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the diphenylcarbonyl group of 4a, was investigated as
reported below. To analyze structure–activity relation-
ships (SAR), we calculated for all compounds the preva-
lent ionic forms of the two possible tautomers at pH 7.4
(physiological), 7.2 (cytoplasm), and 5.5 (FV) (Table 1)
and, accordingly, performed a comprehensive computa-
tional analysis (Insight2005, Accelrys, San Diego) on the
resulting forms of 4a and 4f, in order to investigate the
role played by electronic and conformational parame-
ters on the antimalarial activity. According to the results
reported by Ryckebusch et al.7, the presence of several
nitrogens protonated at cytoplasmic pH in the 1,4-
bis(3-aminopropyl)piperazine linker of 4a–h (Table 1)
probably prevents the access to the FV. Consequently
the compounds elicit their antimalarial activity at the
cytoplasm level. Taking into account this hypothesis,
we focused on the effect of the imidazole (4f) and poly-
cyclic (4a) terminal fragments on electronic and confor-
mational properties at pH 7.2 (cytoplasm).
At pH 7.2 the presence of the diphenylketone moiety of
4a allows the formation of an intramolecular hydrogen
bond between the N1 of piperazine and the aniline nitro-
gen of the quinoline ring. This, in turn, increases the
electronic density at the quinoline heterocyclic nitrogen
and, consequently, improves its iron coordination prop-
erties, thus reproducing the geometry of a multisite iron
chelator (Fig. 2A) (ConQuest 1.9, CSDS). Moreover the
diphenylketone moiety represents a further iron chela-
tion site (Fig. 2A). On the contrary, the 2-imidazolylm-
ethyl group (4f), protonated at pH 7.2 (Table 1),
establishes hydrogen bond interactions with the quino-
line heterocyclic nitrogen thus decreasing the iron coor-
dination properties of 4f and consequently, its
antimalarial activity (Fig. 2B).
Figure 2. Resulting conformers at pH 7.2 of 4a (A, green) and 4f (B,
magenta) are shown. In (A) 4a was superimposed on the X-ray
structure of iron complexes containing the following moieties: diphe-
nylketone (white; CSD code: VESCEB), piperazine (yellow; CSD code:
HAVNUO), N1,N3-dimethylpropane-1,3-diamine (orange; CSD code:
METGIB), and quinoline (pink; CSD code: FOFROH). The super-
imposition was made fitting the putative iron coordinating atoms. Iron
atoms’ vdW volumes (magenta) are scaled (0.3) for clarity. Displayed
lone pair of piperazine nitrogen is colored in cyan. Heteroatoms are
colored: O, red; N, blue; Fe, magenta; and Cl, light green. All
hydrogens, except those involved in hydrogen bonds (green dashed
lines), have been omitted for clarity.
In summary, we identified novel CQ-based heterodimers
characterized by a 1,4-bis(3-aminopropyl)piperazine lin-
ker as potent antimalarials against CQ-S and CQ-R Pf
strains. Among the compounds presented in this study,
4a was the most potent antimalarial, being 16- and 8-
fold more active than CQ against K1 and W2 strains,
respectively. A putative mechanism of action of 4a was
investigated, paving the way for the development of
new multisite iron complexing antimalarials. Further
studies are in progress to assess the in vivo biological
properties of this class of antimalarial agents.
alcoholic group (4b) or to the corresponding sulfonate
(4c) determined a decrease in activity against CQ-S
and CQ-R strains (4b and 4c vs 4a). In order to define
the role played by iron chelating groups in antimalarial
activity (R1, Table 1), we introduced at R1 aromatic and
heteroaromatic systems endowed with different metal
chelating and protonatability properties. Consequently,
as R1 residue, we selected fragments potentially able to
coordinate iron (ConQuest 1.9, CSDS), such as a frag-
ment of the CLT/3 polycyclic scaffold (4e), the 2-imi-
dazolylmethyl group (4f), and the 2-benzimidazole
bicyclic system (4g); on the other hand, compounds 4d
and 4h were characterized by a pyrrolidinyl(di)phenylm-
ethylene system, two residues unable to chelate iron
(pyrrolidine chelates iron when a carbonyl function is
at C-2—ConQuest 1.9, CSDS). Compounds 4d and 4h
as well as 4e–g resulted less potent than 4a against
D10 and W2 strains, confirming the importance of the
iron chelating properties of the R1 substituent. Recently,
we have reported the potent antimalarial activity against
CQ-S and CQ-R strains of quinolines bearing an imid-
Acknowledgments
This investigation received financial support from
the UNICEF/UNDP/World Bank/WHO Special
Programme for Research and Training in Tropical
Diseases (TDR). Authors thank Intesa S. Paolo bank
for financial support.
References and notes
azole moiety,
a known Fe(III)–FPIX complexing
group.11 Surprisingly, introduction of an imidazole sys-
tem in this series (R1, 4f) dropped the activity against
both strains. The effect of imidazole of 4f, as well as of
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