Biomedical Engineering Reference
In-Depth Information
time unacceptable phytotoxic side effects. Mel oquine has been marketed as Lariam, a drug that has
serious hallucinogenic side effects in some patients. Resistance against mel oquine has led to the
use of combination therapy using mel oquine and arteminisin derivatives.
21.5.5.3 Phenanthrenemethanols
The dibutylaminopropyl groups of halofantrine (
21.28
) (Figure 21.15) were found to give optimal
antimalarial effect in the 9-phenanthrene system. Even though the evidence for the mechanism of
action for this compound is less convincing than that for chloroquine the i ndings that mel oquine
only affects erythrocytic stages of the parasite and that some studies show association with hema-
zoin support the suggestion that halofantrine acts by preventing detoxii cation of hemazoin. Like
quinine halofantrine can induce cardiac arrhythmias.
21.5.6 D
RUGS
T
ARGETING
F
OLATE
S
YNTHESIS
Tetrahydrofolic acid is an important coenzyme in parasites as well as their hosts. The coenzyme
is involved in the biosynthesis of thymine, pyrine nucleotide, and several amino acid syntheses.
Malaria parasites are dependent on
de novo
folate synthesis (Scheme 21.4) whereas mammalian
cells take up fully formed folic acid as vitamin B
9
. Consequently, dihydropteroate synthase is absent
in humans. In the mammalian as well as in parasitic cells, the precursors [folate or dihydrofolate
(
21.32
), respectively] have to be reduced to the enzymatically active tetrahydrofolate, a reaction
that is catalyzed by dihydrofolate reductase (DHFR). DHFR and thymidylate synthase are sep-
arate enzymes in mammalians, whereas they are covalently linked to one bifunctional enzyme
(DHFR-TS) in protozoan parasites. The binding site of dihydrofolate in DHFR-TS is sufi ciently dif-
ferent from the binding site in the human DHFR to allow selectivity. The binding site of DHFR-TS
inhibitors like cycloguanil (
21.30
) (Figure 21.16) and pyrimethamine (
21.31
) and the enzyme is
illustrated in Figure 21.17 using pyrimethamine as an example. Proguanil (
21.29
) will metaboli-
cally be converted into cycloguanil in the liver. The negatively charged carboxylate of Asp54 of the
enzyme binds to the positively charged amino group of pyrimethamine. The 4-amino group forms
hydrogen bonds with the backbone carbonyl groups of Ile14 and Ile164. The coenzyme of DHFR,
NADPH, is oriented through a hydrogen bond to Ser108.
Sulfadoxine (
21.33
) (Figure 21.18) and dapsone (
21.34
) act as antimetabolites of
para
-
aminobenzoic acid (
21.35
) (Scheme 21.4), which is a building block in the dihydrofolate synthesis.
An antimetabolite is an agent, which prevents the incorporation of a structural related endogenic
metabolite.
O
Dihydropteroate
synthase
O
O
O
O
OH
O
-
O
-
O
-
N
P
P
N
N
O
O
N
H
O
N
H
N
H
H
2
N
H
2
N
H
2
N
OH
Hydroxymethyldihydropterin
diphosphate
Dihydropteroic acid
21.35
O
OH
O
OH
O
O
OH
Dihydrofolate
reductase
OH
O
O
H
H
N
O
N
O
N
N
H
H
N
H
N
H
H
2
N
H
2
N
Dihydrofolic acid (
21.32
)
Tetrahydrofolic acid
SCHEME 21.4
Simplii ed folate pathway.
