jhllggkkkh jhjh

1. ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB 1
Antiprotozoal drugs

2. ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB 2
Protozoal diseases are highly prevalent in tropical third world
countries. Where, they infect animal and human populations.
Antiprotozoal Agents
1.Malaria, (sleeping sickness)
2. Amebiasis, giardiasis, leishmaniasis
3. Helminthes infection [nematodes, cestodes &trematodes]
4. Insects (scabies, lice & chiggers)
Protozoa infection include
I)_Malaria & antimalarial agents
❑ Malaria in tropical country usually caused by 4 species of plasmodium P.
flaciparum, P. vivax, P. ovale & P. malaria

3. ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB 3
Antiprotozoal Agents
I)_Malaria & antimalarial agents
❑ Malaria in tropical country usually caused by 4 species of
plasmodium P. flaciparum, P. vivax, P. ovale & P. malaria
❑Female Anopheles mosquito is the intermediate host in the life
cycle
❑All plasmodium species have secondary exoerythrocytic stage
except P. flaciparum

4. ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
4
Zygotes
(stomach)
Sporozoites
(salivary gland)
Ooctsts
(stomach epithelium)
Primary schizonts
(liver)
Merozoites
(liver)
Secondary schisonts
(liver)
Merozoites
(blood)
enter RBCS
Multiplication
Rupture
Meroizoites
male gametocyte
female gametocyte
Fertilization
Antigen Fever
1
2
2
3
4
Anopheles Human blood
Life cycle

5. ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
5
Biochemical dependence of malaria on host cell
RBCs
Purine & PO4
Hemoglubine & plasma amino acid
Pentoses DNA & RNA
Glucose
malaria like bacteria must synthsised folic acid
Malaria

6. ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
6
4 Possible site for action of antimalarial drugs
Liver RBCs
Sporozites Gametocytes

7. ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
7

8. (I)-Antimalarial agents Of plant origin:
1)- Cinchona alkaloids: (Quinine, Quinidine, Cinchonidine and cinchonine):
N
O
H
H
N
H
OMe
Quinine
❑ 4 alkaloids in cinchona bark
❑ Inhibit erythrocytic stage (clinical cure) in all species of
plasmodium
❑ They have antipyretic effect due to peripheral vasodilatation
❑ Not used now due to mutation.
❑ Used by I.v route to avoid GIT side effects.
*
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
8

9. (II)-Synthetic Antimalarial agents::
(A)- Quinoline derivatives
1)-4-Aminoquinolines:
*General structure and SAR:
Side effects: Nausea, vomiting, anorexia, diarrhea , headache
and dizziness.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
9

10. *Mechanism of action :
1- Chloroquine is trapped in the protozola lysosome increases the
PH so inactivation of hemoglobin digesting enzymes.
2- Chloroquine forms complex with FPIX(Ferriproteinporphyrin
IX), this complex is toxic to the parasite causing lysis to its
membrane.
*Mechanism of resistance to chloroquine
1. Accumulate less drug in their cells (↓ uptake)
2. Presence of membrane protein (P-glycoprotein) that pump drug
out (verapamil a Ca channel blocker block this protein & reverse
resistance but large doses required → cardiac arrhythmias
3. ↑ Activity of plasmodial cytochrome P-450 →↑ drug metabolism
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
10

11. *Examples: chloroquine
*Has also use in the treatment of rumatoid arthritis as it
decrease the antigens responsible for the symptoms.
HN
N
N
Cl
H
CH3
Chloroquine
7-Chloro-4-[[4-(diethylamino)-1-methylbutyl]-
-aminoquioline
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
11

12. ii)- Biguanides:
N
N
N
NH2
NH2
Cl
Cycloguanil
*Proguanil prodrug converted in vivo to the active Cycloguanil.
Side effects:
1) Not used in patient with kidney impairment.
2) GIT disturbances.
3) Folate supplement is needed if used during pregnancy.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
12

13. II)_Antiamoebic drugs
*Drugs used in the treatment of a parasitic disease caused by
organism called entamoeba in contaminated water so to avoid
infection we should: 1)-drinking bottled water
2)-boiling the water. 3)-disinfecting the water.
*They are classified into:
1-Direct amebicids.
(used in amebic dysentery- Intestinal amebasis).
2-Systemic amebicids. (Extraintestinal amebicids).
3-Mixed amebicids.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
13

14. (A)-Intestinal amebicides:
*8-Hydroxy quinoline:
N
OH
R2
R1
R1= I, R2= SO3H: Chiniofon.
R1= I, R2= Cl: Iodochlorohydroxyquin.
R1 = R2 = I: Diiodohydroxyquin.
*Uses: intestinal amebasis . (poorly absorped from the GIT).
*Side effects: Optic and peripheral neuropathy limited its use.
*NB:
1-Diiodohydroxyquin is as effective as chinifon but much less
toxic.
2- Has poor absorption from the GIT.
**Mechanism of action : Chelate essential metal ions.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
14

15. *SAR:
*Synthesis of Diiodohydroxyquin:
N
OH
I
I
N
OH
ICl or KIO4
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
15

16. b) Diloxanide furoate: )
*Hydrolyzed in the gut to give the active drug.
*Used alone or in combination with Metronidazole in the
cases of Intestinal amebiasis.
*Mechansim of action : Decrease protein synthesis.
Diloxanide furoate
N
Cl
Cl
O
O
O
O
C
H3
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
16

17. (B)-ExtraIntestinal amebicides(hepatic amebicides):
* Nitroheterocyclic compounds:
1)-Metronidazole (Flagyl):
N
N
CH3
CH2CH2OH
O2N
Metronidazole
2-Methyl-5-nitroimidazole-1-ethanol
*Mechansim of action :(prodrug): 5-NO2 group reduced in the
Microorganism to reactive -NO, NHOH, and NH2 together with
production of reactive species (superoxide radical, H2O2, OH.) that
can interact with DNA in the microorganism causing lethal effect.
*NB: Human has catalase reductase enzyme that protect him
from ROS (reactive oxygen species)
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
17

18. *Uses:
1-Active against intestinal and hepatic amebasis.
2-Active against both gm+ve and gm-ve anaerobes bacteria
so used in case of septicemia, peritonitis, meningitis
*Synthesis:
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
18

19. 2)-Tinidazole(Fasigyn):
N
N
CH3
CH2
CH2
SO2
C2
H5
O2N
Tinidazole
*tinidazole derivative of metronidazole with
longer half life so used once daily.
* Synthesis:
N
N
O2N
CH3
H
+
H3C
SO3CH2CH2SO2Et
Tinidazole
3)-Secnidazole (Flagentyl):
N
N
O2N
CH3
CH2
OH
CH3
*It has the longest half life among the
metronidazole derivatives.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
19

20. 4) Nifuroxazide
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
20
*Nifuroxazide
Used for Colitis, and Diarrhoea
❑ has the short half life and have different uses including
anticancer and antivirus .
❑ is a broad-spectrum intestinal anti-infectious agent.
❑ Children. Discontinue if no improvement after 3 days. Not
suitable for invasive infections. Ensure adequate hydration

21. III)-Anthelminitic Drugs
*They are the drugs that have the ability to eliminate parasitic
worms from the body.
*Anthelminitic drug may be broad spectrum or only specific
for one or two parasitic infestations.
*Anthelminitic agent may be active against :
1)- Nematodes: (Pin, Filaria, Hook, or round worms).
2)- Cestodes: (Fish, Beef or Prok tapeworm).
3)- Trematodes: (Schistosoma haematobium,
Schis.mansoni, or Schis.Japonicum).
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
21

22. III)-Anthelminitic Drugs
*According to chemical structure Anthelmintic agents
are classified into:-
1)-Phenols and their derivatives.
3)-Heterocyclic compounds:
a)-Benzimidazole derivatives.
b)-TetrahydroPyrimidine derivatives.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
22

23. N
H
O
Cl
OH
Cl
NO2
Niclosamide
Synthesis:
OH
Cl
COCl
+
N
H2
Cl
NO2
-HCl
DRUG
Mechanism of action :
1) Decrease glucose uptake.
2) Decrease worm respiration.
3) Decrease protein synthesis.
4) Decrease formation of trypsin inhibitor so facility the action
of the digestive enzyme of the host.
*(I)-Phenols and their derivatives:
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB 23

24. (II)-Heterocyclic derivatives:
(A)-Benzimidazole derivatives:
*Mechansim of action :
Inhibits fumarate reductase enzyme which is involved in
oxidation of NADH to NAD and so production of ATP is
inhibited.
1)Mebendazole:
N
H
N
O
NHCOOCH3
2)-Flubendazole:
N
H
N
O
NHCOOCH3
F
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
24

25. (b)-TetrahydroImidazothiazole derivatives:
*Levamizole (Ketrax):
N
N
S
H
.HCl
NB: L-form is the active anthelmintic agent while D-
isomer is active as antidepressant agent.
*M.O.A: The drug and its metabolite can inhibit fumarate
reductase.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
25

26. III-Drug therapy for scabies and pediculosis
1) Benzyl benzoate (Benzanil):
O
O
It is effective as scabicide, when topically applied
cause immediate relief of itching probably due to local
anesthetic effect.
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
26

27. III)-Drug therapy for scabies and pediculosis
2) Lindane
(Gamma benzene hexachloride)
(hexachlorohexane)
(Scabine):
It exerts its insecticidal effect by CNS stimulatory action
which occurs by blockage of GABA
It has the potential for systemic neurotoxicity in the host
.
Cl
Cl
Cl
Cl
Cl
Cl
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
27

28. 3) Crotamiton(Eurax)
C
H3
N
C
H3
O
CH3
•Its antipruritic effect is probably due to the local anesthetic
action.
•It has no neurotoxicity [c.f: Lindane]
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB
28

29. Thank you for attention!
ANTIPROTOZOAL AGENTS EDITED BY PROF. MOHAMED
ABDELWAHAB 29