2. CONTENTS
o INTRODUCTION AND DEFINATION
o CAUSATIVE AGENT’S
o LIFE CYCLE OF MALARIA
o SIGN AND SYMPTOMS
o CHEMICAL CLASSIFICATION
o MODE OF ACTION AND STRUCTURAL ACTIVITY
o RECENT ADVANCES
o COMBINATION THERAPY
o MALARIA VACCINE
o REFERENCES
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3. MALARIA
Defination-
Malaria is a mosquito borne infectious
disease of humans caused by eukaryotic protist of
the genus plasmodium.
In 2008 there was an estimated 243 million cases of
malaria worldwide and it accounted for an estimated
8.63 lakh death.
In 2008 total cases of malaria in India were 1.52
million of these 49.56%(0.76 million) were
p.falciparum cases.
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7. LIFE CYCLE OF MALARIA
PARASITE
Malaria is transmitted by the bite of infected female
anopheles mosquitoes.
During feeding, mosquitoes inject sporozoites, which
circulate to the liver, and rapidly infect hepatocytes, causing
asymptomatic liver infection (hepatic phase)(absent in
falciparum; malariae)
Merozoites released from the liver, rapidly infect
erythrocytes to begin the asexual erythrocytic stage of
infection that is responsible for human disease
Multiple rounds of erythrocytic development, with
production of merozoites that invade additional erythrocytes,
lead to large numbers of circulating parasites and clinical
illness
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8. Release of merozoites subsequent to rupture of
erythrocytes causes the clinical attack of malaria.
Some erythrocytic parasites also develop into sexual
gametocytes, which are infectious to mosquitoes,
allowing completion of the life cycle and infection of
others
In P vivax and P ovale parasites also form dormant liver
hypnozoites, which are not killed by most drugs, allowing
subsequent relapses of illness after initial elimination of
erythrocytic infections
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9. SIGN AND SYMPTOMS
Initial manifestation of malaria are non-specific and
resembles to flu like symptoms.
The presentation includes headache, fever, shivering,
arthralgia, myalgia.
The paroxysm which includes fever spikes, chills and
rigors are classical for malaria
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17. QUININE
It’s an alkaloid derived from cinchona bark
Use in treatment of malaria since 1820.
Quinine contain two fused-ring system i.e aromatic
quinoline and bicyclic quinuclidine.
Bark of trees is source of quinine alkaloid.
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18. MODE OF ACTION
Inhibition of hemozoin biocrystallization which facilitate
the aggrigation of cytotoxic heme
Free cytotoxic heme accumulate in parasite leading to their
death.
It inhibit the parasite haem polymerase
Binding of quinine to DNA
Inhibition of protein synthesis and and DNA replication
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21. Tertiary ‘N’ is necessary for activity.
Quinine and Quinidine are methoxy derivative of cinchonine
and cichonidine reception.
Cinchonine and Cinchonidine are demethoxy derivative of
Quinine and Quinidine.
Methoxy group is not necessary for antimalarial activity.
Quinine has four assymetric center C8, C9, C3, and C4.
Hydroxy group is necessary for activity.
Hydroxy group replaced by NH2, NO2 antimalarial activity
decreses.
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22. Uses
Use in treating chloroquin resistant P.falciparum
infection.
It has antipyretic, analgesic, local anesthetic properties.
Toxicity / Side effect
Cinchonism-depressant effect on heart.
Hypotension and cardiac arythmias.
Hypersensitivity reaction.
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23. CHLOROQUINE
It rises the blood PH and interfere with degradation of
haemoglobin by parasitic lysosome.
Polymerization of toxic haeme to nontoxic parasite pigment
hemozoin is inhibited by formation of chloroquine-heme
complex.
Haeme itself or its complex with chloroquine then damages
the plasmodial membranes. Clumping of pigment and
changes in parasite membranes follow death
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25. 4-amino quinoline ring is essential for antimalarial
activity.
Substitution at 3rd position decreases activity.
Halogen at 7th position increase activity.
(most active compound).
Substitution at 8th position loss of activity.
Addition of hydroxyl group at N-ethyl function (side
chain) will decrease toxicity and increase the blood
concentration.
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26. Toxicity and side effect
Depressant effect on bone marrow.
Blurred vision.
Dermatitis.
Headache, Nausea, Vomiting.
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27. Uses
It is use as antihistamine and anti-inflamantory.
In treatment of hepatic amobiasis.
In all type of malaria except chloroquine resistant falciparum.
Symptomic relief in rhumatoid arthritis.
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29. PRIMAQUINE
Mechanism of action
Primaquine is lethal to P.Vivax and P.Ovale in liver stage.
P.Vivax in the blood stage through its ability to do oxidative
damage to cell.
Toxicity and side effect
Nausea ,vomiting and stomach cramps.
It is use in pneumocytic pneumonia and malaria
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31. QUINARINE
Mechanism of action
It’s against protozoa but is uncertain, but it is thought to act
against the protozoan cell membrane.
It is also act as histamine N-Methyltransferase inhibitor.
Uses
Use in black water fever.
Antiprotozoal, antirhumatic,
Antiprotozoal use include targeting Giardisis.
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32. MEFLOQUINE
Mechanism of action
It block the action of chemical that the parasite produce to
protect one inside the R.B.C.
It also inhibit heme polymerase.
Toxicity and side effect
It cause neurologic, psychiatric disorder and abnormalities with
heart rhythm are visible on E.C.G.
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34. PYRIMETHAMINE
Mechanism of action
It interfere with tetrahudrofolic acid synthesis from folic
acidby inhibiting the enzyme dihydrofolate reductase
(DHFR).
Tetrahydrofolic acid is needed for DNA and RNA synthesis
in many species including protozoa.
Toxicity and side effect
Cardiac arythmia, Magaloblastic anemia, Necrolysis.
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36. TRIMETHOPRIM
Mechanism of action
Trimethoprim acts by interfering with action of bacterial
dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic
acid.
Dihydroptorate phosphate + p-aminobenzoic acid
Dihydropteroic acid
Dihydrofolic acid
Terahydrofolic acid
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Sulfonamide
Trimethoprim
37. RECENT ADVANCES
Use of existing drug in combination.
Development of analogues of existing drugs.
Natural analogues
Compound active against other diseases
Drug resistance reversers
Vaccine for malaria.
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38. NEED OF NEW ANTIMALARIAL
Less treatment
option in
malaria
Multiple dose
of current
therapy non-
compliance
Sulfa reaction
observed with
sulfadoxine
Fat depedent
bioavaliability of
Lumefantrine
Demand
supply and
imbalance of
Artemisin
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New
molecules
are
wanted
45. REFERANCE’S
“Foye’s Principal of Medicinal
Chemistry”,Lemke.T.L. Williams,D.A;Roche,V.F and
Zito.S.W VI(edition), Lippinkott Williams and Wilkins,
printed in philadelphia PA 19106,U.S.A,2008.
John M. Beale Jr.,John H.Block,”Wilson and Gisvold’s
Textbook of Organic Medicinal Chemistry”,12th
edition,publish by Walters Kluwer Lippincott Williams and
Wilkins.
“Antimalarial Drug Combination Therapy”, of Report of
W.H.O Technical Consultation
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46. “A Medicinal Chemistry Perspective on 4- Aminoquinolone
Antimalarial Drugs”, Paul M. O’ Neill*,a,c, Stephen A.
Wardb, Neil G. Berryc, J. Prince Jeyadevanc, Giancarlo A.
Biaginib.
Http;//wiki-antimalarial agents.com
W.W.W. Google search-antimalarials.com
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