Dr.Narmin hamaamin Hussen

1. Anthelmintic Drugs
Medicinal Chemistry IV / 2nd Semester / 4th Class
Lecture 6
Dr.Narmin Hama Amin

2. Introduction
➢ Helminth means worms.
➢ Helminthiasis or worm infestation is an infections caused by parasitic worms.
➢ Helminthiasis, is one of the most prevalent diseases and one of the most serious public health problems in
the world.
➢ Helminthiasis is more common in developing countries with poorer personal and environmental hygiene.
They harm the host by depriving him of food, causing blood loss, injury to organs, intestinal or lymphatic
obstruction and by secreting toxins. Helminthiasis is rarely fatal, but is a major cause of ill health.
➢ Anthelmintics are drugs used to treat parasitic infections due to worms.
Anthelmintics act through two mechanism
▪ Vermicide (kill) used to kill parasitic intestinal worms.
▪ Vermifuge (expel) used to destroy or expel worms in the intestine

3. ▪ Almost 350 species of helminths have been found in humans, and most colonise the gastrointestinal tract
(G.I.T).
Helminths are 3 types:
➢ Nematodes (Round worms) - ascarids (Ascaris), filarias, hookworms, pinworms (Enterobius), and
whipworms (Trichuris trichiura)
➢ Cestodes(Tape worms) - multiple species of flat worms, Taenia saginatum, Taenia solium(cysticercosis,
hydatid(echinococcus)
➢ Trematodes (Flukes) – liver flukes, lung flukes, schistosoma
Classification of helminths

4. Classification of Anthelmintics based on chemical structure
1. Benzimidazoles: Examples: Albendazole, Mebendazole, Thiabendazole
2. Piperazines: Examples: Diethylcarbamazine citrate (DEC), Piperazine citrate
3. Heterocyclics: (Quinolines and Isoquinolines) Examples: Oxamniquine , Praziquantel
4. Vinyl pyrimidines: Pyrantel pamoate, Oxante
5. Amide (Salicylanilide): Example: Niclosamide
6. Natural Products: Example: Ivermectin
7. Organo phosphorus: Metrifonate
8. Imidazothiazoles: Levamisole
9. Nitro derivatives: Niridazol

5. Benzimidazoles
▪ Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound
consists of the fusion of benzene and imidazole
▪ The benzimidazoles are a broad-spectrum group of drugs discovered in the 1960s with
activity against GI helminths.
▪ Several thousand benzimidazoles have been synthesized and screened for anthelmintic
activity, with albendazole, mebendazole, and thiabendazole representing the
benzimidazoles market.
▪ These are highly effective against ascaris, enterobius, trichuris and hookworm
infections.

6. SARs of benzimidazoles : Anthelmintic activity
SAR of 2-phenyl benzimidazoles as anthelmintics. SAR of benzimidazole derivatives as cysticidal agent
In vitro cysticidal activity of new benzimidazole derivatives against
Taenia crassiceps cysts.

7. Mechanism of action:
▪ Two mechanisms have been proposed to account for the action of the benzimidazoles.
1. Fumarate reductase is an important enzyme in helminths that appears to be involved in oxidation
of NADH to NAD. The benzimidazoles are capable of inhibiting fumarate reductase. Inhibition of
fumarate reductase ultimately uncouples oxidative phosphorylation, which is important in
adenosine triphosphate production
2. Benzimidazoles probably acts by inhibiting microtubule synthesis. Its bind with parasite ‘β-tubulin’
and inhibit its polymerization, thus preventing the formation of microtubules and so stopping cell
division. Impaired uptake of glucose, leading to depletion of glycogen, and reduced stores of ATP
,which is responsible for survival and reproduction in helminthes.
▪ They have high affinity for tubulin, the precursor protein, necessary for microtubule synthesis.

8. ➢ Albendazole
▪ Albendazole, a broad-spectrum oral Anthelmintic agent. It is the drug of choice for treatment of hydatid disease and
cysticercosis. It is also used in the treatment of pinworm and hookworm, round worm, whip worm, and thread worm
infections.
Adverse effects:
▪ Well tolerated; gastrointestinal side effects are known, prolonged use as in hydatid or in neurocysticercosis
causes headache, alopecia, jaundice, neutropenia

9. Synthesis of albendazole

10. ➢ Mebendazole
▪ Mebendazole is a synthetic benzimidazole that has a wide spectrum of
anthelmintic activity and a low incidence of adverse effects
▪ Its used for treatment of infections by whipworm eggs, pinworm, hookworms,
and roundworm.
➢ Thiabendazole
▪ Thiabendazole is a fungicide and anti-helminths
▪ Replacement of the 4- thiazolyl ring system by a methyl carbamate grouping gave interesting group of anti-
helminthes

11. Metabolism
▪ The benzimidazoles have limited water solubility and, as a result, are poorly
absorbed from the GI tract (a fatty meal will increase absorption).
▪ Poor absorption may be beneficial, because the drugs are used primarily to treat
intestinal helminths. To the extent that the drugs are absorbed, they undergo rapid
metabolism in the liver and are excreted in the bile .In most cases, the parent
compound is rapidly and nearly completely metabolized with oxidative and
hydrolytic processes predominating. The Phase I oxidative reaction commonly is a
cytochrome P450–catalyzed reaction, which may then be followed by a Phase II
conjugation.
➢ Albendazole is unique in two ways. First, the presence of a thioether substituent at
the five position increases the likelihood of sulfur oxidation. Second, the initial
metabolite, albendazole sulfoxide, is a potent anthelmintic. This initial oxidation is
catalyzed principally (70%) by CYP3A4 and CYP1A2 and(30%) by flavin-containing
monooxygenase, giving rise to a compound that is bound to plasma protein.
➢ Metabolism of mebendazole occurs primarily by reduction of the 5-carbonyl to a
secondary alcohol, which greatly increases the water solubility of this compound.
▪ An additional Phase I metabolite resulting from carbamate hydrolysis has been
reported as well. Both the secondary alcohol and the amine are readily conjugated
(a Phase II metabolism). Evidence would suggest that the anthelmintic activity of
mebendazole resides in the parent drug and none of the metabolites.
➢ Thiabendazole is metabolized through aromatic hydroxylation at the five position
catalyzed by CYP1A2. The resulting phenol is conjugated to 5-
hydroxythiabendazole glucuronide and 5-hydroxythiabendazole sulfate,
respectively. The initial metabolite, along with minor amount of N1-
methylthiabendazole (from a methylation Phase II reaction), have been reported
to be teratogenic in mice and rats.

12. Piperazine derivatives
➢ Piperazine citrate
➢ Diethyl carbamazine citrate
▪ Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen
atoms.
➢ Piperazine citrate
▪ Mode of action:Piperazine is a GABA receptor agonist binds selectively to receptors, causing hyperpolarization
of ascarias muscles, resulting in flaccid paralysis of the worm, then it is dislodged from the intestinal lumen
▪ Piperazine citrate is a white granular powder, soluble in water, and practically insoluble in alcohol, used as an
anthelminthic. It can cause gastrointestinal and allergic reactions. It is contraindicated in epileptic patients.
▪ It is used in veterinary medicine as an anthelmintic in pigs and poultry including laying hens because of its
activity against nematodes especially Ascaris species.

13. ➢ Diethyl carbamazine citrate
▪ An anthelmintic used primarily as the citrate in the treatment of filariasis
Metabolism:
▪ The metabolism of diethyl carbamazepine leads to the compounds of methyl piperazine and piperazine.
Nearly, all of the metabolites appear in the urine.
▪ Diethylcarbamazine + Chlorpheniramine Maleate is a combination of two medicines: Diethylcarbamazine and
Chlorpheniramine Maleate which treat helminths infections.

14. Synthesis of diethyl carbamazine citrate

15. Heterocyclics: (Quinolines and Isoquinolines)
➢ Oxamniquine
▪ An anthelmintic with schistosomicidal activity against Schistosoma mansoni.
▪ Oxamniquine is used only to treat schistosomiasis caused by the worm Schistosoma mansoni. Oxamniquine
may associate with an irreversible inhibition of the nucleic acid metabolism of the parasites.
▪ The most critical and Vital entity present in this drug is the presence of 6 – hydroxymethyl moiety; And the
subsequent metabolic activation of the precursor 6- methyl derivatives is equally critical in nature
▪ It is metabolized by oxidative reaction and it gives inactive
metabolites of acid and alcohol derivatives.
▪ Oxamniquine is a tetrahydroquinoline that is effective in S. mansoni infections

16. ➢ Praziquantel
▪ It is a Novel Anthelmintic. Active against Schistosomes
,Trematodes & Cestodes ,but not nematodes
▪ Praziquantel works by causing severe spasms and paralysis of
the worms' muscles. This paralysis is accompanied - and
probably caused - by a rapid Ca 2+ influx inside the
schistosome. The worms are then either completely
destroyed in the intestine or passed in the stool.
▪ In serum, the major metabolites are 4-hydroxycyclohexyl
carboxylate, but in the urine, 50%–60% of the initial PZQ
exist as dihydroxylated products. Hydroxylation reactions are
catalyzed by CYP2B6 and CYP3A4.

17. Vinyl pyrimidines
➢ Pyrantel palmoate
▪ It is an alternative to mebendazole in the treatment of ascariasis and
enterobiasis
▪ It is also as investigational drug for the treatment of hookworms,
moniliformis, and trichostrongylus infections
▪ Pyrantel is a depolarizing neuromuscular blocking agent. It induces marked persistent activation of the
nicotinic receptors, which result in spastic paralysis of the worm.
Synthesis :

18. Amides
➢ Niclosamide (Niclocide)
▪ It is a Salicylanilide derivative.
▪ Niclosamide is an anthelminthic which is active against most tapeworms. Highly effective against cestodes
infecting man.
▪ It acts by inhibiting oxidative phosphorylation in mitochondria and interfering with anerobic generation of ATP in
tapeworm resulting in energy depletion.

19. Natural Products:
➢ Ivermectin
▪ Ivermectin is an avermectin analogue.
▪ It is a macrocyclic lactones with broad antinematocidal activity.
▪ This class of compound was isolated from a fermentation broth of a soil actinomycetics (Streptomycin
avermitils).
▪ Ivermectin is the drug of choice for the treatment of onchocerciasis (river blindness) caused by Onchocerca
volvulus. Ivermectin
▪ Currently investigated for COVID-19 Treatment
▪ Ivermectin is a mixture of B1 a and B1 b and is prepared by
catalytic reduction of ivermectin B1 (Abamectin)
▪ It is metabolized and it gives 3-O-demethyl-22,23-dihydroavermectin
B1α monosaccharide

20. Organo phosphorus
➢ Metrifonate
▪ Anthelmintic dose is 7.5mg/kg given orally three times at intervals of 2 weeks.
▪ Irreversible organophosphate acetylcholinesterase inhibitor.
▪ It is used as an insecticide.
▪ It is a prodrug which is activated non-enzymatically into the active agent
dichlorvos, which inhibits acetyl cholinesterase

21. Imidazothiazoles
➢ Levamisole
▪ They are active against large number of nematodes but their use is restricted to only ascariasis and
ancyclostomiasis because of poor action against other worms.
▪ It stimulates the ganglion in the worms, causes tonic paralysis, which results in the expulsion of live worms.
These also interfere with the carbohydrate metabolism by inhibiting fumarate reductase.

22. Nitro derivatives
➢ Niridazole (Ambilhar)
▪ Used as an anthelmintic agent.