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


       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


       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


       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


       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


       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


       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


       Used for the treatment of West African sleeping sickness, caused by Trypanosoma brucei gambiense

       It is specifically indicated for the meningoencephalitic stage of the disease

       Eflornithine is a myelosuppressive drug that causes high incidences of anemia, leukopenia, and thrombocytopenia

       Complete blood cell counts must be monitored during the course of therapy

       Supplied as the hydrochloride salt

       It may be administered either intravenously or orally

       Approximately 80% of the unchanged drug is excreted in the urine

       Mechanism- irreversible inactivation of ornithine decarboxylase by eflornithine is accompanied by decarboxylation and release of fluoride ion

       Enzyme is involved in the synthesis polyamines which are regulators of growth processes

Metronidazole- Synthesis

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