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CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

Synthesis and Antimalarial Properties of New Chloro-9H-xanthones with an

Aminoalkyl Side Chain
by Cesar Portelaa ), Carlos M. M. Afonso*a ), Madalena M. M. Pintoa ), Dinora Lopesb ),
Fatima Nogueirab ), and Virg#lio do Rosariob )
a

) Centro de Estudos de Qumica Organica, Fitoqumica e Farmacologia da Universidade do Porto

(CEQOFFUP), Servio de Qumica Organica, Faculdade de Farmacia, Rua Anbal Cunha, 164,
PT-4050-047 Porto (phone: 351-22-207-8916; fax: 351-22-200-3977; e-mail: cafonso@ff.up.pt)
b
) Centro de Malaria e Outras Doenas Tropicais, Instituto de Higiene e Medicina Tropical,
Universidade Nova de Lisboa, Rua da Junqueira, 96, PT-1349-008 Lisboa

The synthesis and antimalarial properties of twelve new chlorinated 9H-xanthones, carrying a [2(diethylamino)ethyl]amino group in position 1, are reported. All compounds were found to be active
towards the chloroquine-susceptible and chloroquine-resistant strains 3D7 and Dd2, resp., of the
protozoa parasite Plasmodium falciparum. Especially one compound, 6-chloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1k), was found to exhibit significant in vitro activity (IC50 3.9 mm)
towards the resistant Dd2 strain.

Introduction. Malaria continues to be one of the most-dangerous diseases in the

world, showing frightful numbers in infected people and deaths [1 3]. Regardless of
these facts, the investment into control of malaria, better public-health conditions, and
treatments are insufficient [4 8]. The problem grows even bigger with the development
of resistance by the Plasmodium parasites [4 8]. One intervention is the development of
new compounds with better efficacy and without resistance by the parasite.
Human malaria is due to four protozoa-parasite types: Plasmodium vivax, P. ovale,
P. malariae, and P. falciparum [1 3]. Thereby, P. falciparum causes most problems due
to its prevalence, virulence, and drug resistance. These Plasmodium species are
intracellular parasites, infecting red-blood cells and feeding on haemoglobin. The
haemoglobin is digested, with the resulting amino acids being used by the Plasmodium
protozoa [9]. From this digestion also results the by-product haem, which is toxic to the
parasite [9]. The avoidance to this toxicity comes as a consequence of a biomineralization process that converts haem (Fe2 protoporphyrin IX) into haematin (Fe3
protoporphyrin IX), and then into haemozoin, known as malaria pigment present in
the parasiteIs vacuoles [9 12].
Several antimalarial drugs have been long used in malaria therapy. The quinoline
drugs, like chloroquine, efficiently eliminate the parasite, are simple and economical to
obtain, and present low toxicity [3]. The problem with these compounds is the
increasing widespread of resistance [6] [7]. Their mechanism of action consists in
preventing the process of haemozoin formation [13 23]. Thus, the consequent
concentration of free haematin would be sufficient to kill the parasite [24 37]. Other,
structurally different compounds have shown the same type of activity [38 42]. A
N 2007 Verlag Helvetica Chimica Acta AG, ZQrich

CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

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group of such compounds are hydroxylated xanthones [40 42]. Some of these
xanthones are active against multi-drug-resistant strains of P. falciparum [40]. The
similar pharmacological mechanism is probably due to similar stereo-electronic
properties between the active quinolines and the hydroxylated xanthones, as evaluated
by theoretical calculations [43] [44]. Both groups of compounds present a central area
of positive electrostatic potential and a peripheral area of negative electrostatic
potential, a stereo-electronic profile complementary to that of the putative receptors
[43] [44]. Docking simulations [44] have provided similar results as NMR studies
[17] [18] [45] [46].
Based on this information, we decided to design a series of new xanthones of type 1,
with a [2-(diethylamino)ethyl]amino group and one to four Cl-atoms in different
positions [47]. The aminated side chain can serve pharmacokinetic purposes due to its
basicity. It becomes protonated and allows accumulation of the molecule inside the
parasite acidic vacuole [48 54]. There are recent evidences that this type of side chain
can be helpful in the interaction with the receptor [53] [54]. Further, the electronwithdrawing effect of Cl-atoms should favor an electronic distribution allowing binding
to putative receptors for haematin derivatives. This group of compounds presents a
central area of positive electrostatic potential and a peripheral area of negative
electrostatic potential [47].
Herein, we describe the synthesis of compounds 1a 1l by Ullmann-type ether
condensation [55] [56], intramolecular Friedel Crafts acylation [57], and Cu-catalyzed
N-arylation [58] as key steps. We also report the toxic action of these new compounds
towards the malarial parasite using the WHO Mark-III test [59] for two different
strains of P. falciparum, i.e., the 3D7 and the Dd2 strains, which are susceptible and
resistant, respectively, to chloroquine, mefloquine, and quinine.
Results and Discussion. 1. Synthesis. 9H-Xanthones have been the target of
several studies over the years [42] [60]. Several methods have been developed that
allow the generation of variously substituted derivatives [60].
The protocol used for the preparation of the new xanthones 1 was very similar in all
cases, their synthesis being outlined in Schemes 1 and 2. The difference between the two
approaches relies on the fact that, in case of compounds 1j 1l, the Cl-atom to be
substituted by the amino side chain, is not present in the phenolic substrate, but in the
benzoic acidic building block. This difference avoids the formation of regio-isomers
upon intramolecular acylation, thus allowing the synthesis of precursor xanthones
always presenting a Cl-atom in position 1.
The synthesis of compounds 1a 1i (Scheme 1) involved two starting materials, the
methyl esters 2, prepared in high yield from the corresponding acids 3 by Fisher
esterification [61] with MeOH/H2SO4 , and the sodium phenoxides 4, which were
obtained in situ by exposure to an equimolar amount NaOH in MeOH followed by
solvent evaporation. Next, Ullmann condensation between 2 and 4 in the presence of a
catalytic amount of Cu powder afforded the diaryl ether 5 1). The latter were dissolved
1)

When the same procedure was followed, but in the presence of phosphazene, no diaryl ether was
obtained [60]. Also, the use of Cu/CuCl/K2CO3 in (i-Pr)2NEt as solvent only allowed the formation
of compounds 1f 1i [61 64].

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CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

in a mixture of THF/MeOH to which 5m NaOH was added to hydrolyze the Me ester

[61]. The resulting free acid 6 was then converted with PCl5 to the correspondent acid
halide 7 for efficient intramolecular acylation to the 9H-xanthone [65]. Cyclization was
induced by AlCl3 in EtNO2 [66], yielding the chlorinated xanthone 8. Finally, the
substituted amino group in position 1 was introduced by heating 8 with 4 equiv. of N,Ndiethylethane-1,2-diamine (9) in MeOH and in the presence of Cu2O as catalyst [58].
Compounds 1j 1l (Scheme 2) were prepared via compounds 10 17 in analogy as
described above, but using methyl 2,6-dichlorobenzoate (12) as the ester component to
guarantee a Cl-atom in position 1 of the xanthone 17.
The overall yields of 1a 1i were higher for compounds carrying fewer Cl-atoms,
due to their deactivating effect in both the Ullmann and Friedel Crafts reactions. In
contrast, the yields of 1j 1i were similar. In general, the yields of these compounds
were lower than expected, probably due to steric hindrance in the Ullmann reaction.
Compounds 1 were identified on the basis of their IR, 1H-NMR, 13C-NMR, and
HR-ESI-MS data. The 1H-NMR spectrum of, e.g., 1a exhibited the following
characteristic signals for the [2-(diethylamino)ethyl]amino group: d(H) 1.09 (t, J
7.1, Me(4)); 2.63 (q, J 7.1, CH2(3)); 2.78 (t, J 6.4, CH2(2)); 3.27 (q, J 6.4, CH2(1)).

CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

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Scheme 1

a) H2SO4 , MeOH, reflux, 8 h. b) Cu, 2, 1608, N2 , 12 24 h. c) 5m NaOH/MeOH/THF 2 : 2 : 1, r.t., 24 h. d)

PCl5 , 1308, N2 , 1 h. e) AlCl3 , EtNO2 , r.t., N2 , 2 h. f) Cu2O, 9, MeOH, reflux, 12 h.

The NH group was observed at d(H) 9.54 (br. s). All compounds showed similar NMR
profiles with respect to the side chain, with similar chemical shifts and coupling
constants. The aromatic 1H-NMR signals of 1a were observed at d(H) 6.59 (s,
HC(2)), 7.44 (d, J 8.6, HC(7)), and 8.05 (d, J 8.6, HC(8)). The other target
compounds showed similar NMR profiles, with additional characteristic aromatic
signals, according to the position of the Cl-atoms. The 13C-NMR spectra of all
compounds showed 17 distinct signals each, in agreement with the proposed structures.
The HR-ESI mass spectra of compounds 1 showed the respective quasi-molecular ion
peaks at the expected m/z values (see Exper. Part)
2. Biological Studies. We tested the in vitro activities of compounds 1 towards two
strains of Plasmodium falciparum, 3D7 being sensitive to several antimalarial drugs,
including chloroquine, and Dd2 being resistant to them. The results of these
experiments are collected in the Table. As can be seen, all twelve compounds were
found to be active towards the two strains. Thereby, a more pronounced effect was

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CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

Scheme 2

a) PCl5 , 1308, N2 , 1 h. b) MeOH, reflux, 8 h. c) Cu, 12, 1608, N2 , 12 24 h. d) 5m NaOH/MeOH/THF

2 : 2 : 1, r.t., 24 h. e) PCl5 , 1308, N2 , 1 h. f) AlCl3 , EtNO2 , r.t., N2 , 2 h. g) Cu2O, 9, MeOH, reflux, 12 h.

observed for strain 3D7, with IC50 values of 1.7 18.1 mm, relative to strain Dd2, with
IC50 values in the range 3.9 66.4 mm. The activity of each compound within the series
1a 1l towards the resistant strain Dd2 was either similar to that of 3D7 (Entries 6, 9,
11, and 12), somewhat lower (Entries 1, 3, 7, and 10), or significantly lower (Entries 2, 4,
5, and 8).
Table. Growth-Inhibiting Activities of Compounds 1 towards Strains 3D7 and Dd2 of Plasmodium
falciparum. For details, see Exper. Part.
Compound

1a
1b
1c
1d
1e
1f

IC50 [mm] a )

Compound

3D7

Dd2

2.4  0.2
4.4  0.7
9.9  0.8
2.8  0.5
1.7  0.5
7.1  0.8

13.5  0.9
25.8  1.12
13.6  1.0
33.3  0.3
66.4  0.7
9.7  0.2

1g
1h
1i
1j
1k
1l

IC50 [mm] a )
3D7

Dd2

18.1  1.3
2.25  0.7
12.5  0.8
3.7  0.5
3.7  0.5
4.1  0.7

38.3  0.6
46.6  2.3
13.7  0.3
8.1  0.6
3.9  0.3
5.9  0.3

a
) Concentration causing 50% inhibition of parasite maturation for the stage of schizont with at least
three nuclei.

The mono-chlorinated xanthones with Cl-atoms in position 5 (1l) or position 6 (1k)

exhibited similar activities in both strains.
The doubly chlorinated xanthones with a Cl-atom in position 3 differed in activity
according to the position of the second Cl-atom. When this second Cl-atom was at
position 5 (1h), a more pronounced activity in the susceptible strain was observed, with

CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

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an evident reduction in activity in the resistant one. The presence of a second Clchlorine atom in position 6 (1i) reduced the activity towards strain 3D7, the IC50 values,
however, being similar for both strains. Further, the doubly chlorinated xanthones with
a Cl-atom in position 4 (1f and 1g) showed similar activity trends towards the two
strains, the compound with a C-atom in 6-position (1f) being more active. Finally,
simultaneous presence of Cl-atoms in positions 5 and 6 (1j) was found to cause a
reduction in activity when comparing 3D7 with Dd2.
The xanthones with three Cl-atoms, one being in 4-position (1b and 1d), gave rise to
a clear reduction in activity when comparing strain 3D7 with strain Dd2. When there
was no Cl-atom at C(4), as in 1c, a relative decrease in activity was observed in the
susceptible strain, the IC50 value being similar in the resistant strain. The trichloro-9Hxanthones with a Cl-atom in position 6 (1b 1d) generally showed higher activities in
strain Dd2.
In case of the tetrachlorinated xanthone 1a, a decrease in activity was observed
when passing from 3D7 to Dd2.
As can be seen from the Table, an increase in the number of Cl-atoms did not
significantly increase activity. And when it happened, as in strain 3D7, there was a
significant decrease in activity in the resistant strain. A Cl-atom in position 6 seems to
be important for activity in both strains; and the same is true for a single Cl-atom in
position 5. This finding is in accordance with the structure of known antimalarial drugs
based on chlorinated 4-aminoquinolines (chloroquine, amodiaquine, quinacrine,
pyronaridine), in which the Cl-atom is in the same relative position as in compounds
1 that have a 6-Cl substituent. This structural similarity between our compounds and
known antimalarial quinolines or hydroxylated xanthones seems to indicate identical
mechanisms of action. These compounds might interact with haematin in the form of a
m-oxo dimer or a dimer of haemozoin. This interaction would lead to stabilization of
haematin in a soluble form, consequently leading to parasite death.
There are other factors that influence activity, determining the amount of drug
available to interact with the receptor, with consequent toxicity to the parasite.
Features such as log P, pKa , molecular volume, size, and H-bonding are further
determinants that can be important during the pharmacokinetic process.
Conclusions. Twelve chlorinated 9H-xanthonic derivatives 1 with a [2-(diethylamino)ethyl]amino substituent in 1-position were prepared and studied for their
antimalarial activities. All compounds were found to be active towards the strains 3D27
and Dd2 of Plasmodium falciparum. All compounds present a stereo-electronic profile
complimentary to the putative receptors, allowing an approximation to haematin m-oxo
dimer and haemozoin dimer. Their antiplasmodial action is most likely due to the
inhibition of haemozoin formation, allowing the development of toxicity to the parasite
by free haematin.
6-Chloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1k) was found to
be the most promising drug. This molecule has a structure with a Cl-atom and a
substituted amino side chain that are in the same relative positions as those in the
potent antimalarial drug chloroquine. The stereo-electronic profile of 1k is very similar
to that of halofantrine, and comparable to those of hydroxylated 9H-xanthones, which
may account for its activity. The activity of 1k towards the two strains is similar,

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CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

showing the capability of overcoming the resistance of the Dd2 strain. Thus, 1k can be
considered a lead compound for future work in the development of new antimalarial
drugs.
We thank Fundaao para a Ciencia e Tecnologia (FCT, Lisbon, Portugal; I&D No. 226/94), POCTI,
FEDER, and PRAXIS XXI for financial support. C. S. kindly acknowledges a Ph.D. grant (SFRH/BD/
3036/2000) from FCT. We also thank Dr. Bruce F. Milne for reviewing the manuscript.

Experimental Part
General. Solvents were of reagent-grade, purchased from commercial suppliers, and used without
further purification. Cu, PCl5 , AlCl3 , and Cu2O were supplied by Sigma Aldrich. Compound 3c was
obtained from 2,3,4-trichlorophenyl methyl ketone (Sigma Aldrich) by an adaptation of the haloform
reaction [66]. Compounds 2a, 2c, and 11 were obtained by Fisher esterification [65] of 3a, 3c, and 10,
resp., supplied by Sigma Aldrich. Compounds 4a 4c were obtained in situ, by adding an equimolar
amount of NaOH in MeOH to the respective phenols (3,5- and 2,5-dichlorophenol, and 2,3,5trichlorophenol, resp.; Sigma Aldrich). Compounds 13a 13c were also obtained in situ by adding an
equimolar amount of NaOH in MeOH to the respective phenols (3- and 2-chlorophenol, and 2,3dichlorophenol, resp.). N,N-Diethylethane-1,2-diamine (9) was supplied by Sigma Aldrich. All
reactions were monitored by GC/MS (Finnigan Thermoquest GCQ-plus system), and interrupted when
one reagent was no longer detectable. TLC: Merck silica gel 60 GF 254. M.p.: Kofler microscope;
uncorrected. IR Spectra: Perkin-Elmer 257 spectrophotometer; KBr microplates; in cm  1. 1H- and
13
C-NMR Spectra: Bruker DRX-500 spectrometer; at r.t. in CDCl3 ; d in ppm rel. to Me4Si, J in Hz. HRESI-MS: VG Autospec-M; in m/z.
General Procedure for the Preparation of 1a 1i. A soln. of the appropriate acid 3 (25 mmol) in
MeOH (100 ml) was treated with 98% H2SO4 (5 ml) and stirred at reflux for 8 h. After evaporation of the
solvent, the product was extracted with Et2O/H2O 1 : 1 (100 ml), the org. layer was washed with 5% aq.
NaHCO3 soln. (25 ml), dried (Na2SO4 ), and concentrated to afford 2. Then, 5m NaOH in MeOH (1 ml,
5 mmol) was added to the corresponding phenol to afford 4 in situ after solvent removal under anh. N2 .
The appropriate compound 2 (10 mmol) and Cu (50 mg) were added to 4 (5 mmol), and the mixture was
stirred at 1608 under anh. N2 (GC/MS control). After the end of the reaction, crude 5 was obtained, which
was taken up in Ac2O, filtered to eliminate Cu, and concentrated in vacuo. To a soln. of the resulting
residue in THF/MeOH 1 : 1 (40 ml) was added 5m aq. NaOH (10 ml), and the mixture was stirred for 24 h
at r.t. (GC/MS control). The solvents were evaporated, the residue was dissolved in H2O, and treated
with conc. HCl (1.0 ml). The acidified hydrolyzate was extracted with Et2O (3  50 ml), dried (Na2SO4 ),
and concentrated. The resulting crude acid 6 was placed in a round-bottom flask, and PCl5 (2.03 g,
10 mmol) was added under anh. N2 . The mixture was stirred at 1308 for 1 h (GC/MS control) to afford, in
situ, the acid chloride 7 (GC/MS control). After cooling, AlCl3 (1.30 g, 10 mmol) and EtNO2 (20 ml) were
directly added, and stirring was continued for 2 h at r.t. under N2 . The reaction was quenched by adding
H2O, and the solvents were removed. The resulting crude was dissolved in Et2O, filtered, washed with
H2O (2  50 ml), sat. aq. NaHCO3 soln. (50 ml), and H2O (50 ml). After solvent removal, a mixture of
crude 8, the diamine 9 (2.32 g, 20 mmol), Cu2O (50 mg), and MeOH (8 ml) was stirred at reflux for 12 h.
The formation of the target compound 1 was checked by GC/MS. The mixture was taken to dryness, the
resulting crude was taken up in Ac2O, and filtered. The final products 1 were purified by prep. TLC
(SiO2 ; Et2O/Et3N 99 : 1).
General Procedure for the Preparation of 1j 1l. Compound 10 (25 mmol) was placed in a roundbottom flask, to which was added PCl5 (2.03 g, 10 mmol) under anh. N2 . The mixture was stirred at 1308
for 1 h (GC/MS control). After cooling, MeOH (100 ml) was added to crude 11, and the soln. was heated
at reflux for 8 h. The solvent was evaporated, and the product was extracted with Et2O/H2O 1 : 1 (100 ml).
The org. phase was washed with aq. 5% NaHCO3 soln. (25 ml), dried (Na2SO4 ), and concentrated to
afford 12. 5m NaOH in MeOH (1 ml, 5 mmol) was added to the corresponding phenol to afford 13 in situ,
and the solvent was removed under a stream of anh. N2 . Then, 12 (10 mmol) and Cu (50 mg) were added

CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

1515

to 13 (5 mmol), and the mixture was stirred at 1608 under anh. N2 (GC/MS control). The resulting crude
14 was taken up in Ac2O, filtered to eliminate the Cu, and concentrated in vacuo. To a soln. of the
resulting residue in THF/MeOH 1 : 1 (40 ml) was added 5m aq. NaOH soln. (10 ml), and the mixture was
stirred for 24 h at r.t. (GC/MS control). The solvents were evaporated, the hydrolysis product was
dissolved in H2O, acidified by adding conc. HCl (1.0 ml), and extracted with Et2O (3  50 ml). The org.
phase was separated, dried (Na2SO4 ), and evaporated. The resulting crude 15 was directly placed in a
round-bottom flask, to which was added PCl5 under anh. N2 , and the mixture was stirred for 1 h at 1308
(GC/MS control). After cooling, AlCl3 and EtNO2 were added to crude 16, and stirring was continued for
2 h at r.t. under anh. N2 . The formation of 17 was controlled by GC/MS. The reaction was quenched by
adding H2O, the solvents were evaporated, the resulting crude was dissolved in Et2O, filtered, and washed
with H2O (2  50 ml), sat. aq. NaHCO3 soln. (50 ml), and H2O (50 ml). The Et2O was evaporated, and
the product 17 was placed in a round-bottom flask, together with 9 (2.32 g, 20 mmol), Cu2O (50 mg) and
MeOH (8 ml). The mixture was stirred at reflux for 12 h (GC/MS control). The mixture was then taken
to dryness. The resulting crude 1 was taken up in Ac2O, and filtered. The target compounds were purified
by prep. TLC (SiO2 ; Et2O/Et3N 99 : 1).
3,4,5,6-Tetrachloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1a). Yield: 3%. Yellow
crystals. M.p. 251 2528 (dec.). IR (KBr): 3259, 2968, 2925, 2852, 2790, 1643, 1558, 1500, 1430, 1248, 1178,
1068, 968, 808, 781. 1H-NMR (300 MHz, CDCl3 ): 9.54 (br. s, HNC(1)); 8.05 (d, J 8.6, HC(8)); 7.44
(d, J 8.6, HC(7)); 6.59 (s, HC(2)); 3.27 (q, J 6.4, CH2(1)); 2.78 (t, J 6.4, CH2(2)); 2.63 (q, J
7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR (75 MHz, CDCl3 ): 177.4 (C(9)); 153.5 (C(4a)); 151.5
(C(10a)); 149.5 (C(1)); 141.1 (C(3)); 139.1 (C(6)); 125.5 (C(8)); 124.5 (C(5)); 121.7 (C(7)); 121.2
(C(8a)); 118.4 (C(4)); 105.9 (C(9a)); 105.8 (C(2)); 50.9 (C(2)); 47.0 (C(3)); 41.3 (C(1)); 11.8 (C(4)).
ESI-MS: 451 (51), 450 (20), 449 (100), 447 (57), 332 (48), 310 (33), 206 (20). HR-ESI-MS: 447.01982
([M H] , C19H19Cl4N2O 2 ; calc. 447.02006).
4,5,6-Trichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1b). Yield: 5%. Yellow crystals. M.p. 230 2338 (dec). IR (KBr): 3278, 2969, 2930, 2872, 2795, 1640, 1560, 1504, 1432, 1260, 1178,
1081, 960, 805, 781. 1H-NMR (300 MHz, CDCl3 ): 9.50 (br. s, HNC(1)); 8.06 (d, J 8.7, HC(8)); 7.49
(d, J 9.1, HC(3)); 7.42 (d, J 8.7, HC(7)); 6.42 (d, J 9.1, HC(2)); 3.30 (q, J 6.4, CH2(1)); 2.78
(t, J 6.6, CH2(2)); 2.63 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR (75 MHz, CDCl3 ): 177.9
(C(9)); 152.5 (C(10a)); 151.6 (C(4a)); 150.5 (C(1)); 136.7 (C(6)); 135.6 (C(3)); 125.9 (C(8)); 125.2
(C(5)); 124.9 (C(7)); 124.5 (C(8a)); 106.9 (C(4)); 105.7 (C(9a)); 105.2 (C(2)); 51.1 (C(2)); 47.1 (C(3));
41.4 (C(1)); 11.0 (C(4)). ESI-MS: 417 (33), 416 (20), 415 (100), 413 (82). HR-ESI-MS: 413.05820 ([M
H] , C19H20Cl3N2O 2 ; calc. 413.05903).
3,5,6-Trichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1c). Yield: 6%. Yellow crystals. M.p. 129 1328. IR (KBr): 3276, 2971, 2933, 2881, 2790, 1641, 1562, 1508, 1431, 1261, 1240, 1199, 1091,
1068, 958, 804, 750. 1H-NMR (300 MHz, CDCl3 ): 9.54 (br. s, HNC(1)); 8.03 (d, J 8.5, HC(8)); 7.38
(d, J 8.5, HC(7)); 6.63 (s, HC(4)); 6.40 (s, HC(2)); 3.27 (q, J 5.2, CH2(1)); 2.78 (t, J 6.3,
CH2(2)); 2.63 (q, J 6.9, CH2(3)); 1.09 (t, J 7.0, Me(4)). 13C-NMR (75 MHz, CDCl3 ): 177.4 (C(9));
157.7 (C(4a)); 151.8 (C(10a)); 151.5 (C(1)); 142.4 (C(3)); 138.7 (C(6)); 124.9 (C(8)); 124.5 (C(5)); 121.6
(C(7)); 121.0 (C(8a)); 104.9 (C(4)); 104.7 (C(2)); 102.8 (C(9a)); 50.9 (C(2)); 47.0 (C(3)); 41.3 (C(1));
11.2 (C(4)). ESI-MS: 417 (34), 416 (21), 415 (100), 413 (91). HR-ESI-MS: 413.05724 ([M H] ,
C19H20Cl3N2O 2 ; calc. 413.05903).
3,4,6-Trichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1d). Yield: 8%. Yellow crystals. M.p. 111 1148. IR (KBr): 3280, 2966, 2927, 2864, 2800, 1639, 1558, 1502, 1435, 1259, 1168, 1072, 960,
806, 781. 1H-NMR (300 MHz, CDCl3 ): 9.59 (br. s, HNC(1)); 8.14 (d, J 8.6, HC(8)); 7.51 (d, J 1.9,
HC(5)); 7.31 (dd, J 8.6, 1.9, HC(7)); 6.55 (s, HC(2)); 3.26 (q, J 6.5, CH2(1)); 2.78 (t, J 6.5,
CH2(2)); 2.63 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR (75 MHz, CDCl3 ): 177.9 (C(9));
154.9 (C(10a)); 153.6 (C(4a)); 149.6 (C(1)); 140.7 (C(6)); 140.5 (C(3)); 127.4 (C(8)); 125.1 (C(7)); 120.2
(C(8a)); 117.6 (C(5)); 106.2 (C(4)); 105.3 (C(9a)); 104.9 (C(2)); 50.9 (C(2)); 47.0 (C(3)); 41.3 (C(1));
11.8 (C(4)). ESI-MS: 417 (34), 416 (21), 415 (100), 413 (93). HR-ESI-MS: 413.05744 ([M H] ,
C19H20Cl3N2O 2 ; calc. 413,05903).
3,4,5-Trichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1e). Yield: 8%. Yellow crystals. M.p. 121 1248. IR (KBr): 3261, 2966, 2929, 2866, 2806, 1631, 1570, 1502, 1430, 1265, 1176, 1068, 956,

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CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

800, 765. 1H-NMR (300 MHz, CDCl3 ): 9.58 (br. s, HNC(1)); 8.12 (dd, J 8.0, 1.5, HC(8)); 7.74 (dd,
J 7.8, 1.6, HC(6)); 7.29 (t, J 7.9, HC(7)); 6.59 (s, HC(2)); 3.28 (q, J 6.4, CH2(1)); 2.79 (t, J
6.5, CH2(2)); 2.63 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR (75 MHz, CDCl3 ): 178.1
(C(9)); 150.6 (C(4a)); 149.6 (C(10a)); 140.9 (C(1)); 136.0 (C(3)); 134.7 (C(6)); 124.6 (C(8)); 124.3
(C(5)); 123.0 (C(7)); 122.6 (C(8a)); 105.9 (C(4)); 105.5 (C(9a)); 105.4 (C(2)); 50.9 (C(2)); 47.0 (C(3));
41.4 (C(1)); 11.8 (C(4)). ESI-MS: 417 (33), 416 (20), 415 (100), 413 (91). HR-ESI-MS: 413.05753 ([M
H] , C19H20Cl3N2O 2 ; calc. 413,05903).
4,6-Dichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1f). Yield: 18%. Yellow crystals.
M.p. 105 1078. IR (KBr): 3268, 2966, 2929, 2860, 2798, 1641, 1562, 1512, 1433, 1251, 1159, 1074, 943, 800.
1
H-NMR (300 MHz, CDCl3 ): 9.56 (br. s, HNC(1)); 8.16 (d, J 8.5, HC(8)); 7.52 (d, J 1.7,
HC(5)); 7.47 (d, J 9.1, HC(3)); 7.30 (dd, J 8.5, 1.7, HC(7)); 6.39 (d, J 9.1, HC(2)); 3.31 (q,
J 6.4, CH2(1)); 2.78 (t, J 6.7, CH2(2)); 2.63 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR
(75 MHz, CDCl3 ): 178.4 (C(9)); 155.1 (C(10a)); 152.7 (C(4a)); 150.6 (C(1)); 140.3 (C(6)); 136.4 (C(3));
127.5 (C(8)); 124.8 (C(7)); 120.5 (C(8a)); 117.6 (C(5)); 107.4 (C(4)); 105.3 (C(9a)); 104.7 (C(2)); 51.2
(C(2)); 47.1 (C(3)); 41.4 (C(1)); 11.8 (C(4)). ESI-MS: 381 (71), 380 (20), 379 (100), 306 (19). HR-ESIMS: 379.09644 ([M H] , C19H21Cl2N2O 2 ; calc. 379.09801).
4,5-Dichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1g). Yield: 15%. Yellow crystals.
M.p. 101 1038. IR (KBr): 3278, 2962, 2925, 2863, 2809, 1625, 1565, 1508, 1437, 1259, 1199, 1064, 887, 794,
765. 1H-NMR (300 MHz, CDCl3 ): 9.54 (br. s, HNC(1)); 8.13 (d, J 8.0, HC(8)); 7.73 (d, J 7.6,
HC(6)); 7.50 (d, J 9.0, HC(3)); 7.27 (t, J 7.8, HC(7)); 6.41 (d, J 9.0, HC(2)); 3.31 (q, J 6.3,
CH2(1)); 2.79 (t, J 6.6, CH2(2)); 2.64 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR (75 MHz,
CDCl3 ): 178.5 (C(9)); 152.4 (C(4a)); 150.7 (C(10a)); 150.5 (C(1)); 136.5 (C(3)); 134.5 (C(6)); 124.6
(C(8)); 123.9 (C(5)); 123.2 (C(7)); 122.5 (C(8a)); 107.1 (C(4)); 105.7 (C(9a)); 104.8 (C(2)); 51.2 (C(2));
47.1 (C(3)); 41.4 (C(1)); 11.8 (C(4)). ESI-MS: 381 (74), 380 (21), 379 (100), 306 (16). HR-ESI-MS:
379.09692 ([M H] , C19H21Cl2N2O 2 ; calc. 379.09801).
3,5-Dichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1h). Yield: 21%. Yellow crystals.
M.p. 96 988. IR (KBr): 3276, 2966, 2929, 2854, 2809, 1643, 1560, 1513, 1434, 1257, 1207, 1089, 937, 796, 767.
1
H-NMR (300 MHz, CDCl3 ): 9.60 (br. s, HNC(1)); 8.12 (dd, J 8.0, 1.3, HC(8)); 7.69 (dd, J 7.8, 1.3,
HC(6)); 7.24 (t, J 7.9, HC(7)); 6.67 (s, HC(4)); 6.42 (s, HC(2)); 3.29 (q, J 6.5, CH2(1)); 2.79
(t, J 6.6, CH2(2)); 2.64 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR (75 MHz, CDCl3 ): 178.2
(C(9)); 157.8 (C(4a)); 151.9 (C(1)); 150.7 (C(10a)); 142.3 (C(3)); 134.3 (C(6)); 124.7 (C(8)); 123.7
(C(5)); 123.5 (C(7)); 122.0 (C(8a)); 105.0 (C(9a)); 104.5 (C(2)); 102.9 (C(4)); 51.0 (C(2)); 47.1 (C(3));
41.4 (C(1)); 11.8 (C(4)). ESI-MS: 381 (72), 380 (20), 379 (100), 306 (18). HR-ESI-MS: 379.09688 ([M
H] , C19H21Cl2N2O 2 ; calc. 379.09801).
3,6-Dichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1i). Yield: 23%. Yellow crystals.
M.p. 111 1138. IR (KBr): 3276, 2966, 2923, 2863, 2790, 1641, 1560, 1509, 1433, 1267, 1201, 1072, 946, 794,
665. 1H-NMR (300 MHz, CDCl3 ): 9.61 (br. s, HNC(1)); 8.14 (d, J 8.5, HC(8)); 7.36 (d, J 1.4,
HC(5)); 7.27 (dd, J 8.5, 1.4, HC(7)); 6.52 (s, HC(4)); 6.40 (s, HC(2)); 3.28 (q, J 6.3, CH2(1));
2.78 (t, J 6.6, CH2(2)); 2.64 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR (75 MHz, CDCl3 ):
178.0 (C(9)); 158.1 (C(4a)); 155.2 (C(10a)); 152.0 (C(1)); 142.1 (C(3)); 140.1 (C(6)); 127.5 (C(8)); 124.5
(C(7)); 120.7 (C(8a)); 117.2 (C(5)); 105.2 (C(9a)); 104.4 (C(2)); 102.6 (C(4)); 51.0 (C(2)); 47.1 (C(3));
41.4 (C(1)); 11.8 (C(4)). ESI-MS: 381 (73), 380 (22), 379 (100), 306 (14). HR-ESI-MS: 379.09733 ([M
H] , C19H21Cl2N2O 2 ; calc. 379.09801).
5,6-Dichloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1j). Yield: 9%. Yellow crystals.
M.p. 116 1198. IR (KBr): 3274, 2964, 2929, 2848, 2805, 1641, 1558, 1511, 1425, 1238, 1184, 1076, 950, 791,
682. 1H-NMR (300 MHz, CDCl3 ): 9.46 (br. s, HNC(1)); 8.08 (d, J 8.6, HC(8)); 7.47 (t, J 8.3,
HC(3)); 7.38 (d, J 8.6, HC(7)); 6.65 (d, J 8.0, HC(4)); 6.46 (d, J 8.6, HC(2)); 3.33 (q, J
6.5, CH2(1)); 2.79 (t, J 6.8, CH2(2)); 2.64 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1, Me(4)). 13C-NMR
(75 MHz, CDCl3 ): 178.3 (C(9)); 157.7 (C(4a)); 151.9 (C(10a)); 151.7 (C(1)); 138.5 (C(6)); 136.5 (C(3));
124.6 (C(8)); 124.5 (C(5)); 121.7 (C(7)); 121.0 (C(8a)); 106.2 (C(9a)); 104.7 (C(2)); 102.2 (C(4)); 51.3
(C(2)); 47.1 (C(3)); 41.3 (C(1)); 11.8 (C(4)). ESI-MS: 381 (73), 380 (21), 379 (100), 306 (25). HR-ESIMS: 379.09637 ([M H] , C19H21Cl2N2O 2 ; calc. 379.09801).

CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

1517

6-Chloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1k). Yield: 7%. Yellow crystals. M.p.

100 1038. IR (KBr): 3274, 2964, 2923, 2856, 2800, 1641, 1590, 1514, 1432, 1238, 1170, 1072, 929, 788, 671.
1
H-NMR (300 MHz, CDCl3 ): 9.50 (br. s, HNC(1)); 8.16 (d, J 8.5, HC(8)); 7.43 (t, J 8.3,
HC(3)); 7.38 (s, HC(5)); 7.26 (d, J 8.5, HC(7)); 6.53 (d, J 8.1, HC(4)); 6.43 (d, J 8.5,
HC(2)); 3.33 (q, J 6.5, CH2(1)); 2.79 (t, J 6.8, CH2(2)); 2.64 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1,
Me(4)). 13C-NMR (75 MHz, CDCl3 ): 178.8 (C(9)); 158.0 (C(10a)); 155.5 (C(4a)); 151.8 (C(1)); 139.9
(C(6)); 136.2 (C(3)); 127.5 (C(8)); 124.1 (C(7)); 120.8 (C(8a)); 117.2 (C(5)); 106.7 (C(9a)); 104.1 (C(2));
102.0 (C(4)); 51.3 (C(2)); 47.2 (C(3)); 41.4 (C(1)); 11.8 (C(4)). ESI-MS: 347 (35), 346 (19), 345 (100),
272 (36). HR-ESI-MS: 345.13561 ([M H] , C19H22ClN2O 2 ; calc. 345.13698).
5-Chloro-1-{[2-(diethylamino)ethyl]amino}-9H-xanthen-9-one (1l). Yield: 8%. Yellow crystals. M.p.
73 768. IR (KBr): 3282, 2968, 2929, 2863, 2794, 1639, 1590, 1515, 1440, 1261, 1201, 1068, 946, 781, 723,
607. 1H-NMR (300 MHz, CDCl3 ): 9.49 (br. s, HNC(1)); 8.15 (d, J 7.8, HC(8)); 7.69 (d, J 7.1,
HC(6)); 7.47 (t, J 8.3, HC(3)); 7.23 (t, J 7.5, HC(7)); 6.66 (d, J 8.1, HC(4)); 6.45 (d, J 8.4,
HC(2)); 3.34 (q, J 6.4, CH2(1)); 2.80 (t, J 6.8, CH2(2)); 2.64 (q, J 7.1, CH2(3)); 1.09 (t, J 7.1,
Me(4)). 13C-NMR (75 MHz, CDCl3 ): 178.9 (C(9)); 157.7 (C(4a)); 151.8 (C(10a)); 151.0 (C(1)); 136.3
(C(3)); 134.1 (C(6)); 124.7 (C(8)); 123.5 (C(5)); 123.3 (C(7)); 121.9 (C(8a)); 106.5 (C(9a)); 104.3 (C(2));
102.2 (C(4)); 51.3 (C(2)); 47.2 (C(3)); 41.4 (C(1)); 11.8 (C(4)). ESI-MS: 347 (35), 346 (19), 345 (100),
272 (35). HR-ESI-MS: 345.13580 ([M H] , C19H22ClN2O 2 ; calc. 345.13698).
Antimalarial-Activity Assay. The in vitro activities of compounds 1 were evaluated by means of the
Mark III test, as developed by the WHO [58]. Two strains of Plasmodium falciparum were used, 3D7
(susceptible to chloroquine) and Dd2 (resistant to chloroquine). P. falciparum was cultivated in recently
collected erythrocytes as host cells in RPMI 1640 medium (Gibco) containing 25 mm HEPES (Sigma)
and 6.8m hipoxantin (Sigma) supplemented with 0.5% AlbuMax II (Invitrogen). Cultures were kept at
378 under an atmosphere of 5% O2 , 3 5% CO2 , and N2 . Drug-sensitivity assays were carried out on 96well micro-plates. The new compounds 1 and chloroquine (pos. control) [58] were dissolved in culture
medium and passed through sterile filters (0.22 mm). The micro-plates were titrated with two-fold serial
dilutions of each compound as well as the control. Each strain was plated (in duplicate) using a
synchronized culture with a parasitaemia of 0.6 0.8%, with a predominance of ring-stage parasites. Each
well received 10 ml of parasite-loaded erythrocytes, 5% haematocrit, and 90 ml of the different drug
dilutions. The plates were incubated at 378 for 24 36 h, after confirmation of presence of mature
schizonts in control wells, without drug. At the end of this period, the blood from each well was harvested,
and a thick film was prepared. The films were fixated with acetone, and stained for 60 min in Giemsa stain
at a dilution of 1 vol-% in buffered H2O (pH 6.8). Three independent optical-microscopy readings of the
number of schizonts with three or more nuclei were carried out in 200 parasitized red cells for each
dilution and duplicate. Growth inhibition was expressed as percent of the number of schizonts for each
concentration, compared with untreated controls. Mean IC50 values were calculated from dose-response
curves (percentage of schizonts vs. logarithm of drug concentration) by linear interpolation.

REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]

P. A. Winstanley, Parasitol. Today 2000, 16, 146.

B. M. Greenwood, Parasitol. Today 1997, 13, 90.
G. A. Biagini, P. M. OINeill, A. Nzila, S. A. Ward, P. G. Bray, Trends Parasitol. 2003, 19(11), 479.
J. C. Koella, Parasitol. Today 1998, 14, 360.
C. Wongrichanalai, A. L. Pickard, W. H. Wernsdorfer, S. R. Meshnick, Lancet 2002, 2, 209.
J. May, C. G. Meyer, Trends Parasitol. 2003, 19(10), 432.
P. G. Bray, M. Mungthin, R. G. Ridley, S. A. Ward, Mol. Pharm. 1998, 54, 170.
H. Ginsburg, M. Krugliak, Drug Resistance Updates 1999, 2, 180.
S. E. Francis, D. J. Sullivan Jr., D. E. Goldberg, Annu. Rev. Microbiol. 1997, 51, 97.
G. Blauer, M. Akkawi, J. Inorg. Biochem. 1997, 66, 145.
S. Pagola, P. W. Stephens, D. S. Bohle, A. D. Kosar, S. K. Madsen, Nature 2000, 404, 307.
D. S. Bohle, R. E. Dinnebier, S. K. Madsen, P. W. Stephens, J. Biol. Chem. 1997, 272, 713.

1518

[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]

[53]
[54]

CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

A. Dorn, R. Stoffel, H. Matile, A. Bubendorf, R. G. Ridley, Nature 1995, 374, 269.

C. D. Fitch, A. C. Chou, Antimicrob. Agents Chemother. 1997, 41, 2461.
J. Zhang, M. Krugliak, H. Ginsburg, Mol. Biochem. Parasitol. 1999, 99, 129.
S. R. Vippagunta, A. Dorn, R. G. Ridley, J. L. Vennerstrom, Biochim. Biophys. Acta 2000, 1475, 133.
S. Moreau, B. Perly, J. Biguet, Biochimie 1982, 64, 1015.
S. Moreau, B. Perly, C. O. Chachaty, C. Deleuze, Biochim. Biophys. Acta 1985, 840, 107.
A. C. Chou, R. Chevli, C. D. Fitch, Biochemistry 1980, 19, 1543.
T. J. Egan, W. W. Mavuso, D. C. Ross, H. M. Marques, J. Inorg. Biochem. 1997, 68, 137.
D. J. Sullivan Jr., I. Y. Gluzman, D. G. Russell, D. E. Goldberg, Proc. Natl. Acad. Sci. U.S.A. 1996, 93,
11865.
D. J. Sullivan Jr., H. Matile, R. G. Ridley, D. E. Goldberg, J. Biol. Chem. 1998, 273, 31103.
A. Dorn, S. R. Vippagunta, H. O. Matile, C. O. Jaquet, J. O. L. Vennerstrom, R. G. Ridley, Biochem.
Pharmacol. 1998, 55, 727.
A. C. Chou, C. D. Fitch, J. Clin. Invest. 1980, 66, 856.
A. U. Orjih, H. S. Banyal, R. Chevli, C. D. Fitch, Science 1981, 214, 667.
H. Ginsburg, R. A. Demel, Biochim. Biophys. Acta 1983, 772, 316.
R. P. Hebbel, J. W. Eaton, Semin. Hematol. 1989, 26, 136.
H. Ginsburg, O. Famin, J. Zhang, M. Krugliak, Biochem. Pharmacol. 1998, 56, 1305.
Y. Sugioka, M. Suzuki, Biochim. Biophys. Acta 1991, 1074, 19.
L. M. B. Ursos, K. F. DuBay, P. D. Roepe, Mol. Biochem. Parasitol. 2001, 112, 11.
T. J. Egan, E. Hempelmann, W. W. Mavuso, J. Inorg. Biochem. 1999, 73, 101.
M. Foley, L. Tilley, Pharmacol. Ther. 1998, 79, 55.
S. R. Hawley, P. G. Bray, M. Mungthin, J. D. Atkinson, P. M. OINeill, S. A. Ward, Antimicrob. Agents
Chemother. 1998, 42, 682.
T. J. Egan, H. M. Marques, Coord. Chem. Rev. 1999, 190 192, 493.
T. J. Egan, Exp. Opin. Ther. Patents 2001, 11, 185.
J. Ziegler, R. Linck, D. W. Wright, Curr. Med. Chem. 2001, 8, 171.
S. R. Vippagunta, A. Dorn, H. Matile, A. K. Battacharjee, J. M. Karle, W. Y. Ellis, R. G. Ridley, J. L.
Vennerstrom, J. Med. Chem. 1999, 42, 4630.
R. W. Winter, K. A. Cornell, L. L. Johnson, M. Ignatushenko, D. J. Hinrichs, M. K. Riscoe,
Antimicrob. Agents Chemother. 1996, 40, 1408.
R. W. Winter, M. Ignatushenko, O. A. T. Ogundahunsi, K. A. Cornell, A. M. J. Oduola, D. J.
Hinrichs, M. K. Riscoe, Antimicrob. Agents Chemother. 1997, 41, 1449.
M. Ignatushenko, R. W. Winter, H. P. Bachinger, D. J. Hinrichs, M. K Riscoe, FEBS Lett. 1997, 409,
67.
M. V. Ignatushchenko, R. W. Winter, M. K. Riscoe, Am. J. Trop. Med. Hyg. 2000, 62, 77.
M. Riscoe, J. X. Kelly, R. Winter, Curr. Med. Chem. 2005, 12, 2539.
C. Portela, C. Afonso, M. M. M. Pinto, M. J. Ramos, Bioorg. Med. Chem. 2004, 12, 3313.
C. Portela, C. Afonso, M. M. M. Pinto, M. J. Ramos, FEBS Lett. 2003, 547, 217.
A. Leed, K. DuBay, L. M. B. Ursos, D. Sears, A. C. Dios, P. D. Roepe, Biochemistry 2002, 41, 10245.
A. C. Dios, R. Tycko, L. M. B. Ursos, P. D. Roepe, J. Phys. Chem., Sect. A 2003, 107, 5821.
C. Portela, C. Afonso, M. M. M. Pinto, M. J. Ramos, J. Comput. Aided Mol. Des. 2003, 17, 583.
S. R. Vippagunta, A. Dorn, H. Matile, A. K. Battacharjee, J. M. Karle, W. Y. Ellis, R. G. Ridley, J. L.
Vennerstrom, J. Med. Chem. 1999, 42, 4630.
D. De, F. M. Krogstad, L. D. Byers, D. J. Krogstad, J. Med. Chem. 1998, 41, 4918.
T. J. Egan, R. Hunter, C. H. Kaschula, H. M. Marques, A. Misplon, J. Walden, J. Med. Chem. 2000,
43, 283.
D. De, F. M. Krogstad, F. B. Cogswell, D. J. Krogstad, Am. J. Trop. Med. Hyg. 1996, 55, 579.
R. G. Ridley, W. Hofheinz, H. Matile, C. Jaquet, A. O. Dorn, R. O. Masciadri, S. O. Jolidon, W. F. O.
Richter, A. O. Guenzi, M. Girometta, H. Urwyler, W. Huber, S. Thaithong, W. Peters, Antimicrob.
Agents Chemother. 1996, 40, 1846.
A. K. Battacharjee, J. Mol. Struct. (Theochem) 2000, 529, 193.
A. K. Battacharjee, J. Mol. Struct. (Theochem) 2001, 549, 27.

CHEMISTRY & BIODIVERSITY Vol. 4 (2007)

[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]

1519

A. A. Moroz, M. S. Shvartsberg, Russ. Chem. Rev. 1974, 43, 679.

J. S. Sawyer, Tetrahedron 2000, 56, 5045.
A. J. Quillinan, F. Scheinmann, J. Chem. Soc., Perkin Trans. 1 1973, 1329.
F. Lang, D. Zewge, I. N. Houpis, R. P. Volante, Tetrahedron Lett. 2001, 42, 3251.
WHO/CTD/MAL/97 20 Rev 2, Geneva, WHO, 2001.
M. E. Sousa, M. M. M. Pinto, Curr. Med. Chem. 2005, 12, 2447.
G. W. Rewcastle, G. J. Atwell, B. C. Baguley, S. B. Calveley, W. A. Denny, J. Med. Chem. 1989, 32,
793.
A. A. Goldberg, A. H. Wragg, J. Chem. Soc. 1958, 4227.
A. A. Goldberg, A. H. Wragg, J. Chem. Soc. 1958, 4234.
G. J. Atwell, G. W. Rewcastle, B. C. Baguley, W. A. Denny, J. Med. Chem. 1990, 33, 1375.
W. T. Jackson, R. J. Boyd, L. L. Froelich, D. M. Gapinski, B. E. Mallet, J. S. Sawyer, J. Med. Chem.
1993, 36, 1726.
J. G. Smith, M. Fieser, WFiezer and FieserIs Reagents for Organic SynthesisI, John Wiley & Sons, New
York, 1990, Vol. 4, p. 357.
Received October 20, 2006