 9
7
6
N
Cl
5 10
1
(CH2)3 N(C2H5)2
1 OCH
3
2
3
4
quinacrine
6-chloro-2-methoxy-9[4-(N,N-diethylamino)
-1- methylbutyl]acridine.
CH3 1)KMnO
4
2)NaOH Cl
2,4-dichlorotoluene
Cl
Cl
COONa p-anisidine
OCH3
H2N
Cl
H3C
CH3
(CH2)3 N(C2H5)2
(CH2)3 NH2
HN
H2N
OCH3
Cl
N
-HCl
Cl
Cl
N
COOH
N
H
OCH3
1)cyclization -H2O
2)POCl3 to convert
OCH3
OH to Cl