Anthelmintics - Medicinal Chemistry III B. Pharma 6th Semester

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

• 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

• 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

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

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

• 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

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

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

• 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

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

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

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

• 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

Ivermectin

• Is a mixture of 22,23-dihydro derivatives of avermectins B_1a and B_1bprepared 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 B_1a, whereas in avermectin B_1b, it is isopropyl

avermectins B_1a(-C₂H₅) and B_1b(-CH₃)

• Ivermectin contains at least 80% of 22,23-dihydroavermectin B_1a and no more than 20% 22,23-dihydroavermectin B_1b

• 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

Diethylcarbamazine citrate- Synthesis