Biguanides (PCC) Proguanil Chloroproquanil Cycloguanil Sulphones (D) Dapsone Polycyclic antimalarial drugs (HD) Doxycycline Halofantrine Pyrimidines (PT) Pyrimethamaine Trimethoprim

1. ANTIMALARIAL AGENTS -
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Department of Pharmacy
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2. CONTENTS
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• Classification of Antimalarials
• Structural Activity Relationship, pharmacokinetics, pharmacological
effects and side effectsn of the following:
cinchona alkaloids
8- aminoquinolines
4- aminoquinolines
9- acridines

3. At the end of this lecture, student will be able to
• Classify Antimalarials
• Compare the structure and activity relations of Antimalarials
• Discuss the metabolism, effects and side effects of Antimalarials
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LEARNING OBJECTIVES

4. CLASSIFICATION
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• Biguanides (PCC)
 Proguanil
 Chloroproquanil
 Cycloguanil
• Sulphones (D)
 Dapsone
• Polycyclic antimalarial drugs (HD)
 Doxycycline
 Halofantrine
• Pyrimidines (PT)
 Pyrimethamaine
 Trimethoprim
BSPP N CAAA KA VIRODH NAHI KIYA

5. CLASSIFICATION CONTD…
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• Newer antimalarials (AAA)
 Artesunate
 Artemether
 Atovoquone
• Cinchona alkaloids (qqcc)
 Quinine
 Quinidine
 Cinchonine
 Cinchonidine
• 4-aminoquinolines (CHMA)
 Chloroquine
 Hydroxychloroquine
 Mefloquine
 Amodiaquine

6. CLASSIFICATION CONTD…
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• 8-aminoquinolines (ppp)
 Primaquine
 Pamaquine
 Pentaquine
• 9-aminoacridines (QA)
 Quinacrine
 Acriquine

7. CINCHONA ALKALOIDS
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Eg. Quinine, Quinidine, Cinchonine, Cinchonidine.
The alkaloids are derivatives of 4-quinoline methanol bearing a
substituted quinuclidine ring system

8. SAR OF CINCHONA ALKALOIDS
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1. All four of the cinchona alkaloids are active antimalarials. Thus the 6-
OCH3 group is not essential for activity.
2. Quinoline methanol portion becomes important in synthetic drugs.

9. 3. All the alkaloids having same configuration at R1 & R2 are diastereoisomers,
differing in configuration at 3rd & 4th chiral centers (C-8 and C-9)

10. SAR OF CINCHONA ALKALOIDS
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4. Although all four alkaloids show antimalarial activity, their C-9
epimers (i.e. having either 8R:9R or 8S:9S configurations) are
inactive.
5. Any modification of the 2˚ alcohol at C-9, through oxidation,
esterification and similar processes diminishes activity.
5. The quinuclidine portion is not essential for activity; however, the
tertiary (3˚) alkyl amine attached to C-9 is important. This forms
the basis for the design of synthetic antimalarials.

11. CINCHONA ALKALOIDS CONTD…
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 Metabolism: -
• Quinine is metabolized in the liver to the 2’ – hydroxyl (carbostyril)
derivative, followed by additional hydroxylation on the quinuclidine
ring to provide the 2,2’-dihydroxy derivative as the major
metabolite.
• This metabolite has low antimalarial activity and is rapidly excreted.
• Excretion is mainly in the urine.

12. CINCHONA ALKALOIDS CONTD…
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 Effects: -
• The cinchona alkaloids act on the erythrocytic merozoites. They do
not effect a radical cure but decrease symptoms.
• Quinine is used in treating some forms of malaria, in which
resistance to other agents has developed.
• Also, cinchona alkaloids are antipyretic by the action on central
temperature regulating mechanism causing peripheral vasodilation

13. CINCHONA ALKALOIDS CONTD…
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 Side effects: -
• Side effects include – skin allergies, deafness, vertigo (giddiness -
dizziness) and slight mental depression.
• Quinine passes the fetal barrier and affects the vision of the new
born.
 Advantages: -
 Quinine is the drug of choice only for chloroquine resistant P.
falciparum. The resistance to quinine has not developed as readily
as it has to the synthetic drugs.

14. QUINOLINE ANALOGUES - 4-AMINOQUINOLINES
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Chloroquine
Amodiaquine Mefloquine
© Ramaiah University of Applied Sciences
Hydroxychloroquine

15. SAR OF 4-AMINOQUINOLONES
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
Substitution of a methyl group on C-8 causes a complete loss of activity.
 The 3˚ amine is important for activity
 Side chain length (4-carbon)& 7-chloro-group are optimal for activity.
 Substitution of –OH gp on one of the ethyl group on the 3˚ amine
reduces toxicity and increase the plasma concentrations(more
effective)- a metabolite of chloroquine (hydroxyl chloroquine).
 Incorporation of an aromatic ring at the 3˚ amino gp, produces a
compound of reduced activity and toxicity e.g amodiaquine
 Incorporation of a methyl group on C-3 on the quinoline ring decreases
activity e.g santoquine

17. ADME OF 4-AMINOQUINOLONES
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Absorption, Distribution and excretion:
 Chloroquine is absorbed readily from the G.I,T
, but amodiaquine
gives lower plasma levels than others in the group.
 Peak plasma concentrations are reached in 1 to 3 hrs, with blood
levels falling off rapidly after administration is stopped.
 About half the drug in the plasma is protein bound.
 These drugs concentrate in the liver, spleen, heart, kidney & brain.
 These compounds are excreted rapidly with most of the
unmetabolized drug being accounted for in the urine.

18. 4-AMINOQUINOLONES- USES & TOXICITY
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aminoquinolines are used.
 Uses: -
 These drugs are active against the erythrocytic forms of all malarial
parasites leading to clinical cure.
 They do not prevent the disease and they are not active against the
liver infecting forms.
 They are also used in the treatment of extra-intestinal amebiasis.
 Toxicity: -
 The toxicity of 4-amino quinolone is quite low. The side effects include
nausea, vomiting, anorexia, abdominal cramps, diarrhea, headache,
dizziness, pruritus and urticaria
 Long-term administration in high doses may have serious effects on the
eyes.
 Patients with liver diseases particularly should be watched when 4-

19. 8-AMINOQUINOLINES
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• 8-aminoquinolines, unlike 4-aminoquinolines, are active against the
pre- or exo-erythrocytic forms of the malarial parasite.
• 8-aminoquinolines are reserved for prophylactic purposes and for the
production of radical cure in infections due to P
. vivax and P
. malariae
 SAR: -
• The 6-methoxy group is essential for activity
• side chain carbon length can vary from 4 to 6 carbons
• The extent of substitution of the amino is not as critical and the drug
of choice, Primaquine, is a primary amine.

20. 8-AMINOQUINOLINES
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Primaquine Pamaquine
Pentaquine

21. 8-AMINOQUINOLINES-ADME
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 The 8-aminoquinolines are absorbed rapidly from the G. I .tract.
Peak plasma concentrations are reached within 2 hours after
ingestion after which the drug rapidly disappears from the blood.
 The drugs are localized mainly in the liver, lung, brain, heart and
muscle tissue.
 Metabolic changes are produced in the drug very rapidly and on
excretion, metabolic products account for nearly all of the drug.
 The antiplasmodial and the toxic properties of these drugs are
produced by metabolic transformation products.

22. 8-AMINOQUINOLINES CONTD…
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 Toxicity: -
• The toxic effects are principally in the CNS and the hematopoietic
system (system pertaining to the formation of blood cells).
• Other side effects are anorexia, abdominal pain, vomiting and cyanosis
(a dark bluish colaration of skin and mucous membrane due to deficient oxygenation
of the blood in the tissues), hemolytic anemia leukopenia (abnormal
decrease in WBC<5000/cu.mm) and methemoglobinemia (condition in
which more than 1% of hemoglobin is blood is oxidized to ferric form Fe+++)
 Uses: - Primaquine is used mainly to prevent relapses due to exo-
erythrocytic forms of the parasites.

23. 9-AMINOACRIDINES
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Act as schizonticides but are inferior to the 4-aminoquinolines
 Quinacrine hydrochloride (Mepacrine HCl)
 6-chloro-9[{4-(diethylamino)-1-methylbutyl}amino]-2-methoxy
acridine dihydrochloride.

24. 9-AMINOACRIDINES
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 Toxicity: -
 Extremely toxic - largely replaced by the 4-aminoquinolines
 The toxicity involves the CNS, blood and fatal drug reactions.
 The toxic effects include-convulsions, psychotomimetic (mental
disturbances) reactions, aplastic anemia [decreased formation of
erythrocytes and hemoglobin from aplastic(defective) bone
marrow] and exfoliate (scabial) dermatitis
 A side effect of therapy is yellow pigmentation of the skin and
yellow color in the urine.

25. SUMMARY
• Classification of Antimalarials
• Structural Activity Relationship, pharmacokinetics,
pharmacological effects and side effects of the following:
 Cinchona alkalois
 8aminoquinolines
 4- aminoquinolines
 9- acridines
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