This document discusses anti-malarial drugs in the 8-aminoquinoline class. It describes the synthesis of primaquine through a multi-step process involving the quinoline nucleus and side chain. Structure-activity relationships are examined, noting the importance of the quinolone ring, pentyl side chain, primary amino group, and methoxy substitution. The pharmacology of primaquine is explained by its interference with the parasite's mitochondria and DNA. It is indicated for eradicating hypnozoites and prophylaxis but contraindicated in G6PD deficient patients due to risk of fatal hemolysis.

1. Anti-Malarial Drugs
8-aminoquinolines
Synthesis, SAR, Pharmacology
Department of Pharmacy
University of Peshawar

2. INTRODUCTION
Drugs in this class has an amino group at position 8
Common drugs include:
a.Pamaquine (No longer used)
b.Primaquine (Widely used)
c.Tefenoquine (Phase 3 clinical trials)

3. SYNTHESIS OF QUINOLINE NUCLEUS

4. STEP:1
P-acetamido anisole may be prepared by the sequential
nitration, reduction and acetylation of
anisole

5. STEP:2
P-acetamido anisole on further nitration yields 3-nitro-4-
acetamido anisole

6. STEP:3
3-nitro-4-acetamido anisole on hydrolysis gives 3-nitro-4-
anisidine

7. STEP:4
3-nitro-4-anisidine on treatment with glycerol in the
presence of concentrated sulphuric acid and nitrobenzene
undergoes cyclization through Skraup’s synthesis to yield
8-methoxy-6-nitro quinoline.

8. STEP:5
Reduction of 8-methoxy-6-nitro quinoline gives rise to 8-
amino-6-methoxy quinoline

9. SYNTHESIS OF SIDE CHAIN

10. STEP:1
2-Bromo-5-phthalimido pentane is prepared by the
interaction of 1, 4-dibromopentane with potassium
phthalimide

11. CONDESATION (NUCLEUS + SIDE CHAIN)

12. STEP:1
2-Bromo-5-phthalimido pentane on reaction with 8-
amino-6-methoxy quinoline yields the condensed
product

13. STEP:2
The condensed product when treated with hydrazine
eliminates the phthalimido residue and yields the
Primaquine base

14. STRUCTURE ACTIVITY RELATIONSHIP
QUINOLINE RING
 Presence of quinolone ring is necessary for activity
 If Pyridine ring is reduced to Piperidine the compound becomes
inactive.
SIDE CHAIN AT POSITION-8
 Introduction of side chain increases activity e.g Pamaquine
 Pentyl side chain has shown maximum activity
 Increase or decrease in side chain length will decrease activity
 Branched side chain if converted into straight chain will decrease
activity e.g Pentaquine

15. STRUCTURE ACTIVITY RELATIONSHIP
TERMINAL AMINO GROUP
 Presence of primary amino group has shown maximum activity and
less toxicity e.g Primaquine
 Substitution of primary amino with tertiary amino results in decreased
activity and increased toxicity e.g Pamaquine
SUBSTITUTION AT POSITION-6
 Methoxy group is necessary for optimum activity
 Methoxy group substitution with Ethoxy group reduces activity.
 Methoxy group substitution with methyl group leads to loss of
activity.
 Methoxy group substitution with Halide increases toxicity.

16. STRUCTURE ACTIVITY RELATIONSHIP
SUBSTITUTION OF PRIMAQUINE
 Substitution (Benzyloxy) at position-2 leads to decrease in activity
 Substitution (Phenyl) at position-3 leads to decrease in activity
 Substitution of Methyl at position-4 leads to almost 2x increase in
activity
 Substitution at position-5 leads to decrease in toxicity while having
almost same activity
 Substitution at position-7 leads to loss of activity

17. PHARMACOLOGY
In the blood, malaria parasites break down hemoglobin.
When this happens hemoglobin is divided into two parts; heme
& globin. Heme is toxic to the malaria parasite to prevent it
from being damaged, the malaria parasite produces an enzyme
which converts the toxic haem into a non-toxic haemozoin.
Primaquine acts by interfering with a part of the parasite
(mitochondria) that is responsible for supplying it with energy;
without energy the parasite dies.
Primaquine also interferes with protozoal DNA and alter its
properties

18. INDICATIONS & CONTRAINDICATIONS
INDICATION:
a. Eradicate malarial hypnozoites in liver (P.Vivax,
P.Ovale)
b.Malaria prophylaxis
c. Used in combination with Chloroquine for complete
eradication of malaria
CONTRAINDICATION:
a. G6PD deficient patients Fatal hemolysis