Antiprotozoal agents - Medicinal Chemistry III B. Pharma 6th Semester

Antiprotozoal agents

• In the United States and other countries of the temperate zone, protozoal diseases are of minor importance

• Protozoal diseases are highly prevalent in tropical Third World countries, where they infect both human and animal populations

• Cause suffering, death, and enormous economic hardship

• Protozoal diseases that are found in the United States are malaria, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and, as a direct consequence of the AIDS epidemic, P. carinii pneumonia (PCP)

• Amebiasis- Entamoeba histolytica

• Can invade the wall of the colon or other parts of the body (e.g., liver, lungs, skin)

• Other protozoal species that colonize the intestinal tract and cause enteritis and diarrhea are Balantidium coli and the flagellates, G. lamblia and Cryptosporidium spp

• Trichomoniasis, a venereal disease caused by the flagellated protozoan T. vaginalis

• P. carinii is an opportunistic pathogen that may colonize the lungs of humans and other animals and, under the right conditions, can cause pneumonia

• Toxoplasma gondii is an obligate intracellular protozoan that is best known for causing blindness in neonates

• Various forms of trypanosomiasis, chronic tropical diseases caused by pathogenic members of the family Trypanosomidae, occur both in humans and in livestock

• African sleeping sickness caused by Trypanosoma gambiense (West African), Trypanosoma rhodesiense (East African), or Trypanosoma congolense; and

• South American sleeping sickness (Chagas disease) caused by Trypanosoma cruzi

• Chagas disease is the most serious and generally the most resistant to chemotherapy

• Leishmaniasis is a chronic tropical disease caused by various flagellate protozoa of the genus Leishmania

• More common visceral form caused by Leishmania donovani, called kala-azar, is similar to Chagas disease

Metronidazole

• Most useful of a group of antiprotozoal nitroimidazole derivatives that have been synthesized in various laboratories throughout the world

• First marketed for the topical treatment of T. vaginalis for vaginitis

• Also possesses useful amebicidal activity and is, in fact, effective against both intestinal and hepatic amebiasis

• Other protozoal diseases as giardiasis and balantidiasis

• It is particularly active against Gram-negative anaerobes, such as Bacteroides and Fusobacterium spp

• It is also effective against Gram-positive anaerobic bacilli (e.g., Clostridium spp.) and cocci (e.g., Peptococcus, Peptidostreptococcus spp.).

• Because of its bactericidal action, metronidazole has become an important agent for the treatment of serious infections (e.g., septicemia, pneumonia, peritonitis, pelvic infections, abscesses, meningitis) caused by anaerobic bacteria

• Mechanism- reactive intermediate formed in the microbial reduction of the 5-nitro group of metronidazole covalently binds to the DNA of the microorganism, triggering the lethal effect

• Potential reactive intermediates include the nitroxide, nitroso,

• hydroxylamine, and amine

• Ability of metronidazole to act as a radiosensitizing agent

• is also related to its reduction potential

Mechanism of metronidazole

• Pale yellow crystalline substance that is sparingly soluble in water

• It is stable in air but is light sensitive

• 2-hydroxy metabolite is active; other metabolites are inactive

• Solutions of metronidazole hydrochloride are unsuitable for intravenous administration because of their extreme acidity

• Must be reconstituted with sterile water to yield 5 mL of a solution having a concentration of 100 mg/mL and a pH ranging from 0.5 to 2.0

• Resulting solution must then be diluted with either 100 mL of normal saline or 5% dextrose and neutralized with 5 mEq of sodium bicarbonate to provide a final solution of metronidazole base with an approximate concentration of 5 mg/mL and a pH of 6 to 7

Tinidazole

• Approved by the U.S. Food and Drug Administration (FDA) for the treatment of amebiasis, giardiasis, and trichomoniasis

• Also to be highly effective against Helicobacter pylori infections

• Drug is rapidly and completely absorbed following oral administration and can be administered with food to reduce GI disturbance

• Mechanism of action- similar to metronidazole

• Tinidazole appears to mimic the actions of metronidazole

• Also effective against some protozoa that are resistant to metronidazole

Ornidazole

• Antibiotic used to treat protozoan infections

• Antimicrobial spectrum is similar to that of metronidazole

• It was first introduced for treating trichomoniasis before being recognized for its broad anti-protozoan and anti-anaerobic-bacterial capacities

Diloxanide

• 2-furoate ester of 2,2-dichloro-4-hydroxy-N-methylacetanilide

• It was developed as a result of the discovery that various ,α-α-dichloroacetamides possessed amebicidal activity in vitro

• Used in the treatment of asymptomatic carriers of E. histolytica

• White crystalline powder and is administered orally only as 500-mg tablets

Iodoquinol

• Diiodohydroxyquin is a yellowish to tan microcrystalline, light-sensitive substance that is insoluble in water

• It is recommended for acute and chronic intestinal amebiasis but is not effective in extraintestinal disease

• Because a relatively high incidence of peripheral neuropathy has occurred with its use, iodoquinol should not be used routinely for traveler’s diarrhea

Pentamidine Isethionate

• Water-soluble crystalline salt that is stable to light and air

• Principal use of pentamidine is for the treatment of pneumonia caused by the opportunistic pathogenic protozoan P. carinii, a frequent secondary invader associated with AIDS

• Drug may be administered by slow intravenous infusion or by deep intramuscular injection for PCP or in an aerosol form

• Both the inhalant (aerosol) and parenteral dosage forms of pentamidine isethionate are sterile lyophilized powders

• Must be made up as sterile aqueous solutions prior to use by sterile water for injection

• Common adverse reactions- cough and bronchospasm (inhalation) and hypertension and hypoglycemia (injection)

• Used for the prophylaxis and treatment of African trypanosomiasis. It also has some value for treating visceral leishmaniasis

• Prophylaxis- treatment given or action taken to prevent disease

• Because, Pentamidine rapidly disappears from the plasma after intravenous injection and is distributed to the tissues, where it is stored for a long period

Atovaquone

• Highly lipophilic, water-insoluble analog of ubiquinone 6, an essential component of the mitochondrial electron transport chain in microorganisms

• Structural similarity between atovaquone and ubiquinone suggests that thereby interfere with the function of electron transport enzymes

• Originally developed as an antimalarial drug, but Plasmodium falciparum was found to develop a rapid tolerance to its action

• Recommended alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment and prophylaxis of PCP in patients intolerant to this combination

• High fat content, increases atovaquone absorption

• It is extensively protein bound (99.9%)

• Half-life of the drug ranges from 62 to 80 hours

• Primary side effect is gastrointestinal intolerance