Mechanism of action

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Transcript Mechanism of action

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-Any living thing that lives in (endoparasite) or on
(ectoparasite) another living organism is called a
parasite.
-It obtains food and/ or shelter from the host and
contributes nothing to its welfare.
-Some parasites cause irritation and interference
with bodily functions, others destroy host tissues and
release toxins into the body, thus injuring health and
causing disease.
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Protozoal infections
Amoebiasis
Giardiasis
Leishmaniasis
Malaria
Trypanosomiasis
Toxoplasmosis
Amebiasis
Protozoa
Schistosomiasis
Malaria
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Helminth infections
Nematode
Cestode
Trematode
Nematode
Nematode
Cestode
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Ectoparasitic infections
Scabies
Pediculosis
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 Disesase of large intestine caused by Entamoeba histolytica
 Organism- 2 forms 1. Motile trophozoite form
2. Dormant cyst form
 Trophozoite form: found in intestine or Wall of colon, expelled with stools
 Cyst form: encased by a chitinous wall, protects the organism from
environment
 Symptoms: intermittent diarrhea (foul smelling loose/ watery stools),
tenderness and enlargement of liver (with extra intestinal form) to acute
amebic dysentery.
 Many patients- no symptoms- organism remains in body as commensal
organism
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 Caused by Giardia lambia, found in duodenum and jejunum.
 Organism- 2 forms 1. Motile trophozoite form
2. Infectious cyst form
 Cyst form- can be deposited in water- contaminated water
infects man.
 Trophozoite- if expelled from G.I, will not survive.
 Symptoms: may be asymptomatic or develop watery
diarrhea, abdominal cramps, distention and flatulence,
anorexia, nausea and vomiting.
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 Caused by Trichomonas vaginalis
 Exists only in trophozoite form.
 Infects vagina, urethra, prostate- so the disease is
considered a veneral infection.
 Infections in male- asymptomatic
 Symptoms in female- vaginitis, profuse discharge
which is foul smelling, burning and soreness upon
urination, vulvar itching
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 Caused by genus Leishmania
 Transmitted from rodents, canines and other mammals, to man
by bites from female sand flies of the genus Phlehotomus, and
then appearing in one of four major clinical syndromes:
1. Visceral leishmaniasis
2. Cutaneous leishmaniasis
Visceral
3. Muco cutaneous leishmaniasis
4. Diffuse cutaneous leishmaniasis
Cutaneous
Muco cutaneous
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 Visceral leishmaniasis
- By Leishmania donovani- disease is systemic
- Symptoms: nocturnal fever, diarrhea, cough, enlarged spleen and
liver.
- Death, if not treated, is due to diarrhea, super infections or gastro
intestinal hemorrhage.
 Cutaneous and mucocutaneous leishmaniasis:
-Single or multiple localised lesions
-These slow healing and possibly painful ulcers can lead to
secondary bacterial infections.
-Old world cutaneous leishmaniasis by L.topica, L.major,
L,aethiopica
-New world cutaneous leishmaniasis by L.peruviana, L.braziliensis,
L.mexicana, etc.
-Incubation period- few weeks to several months
-Symptoms: slow healing lesions on skin, in various regions of the
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body, depending on specific strain of organism.
 Caused by Pneumocystis carinii
 It is an opportunistic pathogen.
 Also in patients receiving immuno suppressive agents.
 Also in malnourished infants, whose immunogenic systems
are impaired.
 Symptoms- severe pneumonia, organism lines the walls of
the alveoli, and gradually fills the alveolar spaces.
 If untreated, fatal
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Two distinct forms1. Chagas’ disease
2. African sleeping sickness
Chagas’ disease:
-Also called American trypanosomiasis
-Caused by Trypanosoma cruzi
-It lives in mammals and is spread by blood sucking insect- reduviid bug
or kissing bug or assassin bug.
-Insect-draws blood from infected mammal- releases protozoa through
faeces- pathogen enters the new host through breaks of the skin.
-Symptoms: inflammatory lesions at the site of entry, malaise, fever,
anorexia and skin edema at the site where the protozoa entered the host.
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African sleeping sickness:
-Also called African trypanosomiasis
-Caused by several sub species of Trypanosoma brucei.
-Infected animal- bitten by blood sucking tsetse fly – it transmits the
protozoa via inoculation during biting of man.
-Infection- 2 stages
-Stage I- fever and high temperatures lasting several days. Hematologic
and immunologic changes occur.
-Stage II- occurs after the organism enters the CNS.
-Symptoms: day time somnolence, loss of spontaneity, halting speech,
listless gaze and extra pyramidal signs like tremors and choreiform
movements, hypoglycemia
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Transmitted by infected female Anopheles
mosquito.
Genus Plasmodium causes malaria:
P.falciparum, P.vivax, P.malariae, P.ovale
Clinical symptoms: chills, fever, sweating, head
aches, fatigue, anorexia, nausea, vomiting,
diarrhea
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• Four main mechanisms
for parasitic transfer:
– Ingestion of eggs from the
fecal material of an infected
individual
• Ascaris lumbricoides
– The larva of the parasite can
burrow into the skin of a
person
• Schistosomes
– The larva of the parasite can
move from person to person
through an insect vector
• Trypanosomes
• Plasmodia
– Sexual transmission
• Trichomonas vaginalis
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Amebiasis and giardiasis:
Prevention
Avoid taking contaminated food and water
Drinking boiled or bottled or disinfected water
Personal hygiene and sanitation
Malaria, leishmaniasis and Trypanosomiasis
Use of insectisides, preventive clothing, using
insect repellants
Early detection and drug therapy
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Pyrimidine related agents:
Pyrimethamine
Trimethoprim
Sulphadoxine
Sulphadiazine
Sulphalene
Pyrantel pamoate
Oxantel
Quinapyramine
Pyrimidine analogues
Arylene bis(methyl ketone) compound
Febrifugine
Isofebrifugine
Purine related agents:
Adenosine analogues
Nucleotide analogues
Allopurinol
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H2N
N
Cl
NH2
N
Uses:
C2H5
Used in suppressive treatment and radical cure agent of
malaria.
Acts on both erythrocytic and exoerythrocytic forms of
P.falciparum and exoerythrocytic forms of P.vivax. It is a
powerful erythrocytic schizonticide.
Combination of pyrimethamine and sulphadoxine- to treat
presumed exposure to P.falciparum and chloroquineresistant malaria.
Combination of pyrimethamine and sulphadiazine- for
chloroquine resistant P.falciparum., toxoplasmosis
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Folic acid
Reduction
Dihydro folic acid (FAH2)
Dihydrofolate reductase
Tetrahydro folic acid(FAH4)
Precursors
Purine/ pyrimidine aminoacids
Mechanism of action:
Pyrimethamine inhibits the dihydrofolate reductase of
malarial parasites.
Metabolism
Primarily by oxidation to pyrimethamine 3-N oxide
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H2N
N
Cl
NH2
N
Pyrimethamine
C2H5
Structure- activity relationship:
Presence of ethyl group at C-6 is essential for activity.
Presence of halogen atom, preferably at 4th position is
essential for interaction with Dihydro folate reductase
enzyme.
The two six membered rings should not be separaed even
by a single carbon atom.
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Synthesis
O
CN
OH
CN
CH2Cl
CH2CN
HC
C
C2H5
C
C
C2H5
KCN
CH3CH2COOC2H5
Cl
Cl
p-chloro benzaldehyde
Cl
Cl
-propionyl-p-chlorophenyl acetonitrile
p-chlorophenyl
acetonitrile
CH2N2
H2N
NH
N
Cl
CN
NH2CNH2
Cl
NH2
C
Cyclization
C
N
C2H5
Pyrimethamine
C2H5
OCH3
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NH2
H2
C
OCH3
N
H2N
N
Uses:
OCH3
OCH3
Antibacterial, effective against chloroquine and
pyrimethamine resistant strains of P.falciparum.
Used in combination with sulfalene.
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Synthesis
CHO
HC
C
CH2OCH3
CN
H3CO
+
CH3OCH2CH2CN
OCH3
-methoxy
propionitrile
Na/ CH3OH
H3CO
OCH3
OCH3
OCH3
3,4,5- Trimethoxy benzaldehyde
Na/ CH3OH
H3CO
NH2
H2
C
OCH3
N
H2N
NH
H3CO
H
CH C CH2
CN
NH2CNH2
N
OCH3
CH3OH
H3CO
trimethoprim
OCH3
OCH3
OCH3
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N
H2N
SO2NH
N
H3CO
OCH3
N
H2N
SO2NH
N
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N
H2N
SO2NH
N
H3CO
Effective against P.falciparum.
Given in combination with quinine or pyrimethamine against chloroquine
resistant strains of P.falciparum.
Mechanism of action:
Active only against the asexual blood forms of malarial parasite, and to
act slowly.
Interfere with maturation of preerythrocytic and exoerythrocytic stages.
Also interfere with development of sporozoites in the mosquito.
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General synthesis
ClSO3H
H3COCHN
-H2O
ACETANILIDE
-HCl
NaOH
SO2NHR
H2N
SO2Cl
H3COCHN
H3COCHN
NH2R
SO2NHR
SULPHONAMIDE
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R
CH3
N
Uses:
Broad spectrum antihelminthic
S
C
H
C
H
C
N
pyrantel pamoate
Treat infections with Ascaris lumbricoides, Enterobius vermiculosis,
Ancyclostoma duodenale (hook worms), Trichostringlylus species and
Necatos americanus
Mechanism of action
Pyrantel depolarizes and paralyses worm muscle by persistent
nicotinic activation.
Intestinal nematodes can then no longer maintain the tone necessary
to attack to host tissues and are expelled by host peristalysis.
Note: pyrantel causes depolarisation where as piperazine causes
hyperpolarisation with mutually antagonistic properties. So,
simultaneous use- avoided.
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Synthesis
R
R
+
CHO
S
CNH2COOH
cyano
acetic acid
knoevenagel
reaction
C
H
S
CHCN
Thiophene-2-carboxaldehyde
R
C
H
S
R
CH3
N
C
H
NH2CH2CHCHNHCH3
N-methyl propylene
1,3- diamine
C
CH3OH
HCl
NH
S
C
H
C
H
COCH3
N
Pamoic acid
R
CH3
N
S
C
H
C
H
HOOC
OH
HO
COOH
H2
C
C
N
pyrantel pamoate
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Structure- activity relationship
The Ar can be varied with the order of reactivity 2-thienyl > 3-thienyl >
phenyl > 2-furyl.
Tetrahydro pyrimidine (n=3) derivatives displayed maximum acivity.
When X is a trans derivative, the activity is more.
In substituents in Ar group, ortho substitution produces active
compounds.
N- methyl substitution produces active derivatives.
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Synthesis
H3C
HCOOC2H5
N
CH3
+
N
HO
CHO
H3C
N
HO
N
3-hydroxy benzaldehyde
Oxantel
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Used to treat Trypanosoma evansi infections in live stock
(camels and horses).
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1063
Mechanism of action:
Inhibitors of Dihydrofolate Reductase/Pteridine Reductase in L.
major.
Compound (72) more active compound, has activity in the low
micromolar range.
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988
Mechanism of action:
It has good activity in vitro against chloroquine and pyrimethamine
resistant P. falciparum in vitro and against P. berghei in vivo.
The drug displayed activity against the plasmodial dihydrofolate
reductase at achievable concentrations.
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997
Mechanism of action:
They were isolated from D. febrifuga
The drug seems to potentiate the production of nitric oxide in acute
immune responses
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Mechanism of action:
Inhibits glyceraldehyde-3-phosphate dehydrogenase in glycolysis cycle.
compound (21) had good activity against cultured L. mexicana, T. brucei,
and T.cruzi
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Mechanism of action:
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MDL 73811, 5'-[(Z-4- amino-2
butenyl)methylamino]-5‘ deoxyadenosine
Mechanism of action:
Inhibitors of S Adenosylmethionine Decarboxylase.
 Intracellular concentrations of putrescine and AdoMet were increased and
the level of spermidine was decreased in trypanosomes treated with (27)
It is a time-dependent irreversible inhibitor to the AdoMetDC in T. b.
brucei,. It also proved to be active against trypanosome infections in animal
models
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Mechanism of action:
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1063
Hydroxyethylthioadenosine; HETA
Mechanism of action:
These two agents strongly inhibit protein methylation enzymes (mostly
carboxyl methylation) that use AdoMet as a cosubstrate.
Trypanocidal activity against T. b. brucei and strains of trypanosomes
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1074
Mechanism of action:
Allopurinol is a substrate for hypoxanthine phospho ribosyl transferase
(HPRT) from L. donovani, forming allopurinol-ribose-5'-phosphate (allo-5'RP).
Allo-5'-RP is a substrate for the rest of the parasite enzymes involved in
converting IMP to ATP and incorporation of ATP into RNA.
 Allo-5'-RP is an inhibitor of GMP reductase and IMP dehydrogenase, and
the allo- 5'-RP compounds cause an increase in the breakdown of RNA in
L. donovani .
 The antileishmanial activity of allopurinol is probably a sum of all of these
toxic effects on purine interconversion.
The clinical efficacy of allopurinol by itself is weak; however, the activity of
allopurinol improves when it is combined with fluconazole.
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Mechanism of action:
Hypoxanthine
phospho ribosyl
transferase
Allopurinol
Allopurinol-ribose-5'phosphate
(Allo-5'-RP).
IMP
ATP
RNA
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Text book of organic medicinal &
pharmaceutical chemistry- wilson & gisvold
Burger’s medicinal chemistry and drug
discovery volume v
Foye’s priniples of medicinal chemistry fifth
edition
Text book of medicinal chemistry- S.PANDEY
volume II
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