Chemistry Reference
In-Depth Information
5.6.6
Another Point of View and Summary
In the early 1980s, Wu and Ji performed the Hansch analysis of antimalarial activity
and the distribution coefficient between oil and water of qinghaosu derivatives and
found that the more lipophilic, the more active the derivative.
306
It is understand-
able that the lipophilic property of the qinghaosu derivative is related to its permeat-
ing ability across the membrane of the cell, but it is just the first step for the mode of
action. Recently, several laboratories have performed the cyclic voltammetry study
of qinghaosu and its derivatives. A correlation of the activities of qinghaosu
derivatives with their reduction potentials was reported.
104
However, it was also
indicated that the electrochemical reduction of qinghaosu and its derivatives was
a two-electron transfer,
100
and it produced deoxyqinghaosu and its derivatives,
but not free radical reduction products, which were confirmed by isolation and iden-
tification of the electrochemical reduction product.
98
The major metabolites of
qinghaosu in vivo are the same as free radical reduction products, so it is confusing
if there is a correlation between the electrochemical reduction and the cleavage of
peroxy bridge of 1 in vivo.
Recently, Jefford has concluded that the killing of the parasite by alkylation with
a carbon radical is a logical and convincing sequel, but the death of the parasite also
may occur by oxygen atom transfer or by the action of an oxy-electrophilic spe-
cies.
285
However, Haynes has argued totally against the C-centered radical proposal
based on the consideration of redox chemistry and SARs.
307
In their recent article,
Haynes et al. conclude that the antimalarial activity does not correlate with the che-
mical reactivity of qinghaosu derivatives against Fe(II) based on an experimental
observation of a special C-12 nitrogen-substituted derivative.
308
Another totally dif-
ferent viewpoint was presented in 2001 that the antimalarial activity of 1 may be
caused by (1) the interaction of the intact compound without chemical reaction,
(2) the chemical reaction of 1 and/or its degradation products with the parasite
biomolecules, or (3) the oxygen free radical occurring during redox reaction.
309
Their consideration is based on an undefined experimental result that dihydroqin-
ghaosu is the product from the reaction of 1 and ferrous sulfate in an aqueous
buffer. The formation of dihydroqinghaosu determined only by TLC has no prece-
dent, and the reduction of lactone to lactol with ferrous ion is also unbelievable in
chemistry.
In a recent account, O'Neill and Posner again mentioned that high-valent iron-
oxo-intermediate is important for high antimalarial activity, but this opinion is not
widely accepted.
16
In summary, the mode of antimalarial action of 1 has been a noticeable research
object since its discovery. Several theories have been postulated until now, however,
their further development has still been difficult as mentioned by Wu.
310
Right now,
from several experimental results and proposed theories, the postulation that the
carbon-centered free radical is the key active species killing the parasite would
most likely be convincing. The additional key point is what might be the genuine
target attacked by these catalytic amount of radicals and what might be destroying
the whole biosystem of the parasite.
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