Antimalarial Drugs: Life cycle of malarial parasite, Symptoms of malaria, Classification of antimalarial drugs, Mechanism of action, side effects

1. Antimalarial Drugs
• Mr. Hitesh Vishwanath Shahare
• Assistant Professor
• Dept. Ph.’ Chem.
• SNJBs Shriman Sureshdada Jain Coll. Ph. Chandwad

2. Introduction
• Malaria: Parasitic disease caused by the protozoan of the genus
Plasmodium.
• 1880: Charles Louis Alphonse Laverana-
• French army doctor, described the malarial parasite and proposed
that it caused malaria.
• Insect vector: Female Anopheles mosquito

3. Plasmodium
Falciparum
Plasmodium
Malariae
Plasmodium
Vivax
Plasmodium
Ovale
Plasmodium Species

4. Symptoms

5. Types of Malaria
• Causes malignant tertian (MT) malaria : Fulminating form of the disease,
and if untreated, it is rapidly fatal
• Causes quartan (Q) malaria, an infection which is not uncommon, but
relapses are rare than in vivax malaria.
• The term quartan indicates that the spikes of fever comes every fourth day.
• Causes benign tertian (BT) malaria: Common infection Relapses are
common.
• The term tertian indicates that the attacks of chills and fever typically tend
to cure every third day
1. Plasmodium
falciparum
2. Plasmodium
Vivax
3. Plasmodium
malariae
4. Plasmodium
Ovale
• Causes a rare form of relapsing malaria (common in west Africa). Its
periodically similar to vivax malaria

6. Life cycle of Malaria Pre-erythrocytic stage
When the mosquito bites another human,
sporozoites are injected with bite.
Erthrocytic stage
Parasite (sporozoites) reach the
liver trough blood
The parasite reproduces asexually
in liver cells, bursting the cell and
releasing into the blood
Exo-erthrocytic stage
Parasites reproduce asexually in red blood
cells, bursting the red blood and causing
cycles of fever and other symptoms.
Released parasites infect new red blood
cells.
Mature infective stages
(sporozoites) escape from gut and
migrate to the mosquito salivary
gland.
Sporozoites
Salivary
Glands
Fertilization and development
take place in the mosquito’s gut.
Female mosquito takes up
gametocytes with blood meal.
Sexual stage develop in red
blood cell
Gametocyte
Erthrocytic stage

7. Chemical Classification
Cinchona Alkaloid
1. Quinine
2. Qunidine
3. Cinchonidine
4. Cinchonine
4-Aminoquinolines
1. Chloroquine
2. Hydroxychloroquine
3. Amodiaquine
8-Aminoqunolines
1. Primaquine
2. Pamaquine
Acridine dyes
Quinacrine
Diaminopyrimidines
1. Pyrimethamine
2. Trimethoprim
4-Quinoline-carbinolamine
Mefloquine
Biguanides
Proguanil
Miscellaneous
1. Artemisinin
2. Sulphonamides
3. Sulphones: Dapsone
4. Tetracyclines
5. Lincomycine

8. Cinchona Alkaloid
Quinine
• Quinine is chief alkaloid obtained from the bark of cinchona tree.
• Four Chiral Carbons
• Its d-isomer, quinidine, is used as an antiarrhythmic
• Quinine: Used for suppressive prophylaxis and clinical cure in all type
of malaria.
Mode of action
• Quinine forms a hydrogen-bonded complex with double stranded DNA
causing inhibition of protein synthesis, DAN replication, and
transcription to RNA.
Quinidine Cinchonidine Cinchonine
Quinine

9. SAR of Quinine
1. Modification of the secondary alcohol at C-9, through
oxidation, Esterification diminishes activity.
3. Activity usually enhanced by the introduction of a halogen.
2. Quinuclidine portion is not necessary for
activity, however, an alkyl tertiary amine attached at
is important. Quinine
6
1
9
Quinuclidine

10. 4-Aminoquinolines
Hydroxychloroquine
• Less toxic , properties & uses are similar
Use of Hydroxychloroquine in treatment of COVID19
Hydroxychloroquine acts on host target respiratory
cell by:
Increases the endosomal pH required for the virus-host
target cell fusion. Increase in the pH disrupts the normal
viral function. In SARS-coronavirus, which is sister of to
COVID-19, Hydroxychloroquine was found to interfere
with the glycosylation of cellular receptor eventually
resulted in on association between the host target cell and
the virus.
Chloroquine
• Synthesized by Germans in 1934 (Resochin)
• D & L isomers, D isomer is less toxic
• Potential blood schizonticidal drug for all type malaria
Amodiaquine
• Effective as Chloroquine
• Pharmacological actions similar
• Chloroquine resistant strains may be
effective
• Adverse effect: GIT, Headache,
Photosensitivity
• Not recommended for prophylaxis

11. 4-Aminoquinolines
Mode of action
Parasite digest the host cells hemoglobin to
obtain essential amino acids
This process releases large amount
of Heme
Toxic to
Parasite
To protect itself the parasite:
Polymerizes the heme to non-toxic
Hemozoin
Chloroquine prevents the
Polymerization process
Accumulation of Heme: Result in Lysis of
parasite & RBCs

12. SAR
1
2
4
3
5
6
7
8
1. Quinoline ring essential 2. At C-4: Diaminoalkyl side chain with
2-5 carbon atoms between two
nitrogen: Optimum activity
3. At C-4: 4-Diethylaminomethyl butylamino side
chain: Chloroquine, Quinacrine
Chloroquine
(RS)-N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-
1,4-diamine

13. 4
6. At C-4: Substitution of Hydroxyl group on
one of ethyl group on tertiary amine:
Hydroxyquinoline
Reduces Toxicity
5. At C-4: Incorporation of aromatic ring in
side chain: Amodiaquine
Reduces Toxicity
and also
Activity
Amodiaquine Hydroxychloroquine

14. 4
7
6. At C-4: Tertiary amine in side chain: Essential
7. At C-7: Presence of Chlorine (R7):
Enhances the activity
6. At C-3: Presence of Methyl:
Reduces the activity
3

15. 8-Aminoqunolines
Primaquine
Primaquine
• Most effective and least toxic of the 8-Aminoqunolines
• Highest therapeutic index
• In this group it is only agent in current use.
• Acts on the exo-erythrocytic stage of plasmodia
Mode of action:
• Primaquine is bio-transformed to a more active 5, 6-
quinolinequinone metabolite
• Further primaquine produce an acute self-limiting intravascular
haemolysis in subjects with mitochondrial function of plasmodia in
the subject with an inherit glucode-6-phosphate dehydrogenase
deficiency.
• Thereby primaquine suppresses the mitochondrial functions
plasmodia in the exo-erythrocytic stage
Pamaquine
(RS)-N-(6-methoxyquinolin-8-yl)
pentane-1,4-diamine

16. 1
2
4
3
5
6
7
8
2. At C-6: Presence of Methoxy (R6) group is
not essential.
But if replaced by ethoxy group Increases
toxicity.
3. Introduction of halogen increases toxicity
1. Quinoline ring essential
4. Pentyl side chain at 8 position gives maximum
activity:
Increase or decrease in chain length result in
decrease in activity
5. Branched side chain can be converted
into straight chain:
Pentaquine: Less activity
SAR

17. Acridine dyes
Quinacrine
Quinacrine ( Mepacrine, Atabrine)
• First effective synthetic antimalarial drug
• Quinacrine is obstolete as an antimalarial drug, but is used in
the management of giardiasis.
MOA:
It acts at many sites within the cell including intercalation of DNA
strands, succinic dehydrogenase and mitochondrial electron
transport, and cholinesterase.

18. Trimethoprim
Pyrimethamine
• Pyrimethamine was developed and
used solely as antimalarial;
Diaminopyrimidines
5-(3,4,5-Trimethoxybenzyl)pyrimidine
-2,4-diamine5-(4-chlorophenyl)-6-ethyl-
2,4-pyrimidinediamine
• By this causing deficiency of tetrahydrofolate, which
result in the inhibition of cell division and
schizogony.
• Trimethoprim was developed as
antibacterial
• Both these agents selectively inhibit dihydrofolate
reductase and thereby inhibit the conversion
dihydrofolic acid to tetrahydrofolic acid.

19. 1. Presence of amino group at 2 and 4
position is essential
4. Aromatic ring should be directly attached
to Pyrimidine ring:
If any atom or group is inserted in between
result in decrease in activity
5. Aromatic ring separated to Pyrimidine
ring by methylene group:
Antiplasmodial
activity
Antibacterial
activity
2. Aromatic ring must contain an EWG at p-
position
3. Presence of Electron Donating group at
6 position is essential
1
2
4

20. 4-Quinoline-carbinolamine
Mefloquine (Lariam)
• Synthetic 4-quinolone methanol derivative chemically-related to
quinine.
• It can only be given orally as intense local irritation occur on
parenteral use.
• Used in the prophylaxis and treatment of chloroquime-resistant
and multidrug-resistant falciparum malaria.
Mefloquine

21. Miscellaneous
Artemisinin
Artemisinin
• Extracted from the plant Artemisia annua in 1972
• Effective against asexual blood forms of the parasite
• It lacks activity against tissue stages.
Mode of action:
• Compounds have presence of endoperoxide bridge that interacts
with heme in parasite
• Heme iron cleaves this endoperoxide bridge and leads to generation
of highly reactive free radicals which damage parasite membrane by
covalently binding to membrane proteins

22. Ring Stage
Early
trophoxoite
Late
trophoxoite
sachizote
gamatocytes
Sporozoites
Red
Blood
cell
merozoites
Ookinete
zygotes
gamete
In mosquito gut
Artemisinin
Artemisinin
Conventional
Treatment
MOA Artemisinin

23. Artemisinin Derivatives
Artemether
• Potent and rapidly acting blood schizoniticidle,
and is highly efficacious in treating Chloroquine-
resistant falciparum malaria
• Dosage a 5 day dose scheme is followed- 80mg IM
BID on day 1,
• Followed by 80mg OD
Artesunate (Falsigo, Arnate)
• Potent blood schizonticide, and available for oral
use in case of Chloroquine-resistant falciparum
malaria
• Dose 100mg BID orally on day 1
• Followed by 50mg BID for 4 days

24. SAR

25. Sulphonamides And Sulphones
• Sulphonamide are active against the asexual blood forms of human malarial parasites.
• Sulfadoxine and Sulfalene have been used for suppression of infection caused by sensitive
strains of P. Falciparum.
• Use of combinations of pyrimethamine with dapsone; and Pyrimethamine with Sulfadoxin
Sulfadoxine Sulfalene

26. Antibiotic commonly used in combination with rifampicin
and clofazimine for the treatment of leprosy
4-[(4-aminobenzene)sulfonyl]aniline
Dapsone
SE:
decrease in blood cells, red blood cell breakdown especially
in those with glucose-6-phosphate dehydrogenase
deficiency (G-6-PD), or hypersensitivity, liver inflammations
MOA:
Inhibits bacterial synthesis of dihydrofolic acid, via
competition with para-aminobenzoate for the active site of
dihydropteroate synthase, thereby inhibiting nucleic acid
synthesis

27. Biguanides
1-[amino-(4-chloroanilino)methylidene]-2-
propan-2-ylguanidine
Proguanil
Prodrug
used together with Chloroquine or Atovaquone
Side effects include diarrhea, constipation, skin
rashes, hair loss, and itchiness
MOA:
Active metabolite, cycloguanil, is an inhibitor of
dihydrofolate reductase (DHFR). Although both mammals
and parasites produce DHFR, cycloguanil's inhibitory
activity is specific for parasitic DHFR. This enzyme is a
critical component of the folic acid cycle. Inhibition of DHFR
prevents the parasite from recycling dihydrofolate back to
tetrahydrofolate (THF). THF is required for DNA synthesis,
amino acid synthesis, and methylation; thus, DHFR
inhibition shuts down these processes
Cycloguanil: Active Metabolite

28. Others
Tetracycline
• Tetracycline in a dose of 250mg 6-hourly for 7 days can
clear asexual forms of Chloroquine-resistant
falciparum infections, but it has no effect against
gametocytes.
Tetracycline
Lincomycine
• Clindamycine and Lincomycine have proved to be
effective against resistant P. falciparum infections.
Lincomycine

29. 25 September 2020 SNJB's SSDJ College of Pharmacy, Chandwad (Nasik) 29
shahare.hvcop@snjb.org
Thank You!
SNJBs Shriman Sureshdada Jain Coll. Ph. Chandwad