SAR of Anthelmintic drugs

1. ANTHELMINTIC DRUGS
DR. MANJOOR AHAMAD SYED,
M.Pharm,Ph.D
Associate. Professor
Department of Medicinal Chemistry,
College of Public Health and Medical Sciences,
Mettu University, Mettu
Post Box No-318
Ethiopia.

2. ANTHELMINTHIC DRUGS
Definition:
Anthelmintic are the drugs or agents which are capable of eradicating worms and helminth
parasite from the body are termed as Anthelmintics.
INTRODUCTION:
Helminthics infections are the major health problem in tropical countries. Helminths
(worms) can cause various Gastrointestinal and general symptoms. They also cause blood
loss, nutrition deficiency, urticaria, allergic manifestations and even intestinal obstruction.
Humans are the primary hosts for many helminth infections. Most of the worms reproduce
sexually in human host producing Eggs and Larvae which pass out of the body and infect
secondary or intermediate host.
Helminths mainly cause infection by living in hosts alimentary canal or in other tissues of
the hosts’ body.

3. Classification of helminth parasites:
1. Nemathelminths
2. Platy helminths
3. NEMATHELMINTHS
They are subdivided into following seven species.
a. Hook worms:
They attach themselves to mucosa of duodenum and sucks blood from surrounding blood
vessels for their nourishment. They are basically two types
i. American variety: Nicator americanus
ii. European variety: Acyclostoma duodenal
b. Round worms:
They will acquire upper part of small intestine. E.g. Ascaris lumbricoides
c. Whip worm:
These are whip like mostly present in the Cecum and also in appendix and lower parts of
Ileum.

4. d. Whip worm:
These are whip like mostly present in the Cecum and also in appendix and lower parts of
Ileum.
e. Pinworm:
These are also called thread worms resides mainly in small intestine, cecum and colon. E.g.
Enterobias vermicularis.
e. Trichinella spiralis:
It is also called Trichinosis; infections mainly result from ingestion of improper cooked pork
which contain larvae of worm.
f. Wucheraria Bancrafti:
It is a kind of filarial worm transmitted usually by mosquito bite, resulting in the blockage of
lymphatic ducts.
g. Strongyloidiasis stercoralis:
Mainly resides in the duodenum.

5. 2. PLATY HELMINTHS
These are also called Flatworms, and they are devided into following two groups.
i. Cestodes (Segmented cestodes) ii. Trematodes (Non-segmented
trematodes)
Cestodes (Segmented cestodes): These include tape worms of following four categories.
a. Beef tapeworm – Taenia saginata
b. Pork tapeworm – Taenia solium
c. Fish tapeworm – Diphyllobothrium latum
d. Dwarf tapeworm – Hymenolepis nana
Trematodes (Non-segmented trematodes)
Flukes present mainly in the blood stream and are known to cause epigastric distress,
abdominal pain, diarrhoea, blood and mucous in the stool etc.
E.g.
Schistosoma Haematobium, Schistosoma Mansoni, Schistosoma Mekongi

6. CLASSIFICATION OF ANTHEMINTIC DRUGS
Based on their chemical structure they are classified in to following types
1 Piperazines Diethylcarbamazine citrate (DEC), Piperazine citrate
2 Benzimidazoles Albendazole, Mebendazole & Thiabendazole.
3 Heterocyclics Oxamniquine, Praziquantel
4 Amides Niclosamide
5 Nitro derivatives Niridazole
6 Imidazothiazole Levamisole.
7 Natural products Ivermectin, Avermectin
8 Vinyl pyrimidines Pyrantel, Oxantel.

7. PIPERAZINE N
H
N
H
piperazine
Synthesis:
NH2
N
H2
NH2
N
H2
Diethylene diamine
Catalytic deamination
Cyclization
NH
N
H
piperazine
Mechanism of Action:
The drug exerts its effect mainly by blocking ASCARIS MUSCLE response towards
Acetylcholine and thereby causes Neuromuscular blocking, which results muscle paralysis of
the worms and consequently dislodged to expelled in the faeces.
Adverse drug reactions:
Abdominal pain, bronchospasm, muscular
incoordination, confusion, blurred vision.
Uses:
Anthelmintics are used in the treatment of
worm infections. Piperazine is used to treat:
common roundworms (ascariasis) and.
pinworms (enterobiasis; oxyuriasis).

8. Synthesis:
Uses:
Diethylcarbamazine is used to treat
certain parasitic diseases caused
by infection with roundworms of
the Filarioidea type, including
lymphatic filariasis caused
by infection with Wuchereria
bancrofti, Brugia malayi, or Brugia
timori; tropical pulmonary
eosinophilia; and loiasis.
DIETHYLCARBAMAZINE CITRATE (DEC)
NH
N
H3C + Cl C N
O
C2H5
C2H5
N-methyl piperazine diethylcarbamic chloride

- HCl
N
N
H3C C N
O
C2H5
C2H5
Citric acid
COOH
CH2COOH
O
H
CH2COOH
N
N
H3C C N
O
C2H5
C2H5
.
DEC Citrate
COOH
CH2COOH
O
H
CH2COOH
N
N
H3C C N
O
C2H5
C2H5
N,N-diethyl-4-methylpiperazine-1-carboxamide
.
citrate

9. Adverse drug reactions:
Common side effects include itching, facial swelling, headaches, and feeling tired.
Other side effects include vision loss and dizziness. It is a recommended treatment in
pregnancy and appears to be safe for the baby.
Mechanism of Action:
The exact mechanism is not known but it believed to alter microfilarial membrane surface
rendering it more susceptible to destruction by the host defence mechanism.

10. ALBENDAZOLE
Adverse drug reactions:
Bone marrow suppression, headache, abnormal
liver function, abdominal pain, nausea,
vomiting, dizziness, vertigo, temporary hair loss
and fever.
Uses:
Albendazole is an anthelmintic or anti-worm medication. It prevents newly hatched insect
larvae (worms) from growing or multiplying in your body. Albendazole is used to treat
certain infections caused by worms such as pork tapeworm and dog tapeworm.
N
H
N
NH
S
O
O
methyl [6-(propylsulfanyl)-1H-benzimidazol-2-yl]carbamate

11. Mechanism of Action:
It causes degenerative alteration in the intestinal cells of the worm by binding to the colchicine-
sensitive site of β-tubulin, thus inhibiting its polymerization or assembly into microtubules (it
binds much better to the β-tubulin of parasites than that of mammals).
It also prevents the formation of spindle fibres which needed for cell division.
At higher concentration it disrupts helminthic metabolic pathway by inhibiting metabolic
enzymes such as Malate dehydrogenase and fumarate reductase which decreases energy
production and the parasite immobilized and dies.

12. MEBENDAZOLE
Adverse drug reactions:
Transient diarrhoea, headache, abdominal pain,
nausea, vomiting, dizziness, fever, dizziness,
hypersensitivity.
Uses:
Mebendazole (MBZ) is a medication used to treat a number of parasitic worm infestations.
This includes ascariasis, pinworm disease, hookworm infections, guinea worm infections,
hydatid disease, and giardia, among others.
N
H
N
NH O
O
O
methyl [6-(phenylcarbonyl)-1H-benzimidazol-2-yl]carbamate

13. Mechanism of Action:
Acts by destroying the cytoplasmic microtubules in the worm intestinal cells by interfering
with the uptake of glucose by helminth parasites and simultaneously glycogen store in
parasite get depleted. Which thereby results in decreases the generation of energy in the
form of ATP and eventually death of parasites.

14. THIABENDAZOLE Adverse drug reactions:
dizziness, drowsiness, or headache, numbness,
nausea, vomiting, diarrhea, upset stomach, or decreased
appetite, unusual urine odor, fever or chills, ringing in the
ears, blurred vision or dryness of the eyes or appearance
of live worms in the mouth or nose.
Uses:
This medication is used to treat roundworm infections such as threadworm,
hookworm/creeping eruption (cutaneous larva migrans), and visceral larva migrans
(toxocariasis).
N
N
H
N
S
2-(1,3-thiazol-4-yl)-1H-benzimidazole

15. Mechanism of Action:
It is a potent inhibitor of enzyme fumarate reductase and brings about supress assembly of
microtubules, leading to inhibition of secretion of parasites acetylcholinesterase and causes
cessation of parasitic activity.

16. Synthesis:
Uses:
Niclosamide is used to treat broad
or fish tapeworm, dwarf
tapeworm, and beef
tapeworm infections. Niclosamide
may also be used for other
tapeworm infections as
determined by your doctor. It will
not work for other types of
worm infections (for example,
pinworms or roundworms).
NICLOSAMIDE
OH
Cl
C
NH
Cl
NO2
O
5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide
OH
Cl
C
OH
O
5-chloro-2-hydroxybenzoic acid
OH
Cl
C
Cl
O
SOCl2
-HCl
-SO2
N
H2
Cl
NO2
2-chloro-4-nitroaniline
- HCl
OH
Cl
C
NH
Cl
NO2
O
Niclosamide
5-chloro-2-hydroxybenzoyl chloride

17. Adverse drug reactions:
Dizziness or light headedness, drowsiness, itching of the rectal area, skin rash, unpleasant taste.
Adverse drug reactions increase with consumption of alcohol, GIT disturbance and pruritis.
Mechanism of Action:
It is acts by inhibiting the anaerobic phosphorylation in the mitochondria of parasite, an
energy producing process which is dependent on CO2 fixation and thereby inhibiting
respiration and glucose absorption by the intestinal adult worms.
Or
It inhibits oxidative phosphorylation in the mitochondria of the worms, results in energy
depletion.

18. PYRANTEL PAMOATE
N
N
S
.
OH
O
O
H
OH
OH
O
Pyrantel
Pamoate
Mechanism of Action:
Pyrantel pamoate acts as a depolarizing neuromuscular blocking agent, thereby causing sudden
contraction, followed by paralysis, of the helminths. This has the result of causing the worm to
"lose its grip" on the intestinal wall and be passed out of the system by natural process.
Uses:
Pyrantel pamoate is an anthelmintic, or dewormer. It is used to treat intestinal roundworm,
hookworm, and stomach worm parasites in dogs. The use of pyrantel pamoate to treat intestinal
parasites in cats is off label or extra-label.
Adverse drug reactions:
Nausea, vomiting, diarrhea, stomach/abdominal
cramps, headache, drowsiness, dizziness,
trouble sleeping, or loss of appetite may occur.
If any of these effects persist or worsen

19. HETEROCYCLICS
OXAMNIQUINE
N
H
NH
O2N
O
H
(2-{[(1-methylethyl)amino]methyl}-7-nitro-1,2,3,4-tetrahydroquinolin-6-yl)methanol
Uses:
Oxamniquine is an antihelmintic, or anti-worm, medication. It prevents worms from
growing or multiplying in your body. Oxamniquine is used only to treat infections caused by
the worm Schistosoma mansoni. This is an uncommon infection usually acquired through
contact with freshwater in Africa.

20. Adverse drug reactions:
the most common adverse effects were headache, dizziness, drowsiness, and abdominal
pain. Patients who took the placebo also had drowsiness and abdominal pain.
Mechanism of Action:
Oxamniquine causes worms to shift from the mesenteric veins to the liver where the male
worms are retained; the female worms return to the mesentery, but can no longer release
egg. Oxamniquine may associate with an irreversible inhibition of the nucleic acid
metabolism of the parasites.

21. PRAZIQUANTEL
N
N
O
O
2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one
Adverse drug reactions:
Headache, dizziness, stomach pain, nausea,
tiredness, weakness, joint/muscle pain, loss of
appetite, vomiting, and sweating may occur.
Mechanism of Action:
Praziquantel effects the permeability of the cell membrane resulting in the contraction of
schistosomes. The drug further causes vacuolization and disintegration of the schistosome
tegument. The effect is more marked on adult worms compared to young worms. An increased
calcium influx may play an important role.
Uses:
Praziquantel is used to treat schistosoma (infection with a type of worm that lives in the
bloodstream) and liver fluke (infection with a type of worm that lives in or near the liver).
Praziquantel is in a class of medications called anthelmintics. It works by killing the worms.

22. NITRODERIVATIVES
NIRIDAZOLE
N
S
N
NH
O2N
O
1-(5-nitro-1,3-thiazol-2-yl)imidazolidin-2-one
Adverse drug reactions:
The side effects of the drug are nausea, vomiting, diarrhea,
anorexia, abdominal pain and headache, which depend largely
on the dose and duration of the treatment.
Mechanism of Action:
Niridazole is rapidly concentrated in the parasite and inhibits oogenesis and spermatogenesis.
The compound also inhibits the phosphofructokinase enzyme, leading to glycogen depletion
and hepatic shift.
Uses:
Niridazole is a schistosomicide. It is used to treat schistosomiasis, the helmintic disease caused
by certain flatworms (trematodes) from the genus Schistosoma (formerly Bilharzia).

23. IMIDAZOTHIAZOLE
LEVAMISOLE
N
S
N
6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole
Adverse drug reactions:
It causes nausea, vomiting, diarrhea, mouth sores, loss of
appetite, stomach pain, change in taste and smell, muscle
aches, fatigue, dizziness, headache and skin rash.
Mechanism of Action:
It is an antiparasitic agent appears to be tied to its agnositic activity towards the L-subtype
nicotinic acetylcholine receptors in nematode muscles. This agonistic action reduces the
capacity of the males to control their reproductive muscles and limits their ability to copulate.
Uses:
It is used to treat parasitic worm infections. Specifically, it is used for ascariasis and
hookworm infections.

24. NATURAL PRODUCTS
IVERMECTIN
Mechanism of Action:
Ivermectin and its related drugs act by interfering with nerve and muscle function of
helminths and insects. The drug binds to glutamate-gated chloride channels that are common
to invertebrate nerve and muscle cells. Ivermectin binding pushes these channels open,
increasing the flow of chloride ions and hyper-polarizing the cell membranes. This
hyperpolarization paralyzes the affected tissue, eventually killing the invertebrate.

25. Adverse drug reactions:
It include skin rash, nausea, vomiting, diarrhea, stomach pain, facial or limb swelling,
neurologic adverse events (dizziness, seizures, confusion), sudden drop in blood pressure,
severe skin rash.
Uses:
Ivermectin is a broad spectrum anti-parasitic agent, included in WHO essential medicines
list for several parasitic diseases. It is used in the treatment of onchocerciasis (river
blindness), strongyloidiasis and other diseases caused by soil transmitted helminthiasis. It is
also used to treat scabies.