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14
1
3
4
10
O O
O
O
O
O
8
5
7
O
O
O
15
O
11
O
O
12
13
OR
OH
O
qinghaosu
1
ethers R = Me(artemether
123
)
Et (arteether
124
)
dihydroartemisinin
98
O
O
O
O
O
O
O
O
O
O
O
O
OCOOR
OCOR
deoxyartemisinin
14
carbonates
esters R = CH
2
CH
2
COOH
(artesunate
125
)
Scheme 5-9
Oil-soluble artemether and water-soluble sodium artesunate were developed and
approved as new antimalarial drugs by the Chinese authorities in 1987. After 1992,
dihydroartemisinin, Coartem (a combination of artemether and benflumetol), and
Artekin (a combination of dihydroartemisinin and piperaquine) were also marketed
as new antimalarial drugs. Since then, over 10 million malaria patients on a global
scale have been cured after administration of these drugs. As a result, artemether,
artesunate, and Coartem were added by the World Health Organization to the ninth,
eleventh, and twelfth Essential Medicine List respectively.
When artemether and sodium artesunate were successfully used by intramuscu-
lar or intravenous administration for treatment of severe malarial patients,
their shortcomings, such as short half-life and instability of aqueous solution of
sodium artesunate, were cognized. Hence, qinghaosu derivatives and analogs num-
bering in the thousands were synthesized and evaluated by many research groups
worldwide.
5.5.1
Modification on C-12 of Qinghaosu
From the view of chemistry, the C-12 position of dihydroartemisin is similar to the
C-1 position of carbohydrates. So, these C-12 derivatives may be divided into three
types: O-glycosides, N-glycosides, and C-glycosides using a similar term in carbo-
hydrate chemistry.
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