Biguanides – biological transformation, SAR, metabolism, effects and side effects Pyrimidines – site of action, SAR Sulphones and sulphonamides – Action and toxicity Mechanism of action of Antimalarials

1. Medicinal Chemistry-III
Antimalarial agents 4
Department of Pharmacy, Indira Gandhi National Tribal
University, Lalpur, Amarkantak (M.P.)
Dr. Akhilesh Tiwari
Assistant Professor
Department of Pharmacy,
IGNTU, Amarkantak

2. CONTENTS
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• Biguanides – biological transformation, SAR, metabolism, effects
and side effects
• Pyrimidines – site of action, SAR
• Sulphones and sulphonamides – Action and toxicity
• Mechanism of action of Antimalarials

3. At the end of this lecture, student will be able to
• Compare the structure with that of activity of antimalarials
• Discuss the biotransformation of specified antimalarials
• Describe the action and toxic effects of antimalarials
• Explain the synthesis of certain antimalarials
LEARNING OBJECTIVES
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4. BIGUANIDES
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 Biguanides are prodrugs for their
dihydrotriazines (cyclized product)
active metabolites-the
 Biological transformation is illustrated with Proguanil (chlorguanide).
 The antimalarial agent formed in this instance is the drug cycloguanil,
which itself is available as the pamoate salt, having a duration of action
of several weeks to months.

5. BIOTRANSFORMATION OF PROGUANIL
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6. BIGUANIDES
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 SAR: -
 Substitution of a halogen on the para-position of the phenyl ring
significantly increases activity e.g. Chlorine substitution in
chloroguanil –
 The 4-bromine analog also is very active.
 A second chlorine at the 3-position of the phenyl ring of proguanil
further enhanced the activity.
 However, the dichloro compound, chlorproguanil, is more toxic
than chlorguanil .

7. BIGUANIDES
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 Absorbtion, distribution and elimination: -
 They are absorbed very quickly from the GIT.
 They are concentrated in the liver, lungs, spleen & kidney but does
not cross the blood brain barrier.
 75% of the drug present in plasma is bound to protein
 They are metabolized and eliminated rapidly, mainly in the urine
 As a result, frequent administration of these drugs is necessary.

8. BIGUANIDES
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 Toxicity: -
• Low toxicity, but with increased doses, haematuria (blood in urine)
and albuminuria(albumin in urine) are observed
 Effects: -
• These derivatives including cycloguanil are potent schizonticides
against both exoerythroctic & erythrocytic forms of P. falciparum
and P.vivax.
• Resistance to these agents develops frequently.

9. PYRIMIDINES
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Pyrimethamine Trimethoprim
• The mechanism of action of pyrimidines is different and their
structures are not related to quinine and aminoquinolines.
• The sites of action for these derivatives include both the
erythrocytic forms of P
. vivax.

10. PYRIMIDINES
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 MOA
 Structurally, these derivatives resemble the pteridine portion of
dihydrofolic acid (FH2)
 And interfere with its reduction to tetrahydrofolic acid (FH4) by
dihydrofolate reductase, thereby interfering with the utilization of
folic acid (in malarial protozoa)
 Pyrimethamine & trimethoprim are used in suppressive treatment
and as radical cure agents.

11. PYRIMIDINES
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 SAR: -
 Maximum activity is obtained when an electron-donating group
was present in the 6-position e.g alkyl.
 When a chlorine atom is present in the para-position of the phenyl
ring a maximum activity is obtained.
 If the two rings are separated by either an oxygen atom or a carbon
atom, antimalarial action is decreased. Eg. Trimethoprim

12. PYRIMIDINES
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 ADME : -
 Pyrimethamine is slowly but completely absorbed from the G.I.T.
 It is localized in the liver, the lungs, the kidney & the spleen.
 It is completely metabolized
 It is slowly excreted through the urine.
 Trimethoprim has a shorter half-life (24hrs) than pyrimethamine.
 Toxicity: -
 Pyrimethamine is relatively nontoxic, but overdoses may lead to
depression of cell growth by inhibition of folic acid activity.

13. SULFONES
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 Dapsone:- 4,4’- diaminodiphenyl sulfone has a prophylactic activity
against resistant P
. falciparum.
• It is was developed for the treatment of leprosy.
• Dapsone act by competing with PABA, in the synthesis of folic acid.
• Dapsone has a prolonged duration of action and a moderate
toxicity. Combination with pyrimethamine have been effective in
suppressing symptoms of malaria due to chloroquine-resistant P.
falciparum.

14. SULFONAMIDES
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• Sulfonamides are used in antimalarial
resistant malarial strains.
• They are effective against erythrocytic
protozoa.
• Medium or long-acting sulfonamides
therapy against drug-
stages of the malarial
are used clinically as
antimalarials particularly sulfadiazine, sulfadoxine and sulfalene.
• Each of the above sulfonamides are much more effective when
given in combination with pyrimethamine.

15. SULFONAMIDES
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 Sulfadoxine: -
 Sulfalene: -
 Sulfadiazine: -

16. ARTESUNATE
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• Artesunate is a medication used to treat malaria.
• The intravenous form is preferred to quinidine for severe malaria.
• Often it is used as part of combination therapy, such as artesunate
plus mefloquine or amodiaquine.
• It is not used for the prevention of malaria

17. ARTEMETHER
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• Artemether is used to treat acute uncomplicated malaria.
• It is administered in combination with lumefantrine for improved
efficacy. This combination therapy exerts its effects against the
erythrocytic stages of Plasmodium spp. and may be used to treat
infections caused by P. falciparum and unidentified Plasmodium
species.

18. ATOVAQUONE
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• Atovaquone is a naphthoquinone used for the prevention and
treatment of Pneumocystis pneumonia (PCP) and,
• in combination with proguanil, used for prevention and treatment
of P
. falciparum malaria

19. CLASSIFICATION BASED ON MOA
• Antimalarials can be divided into two classes based on
their MOA
• 1) The first class of compounds are characterized by
rapid onset of schizoticidal action
• Includes the cinchona alkaloids, aminoquinolines and
acridines and involves a relatively non-specific
mechanism.
• The derivatives in this first group inhibit nucleic acid
and protein synthesis in the protozoal cell.
• Due to the interaction between the drug and DNA.
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20. ANTIMALARIALS- BASED ON MOA CONTD….
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 The flat aromatic quinoline or acridine ring can position or
intercalate between the base pairs in the DNA-α-helix and the
secondary alcohol group in quinine or the amino groups in the
other derivatives provide secondary binding through hydrogen
bond formation.
• Because these events can take place in mammalian host cells as
well as in parasite cells,
• The antimalarial action depends upon selective accumulation of the
drugs in the parasite cell.

21. ANTIMALARIALS- BASED ON MOA CONTD….
• E.g chloroquine, erythrocytic schizonts can concentrate
the drug to a level many times that of the plasma
concentration.
• Host cells require a 100-fold greater concentration to be
affected than is necessary to kill parasite cells.
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22. ANTIMALARIALS- BASED ON MOA CONTD….
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 2) The second class includes the pyrimidines, biguanides and
sulfones and involves interference with the synthesis of
tetrahydrofolic acid (FH4).
 This mechanism is characterized by a slowly developing
schizonticidal action dependent upon the stage of multiplication of
the parasite.
 The pyrimidine and biguanide derivatives are competitive inhibitors
of dihydrofolic acid (FH2), binding to dihydrofolate reductase and
thereby interfering with conversion of FH2 to FH4. FH4 is necessary
for the synthesis of purines and thymidine.

23. ANTIMALARIALS- BASED ON MOA CONTD….
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 The effect occurs in host as well as in parasite cells, but is selective
to the parasite because of a greater effective concentration.
 The sulfones as well as sulfonamides interfere with the synthesis of
dihydrofolic acid by competing with p-amino benzoic acid (PABA)
incorporation.
 The metabolites of the sulfones resemble PABA structurally and
when incorporated, produce an inactive coenzyme.
 This mechanism does not operate in mammalian host cells.

24. SUMMARY
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• Biguanides – biological transformation, SAR, metabolism, effects
and side effects
• Pyrimidines – site of action, SAR
• Sulphones and sulphonamides – Action and toxicity
• Mechanism of action of Antimalarials