Medicinal chemistry-III (BO601T)

1. BP601T
Raj K. Prasad
Medicinal chemistry-III
BP601T
ANTI-PROTOZOAL AGENTS
Raj K. Prasad

2. ANTI-PROTOZOAL
AGENTS
Introduction
• These are drugs useful in infection caused by the anaerobic protozoa Entamoeba
histolytica.
• Amebiasis is an infection of the body by the protozoa Entamoeba histolytica, which
most often affects the large intestine, although they can also affect the lungs, liver,
brain, and other organs.
• E. histolytica, the cause of amebiasis, has a relatively complex life cycle in the
host organism. The secreted cysts (in an unchanged form) are the cause of new
infections.
CLASSIFICATION
1) Tissue amoebicides
(A)For both intestinal and extraintestinal amoebiasis:
a. Nitroimidazoles: Metronidazole, Tinidazole, Secnidazole, Ornidazole,
Satranidazole
b. Alkaloids: Emetine, Dehydroemetine
(B)For extraintestinal amoebiasis only: Chloroquine
2) Luminal amoebicides:
a.
b.
Amide: Diloxanide furoate, Nitazoxanide
8-Hydroxyquinolines: Quiniodochlor (Iodochlorohydroxyquin, Clioquinol),
c.
Diiodohydroxyquin(Iodoquinol)
Antibiotics: Tetracyclines, Paromomycin.
METRONIDAZOLE
(2-Methyl-5-nitroimidazole-1-ethanol)
• Metronidazole was initially introduced for the treatment of vaginal infections caused
by amoeba. This nitroimidazole is also useful orally for the treatment of
trichomoniasis, giardiasis, and Gardnerella vaginalis infections.
• It has found increasing use of late in the parenteral treatment of anaerobic infections
and for treatment of pseudomembranous colitis due to Clostridium difficile.
Synthesis of Metronidazole
• It is synthesized by nitrating 2-methylimidazole to make 2-methyl-5-nitroimidazole, which
is then reacted with 2-chloroethanol or ethylenoxide, which is easily transformed to the
METRONIDAZOLE
(2-Methyl-5-nitroimidazole-1-ethanol)
Raj K. Prasad

3. metronidazole.
MOA
• It is generally agreed that metronidazole is a prodrug and that anaerobic organisms reduce the
nitro group in metronidazole to a hydroxylamine, during which a reactive derivative or reactive
species is produced that causes destructive effects on cell components (i.e., DNA, proteins,
and membranes).
Uses
• Metronidazole is considered to be the drug of choice for treatment for the protozoal infections
amebiasis (intestinal and extraintestinal), giardiasis, and trichomoniasis .
TINIDAZOLE
(1-2-(ethylsulfonyl)-ethyl-2-methyl-5-nitroimidazole)
• Tinidazole has a mechanism of action that parallels that of metronidazole as well as a
similar metabolic pathway leading to hydroxylation at the 2-methyl group catalyzed by
CYP3A4.
Raj K. Prasad

4. Uses
• It is also effective against amoebas, trichomonad, lambliosis, acute ulcerative gingivitis,
and post-operational anaerobic infections.
• It is used for treating practically all protozoan infections.
ORNIDAZOLE
(1-Chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol)
• It has activity similar to metronidazole, but it is slowly metabolized—has longer t½ (12–
14 hr).
Uses
• It has a longer duration of action than metronidazole and used as an antiprotozoal.
• In chronic intestinal amoebiasis and asymptomatic cyst passers 0.5 twice daily for 5 to 7
days has also been used.
Raj K. Prasad

5. DILOXANIDE (2,2-dichloro-N-(4-furoyloxyphenyl)-N-methylacetamide)
and
DILOXANIDE FUROATE (2-furoate ester of 2,2-dichloro-4’-hydroxy-N-
methylacetanilide)
• Diloxanide itself and many of its esters are also active, and drug metabolism studies
indicate that hydrolysis of the amide is required for the amebicidal effect.
• The furoate ester is hydrolysed in intestine and the released diloxanide is largely absorbed.
Diloxanide is a weaker amoebicide than its furoate ester. Diloxanide furoate is a white
crystalline powder.
• Nonpolar esters of diloxanide are more potent than polar ones.
Uses
• Diloxanide furoate has been used in the treatment of asymptomatic carriers of E.
histolytica.
Raj K. Prasad

6. [5]
IODOQUINOL (5,7-diiodo-8-quinolinol)
Strucutre
• It is 8-hydroxyquinolines derivative
• Iodoquinol is an amebocide used against E. histolytica, and it is active against both cysts
and trophozoites that are localized in the lumen of the intestine.
Uses
• It is considered the drug of choice for treating asymptomatic or moderate forms of
amebiasis.
DRUGS FOR TREATING TRYPANOSOMIASIS
• Trypanosomiasis is a disease that is better known by the name sleeping sickness. It is
expressed as chronic sleepiness, headaches, impaired motor coordination, apathy, loss of
intellect, and when not treated, death.
PENTAMIDINEISETHIONATE
(4,4’-(Pentamethylenedioxy)dibenzamidine diisethionate)
• Pentamidine is available as the water-soluble isethionate salt, which is used both IV and as an
aerosol used to reconstitute, to avoid precipitation of the pentamidine salt.
• The drug shows poor penetration of the CNS.
Mechanism of action
• It is believed that pentamidine can act either by inhibiting the process of oxidative
phosphorylation, or by inhibiting the process of glucose metabolism, or by inhibiting the activity
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7. [6]
of dihydrofolate reductase, or by reacting with DNA or nucleotides of the parasite.
• Pentamidine has also been shown to inhibit topoisomerase in P. jirovecii, which leads to double-
strand cleavage of DNA in Trypanosoma.
Uses
• The 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.
ATOVAQUONE
(3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone)
Structure
• It is a highly lipophilic, water-insoluble analog of ubiquinone, an essential component of
the mitochondrial electron transport chain in microorganisms.
MECHANISM OF ACTION
• Atovaquone is thought to produce its antiparasitic action by virtue of its ability to inhibit
the mitochondrial respiratory chain. Atovaquone is a ubiquinone reductase inhibitor,
inhibiting at the cytochrome complex.
• Uses
• Atovaquone also has been reported to be effective for the treatment of toxoplasmosis
caused by Toxoplasma gondii, although it has not been approved for this use.
Raj K. Prasad

8. [7]
EFLORNITHINE (difluoromethyl ornithine [DFMO])
Structure
MOA
• It was prepare ornithine decarboxylase (ODC) inhibitors as tools for studying the role of
polyamines as regulators of growth processes.
• ODC catalyzes the conversion of ornithine to putrescine (1,4-diaminobutane), which in
turn leads to the formation of the polyamines, spermine, and spermidine.
Uses
• Eflornithine is 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.
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Raj K. Prasad

9. [8]
ANTI-HELMINTICDRUGS
• Antihelmintic drugs are intended for exterminating helminthes and removing them from
the host organism.
• Anthelmintics act locally either to expel the worms from the gastrointestinal tract or
systemically to eradicate the species and the developing forms of helmintics that invade
the organs and tissues.
CLASSIFICATION
A. Benzimidazoles
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10. [9]
B. Quinolines and Isoquinolines
Oxamniquine
Praziquantel
C. Piperazinederivatives
Piperazine citrate
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11. [10]
Diethyl carbmazine Citrate
D. Vinyl pyrimidines derivatives
Pyrantel pamoate
Oxantel
E. Amides
Niclosamide
F. Natural products: Avermectins
G. Organo phosphorus: Metrifonate
H. Imidazothiazoles: Levamisole
I. Nitro derivatives: Niridazole
DIETHYLCARBAMAZINE CITRATE (N, N-diethyl-4-methyl-1-
piperazincarboxamidecitrate)
Strucrure
• Diethylcarbamazine (DEC) is a derivative of piperazine.
• DEC is active against falaria and microfalaria. It causes a reduction in muscular activity,
and even paralysis in helminthes.
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12. [11]
Mechanism of action
• The mechanism of its action is not completely understood. More recent study showed that
DEC produced morphologic damage to the microfalaria. The damage consisted of the loss
of the cellular sheath, exposing antigenic determinants to immune defense mechanisms.
• Severe damage then occurred to microfalaria organelles, leading to death.
• The second is inhibition of microtubule polymerization and disruption of preformed
microtubules.
• The third is interference with arachidonic acid metabolism.
Synthesis
• It is synthesizing by acylating 1-methylpiperazine with diethyl carbamoyl chloride.
Uses
• It quickly gets rid of the parasites Brugia malayi, Loa loa, and Wuchereria bancrofti, and
it is also used for diseases caused by Onchocerca volvulus and Mansonella strptocerca.
• Diethylcarbamazine is microfilaricidal. It has a highly selective effect on microfilariae
(Mf).
Raj K. Prasad

13. [12]
THIABENDAZOLE (2-(4’-thiazolyl)-benzimidazole)
Structure
• Thiabendazole is a basic compound with a pKa of 4.7 that forms complexes with metal
ions.
Mechanism of action
• Thiabendazole inhibits the helminth-specific enzyme fumarate reductase.
• Benzimidazole anthelmintic drugs such as thiabendazole also arrest nematode cell division
in metaphase by interfering with microtubule assembly.
• They exhibit a high affinity for tubulin, the precursor protein for microtubule synthesis.
Uses
• It is used to treat enterobiasis, strongyloidiasis (threadworm infection), ascariasis,
uncinariasis (hookworm infection), and trichuriasis (whipworm infection).
Raj K. Prasad

14. [13]
MEBENDAZOLE (methyl-[5-(benzoyl)-1H-benzoimidazol-2-yl]carbamate)
Structure
• It is a broad-spectrum anthelmintic that is effective against various nematode infestations,
including whipworm, pinworm, roundworm, and hookworm.
Mechanism of action
• Mebendazole irreversibly blocks glucose uptake in susceptible helminths, thereby
depleting glycogen stored in the parasite.
• It apparently does not affect glucose metabolism in the host. It also inhibits cell division in
nematodes.
Raj K. Prasad

15. [14]
Synthesis
Uses
• Mebendazole is used for treatment of enterobiasis, ascariasis, ankylostomiasis,
strongyloidiasis, trichocephaliasis, trichuriasis, and mixed helminthoses.
.
ALBENDAZOLE(methyl-[5-(propylthio)-1H-benzoimidazol-2-yl]carbamate)
Structure
• A derivative of benzimidazole, albendazole is a drug with a broad antihelmintic spectrum.
Raj K. Prasad

16. 1
• The oral absorption of Albendazole is enhanced by a fatty meal. The drug undergoes rapid
and extensive first-pass metabolism to the sulfoxide, which is the active form in plasma.
MOA
• It exhibits an antihelmintic effect against sensitive cestodes and nematodes by blocking the
process of glucose uptake by the parasites, which is expressed in the depletion of glycogen
reserves and subsequent reduction in the level of adenosintriphophate. As a result, the
parasite stops moving and dies.
Uses
• Albendazole is widely used throughout the world for the treatment of intestinal nematode
infection.
NICLOSAMIDE (2’,5-dichloro-4’-nitrosaicylanilide)
Structure
• Niclosamide is a derivative of salicylamide and is an effective antihelmintic drug.
MOA
• Its action consists of inhibition of mitochondrial oxidative phosphorylation in both
mammals as well as in parasites.
• It simultaneously inhibits glucose and oxygen uptake by the parasite.
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17. 2
Uses
• Niclosamide is effective against intestinal cestodes.
OXAMNIQUINE
(1,2,3,4-Tetrahydro-2-[(isopropylamino)methyl]-7-nitro-6-
quinolinemethanol)
• It has been shown to inhibit DNA, RNA, and protein synthesis in schistosomes.
• This drug is stage specific, with activity against very young schistosomula and adult
worms and also more effective against adult male worms than against female worms.
Uses
• It is an antischistosomal agent that is used for the treatment of intestinal schistosomiasis
infection.
PRAZIQUANTEL
(2-(cyclcohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4Hpyrazino-[2,1a]isoquinolin- 4-
one)
Structure
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18. 3
• It is a derivative of pyrazino quinoline or an isoquinoline derivative with most of the
biologic activity found in the levo enantiomer.
• Praziquantel is an antihelmintic drug with a broad spectrum of action. It crosses blood-
brain barrier and attains therapeutic concentrations in the brain and CSF.
MOA
• It has an effect on the cellular membrane of schistosomes by increasing the
permeability and consequently the flow of calcium ions into the cell, which results
in paralysis of the parasite’s muscles.
• As a result, the suckers of the parasite cease to work, and it is excreted from the
organism.
Uses
• It is highly effective against cestodes and trematodes. It is used for treatment of all
forms of schizotomoniasis in humans.
IVERMECTIN
Structure
• Avermectins are members of a family of structurally complex antibiotics produced by
fermentation with a strain of Streptomyces avermitilis.
• It contain pentacyclic 16-membered–ring aglycones glycosidically linked at the 3-position to
a disaccharide that comprises two oleandrose sugar residues.
MOA
Raj K. Prasad

19. 4
• The first is an indirect action in which motility of microfalaria is reduced, which in turn
allows cytotoxic cells of the host to adhere to the parasite, resulting in elimination from the
host.
Uses
• Ivermectin is active in low dosage against a wide variety of nematodes and arthropods that
parasitize animals. Product is used for the control of various insects, mite pests, fire ants
and as a veterinary antihelminthic.
Raj K. Prasad