cinchona_alkaloids.ppt

Cinchona Alkaloids

1. Anti-malarial Drugs
Outline
•Chemical Classification
•Medicinal Chemistry of cinchona alkaloids

2. Anti-malarial Drugs: Classification
•Cinchona alkaloids
•4-aminoquinolines
•8-aminoquinolines
•9-aminoacredines
•Pyremidine analogues
•Biguanides
•Miscellaneous agents

3. Cinchona alkaloids
Extracted from Cinchona bark
Include: 4 Major alkaloids;
Quinine
Quinidine
Cinchonidine
Cinchonine

4. Chemistry of cinchona alkaloids
Cinchona alkaloids are derivatives of ruban, which
is made up of quinoline and quinuclidine rings
linked through CH
2
Ruban has little antimalarial activity

5. •When –OH is added on C-9 of ruban, the
compound is called 9-Rubanol, which has
more anti-malarial activity than that of rubanN
OH
H
Rubanol
N
9

6. •By adding two groups, methoxy and venyl in
rubanol, new compound (quinine) is formed
having maximum activity.

7. •Quninidine is a stereoisomer of quinine

8. •If methoxy group is removed from quinine, the
compound formed is called cinchonidine.
•Cinchonine is a stereoisomer of cinchonidine,
(removal of methoxy from quinidine)

9. SAR OF QUININE
•Related to quinoline nucleus
-Any change at position 2, 3, 5, 7 and 8 of
quinoline nucleus will not cause complete loss of
activity but there will be a drastic loss in
therapeutic activity
H

10. SAR OF QUININE
•Related to quinolinenucleus
-If position 8 is halogenated there is no change in
activity but increases toxicity to brain and liver
H
Cl

11. SAR OF QUININE
•Related to quinoline nucleus
-Substitution at position 6 is very important.
Quinine has methoxy group at this position, which
results in high therapeutic activity
H

12. R

13. 6-methoxy group
•This group is not necessary for activity, hence
may be removed
•If methoxy group is removed from quinine, 20%
loss of activity occurs and the resulting compound
is cinchonidine
•If methoxy group is removed from quinidine,
cinchonine
•If methoxy group is replaced by ethoxy group,
there will be no difference of activity, but the
compound becomes more toxic to liver and optic
nerves

14. 9-hydroxyl group
•OH group at position 9 is considered to be
an important group for antimalaril activity,
and if OH is replaced by H, 90% activity is
lost
•In quinine OH group is on front, whereas, is
on back in quinidine
•Quinine has the highest antimalarial activity
whilst quinidine has anti-arrythmic activity
•If OH group is replaced by CN, toxicity is
increased

15. Quiniclidine ring
•Bicyclic ring is not needed for activity which
is evident from chloroqine and primaquine
whereby bicyclic ring has been replaced by
side chain containing tertiary nitrogen
•Tertiary nitrogen is needed for activity

16. Vinyl group
•Vinyl group present on bicyclic ring when
reduced produces the compound named
diydroquinine, and this reduction has no effect on
antimalarial activity rather it is more active
against P. gallinaceum andP. reticulum
•When vinyl group is oxidized the compound
becomes inactive
Oxi or Red

17. Mefloquine
•It is closely related to quinine, and
•Is a synthetic derivative of quinine, in which
–position 2 and 8 have two lipohilic groups (CF
3) that
increase half life: 15-20 days
–bicyclic group has been replaced by piperidine ring
•It is effective as a single dose (750 mg)
•It is not used nowadays due to cardiovascular and
CNS side effects
H

18. piperidine
trifluoromethyl
H

19. Quinine
•Quinineisanaturalcompoundand
whenadministered,hydroxylationtakes
placeatposition2and8ofquinoline
ring,thusthesetwopositionsaremade
hydrophilic
•Ithasbeensynthesizedinlaboratoryby
acomplexprocessbutonlargescaleit
isextractedfromplantsource

21. Extraction
•Powdered bark is mixed with alkali and
extracted with petroleum ether. Then
H
2SO
4 is added and quinine is
precipitated in the form of quinine
bisulphate-because quinine contains two
basic nitrogen groups
•Quinine has 3 molecules of water as a
water of crystallization

22. Therapeutic uses
•Very effective antimalarial agent active at
erythrocytic stage
•Nowadays, it is not a drug of choice because
of undesirable effects-is only a lead
compound
•Antipyretic activity
•Flavoring agent in tonic water, and in some
preparations used to increases digestion

23. •Involves the inhibition of hemozoin
biocrystallization, which facilitates the
aggregation of cytotoxic heme. Free cytotoxic
heme accumulates in the parasites, leading to
their death
•Hemozoinis a disposal product formed from the
digestion of blood by some blood-feeding
parasites, Plasmodium spp
Mechanism of action

24. •The parasites digests hemoglobin and
releases high quantities of free heme, which
is the non-protein component of hemoglobin.
Free heme is toxic to cells, so the parasites
convert it into an insoluble crystalline form
called hemozoin.
•Since, the formation of hemozoin is essential
to the survival of these parasites, it is an
attractive target for developing antimalarial
drugs

25. •Both drugs raised ventricular fibrillation
thresholds, reversed aconitine-induced atrial
fibrillation, decreased ouabain-induced
abnormal ventricular beats, and increased
atrial refractory periods and His-Purkinje
conduction time. In contrast, only quinidine
antagonized acetylcholine-induced atrial
fibrillation. In addition, quinidine increased
ventricular fibrillation thresholds and atrial
refractory periods for a longer time period
than quinine.