Medicinal Chemistry Topic:

Medicinal Chemistry of Antiprotozoal Drugs (Part 1)

The term protozoan refers to unicellular heterotrophic eukaryotes and some parasitic protozoans can cause diseases in humans and other animals. Examples of pathogenic protozoans include Plasmodium falciparum, Trypanosomacruzi, Trypanosomabrucei, Giardia intestinalis, Leishmania species and Toxoplasma gondii. Infection by certain species of the protozoan Plasmodium parasite causes malaria in humans.


Trypanosomiasis (or trypanosomosis) is the name given to diseases caused by parasitic protozoans of the genus Trypanosoma. In humans, these are African trypanosomiasis and Chagas disease:

  • African trypanosomiasis
    • Also known as sleeping sickness
    • Occurs regularly in some regions of sub-Saharan Africa
    • Classed as a Neglected Tropical Disease (NTD)
    • Caused by Trypanosomabruceigambiense or Trypanosomabruceirhodesiense.
    • Transmitted by the bite of an infected tsetse fly
  • Chagas disease
    • Also known as American trypanosomiasis
    • Caused by Trypanosomacruzi
    • Transmitted by infected triatomine bugs (also known as kissing bugs), usually through contact of a person with the faeces of an infected triatomine bug.
    • May also be transmitted through blood transfusion, organ transplantation, eating food contaminated with the parasites, and by vertical transmission
    • Triatomines are sanguivores

Treatments for Trypanosomiasis

Examples of drugs used to treat trypanosomiasis include:

  • Benznidazole (Chagas disease)
  • Nifurtimox (Chagas disease)
  • Nifurtimox/Eflornithinecombination (African trypanosomiasis)
  • Melarsoprol (African trypanosomiasis)


Benznidazole is an orally-administered nitroaromatic drug with an estimated Log P of about 1.3 – 1.6. Benznidazole is metabolised by Trypanosome nitroreductases and human cytochrome p450 enzymes. Preclinical research suggests that benznidazole undergoes hepatic metabolism and that the metabolites and a small percentage of the parent drug (~5%) are excreted primarily in the urine.


The trypanocidal parenterally-administered melarsoprol, as shown above, contains a dithiarsolane ring, which is associated with the toxic effects of the compound. Although melarsoprol has been in clinical use for more than 60 years, its pharmacokinetics and pharmacodynamics are still not well understood. Melarsoprol is thought to interfere with protozoan trypanothione synthesis and activity and also interacts with thiol groups of parasite proteins.


Eflornithine (α-difluoromethylornithine or DFMO) is an anti-trypanosomal drug used for the 2nd stage of sleeping sickness caused by T. b. gambiense. Eflornithine can be administered to patients as a combination with nifurtimox. Although given to patients as a racemic mixture, the laevorotatory optical isomer is believed to be the more biologically active one.


Nifurtimox is a nitrofuran-type anti-trypanosomal agent that can be used to treat Chagas disease and in combination with eflornithine, sleeping sickness. As with the other anti-trypanosomal drugs, the pharmacokinetics and pharmacodynamics of nifurtimox is not yet fully understood. Evidence from studies involving radiolabelled nifurtimox using murine and canine models suggest that orally administered nifurtimox is absorbed well from the GI tract.


Leishmaniasis is name given to the disease caused by protozoan parasites of the Leishmania genus.

  • Spread by sanguivorous phlebotomine sand flies
  • Like African trypanosomiasis, classed as a NTD
  • Common forms include:
    • Cutaneous leishmaniasis: Causes skin sores
    • Visceral leishmaniasis: Affects internal organs such as the liver

Skin sores may heal on their own but would likely result in severe scarring. In contrast, visceral leishmaniasis may be potentially fatal if left untreated. Examples of drugs used to treat leishmaniasis include:

  • Liposomal amphotericin B
  • Sodium stibogluconate
  • Miltefosine


Miltefosine is an orally-administered alkylphosphocholine lipid analog anti-leishmanial drug approved by the FDA in 2014 for treating leishmaniasis (cutaneous, mucosal and visceral). Currently, the mechanism of anti-protozoal activity is not fully understood but several mechanisms have been proposed:

  • Direct insertion into the protozoan cell membrane
  • Disrupting protozoan lipid metabolism and other metabolic pathways
  • Triggering an apoptosis-like cell death

Phospholipase D is mainly responsible for the metabolism of miltefosine, giving choline as well as other metabolites such as phosphocholine and hexadecanol.


Learn more about the medicinal chemistry of antimalarial drugs.

Further Reading

  • Comprehensive Pharmacy Review for NAPLEX 8th Edition; Shargel, L, Mutnick, A H, Souney, P F, Swanson, L N, Eds.; Lippincott Williams & Wilkins: Baltimore, MD, USA, 2013.
  • Kucers’ The Use of Antibiotics. A Clinical Review of Antibacterial, Antifungal, Antiparasitic and Antiviral Drugs. 7th Edition, Grayson, M L; Cosgrove, S E; Crowe, S M; Hope, W; McCarthy, J S; Mills, J; Mouton, J W; Paterson DL (ed). CRC Press, Taylor & Francis Group: Boca Raton, FL, USA, 2018
  • Medicinal Chemistry of Antiprotozoal Drugs – Part II of II.