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Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Anti-Parasitic Drugs
Parasites are organisms that live off other organisms, or hosts, to survive. Some
parasites don’t noticeably affect their hosts. Others grow, reproduce, or invade
organ systems that make their hosts sick, resulting in a parasitic infection.
Although any microbe that infects a human (virus, bacteria, fungus, etc.) could
theoretically be considered to be a parasite, the term parasite tends to be reserved
for three types of infectious agents:
1. Protozoa (unicellular forms)
2. Helminthes (worms)
3. Arthropods
1-Protozoa:
• Protozoal diseases are less easily treated than bacterial infections.
Unicellular protozoal cells have metabolic processes closer to human cells
than bacteria. Many of antiprotozoal drugs cause serious toxic effects and
most of them are not safe in pregnancy.
Protozoal diseases:
Giardiasis:
Giardiasis is a disease that shows considerable similarity to
amebiasis. It is caused by Giardia lamblia, an organism that can be
found in the duodenum and jejunum. The organism exists in a motile
trophozoite form and an infectious cyst form. The cyst form can be
deposited in water (lives up to 2 months), and the contaminated water
can then be ingested by the human. The trophozoite, if expelled from
the gastrointestinal (GI) tract, normally will not survive. Giardia
lamblia is the single most common cause of waterborne diarrhea in the
United States.
The organism can attach to the mucosal wall via a ventral sucking
disk, and similar to amebiasis, the patient can be asymptomatic or
develop watery diarrhea, abdominal cramps, distention and flatulence,
anorexia, nausea, and vomiting. Usually, the condition is self-limiting
in 1 to 4 weeks.
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Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Amebiasis:
• Amebiasis is a disease of the large intestine caused by Entamoeba
histolytica. The disease occurs mainly in the tropics, but it is also seen in
temperate climates. Amebiasis can be carried without
significant symptoms or can lead to severe, life-threatening
dysentery. The organism exists in one of two forms, the
motile trophozoite form or the dormant cyst form. The
trophozoite form is found in the intestine or in the wall of
the colon and can be expelled from the body with the feces.
The cyst form is encased by a chitinous wall that protects
the organism from the environment, including chlorine used in water
purification; thus, the organism can be transmitted through contaminated
water and foods. The cyst form is responsible for transmission of the
disease. The cyst is spread by direct person-to-person contact and is
commonly associated with living conditions in which poor personal hygiene,
poor sanitation, poverty, and ignorance exist.
Symptoms can range from intermittent diarrhea (foul smelling, loose/watery
stools) to tenderness and enlargement of the liver (with the extraintestinal
form) to acute amoebic dysentery. Many patients can experience no
symptoms, and the organism remains in the bowels as a commensal
organism.
Trichomoniasis:
• Trichomoniasis is a protozoal infection caused by
Trichomonas vaginalis, which exists only in a trophozoite form. The
organs most commonly involved in the infection include the vagina,
urethra, and prostate; thus, the disease is considered to be a venereal
infection. The condition is transmitted by sexual contact, and it is
estimated that trichomoniasis affects 180 million individuals
worldwide.
Infections in the male can be asymptomatic, whereas in the female,
the symptoms can consist of vaginitis, profuse and foul-smelling
discharge, burning and soreness on urination, and vulvar itching.
Diagnosis is based on microscopic identifi cation of the organism in fl
uids from the vagina, prostate, or urethra.
3
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Drug therapy for protozoal infections
Treatment of Amebiasis, Giardiasis, and Trichomoniasis:
Metronidazole (Flagyl):
▪ Metronidazole was initially introduced for the treatment of vaginal
infections caused by Trichomonas vaginalis but has since
been shown to be effective for treatment of amebiasis,
giardiasis, and anaerobic bacterial infections, including
Clostridium difficile.
▪ Despite the availability of metronidazole since the late
1950s, the mechanism of action of the drug is still unknown.
▪ 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).
▪ Specifically, DoCampo has reported that nitroaryl compounds
(nitroimidazoles, metronidazole, nitrofurans, nifurtimox) are reduced to nitro
radical anions, which in turn react with oxygen to regenerate the nitroaryl
and the superoxide radical anion. Further reduction of superoxide radical
anion leads to hydrogen peroxide, and homolytic cleavage of the latter leads
to hydroxyl radical formation. Superoxide radical anion, hydrogen peroxide,
and hydroxyl radicals are referred to as reactive oxygen species (ROS) and
are the reactive substances that are implicated in damage to critical cellular
components of the parasite.
4
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Metabolism: Liver metabolism of metronidazole leads to two major metabolites:
hydroxylation of the 2-methyl group to 2-hydroxymethylmetronidazole (HM) and
its oxidation to metronidazole acetic acid. Both compounds possess biologic
activity. Additionally, HM is found in the urine as glucuronide and sulfate
conjugates. In addition, a small amount of metronidazole is oxidized to acetamide,
a known carcinogen in rats but not in humans, and to the oxalate derivative.
Metabolism of metronidazole
Tinidazole (Tindamax):
▪ Tinidazole has been approved by the U.S. Food and Drug Administration
(FDA) for the treatment of amebiasis, giardiasis, and
trichomoniasis.
▪ It appears also to be highly effective against Helicobacter
pylori infections, although it is not approved for this use.
The drug is rapidly and completely absorbed following oral
administration and can be administered with food to reduce GIdisturbance.
5
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
▪ 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. Basically, tinidazole appears to mimic the
actions of metronidazole, although there are reports that it is effective
against some protozoa that are resistant to metronidazole.
Nitazoxanide (Alinia):
▪ Nitazoxanide (NTZ) has been approved as an orphan drug for the treatment
of diarrhea in children (age 1 to 11 years) associated with giardiasis, but it is
also approved for diarrhea caused by cryptosporidiosis in
patients with AIDS. Cryptosporidiosis is a protozoal
infection caused by Cryptosporidium parvum. The
condition is uncommon in healthy individuals but can be
life-threatening in immunosuppressed patients and those
with HIV infections.
▪ In addition, the drug has been shown to be effective
against the protozoa Entamoeba histolytica and Trichomonas vaginalis, the
bacteria Helicobacter pylori and Clostridium perfringens, and various
helminths, including Ascaris lumbricoides, Enterobius vermicularis,
Ancylostoma doudenale, and Strongyloides stercoralis
Mechanism of action
▪ NTZ is a prodrug that is metabolically converted into the deacetylated drug
tizoxanide (TIZ). TIZ then undergoes a four-electron reduction of the 5-nitro
group giving various short-lived intermediates, which can include the
hydroxylamine derivative. These reduced products represent the active
forms of NTZ. Whereas these intermediates would suggest that NTZ has the
same mechanism of action as metronidazole, this does not appear to be the
case. NTZ is thought to inhibit the enzyme pyruvate:ferredoxin
oxidoreductase in Trichomonas vaginalis, Entamoeba histolytica, and
Clostridium perfringens.
▪ The result of this inhibition is disruption of the bioenergetics of these
organisms. Unlike metronidazole and tinidazole, which fragment DNA and
are suspected mutagenic agents, NTZ and TIZ do not cause DNA
fragmentation and are not considered to be mutagenic. This might be
associated with the higher redox potential found for NTZ, a nitrothiazole, in
comparison with very low redox potential found for the nitroimidazoles,
such as metronidazole and tinidazole. Additional metabolites of TIZ include
6
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
the glucuronide, which shows some biologic activity, and small amounts of
an aromatic hydroxylation product.
Metabolic activation of nitazoxanide
Diloxanide Furoate :
▪ Diloxanide furoate (available from the Centers for Disease
Control and Prevention [CDC]) is prescribed
for the treatment of asymptomatic amebiasis but is
ineffective as a single agent for the extraintestinal form of
the disease.
The drug is administered orally and is hydrolyzed in the
gut to give diloxanide, which is considered to be the active drug. Diloxanide
is the only form identifi ed in the bloodstream. The drug is found in the urine
as the glucuronide.
Metabolism of diloxanide furoate
7
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Leishmaniasis:
• Leishmaniasis is a disease caused by a number of protozoa in the genus
Leishmania. The protozoa can be harbored in diseased
rodents, canines, and various other mammals and
transmitted from the infected mammal to man by bites from
female sandflies of the genus Phlehotomus and then appear
in one of four major clinical syndromes: visceral
leishmaniasis, cutaneous leishmaniasis , mucocutaneous
leishmaniasis , or diffuse cutaneous leishmaniasis. The
sandfly, the vector involved in spreading the disease, breeds
in warm, humid climates; thus, the disease is more common
in the tropics. As many as 12 million individuals worldwide are infected by
this organism.
The visceral leishmaniasis, also known as kala azar (black
fever), is caused by Leishmania donovani. This form of the
disease is systemic and is characterized in patients by fever,
typically nocturnal, diarrhea, cough, and enlarged liver and
spleen. The skin of the patient can become darkened. Without
treatment, death can occur in 20 months and is commonly
associated with diarrhea, superinfections, or GI hemorrhage.
Visceral leishmaniasis is most commonly found in India and
Sudan.
Treatment of Leishmaniasis:
Sodium Stibogluconate (Pentostam; Available from the CDC) :
▪ Leishmaniasis was first described in the medical literature by Deishman and
Donovan in 1903, and shortly after that, antimony-based drugs were
introduced as therapeutic agents to treat this disease. Although the structure
of sodium stibogluconate is commonly drawn as shown, the actual
compound probably is much more complex.
8
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
▪ The drug is a water-soluble preparation that is administered intramuscularly
or IV. Pentavalent antimony compounds are thought to inhibit bioenergetic
processes in the pathogen, with catabolism of glucose and inhibition of
glycolytic enzymes being the primary sites of action (glucose catabolism is
86% to 94% inhibited). This in turn results in inhibition of adenosine
triphosphate/guanosine triphosphate formation.
▪ Sodium stibogluconate is the drug of choice for the treatment of most forms
of leishmaniasis (or meglumine antimonate, another pentavalent antimony
agent). The recommended dose is 20 mg antimony/kg/d, not to exceed 850
mg antimony/d.
▪ A number of other drugs have been reported to be effective in the treatment
of leishmaniasis, and these include pentamidine, amphotericin B,
paromomycin, alkylphosphocholine analogs, rifampicin, and ketoconazole.
Miltefosine (Impavido):
▪ Miltefosine is an orally active drug that is effective against visceral and
cutaneous leishmaniasis. Although the drug has not been approved by the
FDA, a compassionate use protocol is pending.
▪ This drug is especially important since the only other drug available is
sodium stibogluconate, which is administered intramuscularly or IV, thus
limiting its utility, and has a high potential for toxicity associated with the
antimony component of the drug.
▪ Miltefosine has been reported to exhibit activity in vitro against a broad
range of leishmanial strains. Although the mechanism of action of the drug
remains unknown, it has been suggested that the drug acts directly on the
promastigote and amastigote stages of the parasite and not through
stimulation of the immune system. This distinction is important because
patients who are immunocompromised may also suffer from leishmaniasis.
9
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Pneumocystis :
• The disease pneumocystis, commonly referred to as pneumocystis pneumonia
(PCP), incorrectly derived its name from what was thought to be the causative
organism, Pneumocystis carinii and the disease state of pneumonia. The organism
P. carinii was originally isolated and reported to grow in both humans and rats.
The organism itself was difficult to characterize since it had morphologic
characteristics of a protozoan (i.e., lack of ergosterol in its cell membrane), but it’s
rRNA and mitochondrial DNA pattern resembles that of fungi. It was only later
recognized that the organism infecting humans and responsible for the disease
PCP was actually Pneumocystis jirovecii, a yeast-like fungus that can only be
cultured in humans.
• Acute pneumocystis rarely strikes healthy individuals, although the organism is
harbored in most humans without any apparent adverse effect. P. jirovecii becomes
active only in individuals who have a serious impairment of their immune systems.
Thus, the organism is considered to be an opportunistic pathogen. More recently,
this disease has appeared in patients with HIV/AIDS, 80% of whom ultimately
contract P. jirovecii pneumonia, as one of the main causes of death. The disease
also occurs in those receiving immunosuppressive drugs to prevent rejection
following organ transplantation or for the treatment of malignant disease.
• Additionally, pneumocystis is seen in malnourished infants whose immunologic
systems are impaired. The disease is thought to be transmitted via an airborne
route. PCP is characterized by a severe pneumonia caused by rapid multiplication
of the organisms, almost exclusively in lung tissue, with the organism lining the
walls of the alveoli and gradually fi lling the alveolar spaces. Untreated, the acute
form of the disease is generally fatal. Even patients who recover from
pneumocystosis are at risk of recurrent episodes. Patients with AIDS experience a
recurrence rate of approximately 50%.
• Extrapulmonary pneumocystosis—that is, pneumocystosis outside of the lungs—is
also known to exist and can be more common than presently recognized. This
infection can be complicated by the presence of coinfectious organisms.
Fortunately, drug therapy used for treatment of the pulmonary infection is benefi
cial for the extrapulmonary condition, although intravenous (IV) administration of
the drugs can be necessary. The common therapy for PCP uses antibacterial and
antiprotozoal drugs.
10
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Treatment of Pneumocystis:
Sulfamethoxazole–Trimethoprim; Cotrimoxazole (Bactrim):
• The combination of sulfamethoxazole and trimethoprim has
proven to be the most successful method for treatment and
prophylaxis of pneumocystis in patients with AIDS. This
combination was first reported as being effective against PCP in
1975, and by 1980, it had become the preferred method of
treatment, with a response rate of 65% to 94%.
• The combination is effective against both pneumocystic
pneumonia and the extrapulmonary disease. P. jirovecii appears
to be especially susceptible to the sequential blocking action of
cotrimoxazole, which inhibits both the incorporation of p-
aminobenzoic acid (PABA) into folic acid as well as the reduction
of dihydrofolic acid to tetrahydrofolic acid by dihydrofolate
reductase (DHFR).
• Depending on the severity of the infection, the combination is administered
in doses of 20 mg/kg/d of trimethoprim and 100 mg/ kg/d of
sulfamethoxazole in four divided doses over a period of 14 to 21 days. The
incidence of side effects of this combination is high and reflects generally the
effects of the sulfa drug component. Side effects can be significant enough to
terminate treatment.
11
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Pentamidine Isethionate (Pentam):
• Pentamidine is available as the water-soluble isethionate salt, which is used
both IV and as an aerosol. The drug can be used via the intramuscular route,
but significant complications have been reported, and therefore, this route of
administration is not recommended. The drug has fungicidal and
antiprotozoal activity but is used primarily for treatment of PCP.
• The mechanism of action of pentamidine is not known with certainty, but
strong evidence supports various mechanisms of action for pentamidine.
Pentamidine selectively binds to the DNA in the Trypanosoma.
• Pentamidine has also been shown to inhibit topoisomerase in P. jirovecii,
which leads to double-strand cleavage of DNA in Trypanosoma . It has been
suggested that pentamidine’s mechanism of action might be different in
different organisms and, therefore, that the actions reported for Trypanosoma
might not carry over to pneumocystis.
• Pentamidine is used as a secondline agent either by itself or in combination
for the treatment and prophylaxis of PCP. For prophylaxis, the aerosol form
of the drug is indicated and has minimum toxicity.
Atovaquone (Mepron):
• Atovaquone, a chemical with structural similarity to the ubiquinone
metabolites, was initially synthesized and investigated as an
antimalarial, a use for which it has recently gained
acceptance when used in combination therapy with other
antimalarial agents. Today, its usefulness is primarily
directed toward the treatment of PCP.
• 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.
• Atovaquone is thought to produce its antiparasitic action by virtue of its
ability to inhibit the mitochondrial respiratory chain. More specifically,
atovaquone is a ubiquinone reductase inhibitor, inhibiting at the cytochrome
bc1 complex .This action leads to a collapse of the mitochondrial membrane
potential. The compound shows stereospecific inhibition, with the trans
isomer being more active than the cis isomer.
12
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
• Atovaquone is poorly absorbed from the GI tract because of its poor water
solubility and high fat solubility, but the absorption can be significantly
increased if taken with a fat-rich meal.
• 60% of the patients on cotrimoxazole developing serious side effects to this
combination, atovaquone is an important alternative drug.
Trimetrexate Glucuronate (Neutrexin):
• Trimetrexate (TMQ) has been approved for the treatment of P. jirovecii in
patients with AIDS and also exhibits antiprotozoal activity against T. cruzi.
The drug is available as a single-ingredient medication, but it can be
administered along with folinic acid in much the same way that methotrexate
is administered with calcium leucovorin in cancer chemotherapy. TMQ is a
derivative of methotrexate.
• TMQ is considered to be a non-classical folate antagonist, whereas methotrexate,
the structurally similar analog of TMQ, is a classical folate antagonist. The
difference between these two drugs is that methotrexate, with its polar glutamate
side chain, is transported into the cell via a carrier-mediated transport system,
whereas TMQ, without the glutamate moiety, is absorbed by the cell via a passive
diffusion. Once in the cell, TMQ inhibits DHFR. TMQ binds to P. jirovecii DHFR
1,500 times more strongly than trimethoprim and somewhat more strongly than
methotrexate.
• It has also been reported that TMQ readily enters the P. jirovecii cell because of the
lipophilic nature of this drug. Methotrexate and leucovorin are not able to enter the
cell, however, because the cell membrane of P. jirovecii does not possess the
transporter protein.
• TMQ, when combined with the cytoprotective agent leucovorin (folinic acid), is
more effective and better tolerated than pentamidine in the treatment of PCP
.Because the first- and second-line agents are successful in only 50% to 75% of
these cases and because adverse reactions severely limit the use of some of the
older agents, TMQ can offer some advantages in treatment.
• Additionally, TMQ has been reported to be effective in the treatment of Chagas
disease.
13
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Trypanosomiasis :
• There are two distinct forms of trypanosomiasis: Chagas disease and
African sleeping sickness.
Chagas Disease :
• Chagas disease, also known as American trypanosomiasis, is caused by the
parasitic protozoa T. cruzi and is found only in the Americas, primarily in
Brazil but also in the southern United States.
• The protozoa lives in mammals and is spread by the bloodsucking insect
known as the reduviid bug, assassin bug, or kissing bug. The insect becomes
infected by drawing blood from an infected mammal and releasing the
protozoa with discharged feces. The pathogen then enters the new host
through breaks in the skin. Inflammatory lesions are seen at the site of entry.
The disease can also be spread through transfusion with contaminated blood.
• Signs of initial infection can include malaise, fever, anorexia, and skin edema
at the site where the protozoa entered the host. The disease ultimately can
invade the heart, where after decades of infection with chronic Chagas
disease, the patient can experience an infection-associated heart attack. It is
estimated that 5% of the Salvadorian and Nicaraguan immigrants to the
United States can have chronic Chagas disease.
African Trypanosomiasis :
• African trypanosomiasis, or sleeping sickness, is caused by several
subspecies of T. brucei (T. brucei rhodesiense [east African sleeping
sickness] and T. brucei gambiense [west African sleeping sickness]). In
this case, the infected animal is bitten by the bloodsucking tsetse fly,
which in turn transmits the protozoa via inoculation during a subsequent
bite of a human.
• The protozoa, initially present in the gut of the vector, appear in the
salivary gland for inoculation during the subsequent biting of a human. It
is estimated that some 50 million people are at risk of African sleeping
sickness, with 300,000 to 500,000 cases occurring in sub-Saharan Africa
each year.
The infection progresses through two stages:
• Stage I can present as fever and high temperatures lasting several days;
hematologic and immunologic changes occur during this stage.
• Stage II occurs after the organism enters the central nervous system
(CNS) and can involve symptoms suggesting the disease name— daytime
somnolence, loss of spontaneity, halting speech, listless gaze, and
extrapyramidal signs (e.g., tremors and choreiform movements). A
14
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
breakdown of neurologic function leading to coma and death can occur.
Death can occur within weeks if untreated (T. brucei rhodesiense) or only
after several years (T. brucei gambiense).
• It should be noted that the sole source of energy for the trypanosomal
organism is glycolysis, which in turn can account for the hypoglycemia
seen in the host. In addition, the migration of the organism into the CNS
can be associated with the organism’s search for a rich source of
available glucose.
Treatment of Trypanosomiasis:
Suramin Sodium:
• Introduced into therapy for the treatment of early trypanosomiasis in the
1920s, suramin, a bis-hexasulfonatednaphthylurea, is still considered to be
the drug of choice for treatment of non–CNS-associated African
trypanosomiasis.
• Suramin sodium is a water-soluble compound that is poorly absorbed via
oral administration and must be administered IV in multiple injections.
Because of its highly ionic nature, suramin will not cross the blood–brain
barrier and, therefore, is ineffective for the treatment of trypanosomal
infections that reach the CNS.
Pentamidine, Isethionate (Pentam):
• First introduced as a therapy for trypanosomiasis in 1937, pentamidine is now
used in a variety of protozoal and fungal infections and finds use in the
treatment of trypanosomiasis, leishmaniasis, and pneumocystis (PCP).
• When used for trypanosomiasis, pentamidine is only effective against
Trypanosoma brucei rhodesiense (east African sleeping sickness) and, even
then, only during the early stage of the disease, because the drug does not
readily cross the blood–brain barrier.
15
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Eflornithine (Ornidyl):
• Metcalf reported the synthesis of eflornithine
(difluoromethyl ornithine [DFMO]) in 1978. Their interest
arose from the desire to 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. It was not until 1980 that Bacchi demonstrated the potential of
DFMO in the treatment of trypanosomiasis.
• DFMO is a suicide inhibitor of ODC, a pyridoxal phosphate–dependent
enzyme. Evidence suggests that cysteine-360 in ODC is the site of efl
ornithine alkylation (25). Alkylation of ODC blocks the synthesis of
putrescine, the rate-determining step in the synthesis of polyamines.
Mammalian ODC can also be inhibited, but because the turnover of ODC is
so rapid in mammals, eflornithine does not produce serious side effects.
Inhibition of ornithine decarboxylase (Enz-Cys-SH) by eflornithine.
16
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Nifurtimox (Lampit):
• Another of the nitroaryl compounds, nifurtimox has proven
to be useful as a drug for the treatment of trypanosomiasis. It
is one of two drugs approved for use in treatment of Chagas
disease.
• As discussed for metronidazole, nifurtimox is thought to
undergo reduction followed by oxidation and, in the process, generate ROS,
such as the superoxide radical anion, hydrogen peroxide, and hydroxyl
radical. These species are potent oxidants, producing oxidative stress that
can produce damage to DNA and lipids that can affect cellular membranes.
In addition, Henderson have reported that nifurtimox inhibits trypanothione
reductase, which results in the inhibition of trypanothione formation (93%
inhibition). Trypanothione is a critical protective enzyme found uniquely in
trypanosomal parasites
Formation of ROS from nitroaryl compounds.
Benznidazole (Rochagan):
• Benznidazole is the second of the drugs approved for treatment
of Chagas disease. Like nifurtimox, it is effective against the
circulating form of Trypanosoma cruzi during the acute phase
of the disease, but also like nifurtimox, it is ineffective during
the chronic stage of the disease.
• It has been proposed that benznidazole undergoes a one-
electron transfer to the nitro group, which in turn dismutates to give back the
nitroimidazole and a nitrosoimidazole. The latter product can then undergo
an electrophilic addition to trypanothione, which leads to depletion of
trypanothione, an essential enzyme system in T. cruzi . Benznidazole is not
available in the United States but is available in South American countries. It
is administered orally in a tablet form.
17
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin
Proposed mechanism of action of benznidazole.
Melarsoprol:
• Arsenic-containing drugs have been used for treatment of parasitic conditions
for thousands of years. In the late 1800s and early 1900s, Paul Ehrlich
introduced the use of trivalent arsenicals. Melarsoprol, an organ arsenical,
came into use in the late 1940s, and it remains the first- choice drug in the
treatment of trypanosomiasis. Until 1990, it also was the only treatment for
late-stage sleeping sickness.
• More recently, Fairlamb have proposed a mechanism of action that results in
the inhibition of trypanothione reductase through the formation of a stable
complex between melarsoprol and trypanothione. Melarsoprol reacts with the
cysteine sulfhydryl of trypanothione to form the stable adduct. Supportive of
this mechanism is the synergistic action of melarsoprol with eflornithine, two
drugs that produce sequential blockage of the synthesis of trypanothione.
Structure of melarsoprol trypanothione complex.
▪ Because the drug has the potential for serious nervous system toxicities
(e.g., convulsions, acute cerebral edema, and coma), the drug is usually
administered in a hospital setting with supervision. An additional problem
with melarsoprol is the development of resistance by the parasite
18
Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin

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Antiparasitic drugs-Medicinal Chemistry

  • 1. 1 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Anti-Parasitic Drugs Parasites are organisms that live off other organisms, or hosts, to survive. Some parasites don’t noticeably affect their hosts. Others grow, reproduce, or invade organ systems that make their hosts sick, resulting in a parasitic infection. Although any microbe that infects a human (virus, bacteria, fungus, etc.) could theoretically be considered to be a parasite, the term parasite tends to be reserved for three types of infectious agents: 1. Protozoa (unicellular forms) 2. Helminthes (worms) 3. Arthropods 1-Protozoa: • Protozoal diseases are less easily treated than bacterial infections. Unicellular protozoal cells have metabolic processes closer to human cells than bacteria. Many of antiprotozoal drugs cause serious toxic effects and most of them are not safe in pregnancy. Protozoal diseases: Giardiasis: Giardiasis is a disease that shows considerable similarity to amebiasis. It is caused by Giardia lamblia, an organism that can be found in the duodenum and jejunum. The organism exists in a motile trophozoite form and an infectious cyst form. The cyst form can be deposited in water (lives up to 2 months), and the contaminated water can then be ingested by the human. The trophozoite, if expelled from the gastrointestinal (GI) tract, normally will not survive. Giardia lamblia is the single most common cause of waterborne diarrhea in the United States. The organism can attach to the mucosal wall via a ventral sucking disk, and similar to amebiasis, the patient can be asymptomatic or develop watery diarrhea, abdominal cramps, distention and flatulence, anorexia, nausea, and vomiting. Usually, the condition is self-limiting in 1 to 4 weeks.
  • 2. 2 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Amebiasis: • Amebiasis is a disease of the large intestine caused by Entamoeba histolytica. The disease occurs mainly in the tropics, but it is also seen in temperate climates. Amebiasis can be carried without significant symptoms or can lead to severe, life-threatening dysentery. The organism exists in one of two forms, the motile trophozoite form or the dormant cyst form. The trophozoite form is found in the intestine or in the wall of the colon and can be expelled from the body with the feces. The cyst form is encased by a chitinous wall that protects the organism from the environment, including chlorine used in water purification; thus, the organism can be transmitted through contaminated water and foods. The cyst form is responsible for transmission of the disease. The cyst is spread by direct person-to-person contact and is commonly associated with living conditions in which poor personal hygiene, poor sanitation, poverty, and ignorance exist. Symptoms can range from intermittent diarrhea (foul smelling, loose/watery stools) to tenderness and enlargement of the liver (with the extraintestinal form) to acute amoebic dysentery. Many patients can experience no symptoms, and the organism remains in the bowels as a commensal organism. Trichomoniasis: • Trichomoniasis is a protozoal infection caused by Trichomonas vaginalis, which exists only in a trophozoite form. The organs most commonly involved in the infection include the vagina, urethra, and prostate; thus, the disease is considered to be a venereal infection. The condition is transmitted by sexual contact, and it is estimated that trichomoniasis affects 180 million individuals worldwide. Infections in the male can be asymptomatic, whereas in the female, the symptoms can consist of vaginitis, profuse and foul-smelling discharge, burning and soreness on urination, and vulvar itching. Diagnosis is based on microscopic identifi cation of the organism in fl uids from the vagina, prostate, or urethra.
  • 3. 3 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Drug therapy for protozoal infections Treatment of Amebiasis, Giardiasis, and Trichomoniasis: Metronidazole (Flagyl): ▪ Metronidazole was initially introduced for the treatment of vaginal infections caused by Trichomonas vaginalis but has since been shown to be effective for treatment of amebiasis, giardiasis, and anaerobic bacterial infections, including Clostridium difficile. ▪ Despite the availability of metronidazole since the late 1950s, the mechanism of action of the drug is still unknown. ▪ 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). ▪ Specifically, DoCampo has reported that nitroaryl compounds (nitroimidazoles, metronidazole, nitrofurans, nifurtimox) are reduced to nitro radical anions, which in turn react with oxygen to regenerate the nitroaryl and the superoxide radical anion. Further reduction of superoxide radical anion leads to hydrogen peroxide, and homolytic cleavage of the latter leads to hydroxyl radical formation. Superoxide radical anion, hydrogen peroxide, and hydroxyl radicals are referred to as reactive oxygen species (ROS) and are the reactive substances that are implicated in damage to critical cellular components of the parasite.
  • 4. 4 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Metabolism: Liver metabolism of metronidazole leads to two major metabolites: hydroxylation of the 2-methyl group to 2-hydroxymethylmetronidazole (HM) and its oxidation to metronidazole acetic acid. Both compounds possess biologic activity. Additionally, HM is found in the urine as glucuronide and sulfate conjugates. In addition, a small amount of metronidazole is oxidized to acetamide, a known carcinogen in rats but not in humans, and to the oxalate derivative. Metabolism of metronidazole Tinidazole (Tindamax): ▪ Tinidazole has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of amebiasis, giardiasis, and trichomoniasis. ▪ It appears also to be highly effective against Helicobacter pylori infections, although it is not approved for this use. The drug is rapidly and completely absorbed following oral administration and can be administered with food to reduce GIdisturbance.
  • 5. 5 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin ▪ 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. Basically, tinidazole appears to mimic the actions of metronidazole, although there are reports that it is effective against some protozoa that are resistant to metronidazole. Nitazoxanide (Alinia): ▪ Nitazoxanide (NTZ) has been approved as an orphan drug for the treatment of diarrhea in children (age 1 to 11 years) associated with giardiasis, but it is also approved for diarrhea caused by cryptosporidiosis in patients with AIDS. Cryptosporidiosis is a protozoal infection caused by Cryptosporidium parvum. The condition is uncommon in healthy individuals but can be life-threatening in immunosuppressed patients and those with HIV infections. ▪ In addition, the drug has been shown to be effective against the protozoa Entamoeba histolytica and Trichomonas vaginalis, the bacteria Helicobacter pylori and Clostridium perfringens, and various helminths, including Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma doudenale, and Strongyloides stercoralis Mechanism of action ▪ NTZ is a prodrug that is metabolically converted into the deacetylated drug tizoxanide (TIZ). TIZ then undergoes a four-electron reduction of the 5-nitro group giving various short-lived intermediates, which can include the hydroxylamine derivative. These reduced products represent the active forms of NTZ. Whereas these intermediates would suggest that NTZ has the same mechanism of action as metronidazole, this does not appear to be the case. NTZ is thought to inhibit the enzyme pyruvate:ferredoxin oxidoreductase in Trichomonas vaginalis, Entamoeba histolytica, and Clostridium perfringens. ▪ The result of this inhibition is disruption of the bioenergetics of these organisms. Unlike metronidazole and tinidazole, which fragment DNA and are suspected mutagenic agents, NTZ and TIZ do not cause DNA fragmentation and are not considered to be mutagenic. This might be associated with the higher redox potential found for NTZ, a nitrothiazole, in comparison with very low redox potential found for the nitroimidazoles, such as metronidazole and tinidazole. Additional metabolites of TIZ include
  • 6. 6 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin the glucuronide, which shows some biologic activity, and small amounts of an aromatic hydroxylation product. Metabolic activation of nitazoxanide Diloxanide Furoate : ▪ Diloxanide furoate (available from the Centers for Disease Control and Prevention [CDC]) is prescribed for the treatment of asymptomatic amebiasis but is ineffective as a single agent for the extraintestinal form of the disease. The drug is administered orally and is hydrolyzed in the gut to give diloxanide, which is considered to be the active drug. Diloxanide is the only form identifi ed in the bloodstream. The drug is found in the urine as the glucuronide. Metabolism of diloxanide furoate
  • 7. 7 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Leishmaniasis: • Leishmaniasis is a disease caused by a number of protozoa in the genus Leishmania. The protozoa can be harbored in diseased rodents, canines, and various other mammals and transmitted from the infected mammal to man by bites from female sandflies of the genus Phlehotomus and then appear in one of four major clinical syndromes: visceral leishmaniasis, cutaneous leishmaniasis , mucocutaneous leishmaniasis , or diffuse cutaneous leishmaniasis. The sandfly, the vector involved in spreading the disease, breeds in warm, humid climates; thus, the disease is more common in the tropics. As many as 12 million individuals worldwide are infected by this organism. The visceral leishmaniasis, also known as kala azar (black fever), is caused by Leishmania donovani. This form of the disease is systemic and is characterized in patients by fever, typically nocturnal, diarrhea, cough, and enlarged liver and spleen. The skin of the patient can become darkened. Without treatment, death can occur in 20 months and is commonly associated with diarrhea, superinfections, or GI hemorrhage. Visceral leishmaniasis is most commonly found in India and Sudan. Treatment of Leishmaniasis: Sodium Stibogluconate (Pentostam; Available from the CDC) : ▪ Leishmaniasis was first described in the medical literature by Deishman and Donovan in 1903, and shortly after that, antimony-based drugs were introduced as therapeutic agents to treat this disease. Although the structure of sodium stibogluconate is commonly drawn as shown, the actual compound probably is much more complex.
  • 8. 8 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin ▪ The drug is a water-soluble preparation that is administered intramuscularly or IV. Pentavalent antimony compounds are thought to inhibit bioenergetic processes in the pathogen, with catabolism of glucose and inhibition of glycolytic enzymes being the primary sites of action (glucose catabolism is 86% to 94% inhibited). This in turn results in inhibition of adenosine triphosphate/guanosine triphosphate formation. ▪ Sodium stibogluconate is the drug of choice for the treatment of most forms of leishmaniasis (or meglumine antimonate, another pentavalent antimony agent). The recommended dose is 20 mg antimony/kg/d, not to exceed 850 mg antimony/d. ▪ A number of other drugs have been reported to be effective in the treatment of leishmaniasis, and these include pentamidine, amphotericin B, paromomycin, alkylphosphocholine analogs, rifampicin, and ketoconazole. Miltefosine (Impavido): ▪ Miltefosine is an orally active drug that is effective against visceral and cutaneous leishmaniasis. Although the drug has not been approved by the FDA, a compassionate use protocol is pending. ▪ This drug is especially important since the only other drug available is sodium stibogluconate, which is administered intramuscularly or IV, thus limiting its utility, and has a high potential for toxicity associated with the antimony component of the drug. ▪ Miltefosine has been reported to exhibit activity in vitro against a broad range of leishmanial strains. Although the mechanism of action of the drug remains unknown, it has been suggested that the drug acts directly on the promastigote and amastigote stages of the parasite and not through stimulation of the immune system. This distinction is important because patients who are immunocompromised may also suffer from leishmaniasis.
  • 9. 9 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Pneumocystis : • The disease pneumocystis, commonly referred to as pneumocystis pneumonia (PCP), incorrectly derived its name from what was thought to be the causative organism, Pneumocystis carinii and the disease state of pneumonia. The organism P. carinii was originally isolated and reported to grow in both humans and rats. The organism itself was difficult to characterize since it had morphologic characteristics of a protozoan (i.e., lack of ergosterol in its cell membrane), but it’s rRNA and mitochondrial DNA pattern resembles that of fungi. It was only later recognized that the organism infecting humans and responsible for the disease PCP was actually Pneumocystis jirovecii, a yeast-like fungus that can only be cultured in humans. • Acute pneumocystis rarely strikes healthy individuals, although the organism is harbored in most humans without any apparent adverse effect. P. jirovecii becomes active only in individuals who have a serious impairment of their immune systems. Thus, the organism is considered to be an opportunistic pathogen. More recently, this disease has appeared in patients with HIV/AIDS, 80% of whom ultimately contract P. jirovecii pneumonia, as one of the main causes of death. The disease also occurs in those receiving immunosuppressive drugs to prevent rejection following organ transplantation or for the treatment of malignant disease. • Additionally, pneumocystis is seen in malnourished infants whose immunologic systems are impaired. The disease is thought to be transmitted via an airborne route. PCP is characterized by a severe pneumonia caused by rapid multiplication of the organisms, almost exclusively in lung tissue, with the organism lining the walls of the alveoli and gradually fi lling the alveolar spaces. Untreated, the acute form of the disease is generally fatal. Even patients who recover from pneumocystosis are at risk of recurrent episodes. Patients with AIDS experience a recurrence rate of approximately 50%. • Extrapulmonary pneumocystosis—that is, pneumocystosis outside of the lungs—is also known to exist and can be more common than presently recognized. This infection can be complicated by the presence of coinfectious organisms. Fortunately, drug therapy used for treatment of the pulmonary infection is benefi cial for the extrapulmonary condition, although intravenous (IV) administration of the drugs can be necessary. The common therapy for PCP uses antibacterial and antiprotozoal drugs.
  • 10. 10 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Treatment of Pneumocystis: Sulfamethoxazole–Trimethoprim; Cotrimoxazole (Bactrim): • The combination of sulfamethoxazole and trimethoprim has proven to be the most successful method for treatment and prophylaxis of pneumocystis in patients with AIDS. This combination was first reported as being effective against PCP in 1975, and by 1980, it had become the preferred method of treatment, with a response rate of 65% to 94%. • The combination is effective against both pneumocystic pneumonia and the extrapulmonary disease. P. jirovecii appears to be especially susceptible to the sequential blocking action of cotrimoxazole, which inhibits both the incorporation of p- aminobenzoic acid (PABA) into folic acid as well as the reduction of dihydrofolic acid to tetrahydrofolic acid by dihydrofolate reductase (DHFR). • Depending on the severity of the infection, the combination is administered in doses of 20 mg/kg/d of trimethoprim and 100 mg/ kg/d of sulfamethoxazole in four divided doses over a period of 14 to 21 days. The incidence of side effects of this combination is high and reflects generally the effects of the sulfa drug component. Side effects can be significant enough to terminate treatment.
  • 11. 11 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Pentamidine Isethionate (Pentam): • Pentamidine is available as the water-soluble isethionate salt, which is used both IV and as an aerosol. The drug can be used via the intramuscular route, but significant complications have been reported, and therefore, this route of administration is not recommended. The drug has fungicidal and antiprotozoal activity but is used primarily for treatment of PCP. • The mechanism of action of pentamidine is not known with certainty, but strong evidence supports various mechanisms of action for pentamidine. Pentamidine selectively binds to the DNA in the Trypanosoma. • Pentamidine has also been shown to inhibit topoisomerase in P. jirovecii, which leads to double-strand cleavage of DNA in Trypanosoma . It has been suggested that pentamidine’s mechanism of action might be different in different organisms and, therefore, that the actions reported for Trypanosoma might not carry over to pneumocystis. • Pentamidine is used as a secondline agent either by itself or in combination for the treatment and prophylaxis of PCP. For prophylaxis, the aerosol form of the drug is indicated and has minimum toxicity. Atovaquone (Mepron): • Atovaquone, a chemical with structural similarity to the ubiquinone metabolites, was initially synthesized and investigated as an antimalarial, a use for which it has recently gained acceptance when used in combination therapy with other antimalarial agents. Today, its usefulness is primarily directed toward the treatment of PCP. • 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. • Atovaquone is thought to produce its antiparasitic action by virtue of its ability to inhibit the mitochondrial respiratory chain. More specifically, atovaquone is a ubiquinone reductase inhibitor, inhibiting at the cytochrome bc1 complex .This action leads to a collapse of the mitochondrial membrane potential. The compound shows stereospecific inhibition, with the trans isomer being more active than the cis isomer.
  • 12. 12 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin • Atovaquone is poorly absorbed from the GI tract because of its poor water solubility and high fat solubility, but the absorption can be significantly increased if taken with a fat-rich meal. • 60% of the patients on cotrimoxazole developing serious side effects to this combination, atovaquone is an important alternative drug. Trimetrexate Glucuronate (Neutrexin): • Trimetrexate (TMQ) has been approved for the treatment of P. jirovecii in patients with AIDS and also exhibits antiprotozoal activity against T. cruzi. The drug is available as a single-ingredient medication, but it can be administered along with folinic acid in much the same way that methotrexate is administered with calcium leucovorin in cancer chemotherapy. TMQ is a derivative of methotrexate. • TMQ is considered to be a non-classical folate antagonist, whereas methotrexate, the structurally similar analog of TMQ, is a classical folate antagonist. The difference between these two drugs is that methotrexate, with its polar glutamate side chain, is transported into the cell via a carrier-mediated transport system, whereas TMQ, without the glutamate moiety, is absorbed by the cell via a passive diffusion. Once in the cell, TMQ inhibits DHFR. TMQ binds to P. jirovecii DHFR 1,500 times more strongly than trimethoprim and somewhat more strongly than methotrexate. • It has also been reported that TMQ readily enters the P. jirovecii cell because of the lipophilic nature of this drug. Methotrexate and leucovorin are not able to enter the cell, however, because the cell membrane of P. jirovecii does not possess the transporter protein. • TMQ, when combined with the cytoprotective agent leucovorin (folinic acid), is more effective and better tolerated than pentamidine in the treatment of PCP .Because the first- and second-line agents are successful in only 50% to 75% of these cases and because adverse reactions severely limit the use of some of the older agents, TMQ can offer some advantages in treatment. • Additionally, TMQ has been reported to be effective in the treatment of Chagas disease.
  • 13. 13 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Trypanosomiasis : • There are two distinct forms of trypanosomiasis: Chagas disease and African sleeping sickness. Chagas Disease : • Chagas disease, also known as American trypanosomiasis, is caused by the parasitic protozoa T. cruzi and is found only in the Americas, primarily in Brazil but also in the southern United States. • The protozoa lives in mammals and is spread by the bloodsucking insect known as the reduviid bug, assassin bug, or kissing bug. The insect becomes infected by drawing blood from an infected mammal and releasing the protozoa with discharged feces. The pathogen then enters the new host through breaks in the skin. Inflammatory lesions are seen at the site of entry. The disease can also be spread through transfusion with contaminated blood. • Signs of initial infection can include malaise, fever, anorexia, and skin edema at the site where the protozoa entered the host. The disease ultimately can invade the heart, where after decades of infection with chronic Chagas disease, the patient can experience an infection-associated heart attack. It is estimated that 5% of the Salvadorian and Nicaraguan immigrants to the United States can have chronic Chagas disease. African Trypanosomiasis : • African trypanosomiasis, or sleeping sickness, is caused by several subspecies of T. brucei (T. brucei rhodesiense [east African sleeping sickness] and T. brucei gambiense [west African sleeping sickness]). In this case, the infected animal is bitten by the bloodsucking tsetse fly, which in turn transmits the protozoa via inoculation during a subsequent bite of a human. • The protozoa, initially present in the gut of the vector, appear in the salivary gland for inoculation during the subsequent biting of a human. It is estimated that some 50 million people are at risk of African sleeping sickness, with 300,000 to 500,000 cases occurring in sub-Saharan Africa each year. The infection progresses through two stages: • Stage I can present as fever and high temperatures lasting several days; hematologic and immunologic changes occur during this stage. • Stage II occurs after the organism enters the central nervous system (CNS) and can involve symptoms suggesting the disease name— daytime somnolence, loss of spontaneity, halting speech, listless gaze, and extrapyramidal signs (e.g., tremors and choreiform movements). A
  • 14. 14 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin breakdown of neurologic function leading to coma and death can occur. Death can occur within weeks if untreated (T. brucei rhodesiense) or only after several years (T. brucei gambiense). • It should be noted that the sole source of energy for the trypanosomal organism is glycolysis, which in turn can account for the hypoglycemia seen in the host. In addition, the migration of the organism into the CNS can be associated with the organism’s search for a rich source of available glucose. Treatment of Trypanosomiasis: Suramin Sodium: • Introduced into therapy for the treatment of early trypanosomiasis in the 1920s, suramin, a bis-hexasulfonatednaphthylurea, is still considered to be the drug of choice for treatment of non–CNS-associated African trypanosomiasis. • Suramin sodium is a water-soluble compound that is poorly absorbed via oral administration and must be administered IV in multiple injections. Because of its highly ionic nature, suramin will not cross the blood–brain barrier and, therefore, is ineffective for the treatment of trypanosomal infections that reach the CNS. Pentamidine, Isethionate (Pentam): • First introduced as a therapy for trypanosomiasis in 1937, pentamidine is now used in a variety of protozoal and fungal infections and finds use in the treatment of trypanosomiasis, leishmaniasis, and pneumocystis (PCP). • When used for trypanosomiasis, pentamidine is only effective against Trypanosoma brucei rhodesiense (east African sleeping sickness) and, even then, only during the early stage of the disease, because the drug does not readily cross the blood–brain barrier.
  • 15. 15 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Eflornithine (Ornidyl): • Metcalf reported the synthesis of eflornithine (difluoromethyl ornithine [DFMO]) in 1978. Their interest arose from the desire to 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. It was not until 1980 that Bacchi demonstrated the potential of DFMO in the treatment of trypanosomiasis. • DFMO is a suicide inhibitor of ODC, a pyridoxal phosphate–dependent enzyme. Evidence suggests that cysteine-360 in ODC is the site of efl ornithine alkylation (25). Alkylation of ODC blocks the synthesis of putrescine, the rate-determining step in the synthesis of polyamines. Mammalian ODC can also be inhibited, but because the turnover of ODC is so rapid in mammals, eflornithine does not produce serious side effects. Inhibition of ornithine decarboxylase (Enz-Cys-SH) by eflornithine.
  • 16. 16 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Nifurtimox (Lampit): • Another of the nitroaryl compounds, nifurtimox has proven to be useful as a drug for the treatment of trypanosomiasis. It is one of two drugs approved for use in treatment of Chagas disease. • As discussed for metronidazole, nifurtimox is thought to undergo reduction followed by oxidation and, in the process, generate ROS, such as the superoxide radical anion, hydrogen peroxide, and hydroxyl radical. These species are potent oxidants, producing oxidative stress that can produce damage to DNA and lipids that can affect cellular membranes. In addition, Henderson have reported that nifurtimox inhibits trypanothione reductase, which results in the inhibition of trypanothione formation (93% inhibition). Trypanothione is a critical protective enzyme found uniquely in trypanosomal parasites Formation of ROS from nitroaryl compounds. Benznidazole (Rochagan): • Benznidazole is the second of the drugs approved for treatment of Chagas disease. Like nifurtimox, it is effective against the circulating form of Trypanosoma cruzi during the acute phase of the disease, but also like nifurtimox, it is ineffective during the chronic stage of the disease. • It has been proposed that benznidazole undergoes a one- electron transfer to the nitro group, which in turn dismutates to give back the nitroimidazole and a nitrosoimidazole. The latter product can then undergo an electrophilic addition to trypanothione, which leads to depletion of trypanothione, an essential enzyme system in T. cruzi . Benznidazole is not available in the United States but is available in South American countries. It is administered orally in a tablet form.
  • 17. 17 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin Proposed mechanism of action of benznidazole. Melarsoprol: • Arsenic-containing drugs have been used for treatment of parasitic conditions for thousands of years. In the late 1800s and early 1900s, Paul Ehrlich introduced the use of trivalent arsenicals. Melarsoprol, an organ arsenical, came into use in the late 1940s, and it remains the first- choice drug in the treatment of trypanosomiasis. Until 1990, it also was the only treatment for late-stage sleeping sickness. • More recently, Fairlamb have proposed a mechanism of action that results in the inhibition of trypanothione reductase through the formation of a stable complex between melarsoprol and trypanothione. Melarsoprol reacts with the cysteine sulfhydryl of trypanothione to form the stable adduct. Supportive of this mechanism is the synergistic action of melarsoprol with eflornithine, two drugs that produce sequential blockage of the synthesis of trypanothione. Structure of melarsoprol trypanothione complex. ▪ Because the drug has the potential for serious nervous system toxicities (e.g., convulsions, acute cerebral edema, and coma), the drug is usually administered in a hospital setting with supervision. An additional problem with melarsoprol is the development of resistance by the parasite
  • 18. 18 Medicinal Chemistry IV/4th Class / 2nd Semester/ Lecture 4 Dr. Narmin Hama Amin