Anti-Malarial; 8-aminoquinolines

Anti-Malarial; 8-aminoquinolines

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: Pamaquine (No longer used) Primaquine (Widely used) 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: Eradicate malarial hypnozoites in liver (P.Vivax, P.Ovale) Malaria prophylaxis Used in combination with Chloroquine for complete eradication of malaria CONTRAINDICATION: G6PD deficient patients  Fatal hemolysis