Introduction to Anthelmintic Drugs

What are anthelmintic drugs?

Anthelmintic drugs (or antihelmintic drugs) is the name given to a group of antiparasitic drugs used to treat infections caused by parasitic worms(also known as helminths). People infected / infested with helminths have a medical condition referred to as helminthiasis. Other terms used to describe these drugs include:

  • Vermicides: anthelmintic drugs that, at certain doses, kill helminths.
  • Vermifuges: anthelmintic drugs whose pharmacological action result in the parasite getting expelled from the intestinal tract by peristaltic activity or catharsis.

Many helminths are intestinal worms transmitted through contaminated soil and infect the gastrointestinal tract. As such, these soil-transmitted worms are sometimes collectively referred to as geohelminths. Individuals with helminthias is excrete helminth eggs in their feces, which may result in contamination of soil.

Examples of Anthelmintic Drugs

To fully appreciate the medicinal chemistry of this topic, it’s worthwhile to take a few minutes to learn more about drug metabolism that we’ve previously covered.

Diethylcarbamazine

Diethylcarbamazine (DEC) belongs to a class of anthelmintics known as piperazines. As the name suggests, DEC is derived from piperazine, a heterocyclic six-membered nitrogenous compound bearing two nitrogen atoms at opposite positions in the ring (Piperazine: C4H10N2). The mode of action of DEC is not fully understood, but three mechanisms of action have been proposed:

  • Interference with arachidonic acid metabolism
  • Morphological damage to the microfilaria
  • Inhibition microtubular polymerisation

Question 1: Can you name the six-membered heterocyclic secondary amine similar to piperazine, but possesses five carbons, one nitrogen and eleven hydrogens?

Metabolism of DEC

DEC can undergo:

  • N-oxidation
  • N-dealkylation, specifically ethyl groups.

Methylpiperazine and piperazine are also known metabolism products of DEC.

Question 2:
a) Draw a scheme for the N-dealkylation of DEC.
b) Are the metabolites more hydrophilic than its parent compound?
c) Why are drug metabolites typically more polar & hydrophilic than their parent compounds?

Benzimidazoles

Examples of anthelmintic drugs in this class include albendazole and mebendazole and, as the name suggests, both drugs bear an imidazole ring in their structure.

Albendazole

Albendazole, a drug on the World Health Organization’s List of Essential Medicines, is a vermicide used to treat conditions such as ascariasis, intestinal nematode infections, pinworm disease and giardiasis. The precise mechanism of action has not yet been fully elucidated, but albendazole is thought to result in degenerative alterations in the intestinal cells of helminths.

Case Study: Albendazole

Albendazole undergoes S-oxidation to the dextrarotatory metabolite R(+)-albendazole sulfoxide (flavin-containing monooxygenase [FMO] catalysed) and the levorotatorymetabolite S(-)-albendazole sulfoxide (cytochrome P450 oxidases [CYP] catalysed). Both optical isomers can undergo further oxidation (CYP-catalysed) to form albendazole sulfone.

Question 3: Name one analytical chemistry technique for distinguishing between optical isomers.

Mebendazole

Mebendazole is a vermicide used in the treatment of infections caused by helminths such as roundworms, pinworms, and whipworm. Its mechanism of action is thought to involve glucose uptake blockage.

Metabolism of Mebendazole

Mebendazole can undergo the following Phase 1 biotransformations:

  • Reduction to the hydroxy derivative
  • Hydrolysis to the 2-aminobenzimidazole

Answers

Q1 Piperidine

Q2
a)
b) Yes
c) Greater hydrophilicity confers greater urine excretion as water solubility has increased.

Q3 Polarimetry

Further Reading

(1) Sangster, N. C.; Cowling, A.; Woodgate, R. G. Ten Events That Defined Anthelmintic Resistance Research. Trends Parasitol.2018, 34 (7), 553–563 DOI: 10.1016/j.pt.2018.05.001.

(2) Brown, R. W.; Hyland, C. J. T. Medicinal Organometallic Chemistry – an Emerging Strategy for the Treatment of Neglected Tropical Diseases. Medchemcomm2015, 6 (7), 1230–1243 DOI: 10.1039/C5MD00174A.

(3) Bahmani, M.; Rafieian-Kopaei, M.; Hassanzadazar, H.; Saki, K.; Karamati, S. A.; Delfan, B. A Review on Most Important Herbal and Synthetic Antihelmintic Drugs. Asian Pac. J. Trop. Med.2014, 7, S29–S33 DOI: 10.1016/S1995-7645(14)60200-5.

(4) Ojha, S. C.; Jaide, C.; Jinawath, N.; Rotjanapan, P.; Baral, P. Geohelminths: Public Health Significance. J. Infect. Dev. Ctries.2014, 8 (01) DOI: 10.3855/jidc.3183.