Antibilharzial agents
Dr\ Moustafa K Soltan
I] Antimonial drugs: Antimony potassium tartarate, Stipophen, Sodium
stipocaptate.
(containing trivalent antimony).
II] Non antimonial drugs: classified chemically into the following classes:
Quinoline derivatives: Oxamniquine, Praziquantil (broad spectrum
anthelmintic).
Thioxanthenone derivatives: Lucanthone, Hycanthone.
Organic phosphates: Metrifonate.
Nitro heterocyclic derivatives: Niridazole.
Antimonial drugs.
stibophen
COONa
sodium stibocabtate.
S
COONa
NaOOC
S
S
H
2
COONa
S
H
S
H
COONa
sodium antimony dimercaptosuccinate.
COONa
antimony potassium
tartarate.
COO
H
O
H
O
C
O
O
O
Sb
Sb
O
O
O
3 4 O
SO3Na
5
1 SO3Na
4
NaO
2
3
.7H2O
SO3Na
pentasodium salt of bis-(4,5-dihydroxy
-1,3-benzenedisulfonate)-4,5-antimonate
OR (catechol disulfonate) derivative
Synthesis:
O
COOK
OH
2H
H
OH
C
H
H
COO
5 O
Sb
Sb
S
Sb
1
NaO3S
H
.2K .3H2O
heating
+ Sb2O3
COOK
pot tartarate
antimony potassium
tartarate
Antimony pot tartarate
Uses
Used formerly for treatment of S. Japonicum
Stibophen
Alternative drug for S. Mansoni
Sod stibocaptate
Effective against the 3 forms of schistosoma.(japonicum, mansoni,
haematopium)
Mechanism of action
antimonial drugs inhibit phosphofructokinase enzyme that is
involved in glycolysis what lead to their death.(by covalent binding
with SH gp)
* Host phosphofructokinase is less sensitive 80 times to these drugs
than that of schistosoma and so these drugs exhibit selective
toxicity.
Generally all antimonial compounds are not used now due to their
toxicity and main side effects.
The trivalent are generally more toxic than pentavalent ones as former
are poorly absorbed from the GIT and also less excreted.
Non antimonial drugs
1)quinoline derivatives
CH3
Oxamniquine
O2N 7
HO
8
H
1N 2
HN
CH3
O
1 N2
3
6 5
11
4
1,2,3,4-tetrahydro-2-[(isopropylamino)methyl]
-7-nitro-6-quinoline methanol
( you can replace methanol in the last of name by
6-hydroxymethyl in the first)
2-(cyclohexycarbonyl)1,2,3,6,7,11b-hexahydro
4H-pyrazino[2,1-a]
isoquinolin-4-one
4
N
praziquantel
4
10
9
N5
6
8
3
7
O
3
2
1
aN
b
Oxamniquine.
Uses: Used for treatment of S. Mansoni.
Mechanism of action: It inhibit DNA, RNA and protein synthesis
Oxamniquine is biotransformed into inactive 6-carboxymethyl and so 6hydroxymethyl group is important for activity.
Praziquantel.
Uses: Broad spectrum anthelmintic drug used in:
1) All types of schistosoma.
2) Treatment of intestinal and liver flukes.
3) Treatment of taeniasis and no purgative is needed after its
administration.
Mechanism of action: The drug increases the permeability of the worm
cell membrane to the Ca++ ions what causes massive contractions and
paralysis of the fluke musculature, followed by phagocytosis of the
parasite.
O
O
base catalyzed
cyclization
N
N
O
isoquinoline
NH
O
O
O
NH
Cl
Cl
N
O
N
Cl
hydrogenation
O
-HCl
NH
NH
NH
O
Synthesis of praziquantel.
benzoyl
selective chloride
acylation
Cl
Cl
1) R
2) KCN
3) -KCl
O
NH
CN
N
R
NH 2
O
R
NH
3H2
high pressure
rearrangement
hydrolysis
NH
2) thioxanthenone derivatives:
Lucanthone
8
7
6
5
O
Hycanthone
1
N(Et)2
HN
S
10
8
2
1
9
2
3
4
O
9
7
6
1-[2-(diethylamino)
ethylamino]-4-methyl
-9H-thioxanthen-9-one.
S
10
5
CH3
1
HN
1
4
2
2
3
CH2OH
microbiological transformation
or metabolism in body.
N(Et)2
1-[2-(diethylamino)
ethylamino]
-4-hydroxymethyl
-9H-thioxanthen-9-one.
increase the
attachement to the
receptor in worm.
Synthesis of lucanthone.HCl
Cl
O
H2SO4
heat
OH
+
SH
thiosalicylic acid
O
CH 3
p-chloro
toluene
O
Cl
-HCl
CH 3
H
N(Et)2
N
N(Et)2
H2 N
S
H
Cl
S
CH 3
Lucanthone.HCl
Hycanthone & Lucanthone.
Uses: Treatment of S. Haematobium., S. Mansoni
But now, they are seldom used as they have mutagenic and carcinogenic
activity.
Hycanthone is the metabolic product of lucanthone and it is less toxic and more
active than lucanthone.
3)organic phosphate drugs :
H3CO
O P
1
Synthesis of metrif onate.
OH
Cl
H3CO
Cl Cl
2
metrifonate
O,O-dimethyl-2,2,2-trichloro
-1-hydroxythyl phosphonate
O
H3 CO
P OH
H3 CO
dimethyl
phosphonate
H 3CO
H
Cl
+
Cl
Cl
chloral
trichloroacetaldehyde
O
OH
P
Cl
H3 CO
Cl
Cl
metrif onate
Metrifonate.
Uses:Alternative drug for treatment of S. Haematobium.**
It is not used now due to its severe side effects, praziquantel is used
instead of it,
cause side effects that are due to parasympathetic system stimulation,
diarrhea, abdominal pain, headache, vertigo, vomiting, others.
Mechanism of action: It is an acetyl choline esterase inhibitor, causes
persistant depolarization of the musculature of parasite, causing paralysis
followed by phagocytosis.
4) nitroheterocyclic drugs.
niridazole
O2N
O
S
N
NH
N
1-(5-Nitrothiazol-2-yl)
-2-imidazolidinone
2
Cl
N
O 2N
S
1
NH2
+
C
Synthesis of niridazole.
N
N
O
2-amino-5-nitro 2-chloroethyl
thiazole.
isocyanate
O2N
Cl
NH
S
NH
base
-HCl
O2 N
O
N
N
NH
S
O
Niridazole.
Uses:
Treatment of S. Haematobium..
moderately for treatment of S. Mansoni.
Intestinal amoebiasis.
Side effects are severe:
mental disorientation, mania, convulsions.
Mutagenic, carcinogenic.
Serious effect on heart.