Antimalarial.pdf Introduction, Classification, SAR and MOA

Introduction, Classification, SAR and MOA

1. Antimalarials
Prepared by
Dr. Girish Kashid
Asst. Prof.
Sanjivani College of Pharmaceutical
Education & Research
Prepared by- Dr. Kashid Girish, SCPER

2. Malaria, one of the most widespread diseases, is caused by
a Plasmodium parasite.
Its name is derived from mala aria (bad air).
The name is based on the early knowledge that malaria was
associated with swamps and badly drained areas.
The Anopheles mosquito is the carrier of the causative
protozoa was obtained by Dr. Ronald Ross, who was recognized
in 1902 with the Nobel Prize in Medicine.
Prepared by- Dr. Kashid Girish, SCPER

3. Malaria is caused by four species of a one-cell protozoan
of the plasmodium genus:
1.P. falciparum:
This species is estimated to cause approximately 50% of all
malaria. It causes the most severe form and the most
debilitating form of the disease, because patients feel ill
between acute attacks. One reason why it leaves the patient so
weak is that it infects up to 65% of the patient's
erythrocytes.
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4. 2. P. Vivax:
This species is the second most common species,
accounting for about 40% of all malaria cases.
3. P. malariae:
While causing only 10% of all malarial cases, relapses
are very common.
4. P. ovale:
This species is the least common.
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5. Prepared by- Dr. Kashid Girish, SCPER
Life Cycle of the Malarial Parasite :
Broadly speaking, the parasite runs its asexual cycle in man, and the sexual cycle in the
mosquito. The human phase begins when an infected female Anopheles mosquito bites
man and injects sporozoites from her salivary glands.
The injected sporozoites rapidly leave the circulation, and localize in the liver
parenchyma cell develop into primary tissue schizonts, and mature within 8-21 days to
form merozoites.
This constitutes the pre-
erythrocytic stage during
which the subject remains
symptom-free.

6. Prepared by- Dr. Kashid Girish, SCPER
On maturity, the merozoites of all four species, are liberated from the
liver cells and invade the erythrocytes, and begin the erythrocytic cycle of
asexual development.
In all except falciparum malaria, a proportion of merozoites infects more
tissue cells, forming secondary tissue schizonts, and this constitutes the
exoerythrocytic cycle, which may continue for several years and accounts for the
relapse of infection (secondary exoerythrocytic forms do not occur with P.
falciparum, hence no relapse of infection).
At the end of the erythrocytic cycle the infected red cells rupture releasing
merozoites (they reinvade other red cells), pigments and other products into the
blood.

7. Prepared by- Dr. Kashid Girish, SCPER
This point of time marks the clinical attack of malaria manifested by chills,
fever and profound sweating. After several cycles some erythrocytic parasites
differentiate into male and female gametocytes.
No further development of these forms takes place in man. They may be
ingested by a female Anopheles mosquito from the blood stream of the infected
individual. In the gut of the mosquito, exflagellation of the male gametocyte is
followed by of the female gametocyte, forming the zygote, which develops in the
gut wall as an oocyst, eventually giving rise to the infective sporozoites, which on
rupture of the oocyst make their way to the mosquito's salivary glands.
Hence, the cycle is completed.

8. Prepared by- Dr. Kashid Girish, SCPER
In man there are two complete cycles (exoerthrocytic schizogony and
erythrocytic schizogony), and one partial cycle (gametogony),
while in the mosquito there is one partial cycle (completion of
gametogony), and one complete cycle (sporogony).
To control malaria the attack has to be two-fold:
(i)measures taken against the mosquito vector; and
(ii) treatment of the disease in man.

9. Prepared by- Dr. Kashid Girish, SCPER
Sexual Cycle in Mosquito Asexual Cycle in Man
The life cycle of malarial parasite

10. Prepared by- Dr. Kashid Girish, SCPER

11. Prepared by- Dr. Kashid Girish, SCPER
Drainage of swamps and marshes, and chemical sprays (DDT,
and organophosphates) are of importance. Many strains of Anopheles
have developed resistance to chemical sprays.
In man, it has not been possible to induce artificial immunity by the
use of vaccine. However, patients with malaria do develop a gradual
immunity which is of importance in their recovery.
swamps :दलदल

12. Prepared by- Dr. Kashid Girish, SCPER
From the clinical standpoint, patients of malaria may be divided into
non-immune and semi-immune subjects.
In the non-immune patient the object of therapy is complete
eradication of the parasites, whereas in the semi-immune, it is the control of
the attack.

13. There are four possible sites for drug therapy:
1. Kill the sporozoites injected by the mosquito and/or prevent
the sporozoites from entering the liver.
2. Kill the schizonts residing in hepatocytes and/or prevent
from becoming merozoites.
3. Kill the merozoites in the blood and/or prevent them from
developing into gametocytes.
4) Kill he gametocytes before they can enter the mosquito and
reproduce in to zygotes.
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14. 1.Cinchona alkaloid Quinine, Quinidine
24-Aminoquinoline Chloroquine, Amodiaquine, Mefloquine
38-Aminoquinoline Primaquine, Pamaquine
4Acridines Quinacrine
5Biguanides Proguanil (Chloroguanide), Cycloguanilpamoate
6Dianinopyrimidine Pyrimethamine
7Tetracycline Tetracycline, Doxycycline
8Sesquiterpene lactones
(ARTEMISININ DERIVATIVES)
Artesunate, Artemether
9Amino alcohols Halofantrine, Lumefantrine
10Naphthoquinone Atovaquone
CLASSIFICATION
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15. 1.Cinchona alkaloid
The cinchona tree produces four alkaloids.
cinchona bark.
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16. Quinine and Quinidine:
Quinine has been used for "fevers' in South America
since the 1600s.
The pure alkaloids quinine and cinchonine were
isolated in 1820.
The stereoisomer, quinidine, is a more potent
antimalarial, but it also is more toxic.
Quinine is lethal for all Plasmodium schizonts and
the gametocytes from P. vivax and P. malariae but not for
P. falciparum.
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17. Rubane
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18. Prepared by- Dr. Kashid Girish, SCPER

19. 24-Aminoquinoline
The 4-aminoquinolines are the closest of the antimalarial
that are based on the quinine structure.
Chloroquine:
The phosphate salt is use in oral dosage forms
(tablets), and the hydrochloride salt is administered
parenterally.
It is a rapidly acting erythrocytic schizonticide against all
species of plasmodia
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20. Prepared by- Dr. Kashid Girish, SCPER

21. Amodiaquine:
It is very similar to chloroquine and does not have any
advantages over the other 4-aminoquinoline drugs.
Studies over the past 20 years in Africa have found it to be
somewhat faster acting than chloroquine.
There is evidence now that amodiaquine maybe effective
even in areas with chloroquine-resistant P. falciparum.
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22. Mefloquine:
It is marketed as the R,S isomer. It Was developed
in the I960s.
It having two trifluoromethyl
moieties, at positions 2’ and 8’.
No electronegative substituents
at either position 6' (quinine) or 7'
(chloroquine).
It acts as schizonticide acting
before the parasite can enter the
erythrocyte.
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Piperidine

23. Prepared by- Dr. Kashid Girish, SCPER

24. Prepared by- Dr. Kashid Girish, SCPER

25. Prepared by- Dr. Kashid Girish, SCPER

26. 38-Aminoquinoline
The first compound introduced in this series was
pamaquine.
During World War II, pentaquine, isopentaquine.
and primaquine became available.
Primaquine is the only 8-antinoquinoline currently in
use for the treatment of malaria
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27. Primaquine is a poor erythrocytic schizontocide:
has weak action on P. vivax.
On the other hand, it is more active against the
preerythrocytic stage of P. falciparum than that of P.
vivax.
Its effect of primary as well as secondary tissue
phases of the malarial parasite. It is highly active against
gametocytes and hypnozoites.
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28. Prepared by- Dr. Kashid Girish, SCPER

29. Prepared by- Dr. Kashid Girish, SCPER

30. SAR:
1. All four agents have a 6-methoxy moiety like quinine.
2. Substituents on quinoline are located at position 8 rather than
carbon-4 as found in the cinchona alkaloids.
3. All have a four to five carbon alkyl linkage or bridge between
the two Nitrogen.
4. With the exception of pentaquine the other three 8-
Aminoquinoline have one asymmetric carbon
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31. Prepared by- Dr. Kashid Girish, SCPER
Quinacrine HCl. Qunacrine is no longer available in the United States. It can be
considered one of the most toxic of the antimalarial drugs even though, at one
time, it was commonly used. It acts at many sites within the cell including
intercalation of DNA strands, succinic dehydrogenase and mitochondrial
electron transport, and cholinesterase
4Acridines Quinacrine
Acridine

32. 5Biguanides
Proguanil:
It is developed in 1945 is an early example of a
prodrug. It is metabolized to cycloguanil.
cycloguanil is a dihydrofolate reductase inhibitor.
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33. Prepared by- Dr. Kashid Girish, SCPER
Cycloguanil is a dihydrofolate reductase inhibitor, and is a metabolite of the
antimalarial drug proguanil; its formation in vivo has been thought to be primarily
responsible for the antimalarial activity of proguanil.

34. Prepared by- Dr. Kashid Girish, SCPER
Mechanism of action

35. 6Dianinopyrimidine
Pyrimethamine
pyrimethamine inhibits the reduction of folic acid
to its active tetrahydrofolate coenzyme form.
The combination of sulfadoxine and pyrimethamine
uses a drug from the sulfonamide antibacterial group and a
pyrimidinediamine similar to trimothoprim.
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Pyrimidine

36. 7Tetracycline
Tetracyclines, doxycycline inhibits the pathogen's
protein synthesis by reversibly inhibiting the 30S ribosomal
subunit.
Bacterial and plasmodial ribosomal subunits differ
significantly from mammalian ribosomes, and this group of
antibiotics does not bind to mammalian ribosomes readily and
thus shows good selective toxicity.
Although doxycycline is a good antibacterial, its use for
malaria is limited to prophylaxis against strains of P.
falciparum resistant to chloroquine and sulfadoxine—
pyrimethamine.
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37. Prepared by- Dr. Kashid Girish, SCPER

38. 8Sesquiterpene lactones (ARTEMISININ DERIVATIVES)
Artemisinin:
Drugs in the artemisinin series are the newest of the
antimalarial drugs and are structurally unique, compared with the
compounds in current use.
The parent compound artemisinin is a natural product
extracted from the dry leaves of Artemisia annua (sweet
wormwood).
The plant must be grown each year from seed because
mature plants may lack the active drug.
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39. Artemisia annua
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40. The key structure characteristic appears to be a
"trioxane" consisting of the endoperoxide and doxepin
oxygens. This is shown by the somewhat simpler series of 3-
aryltrioxanes.
artemether
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41. Prepared by- Dr. Kashid Girish, SCPER

42. Prepared by- Dr. Kashid Girish, SCPER
Structural Activity Relationship

43. Prepared by- Dr. Kashid Girish, SCPER

44. 9Amino alcohols
Halofantrine:
It is a good example of drug design that incorporates bio
isosteric principles, a evidenced by the trifluoroethyl moiety.
Halofantrine is schizonticide and has no effect on the
sporozoite, gametocyte or hepatic stages.
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45. Prepared by- Dr. Kashid Girish, SCPER
Lumefantrine. Lumefantrine was developed in
China.
Its mechanism of action is poorly understood.
There is some evidence that it inhibits the
formation of -hematin by forming a complex
with hemin. Lumefantrine is very lipophilic
and is marketed in combination with the
lipophilic artemesinin derived artemether

46. 10Naphthoquinone
Atovaquone:
Atovaquone's chemistry is based on it being a
naphthoquinone that participates in oxidation—reduction
reactions as part of its quinone—hydroquinone system.
The drug selectively interferes with mitochondrial
electron transport, particularly at the parasite's cytochrome
site.
Atovaquone and proguanil HCI are administered in
combination in an atovaquone-to-proguanil HCI ratio of
2.5:1 measured in milligrams.
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47. Prepared by- Dr. Kashid Girish, SCPER