Medicinal chemistry of Anit malarial agent

1. ANTI MALARIAL
AGENTS
PREPARED BY
K.SATTANATHAN., M.PHARM .,
ASST.PROFESSOR ,

2. INTRODUCTION
• Malaria is caused by infection with a single-cell parasite, Plasmodium and it is
transmitted by Anopheles mosquito.
• Four Plasmodium spp. cause malaria in human beings: Plasmodium falciparum, P.
vivax, P. ovale, and P. malariae.
• P. falciparum is the most important because it accounts for the majority of
infections and causes the most severe symptoms.

3. LIFE CYCLE OF MALARIA

4. LIFE CYCLE OF MALARIA

5. DRUGS USED TO PREVENT AND TREAT
MALARIA
• Kill the sporozoites injected by the mosquito and/or preventthe sporozoites from
entering the liver.
• Kill the schizonts residing in hepatocytes and/or prevent them from becoming
merozoites.
• Kill the merozoites in the blood and/or prevent them from developing into
gametocytes.
• Kill the gametocytes before they can enter the mosquito and reproduce into
zygotes. Some have argued that the focus at this stage should be on the male
gametocytes. This would block the female gametocytes from mating.

6. CLASSIFICATION OF ANTIMALARIAL AGENTS
• CINCHONAALKALOIDS
 CINCHONINE, QUININE
• 7-CHLORO 4- AMINO QUINOLINE
 CHLOROQUINE, AMODIA QUINE, HYDROXY QUINE, SONTOQUIN
• 8- AMIN0 QUINOLINE
 PRIMAQUININE, PAMAQUINE, PENTAQUINE PHOSPHATE, ISO PENTA QUINE

7. CLASSIFICATION OF ANTIMALARIAL AGENTS
• ACRIDINE DERIVATIVES
 ACRIQUINE
• BIGUANIDES
 PROGUANIL, CHLOROPROGUANIL, BROMOGUANIL
• DIAMINOPYRIMIDINE
 PYRIMETHAMINE, TRIMETHOPRIM
• MISCELLANEOUS DRUGS
 HALOFANTRINE, DAPSONE, ARTEMETHER, MEFLOQUININE

8. STRUCTURE OF ANTI MALARAIAL DRUGS
• QUININE SULPHATE

9. STRUCTRE OF ANTI MALARIAL AGENTS
• CHLORQUINIE AMODIAQUINE

10. • PRIMAQUININE PENTAQUINE

11. • PAMAQUININE PROGUANIL

12. STRUCTURE OF ANTIMALARIAL DRUGS
• PYREMETHAMINE TRIMETHOPRIM

13. STRUCTURES OF ANTI MALARIAL DRUGS
• HALOFANTRINE ARTEMETHER

14. STRUCTURE OF ANTI MALARIAL DRUGS
• MEFLOQUINE

15. SYNTHESIS OF AMDODIAQUINE

16. SYNTHESIS OF CHLORQUININE STEP 1

17. SYNTHESIS OF CHLORQUININE STEP 2

18. SYNTHESIS OF CHLORQUININE STEP 3

19. MECHANISM AND ACTION OF QUININE AND
CHLORO QUININE
• 4-amino quinoline drug inhibits DNA and RNA biosynthesis and induces the
rapid degradation of ribosomes and the dissimilation of ribosomal RNA.
• The inhibition of protein synthesis is also observed evidently as a secondary
effect.
• It has been proposed that the inhibition of DNA replication is the general
antimicrobial mechanism of action of chloroquinine

20. MECHANISM OF QUININE AND
CHLOROQUININE
• Chloroquine accumulates in very high concentrations in the parasite food vacuole. Once in the
food vacuole, chloroquine is thought to inhibit the detoxification of heme.
• Chloroquine becomes protonated (to CQ2+) because the digestive vacuole is acidic (pH 4.7) and
subsequently cannot leave the vacuole by diffusion.
• Chloroquine caps hemozoin molecules and prevents the further biocrystallization of heme,
thus leading to heme buildup.
• Chloroquine binds to heme (or FP) to form what is known as the FP-chloroquine complex; this
complex is highly toxic to the cell and disrupts membrane function.
• Quinine acts as similar in chloroquinine. Quinine is a weaker base than chloroquine and has
less affinity for heme, implying that mechanisms other than ion transport into the food vacuole
and heme-drug interactions are required for the action of these drugs

21. MECHANISM OF ANTI FOLATE
• The antifolate drugs inhibit either dihydro folate reductase inhibitor (DHFR)
(pyrimethamine, cycloguanil) or dihydropteroate synthase (DHPS)
(sulfadoxine).
• These are two key enzymes in de novo folate biosynthesis; inhibition of this
• metabolic pathway leads to the inhibition of the biosynthesis of pyrimidines,
purines, and some aminoacids.
• Antifolate antimalarial drugs interfere with folate metabolism, a pathway
essential to malaria parasite survival.

22. SAR OF 4- AMINO QUINOLINES
• At C-4 position, the dialkyl aminoalkyl side chain has 2-5 carbon atoms between the nitrogen atoms, particularly
the 4-diethylaminomethyl butyl amino side chain that is optimal for activity, as in chloroquine and quinacrine.
• The substitution of a hydroxyl group on one of the ethyl groups on the tertiary amine (hydroxy quinoline), reduces
toxicity.
• Incorporation of an aromatic ring in the side chain (e.g. amodiaquine) gives a compound with reduced toxicity and
activity.
• The tertiary amine in the side chain is important.
• The introduction of an unsaturated bond in the side chain was not detrimental to activity.
• The 7-chloro group in the quinoline nucleus is optimal, the methyl group in position 3 reduces activity, and an
additional methyl group in position 8 abolishes activity.
• The D-isomer of chloroquine is less toxic than its L-isomer.