This document discusses 9-phenethrenyl methanol class derivatives that are used as antimalarial drugs, specifically halofantrine. It notes that halofantrine contains one chiral center and is administered as a racemic mixture. It is an alternative treatment for chloroquine sensitive and resistant malaria. However, it can cause serious heart problems and its effectiveness is limited by low bioavailability and development of resistance due to its long half-life. The document also briefly discusses the natural antimalarial compound artemisinin and its derivative artemether, noting its mechanism of action involves free radicals produced from its unusual peroxide bridge.

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.