Download Antiparasitic Drugs

Chapter 9
Chemotherapeutic
Agents
Prof. Wei-Min Chen
Topic In This Class


Antimalarials
Quiz
Antimalarials


Malaria, one of the most
widespread disease, is caused by
a Plasmodium parasite. Its name
is derived from mala aria (bad air),
and it has been called ague,
intermittent fever, marsh fever,
and The Fever. The name is
based on the early knowledge
that malaria was associated with
swamp and badly drained areas.
The disease was spread by
mosquito.
Proof
that
the
Anopheles mosquito is the carrier
of the causative protozoa was
obtained by Dr. Ronald Ross, who
was recognized in 1902 with the
Nobel Prize in Medicine.
Stimulation of Antimalarial
Research By War

From 1941 to 1946 (World war II), more than 15,000
substances were synthesized and screened as
possible antimalarial agents by US, Australia and
Great Britain. Activity increased again during the
Vietnam War, especially because of the increasing
problem of resistance to commonly used
antimalarials. During the decade 1968 to 1978,
more than 250,000 compounds were investigated as
part of a U.S. Army research program.
Antimalarial agents
H
N
HO
H
H
O
N
HO
O
O
H
H
N
F
O
N
O
F
N
N
F
F
FF
奎宁
优奎宁
甲氟喹
Quinine
Euquinine
Mefloquine
Cl
H
Cl
N
HN
Cl
O
O
O
Cl
N
HO
H
O
O
N
苯芴醇
氯喹
青蒿素
Benflumetol
Chloroquine
Artemisinin
O
O
O
O
O
O
O
O
O
O
O
HO
O
O
O
蒿乙醚
蒿甲醚
二氢青蒿素
Arteether
Artemether
Dihydroartemisinin
Quinine

6-Methoxy-a-（vinyl-2-quiniclidinyl）-4-quinoline
methanol
Discovery


The
cinchona
tree
produces four alkaloids
that were, until recently,
the prototypical molecules
on which most antimalarial
drugs based.
Quinine has been used for
“fevers” in South America
since 1600s. The pure
alkaloids
quinine
and
cinchonine were isolated in
1820.
Structural Characteristic of
Quinine


There are four chiral
centers in the structure.
C-3、C-4、C-8、C-9

The stereoisomer, quinidine, is a more potent
antimalarial, but it also is more toxic ( less
selectively toxic). Its primary indication is
cardiac arrhythmias. It is a good example of
the importance of stereochemistry because it
provides
a
significantly
different
pharmacological spectrum.
Prodrug- Euquinine

Euquinine is the
esterification product of
quinine with chloroformic acid ethyl ester
H
H
O
N
O
HO
+
O
N
O
Cl
O
H
H
N
O
O
N
ÓÅ¿üÄþ
Enquinine
Metabolism of Quinine

Quinine is metabolized in the liver to the 2’-hydroxy
derivative, followed by additional hydroxylation on
the quinuclidine ring, with the 2,2’-dihydroxy
derivative as the major metabolite. This metabolite
has low activity and is rapidly excreted. The
metabolizing enzyme of quinine is CYP3A4.
Drugs from modification
Cl
H
N
HO
Cl
Cl
F
N
F
F
FF
HO
H
¼×·ú àMefloquine
±½ÜÌ´¼
Benflumetol
F
N
Chloroquine phosphate
4
HN
4
7
Cl

N
1
.2H3PO4
N1
N4-（7-Chloro-4-quinolinyl）-N1，N1-diethyl-1，4pentanediamine diphosphate

Chloroquine can be considered the prototypical
structure that succeeded quinine and come into use
in the mid-1940s. The phosphate salt is used in oral
dosage forms (tablets), and the hydrochloride salt is
administered parenterally. Until recently, chloroquine
was the main antimalarial drug used both for
prophylaxis and treatment.
Mechanism of Action

Over the years many proposals have been put
forward on the mechanism of action of chloroquine
and related antimalarials. Most researchers in the
field have focused attention recently on the inhibition
of hemozoin formation by quinoline agents.

DNA Intercalation: The earliest proposal was that the
drug intercalated into the DNA of the parasite. This
mechanism was soon discarded based on the fact that
the concentration required for inhibition of nucleic acid
synthesis is significantly higher than that necessary for
inhibition of the plasmodium parasite.(In Chinese
textbook)
Synthesis
Cl
+ H2N
Cl
C6H5OH
N
50oC
N
HN
N
HN
N
H3PO4
.2H3PO4
C2H5OH
Cl
N
Cl
N
Artemisinin (青蒿素)

Artemisinin is a drug used to treat
multi-drug resistant strains of
falciparum malaria. The compound
(a sesquiterpene lactone) is
isolated from the plant Artemisia
annua. Not all plants of this species
contain artemisinin. Apparently it is
only produced when the plant is
subjected to certain conditions,
most likely biotic or abiotic stress.
Artemisinin (青蒿素)

The weed Artemisia annua has been used for many
centuries in Chinese herbal medicine as a treatment for
fever and malaria. In 1971, Chinese chemists isolated
from the leafy portions of the plant the substance
responsible for its reputed medicinal action. The
compound, artemisinin (qinghaosu, arteannuin), was
determined by X-ray crystallography to be a
sesquiterpene lactone bearing an endoperoxide
Artemisinin

The plant must be grown each year from seed
because mature plants may lack the active drug. The
growing conditions are critical to maximize
artemisinin yield. Thus far, the best yield have been
obtained from plants grown in Sichuan region in our
country, and Vietnam, Tanzania.

For many years, access to the purified drug and the
plant it was extracted from were restricted by the
Chinese government. It was not until the late 1970s
and early 80s that news of the discovery reached
scientists outside China.
Structure and name


3R,5aS,6R,8aS,9R,12S,12aR)
-Octahydro-3，6，9trimethyl-3，12-epoxy-12Hpyrano[4，3-j]-1，2Benzodioxepin-10（3H）one
The key structure
characteristic appears to be a
“trioxane” consisting of the
endoperoxide and doxepin
oxygens.
Structure modification

With the reduction of artemisinin to
dihydroartemisinin, an asymmetric
carbon forms, and it is possible to
form oil-soluble and water-soluble
prodrugs. Both stereoisomers are
active. The chemistry froming each
of the artemisinin pro-drugs results
in the predominance of one isomer.
The βisomer predominates when
producing the nonpolar methyl and
ethyl ethers, whereas the αisomer
is the predominant product when
forming the water-soluble
hemisuccinate ester.
The Derivatives of Artemisinin
The Derivatives of Artemisinin
O O
O O
O
O
O
O
OMe


OCOCH2CH2COOH
1987, artemether(蒿甲醚), artesunate(青蒿琥酯) were
approved for new drug for treatment of malaria in China
WHO
 artemether(蒿甲醚) “Essential Medicine List” 9th edition
（1997）
 artesunate(青蒿琥酯) “Essential Medicine List” 11th
edition（2000）
Mechanism of Action, SAR


The artemisinin appear to kill the parasite by a free
radical mechanism. Not by the generation of reactive
oxygen species, but by virtue of a free-radical associated
with the endoperoxide, possibly involving a carbon
radical. The radical in turn produces oxidative damage to
the parasites membrane.
The endoperoxide is essential for activity;
deoxyartemisinin, in which the dioxy bridge has been
reduced to mono-oxy, is completely inactive.
Key Notes

Antimalarial agents





Quinine
Chloroquine phosphate
Artemisinin
Synthesis of Chloroquine
SAR of Artemisinin
Homework

Question:


Do you think that artemisinin is the model for
modernization of Traditional Chinese Medicines?
Assignment:


1.Read textbook pp367-389, 282-298
2.Do homework Exercises of medicinal chemistry
and药物化学学习指导,第9章