Medicinal Chemistry-III

Anthelmintics

Course Leader: Dr. Manikanta Murahari

manikanta.py.ph@msruas.ac.in

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 ANTHELMINTICS
• Anthelmintics are drugs that have the capability of ridding the body of parasitic
worms or helminths
• Helminths that infect human hosts are divided into two categories, or phyla:

• a) Platyhelminthes (flatworms)- include the classes Cestode (tapeworms) and

Trematode (flukes or schistosomes)
• b) Aschelminthes or nematodes (roundworms)- roundworm, hookworm, pinworm,
and whipworm. These worms are cylindrical in shape, with significant variations in
size, proportion, and structure

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 ANTHELMINTICS
• Nematode Infections
• Ancylostomiasis or Hookworm Infection- American hookworm (Necator
americanus) and the “Old World” hookworm (Ancylostoma doudenale).
• Enterobiasis or Pinworm Infection- Enterobius vermicularis
• Ascariasis or Roundworm Infections- Ascaris lumbricoides
• Trichuriasis or Whipworm Infections- Trichuris trichiura

• Trichinosis or Trichina Infection- Trichinella spiralis

• Filariasis- Wuchereria bancrofti, Brugia malayi, and Brugia timori

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 ANTHELMINTICS
• Cestode and Trematode Infections

• Cysticercosis or Tapeworm Infection

• Beef tapeworm (Taenia saginata)
• Pork tapeworm (Taenia solium)

• Dwarf tapeworm (Hymenolepis nana)

• Fish tapeworm (Diphyllobothrium latum)
• Schistosomiasis or Blood Flukes- Schistosoma hematobium, Schistosoma mansoni,
and Schistosoma japonicum

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 Diethylcarbamazine citrate
• Highly water-soluble crystalline compound that has selective anthelmintic activity
• It is effective against various forms of filariasis, including Bancroft, onchocerciasis,
and laviasis
• It is also active against ascariasis
• Mechanim- not clearly known

• Suggestion- inhibition of microtubule polymerization and disruption of preformed

microtubules
• Or interference with arachidonic acid metabolism
• Adverse reactions- anaphylactic reactions, intense pruritus, and ocular complications
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 Thiabendazole
• occurs as a white crystalline substance that is only slightly soluble in water but is
soluble in strong mineral acids.
• Thiabendazole is a basic compound with a pKa of 4.7 that forms complexes with
metal ions
• Mechanism- inhibits the helminth-specific enzyme fumarate reductase (important
enzyme in helminthes that appears to be involved in oxidation of NADH to NAD for
ATP production)
• Also arrest nematode cell division in metaphase by interfering with microtubule
assembly and exhibit a high affinity for tubulin, the precursor protein for microtubule
synthesis 6
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 Thiabendazole
• Has broad-spectrum anthelmintic activity

• It is used to treat enterobiasis, strongyloidiasis (threadworm infection), ascariasis,

uncinariasis (hookworm infection), and trichuriasis (whipworm infection)
• Also used to relieve symptoms associated with cutaneous larva migrans (creeping
eruption) and the invasive phase of trichinosis.
• Widely used in veterinary practice to control intestinal helminths in livestock

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 Mebendazole
• Broad-spectrum anthelmintic that is effective against various nematode infestations,
including whipworm, pinworm, roundworm, and hookworm
• Mechanism- irreversibly blocks glucose uptake in susceptible helminths, thereby
depleting glycogen stored in the parasite
• It apparently does not affect glucose metabolism in the host. It also inhibits cell
division in nematodes
• Poorly absorbed by the oral route

• Adverse reactions are uncommon and usually abdominal discomfort

• It is teratogenic in laboratory animals and should not be given during pregnancy 8
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 Albendazole
• Broad-spectrum anthelmintic that is not currently marketed in North America

• Widely used throughout the world for the treatment of intestinal nematode infection
• It is effective as a single-dose treatment for ascariasis, New and Old World
hookworm infections, and trichuriasis
• Multiple-dose therapy with albendazole can eradicate pinworm, threadworm,
capillariasis, clonorchiasis, and hydatid disease
• Effectiveness of albendazole against tapeworms (cestodes) is generally more variable
and less impressive
• White crystalline powder that is virtually insoluble in water
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 Albendazole
• Oral absorption of albendazole is enhanced by a fatty meal
• Drug undergoes rapid and extensive first-pass metabolism to the sulfoxide, which is
the active form in plasma
• Elimination half-life of the sulfoxide ranges from 10 to 15 hours

• High dose can result in adverse effects such as bone marrow depression, elevation of
hepatic enzymes, and alopecia

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 Niclosamide
• Occurs as a yellowish white, water-insoluble powder
• Potent taeniacide that causes rapid disintegration of worm
segments and the scolex
• Penetration of the drug into various cestodes appears to be
facilitated by the digestive juices of the host
• Niclosamide is well tolerated following oral administration, and
little or no systemic absorption of it occurs
• A saline purge 1 to 2 hours after ingestion of the taeniacide is
recommended to remove the damaged scolex and worm
segments- mandatory 11
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 Oxamniquine
• Antischistosomal agent that is indicated for the treatment of Schistosoma mansoni
(intestinal schistosomiasis) infection
• Mechanism- Shown to inhibit DNA, RNA, and protein synthesis in schistosomes

• 6-hydroxymethyl group is critical for activity;

• metabolic activation of precursor 6-methyl derivatives is critical
• Free base occurs as a yellow crystalline solid that is slightly soluble in water but
soluble in dilute aqueous mineral acids and soluble in most organic solvents
• Dizziness and drowsiness are common, but transitory, side effects
• Serious reactions, such as epileptiform convulsions, are rare

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 Praziquantel
• Broad-spectrum agent that is effective against various trematodes (flukes)
• It has become the agent of choice for the treatment of infections caused by
schistosomes (blood flukes)
• Effective treatment for fasciolopsiasis (intestinal fluke), clonorchiasis (Chinese liver
fluke), fascioliasis (sheep liver fluke), opisthorchosis (liver fluke), and paragonimiasis
(lung fluke)
• Mechanism- increases cell membrane permeability of susceptible worms, resulting in
the loss of extracellular calcium. Massive contractions and ultimate paralysis of the
fluke musculature occurs, followed by phagocytosis of the parasite
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 Praziquantel
• Oral administration, about 80% of the dose is absorbed
• Drug is rapidly metabolized in the liver in the first-pass

• White crystalline solid that is insoluble in water

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 Ivermectin
• Is a mixture of 22,23-dihydro derivatives of avermectins B1a and B1b prepared by
catalytic hydrogenation
• Avermectins are members of a family of structurally complex antibiotics produced by
fermentation with a strain of Streptomyces avermitilis
• Ivermectin is active in low dosage against a wide variety of nematodes and
arthropods that parasitize animals
• Structure- pentacyclic 16-membered–ring aglycones glycosidically linked at the 3-
position to a disaccharide that comprises two oleandrose sugar residues

• Side chain at the 25-position of the aglycone is sec-butyl in avermectin B1a, whereas

in avermectin B1b, it is isopropyl 15

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 avermectins B1a (-C2H5) and B1b (-CH3)

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 Ivermectin
• Ivermectin contains at least 80% of 22,23-dihydroavermectin B1a and no more than

20% 22,23-dihydroavermectin B1b

• Widespread use in veterinary practice in the United States and many countries
throughout the world for the control of endoparasites and ectoparasites in domestic
animals
• It has been found effective for the treatment of onchocerciasis (“river blindness”) in
humans, an important disease caused by the roundworm Oncocerca volvulus
• Mechanism- It blocks interneuron–motor neuron transmission in nematodes by
stimulating the release of the inhibitory neurotransmitter GABA
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 Diethylcarbamazine citrate- Synthesis

N, N-diethyl-4-methyl-1-piperazin 1-methylpiperazine
Carbonyl chloride

Citric acid

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 Mebendazole- Synthesis
Nitration Reduction

4-chlorobenzophenone 3,4-diaminobenzophenone

methyl chloroformate
S-methylthiourea N-methoxycarbonyl-S-methylthiourea

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