Medicinal Chemistry-III

Anti-protozoal agents

Course Leader: Dr. Manikanta Murahari

[email protected]

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 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)

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 Antiprotozoal agents
• 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
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 Antiprotozoal agents
• 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 4
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 Antiprotozoal agents

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 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.). 6
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 Metronidazole
• 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 7
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 Mechanism of metronidazole

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 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
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 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

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 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

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 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

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 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

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 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 14
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 Pentamidine Isethionate
• 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

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 Pentamidine Isethionate

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 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
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 Atovaquone

• It is extensively protein bound (99.9%)

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

• Primary side effect is gastrointestinal intolerance

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 Eflornithine
• 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
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 Eflornithine
• 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

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 Metronidazole- Synthesis

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