X. Wu et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2299–2302
2301
properties of the ferrocene ring do not contribute sig-
nificantly to antimalarial activity. The Ring B ferrocenyl
chalcones like 13, 14, 15 and 19 have the same mole-
cular weight (size) and comparable lipophilicity as their
counterparts with ferrocene as Ring A (1–3, 7). Yet the
Ring B ferrocenyl chalcones show greater activity.
Similarly, it would be difficult to use physicochemical
differences to explain the difference in activity between
the structurally related analogues 4/16 and 6/18. The
preliminary QSAR study carried out with the Series B
ferrocenyl chalcones also shows that size, lipophilicity
and electronic factors have a limited role in activity but
these results may be due to the small number of com-
pounds investigated (n=14) and the type of physico-
chemical parameters used in the quantification. If
physicochemical properties are not important factors
for activity, one may then query the biological character
of the ferrocene ring and its role in antimalarial activity.
This question remains unanswered but investigations in
this direction would be useful in identifying the target of
action for these compounds and, ultimately, the design
of more effective antimalarial drugs.
2 2
Scheme 2. (a) Pyridinium p-toluenesulfonate in CH Cl ; (b) KOH,
EtOH, rt; (c) 4 M HCl, rt.
B=ferrocene, Ring A=phenyl) is 9 times more active
than 1 (Ring B=phenyl, Ring A=ferrocene). Other
compound pairs, namely 2/14, 3/15, 7/19, further attest
to this observation. In all these cases, the other ring is a
substituted phenyl ring. Interestingly, when the other
ring is a heterocyclic or bicyclic ring, the compound
with ferrocene as Ring A is now more active. The
2
-naphthalenyl derivatives 4 and 16, and the 3-pyridinyl
derivatives 6 and 18 are such examples. However, an
exception is seen in the 1-naphthalenyl derivatives 5 and
1
7.
Acknowledgements
When compared with the previous series of chalcones,10
the ferrocenyl chalcones are seen to be less active. For
example, a comparison of chalcones 3, 7, 10, 11 (Ring
A=ferrocene) with previously investigated derivatives
in which Ring A is phenyl shows that only 3 (IC50 24.5
mM) is more active than its Ring A phenyl derivative
Wu Xiang gratefully acknowledges the National Uni-
versity of Singapore for granting him a research scho-
larship. This work has been supported by a grant RP-
140-000-016-112 from the National University of Sin-
gapore (M.L.G.) and the Thailand Research Fund
(P.W.).
1
0
(
IC50 55.5 mM ). The rest are less active than their
phenyl counterparts.
Several Series B ferrocenyl chalcones (Ring B=ferro-
cene) have been synthesized in which Ring A is a phenyl
ring substituted with groups of varying electronic and
lipophilic characteristics (13–15, 19–29). A few interest-
ing structure–activity observations can be made for this
subset. It is evident that the unsubstituted phenyl ring
References and Notes
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Maciejewski, L.; Brocard, L.; Camus, D.; Dive, D. Parasitol.
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2
. Domarle, O.; Blampain, G.; Agnaniet, H.; Nzadiyabi, T.;
(13) is quite active per se (IC50 19 mM). In general,
Lebibi, J.; Delhaes, L; Abessiki, H.; Biot, C.; Berry, L.; Del-
court, P.; Maciejewski, L.; Brocard, J.; Maciejewski, L.; Biot,
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inclusion of electron donating or withdrawing groups
adversely affects activity (4-methyl 20, 4-CF3 27) or
leave it unchanged (2,4-dimethoxy 15, 2,4-difluoro 26).
Only substitution with 4-nitro markedly enhanced
activity (28, IC50 5.1 mM). The 4-cyano derivative 29 is
significantly less active, despite the fact that both nitro
and cyano are polar, electron withdrawing groups. An
attempt was made to quantify the structure–activity
relationships using the p values of the Ring A phenyl
3
4
5
8
6
1
3
13
substituent, molecular weight and C chemical shifts
0
(
of these compounds using multiple linear regression.
However, no significant relationship could be obtained.
to denote electronic effects of the Ring A substituent)1
1
4
8. Hansch, C.; Leo, A. Substituent Constants for Correlation
Analysis in Chemistry andBiology ; John Wiley and Sons: New
York, 1979.
9. Liu, W. Y.; Xie, T.; Liang, Y. M.; Liu, W. M.; Ma, Y. X.
J. Organometallic Chem. 2001, 627, 93.
Another interesting observation is the reasonably good
activity associated with the quinolinyl derivatives (30,
31). This is in contrast to the poorer activities of naph-
thalenyl derivatives (16, 17), which have a comparable
size but lack a basic center.
1
4
1
0. Liu, M.; Wilairat, P.; Go, M. L. J. Med. Chem. 2001, 44,
443.
1. Series A and B ferrocenyl chalcones (except hydroxyl
The results gathered from this fairly limited number of
ferrocenyl chalcones suggest that the physicochemical
containing analogues 7, 8, 19) were synthesized in the following
way: The substituted ketone (3 mmol) and KOH (0.2 g) were