Lecture

1. 9-phenethrenyl methanol class

2. Phenanthrene
• It is a polycyclic aromatic system comprising
three fused benzene rings
• The name phenanthrene is a composite
of phenyl and anthracene

3.  The methanol group is present at position 9.

4.  Its derivatives are antimalarials
 For example: halofantrine

5. • This compound was synthesized in World War-II
• Developed into a drug in 1960s
• It contains one chiral center;
– Two enantiomers
– Which are active equally
– Hence, the drug is a racemic mixture

6. • It is an alternative drug for both chloroquine sensitive
and chloroquine resistant falciparum
• The drug is metabolized via N-dealkylation by CYP 3A4
to desbutylhalofentrine;
– Which is many fold more sensitive than the parent drug

7. • Only available in oral dosage forms
• Main problems associated are low bioavailability
(Excretion in feces)-treatment failure and resistance
• Prolong half-life of the drug and its metabolite is
responsible for resistance
• Fatty meal may enhance bioavailability

8. • Halofantrine has caused serious, even fatal,
heart problems (ventricular arrhythmias), even
at the recommended dose.
• Halofantrine is not recommended for use while
other medicines known to cause heart
problems (prolonged QT interval)

9. Mode of action
• The mode of action is unknown, although
• Crystallographic study showed that it binds
to hematin in vitro, suggesting a possible
mechanism of action
• Halofantrine has also been shown to bind
to plasmpesin, a hemoglobin degrading
enzyme

10. • In addition there is evidence to suggest that
halofantrine may inhibit the energy-dependent
proton pump on the external surface of the
plasmodia in erythrocytes, thereby destroying
the membrane integrity of the parasite

11. Synthesis
2, 4 dichloro, 6 nitro benzyldehyde reacts with triflurophenyl acetic acid

12. 2-Artemisnin
• Is a natural compound separated from a
herb named Artemisia annua, which has
been used by Chinese for thousands years
for treating malaria
• Nowadays, a derivative of artemisnin
(artemether) is being used for treating
malaria
- Is active against erythrocytic stage
- In body converted to free radicals
which cause oxidative decomposition of
plasmodium cell membrane
Artemether
Artemisnin

13. • Chemically, artemisinin is a sesquiterpene
lactone containing an unusual peroxide
bridge. It is believed that this peroxide is
responsible for the drug's mechanism of
action.