(2-Arylhydrazonomethyl)-substituted xanthones as antimycotics: Synthesis and fungistatic activity against Candida species

Article abstract of DOI:10.1016/S0223-5234(01)01332-0

A series of arylhydrazones derived from various 6,8-diacetoxy- or 6,8-dihydroxy-9-oxo-9H-xanthene carboxaldehydes were synthesized and evaluated for their in vitro antifungal properties against two human pathogenic yeasts (Candida albicans and C. krusei) according to a diffusion method. The activity was strongly dependent from the position of the (1-arylhydrazinyl-2-ylidene)methyl chain in the xanthone molecular skeleton. Compounds having the nitrogen side chain in the 4-position, with a further halogen substitution on the terminal phenyl ring showed fungistatic effects. Within this series, the 4-fluorophenylhydrazinyl derivative 13g exhibited the highest activity, particularly against C. krusei, with a greater efficacy than that of econazole, used as reference.

Full text of DOI:10.1016/S0223-5234(01)01332-0

European Journal of Medicinal Chemistry 37 (2002) 237–253
www.elsevier.com/locate/ejmech
Laboratory note
(2-Arylhydrazonomethyl)-substituted xanthones as antimycotics:
synthesis and fungistatic activity against Candida species
Ste´phane Moreau, Martine Varache-Lembe`ge, Ste´phane Larrouture, Djibril Fall,
Arlette Neveu, Ge´rard Deffieux, Joseph Vercauteren, Alain Nuhrich *
´
Groupe d’Etude des Substances Naturelles d’Inte´reˆt The´rapeutique (GESNIT, EA 491), Uni6ersite´ Victor-Segalen Bordeaux 2, 146 rue
Le´o-Saignat, F-33076 Bordeaux cedex, France
Received 4 September 2001; received in revised form 30 November 2001; accepted 6 December 2001
Abstract
A series of arylhydrazones derived from various 6,8-diacetoxy- or 6,8-dihydroxy-9-oxo-9H-xanthene carboxaldehydes were
synthesized and evaluated for their in vitro antifungal properties against two human pathogenic yeasts (Candida albicans and C.
krusei ) according to a diffusion method. The activity was strongly dependent from the position of the (1-arylhydrazinyl-2-yli-
dene)methyl chain in the xanthone molecular skeleton. Compounds having the nitrogen side chain in the 4-position, with a further
halogen substitution on the terminal phenyl ring showed fungistatic effects. Within this series, the 4-fluorophenylhydrazinyl
derivative 13g exhibited the highest activity, particularly against C. krusei, with a greater efficacy than that of econazole, used as
´
reference. © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: Arylhydrazono-xanthones; Synthesis; Structural study; In vitro anticandida activity
1. Introduction
transporters [11]. Furthermore, an increased constitu-
tive expression of the ABC1 transporter gene in C.
krusei was recently described [12].
During the last years, antifungal drug research
mainly focused on the pharmacomodulation of azole
compounds. Although numerous derivatives of this
class are actually at various stages of development [13],
Development of fungal infections remains a major
therapeutic problem in immunocompromised patients
due to AIDS, cancer chemotherapy, or bone marrow
transplantation [1,2]. Among the responsible agents of
these opportunistic mycoses, Candida albicans is pre-
dominantly encountered; however other Candida spe-
cies such as C. krusei are also emerging as clinically
significant pathogens [3–5].
The triazoles (fluconazole and itraconazole) are the
most widely used agents for the treatment of fungal
infections. However, the emergence of Candida resistant
species is a crucial and growing problem [6–8]. This
resistance may act via various mechanisms (alteration
of 14 a-demethylase, defect in D 5,6-sterol desaturase)
[9,10], but the main pathway seems related to an en-
hanced drug efflux by ATP binding cassette (ABC)
* Correspondence and reprints: Present address: Laboratoire de
Chimie The´rapeutique, 3, Place de la Victoire, 33076 Bordeaux
Cedex, France.
E-mail address: alain.nuhrich@chimthera.u-bordeaux2.fr (A.
Nuhrich).
Fig. 1. Some natural xanthones with antifungal activity.
´
0223-5234/02/$ - see front matter © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
PII: S0223-5234(01)01332-0

238
S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
have been reported as interesting fungal growth inhi-
bitors [18–20]. Thus, based on these findings, we have
hypothesized in the present work that the combination
of a xanthone nucleus with a 1-hydrazinyl-2-ylidene
(ꢀNHꢀNꢁ) side chain might be an intriguing pharma-
cophore for antifungal drug design. Consequently, dif-
ferent arylhydrazones derived from 9-oxo-9H-
xanthenecarboxaldehydes were synthesized and evalu-
ated for their in vitro activity against yeasts. In this
paper, we mainly focused on the derivatives obtained
from 9-oxo-9H-xanthene-4-carboxaldehyde, but some
isomers in which the hydrazonomethyl chain is at-
tached to position 2 or 3 were also considered, for
comparison (Fig. 2).
Fig. 2. General structure of the target compounds.
the search for new lead structures, particularly those
interacting with novel biological targets, is necessary.
The xanthone nucleus is present in many natural
products, including some compounds that have activity
against pathogenic fungi [14–17]. These antifungal
agents are often characterized either by an acyclic sub-
stituent attached to the tricyclic system, or by hetero-
cyclic rings fused to the molecular skeleton (Fig. 1).
Compound 4 (Sch 56036) is an example of nitrogen
derivative with a strong activity [16].
2. Chemistry
In addition, various dinitrogen compounds, contain-
ing hydrazone or hydrazide subunits in their structure
The general synthetic route used for the target xan-
thones is outlined in Fig. 3.
Fig. 3. General synthetic pathway. Reagents: (a) P2O5ꢀCH3SO3H; (b) SO2Cl2/CH2Cl2; (c) Ac2O/pyridine; (d) NBS/DBP/hw; (e) (Bu4N)2Cr2O7/
CHCl3; (f) ArꢀNHꢀNH2/EtOH; (g) NaHCO3/H2O; (h) a+c+d+e+f+(g).

S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
239
tocol appeared unsuitable in our synthetic pathway,
which required a bromination step. In fact, a competing
aromatic halogenation was observed when the benzy-
loxy analogue of 9 was treated with NBS. Nevertheless,
protection of hydroxyl groups as acetyl esters success-
fully led to the expected bromomethyl derivatives 10
and 16, respectively.
The carboxaldehydes 11 and 17 were accessible via a
controlled oxidation of the bromomethyl precursor
with bis tetrabutylammonium dichromate in chloro-
form. Subsequent reaction with an appropriate arylhy-
drazine yielded the desired hydrazones 12 or 18, which
The original procedure for preparing hydroxylated
xanthones is the cyclization reaction between
phloroglucinols and appropriate substituted salicylic
acids, in the presence of a phosphorus oxychloride–zinc
chloride as catalyst [21]. Later studies described better
results by using a mixture of phosphorus pentoxide–
methanesulfonic acid (Eaton’s reagent) [22]. For xan-
thones bearing the nitrogen side chain at position 4, in
our experiments, this acylation catalyst was found to be
an excellent condensing agent between phloroglucinol
(5) and 3-methylsalicylic acid (6), thus providing high
yields of the xanthone 8 and no detectable amounts of
the possible benzophenone 7. The crude product ob-
tained consisted in a mixture of large amount of 8
(average conversion 90–95%) containing a very small
amount of starting material and therefore could be used
for the next step without any purification. Thus, com-
pound 14 was directly obtained by chlorination of 8
using sulfuryl chloride in dichloromethane.
upon mild treatment, using
a propanol–aqueous
sodium hydrogencarbonate, gave the dihydroxyxan-
thones 13 or 19. Physical data for the derivatives ob-
tained are given in Tables 1 and 2.
Following a similar procedure, some isomers in
which the hydrazonomethyl chain occupies either the
position 3 (compounds 20–21, see Table 3) or the
position 2 (compounds 22–23, see Table 4) on the
xanthone system were prepared from suitable methyl-
salicylic acids (Fig. 3). The synthesis of these com-
pounds will be reported elsewhere.
Synthetic hydroxyxanthones are usually prepared via
O-benzylated intermediates and subsequent Pd/C cata-
lyzed hydrogenation [23]. However, this protective pro-
Table 1
Physical data for 6,8-diacetoxy-4-(2-arylhydrazonomethyl)xanthones 12 and 18
No.
X
R%
Method
recrystallization solvent a
Yield (%)
Mp (°C)
formula
12a
12b
12c
12d
12e
12f
12g
12h
12i
H
H
H
H
H
H
H
H
H
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
2,4-diCl
2,5-diCl
2,4-diF
H
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
A
B
A
A
D
D
A
B
B
B
E
E
E
E
E
E
E
E
E
E
i
i
i
i
i
i
ii
i
i
63
86
43
65
98
67
31
80
90
70
58
67
72
35
91
37
75
97
82
98
196
218
220
226
198
222
200
256
272
216
277
306
316
260
271
269
248
274
279
239
C24H18N2O6
C24H17ClN2O6
C24H17ClN2O6
C24H17ClN2O6
C24H17FN2O6
C24H17FN2O6
C24H17FN2O6
C24H16Cl2N2O6
C24H16Cl2N2O6
C24H16F2N2O6
C24H16Cl2N2O6
C24H15Cl3N2O6
C24H15Cl3N2O6
C24H15Cl3N2O6
C24H15Cl2FN2O6
C24H15Cl2FN2O6
H
H
12j
i
18a
18b
18c
18d
18e
18f
18g
18h
18i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
ii
iii
i
iii
iv
iii
ii
iii
iii
iii
C24H15Cl2FN2O6
2,4-diCl
2,5-diCl
2,4-diF
C24H14Cl4N2O6
C24H14Cl4N2O6
C24H14Cl2F2N2O6
18j
a i, ethanol; ii, acetone–H2O; iii, H2O; iv, ethanol–H2O; v, acetone.

240
S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
3. Structural study
fragmentation pattern of a diphenolic xanthone struc-
ture [31].
Structure of all the prepared compounds was esta-
blished on the basis of elemental and spectral analyses
(IR, NMR and MS), and by comparison with the
available literature data.
4. Antifungal evaluation and discussion
As an example, spectral data of compound 12a are
presented here while spectral features of other deriva-
tives are given in the experimental part. In the 1H
NMR spectrum (Table 5), two singlets respectively at
8.44 ppm (methine proton, ꢀCHꢁNꢀ) and 10.71 ppm
(NH) agreed with the values expected for the protons of
a hydrazone group [24]. The aromatic region revealed
unambiguous signals for the H5 and H7 atoms (dou-
blets at 7.43 and 7.07 ppm, with a meta coupling
J=2.2 Hz). On the other hand, 13C NMR chemical
shifts were consistent with the abundant reported data
on xanthone derivatives [25–30].
EI–mass spectra of two prototypes 12a and 12c
confirmed their molecular weights and displayed cha-
racteristic fragment ions (protonated ions were often
more intense) as shown in Figs. 4 and 5. Initial loss of
one cetene molecule (m/z 42) explained the base peaks
m/z 388 for 12a and m/z 422 for 12c (Fig. 4). The latter
ions m/z 198 and 171 (Fig. 5) exhibited the expected
All final phenolic compounds (13, 19) and their re-
spective acetylated precursors (12, 18) were investigated
for their in vitro antifungal activity against two human
pathogenic yeasts (C. albicans, C. krusei ) according to
an agar diffusion method [32]. In a primary screening
assay, compounds have been tested at a fixed amount
of 100 mg applied on each test disk.
From the results reported in Table 6, it appears that
the unsubstituted phenylhydrazones (‘a’ products, in all
series) were found to be inactive. On the contrary,
derivatives with
a monohalogenated phenyl ring
showed a significant efficacy (b, c, and e–g series) with,
in general, a more pronounced activity against C. krusei
compared to C. albicans. Moreover, considering the
terminal phenyl ring, dichloro (h,i series) or difluoro-
derivatives (j series) unambiguously were less active
compared to their monosubstituted analogues. The ef-
fect of a chlorine disubstitution on the xanthone system
was less clearly established, since quite comparable
Table 2
Physical data for 6,8-dihydroxy-4-(2-arylhydrazonomethyl)xanthones 13 and 19
No.
X
R%
Method
Recrystallization solvent a
Yield (%)
Mp (°C)
Formula
13a
13b
13c
13d
13e
13f
13g
13h
13i
H
H
H
H
H
H
H
H
H
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
2,4-diCl
2,5-diCl
2,4-diF
H
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
A
C
A
A
B
B
A
B
B
D
F
E
E
E
E
E
E
E
E
E
ii
i
ii
i
i
i
i
i
i
i
ii
iii
iv
iii
iii
iii
iii
iii
iii
i
66
97
56
35
87
62
73
88
87
87
87
80
53
95
81
80
92
91
99
88
256
257
257
236
267
262
200
311
328
259
250
300
279
331
293
270
243
273
308
350
C20H14N2O4
C20H13ClN2O4
C20H13ClN2O4
C20H13ClN2O4
C20H13FN2O4
C20H13FN2O4
C20H13FN2O4
C20H12Cl2N2O4
C20H12Cl2N2O4
C20H12F2N2O4
C20H12Cl2N2O4
C20H11Cl3N2O4
C20H11Cl3N2O4
C20H11Cl3N2O4
C20H11Cl2FN2O4
C20H11Cl2FN2O4
H
H
13j
19a
19b
19c
19d
19e
19f
19g
19h
19i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
C20H11Cl2FN2O4
2,4-diCl
2,5-diCl
2,4-diF
C20H10Cl4N2O4
C20H10Cl4N2O4
C20H10Cl2F2N2O4
19j
a See corresponding footnotes in Table 1.

S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
241
Table 3
Physical data for 3-(2-arylhydrazonomethyl)xanthones 20–21
No.
R
R%
Method
Recrystallization solvent a
Yield (%)
Mp (°C)
Formula
20a
20c
20g
21a
21c
21g
Ac
Ac
Ac
H
H
H
H
A
B
B
E
E
E
ii
i
ii
iv
ii
ii
42
88
59
81
39
66
210
206
240
260
258
258
C24H18N2O6
C24H17ClN2O6
C24H17FN2O6
C20H14N2O4
C20H13ClN2O4
3-Cl
4-F
H
3-Cl
4-F
C20H13FN2O4
a See corresponding footnotes in Table 1.
Table 4
Physical data for 2-(2-arylhydrazonomethyl)xanthones 22–23
No.
R
R%
Method
Recrystallization solvent a
Yield (%)
Mp (°C)
Formula
22a
22c
22g
23a
23c
23g
Ac
Ac
Ac
H
H
H
H
A
A
A
E
E
E
i
i
v
ii
iv
ii
61
62
37
48
79
88
214
219
241
272
260
257
C24H18N2O6
3-Cl
4-F
H
3-Cl
4-F
C
24H17ClN2O6
C24H17FN2O6
20H14N2O4
C20H13ClN2O4
C20H13FN2O4
C
a See corresponding footnotes in Table 1.
substantially inhibit C. krusei growth (12c, 12g), the
most effective agents were found among the free dihy-
droxylated derivatives (13e–g, 19b,c,f,g,j).
levels of efficacy were observed either for dichloroxan-
thones or the unsubstituted parent compounds: as ex-
amples, 13a (unhalogenated) and 19a (5,7-dichloro-
substituted) were both inactive, whereas 13g and 19g
displayed a high efficacy.
In view of the above results, we have further exami-
ned the influence of the hydrazonomethyl moiety by
varying its position on the xanthone skeleton. Thus,
some compounds bearing the side chain at position 2 or
3 have been synthesized and are listed in Tables 3 and
4. Due to inconclusive data previously obtained with
5,7-dichloroxanthones (see discussion above), we omit-
ted to prepare the equivalent molecules in the subse-
quent series. Strikingly, all of these new compounds
derivatives (j series) unambiguously were less active
compared to their monosubstituted analogues. The ef-
fect of a chlorine disubstitution on the xanthone system
was less clearly established, since quite comparable
were devoid of any antifungal properties against the
yeasts tested (Table 6). These findings demonstrate the
importance of the nitrogen side chain-positioning, sug-
gesting that the antifungal properties are probably
linked to steric factors.
Thus, the molecular features providing the greatest
influence for antifungal properties in this series ap-
peared to be the phenyl substituents in the arylhydra-
zone unit. The presence of a chlorine at position 2
(compound 12b) or better at position 3 (compound 12c)
induced a greater activity against C. krusei than against
C. albicans. Noteworthy, compounds carrying a 4-
fluoro atom (13g and 19g) were the most potent. How-
ever, no clear distinction could be observed in
comparing the potency of the 2-fluoro (13e) and the
3-fluoro isomers (13f) against C. krusei. Taken together,
these results suggest that factors other than electronic
and steric properties of the halogen substituents should
be considered to explain the antifungal activity.
The phenolic OH groups attached in the tricyclic
framework also seemed involved in the biological activi-
ty profile. Although some acetylated products might
Although an accurate MIC value could not be deter-
mined according to a diffusion protocol, we attempted

242
S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
to compare the anticandida potency of the most inte-
resting derivatives (13g, 19g) to that of econazole, used
as reference. Thus, experiments were performed intro-
ducing lower amounts (50 mg, then 25 mg) of product,
per test disk. Efficacy of the compounds on fungal
growth was evaluated by measurement of the inhibited
zone size. From the data summarized in Fig. 6, com-
pounds 13g and 19g exhibited a different antimycotic
profile to that of the chosen reference drug. Against C.
albicans (Fig. 6a), both compounds 13g and 19g
showed fungal growth inhibition in a dose-dependent
behaviour. However, the most prominent compound,
19g, resulted less potent than econazole, with an
activity level approximately reduced by half. In con-
trast, the responses observed against C. krusei (Fig. 6b)
are much more promising. In terms of fungistatic acti-
vity, at 50 mg range, 19g has been found to inhibit the
yeast growth more intensely (inhibition zone: ]35
mm) than econazole (inhibition zone: 23 mm). This
preliminary study was performed in order to establish
the ability to inhibit Candida proliferation of our newly
synthesized compounds. With the aim of quantifying
the efficacy of these derivatives, further antifungal eva-
luation (i.e. determination of the MIC values by a
microdilution test) is in progress.
Table 5
1H NMR (500 MHz) and 13C NMR (125 MHz) data a and main
correlations (1H–13C HMBC, and 1H–1H COSY) for compound 12a b
Position
1
1H
13C
HMBC
C1, H3
COSY
5. Conclusion
8.01 (dd,
3J=7.8,
4J=1.4)
7.46 (t,
124.7
H1, H2
H1, H3
The present study shows that the xanthone frame-
work may be considered as a potential prototype for
the synthesis of new antimycotics, unrelated to the
classical azole agents. Considering the xanthone nu-
cleus, introduction at position 4 of a hydrazonomethyl
chain bearing a fluorophenyl group led to a derivative
having in these tests a significantly enhanced activity
against Candida krusei, by comparison with econazole.
These encouraging results against a pathogenic yeast
whose incidence is rising, prompt us to further explore
this new class of antifungal agents in order to elucidate
their mechanism of action.
2
3
124.4
129.8
H2, H3
3J=7.8)
8.34 (dd,
3J=7.6 ,
4J=1.5)
C3, H10
4
124.9
151.5
156.6
108.9
C4, H10
C4a, H10
C4b, H5
4a
4b
5
7.43 (d,
H5, H7
4J=2.2)
6
7
154.8
113.1
7.07 (d,
4J=2.2)
8
150.5
C8a, H5
C8a, H7
6. Experimental protocols
8a
9
9a
10
112.0
173.9
121.8
128.7
168.1 and
168.7
20.8 and
20.9
6.1. Chemistry
8.44 (s)
–
C10, H3
CꢁO (Ac)
Melting points (m.p.) were obtained using an Elec-
trothermal capillary melting point apparatus (Digital
Mel-Temp 3.0, Model 1402) and are uncorrected. Nu-
clear magnetic resonance spectra were all performed in
DMSO-d6 solution, on a Bruker AMX 500 spectrome-
ter (1H: 500 MHz, 13C: 125 MHz). Chemical shifts are
given as l units using TMS as an internal standard.
Multiplicities in 13C NMR spectra were derived from
JMOD experiments. When necessary, 2D experiments
(HMQC, HMBC and 1H–1H COSY) were used to
assign the signals (for general atom numbering used in
description of NMR spectra, see formula included in
Table 5). IR spectra were recorded as KBr disks on a
Shimadzu IR 470 spectrometer. Positive electronic ioni-
sation mass spectra were obtained on a Fisons autospec
(70 eV) spectrophotometer. Analytical thin-layer chro-
CH3 (Ac)
2.39 and
2.45
10.71 (s)
NH
1%
2%
–
144.8
112.2
7.14 (d,
3J=8.3)
7.26 (t,
H2%, H3%
H2%, H4%
H3%, H4%
3%
4%
5%
6%
129.2
119.3
129.2
112.2
3J=7.9)
6.81 (t,
H4%, H5%
H5%, H6%
H6%, H4%
3J=7.3)
7.26 (t,
3J=7.9)
7.14 (d,
3J=8.3)
a Chemical shifts, ppm (multiplicity, J in Hz).
b In DMSO-d6 solution.

S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
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S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
Fig. 4. Mass fragmentation pattern of 12a and 12c. a ML=McLafferty rearrangement.
Fig. 5. Mass fragmentation pattern of the xanthone moiety of 12a and 12c.
matography (TLC) was performed using aluminium
precoated plates (silica gel SDS 60F 254 Whatman, 200
mm thick), and spots were visualized with UV light.
Column chromatography was carried out with Merck
silica gel, 60–200 mm, according to the flash chro-
matography technique. Elemental analyses performed
on the terminal products were within 90.4% of the
calculated values (for elements indicated in brackets).
overnight, and 3-methylsalicylic acid (9.13 g, 60 mmol)
was added slowly 100 mL of Eaton’s reagent (P2O5–
CH3SO3H, Aldrich). The mixture was stirred for 20 min
at 80 °C, cooled to room temperature (r.t.), and poured
onto ice. After vigorous stirring at ambient temperature
for 2 h, a thin slurry formed. The solid was collected by
filtration, washed with water to adjust the pH to ap-
proximately 6, and dried at 60 °C to give 8 as a reddish
brown solid (96% yield) which was used without further
purification: m.p. 295 °C (lit. [33]); IR (cm−1) 3200
6.1.1. 1,3-Dihydroxy-5-methylxanthen-9-one (8)
To a mixture of commercially available phloroglu-
cinol dihydrate (9.73 g, 60 mmol), dried at 120 °C
1
(OH), 1650 (CO), H NMR (l) 2.35 (s, 3H, CH3), 6.25
4
4
(d, 1H, H2, J=2.2 Hz), 6.43 (d, 1H, H4, J=2.2 Hz),

S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
245
7.10–7.90 (m, 3H, H6+H7+H8), 9.60 (m, 1H, OH),
12.90 (m, 1H, OH). Anal. C14H10O4 (C, H).
producing a homogeneous dark amber solution. The
reaction mixture was allowed to slowly cool to r.t., then
poured into ice-water (400 g) and acidified with 12 N
hydrochloric acid. The resulting precipitate was sepa-
rated by filtration and washed with water to pH 7.
After drying at 50 °C overnight, the solid was recrystal-
lized from ethanol to afford the required diacetate 9 or
15.
6.1.2. 2,4-Dichloro-1,3-dihydroxy-5-methylxanthen-
9-one (14)
An amount of 9.45 g (39 mmol) of the xanthone 8
was dissolved in anhydrous dichloromethane (60 mL)
and 7.6 mL (93 mmol) of sulfuryl chloride diluted in
the same solvent (40 mL) was carefully added. The
mixture was stirred at r.t. until all gas release ceased,
and then refluxed for 3 h. The reddish solid formed was
collected by filtration, washed with water and ethanol
to afford crude 14 which was used without any purifica-
tion: m.p. 250 °C; IR (cm−1) w 3300, 3200 (OH), 1640
9: m.p. 173 °C (62% yield); IR (cm−1) w 1770 (CO
1
ester), 1650 (CO ketone); H NMR (l) 2.34 and 2.39
2[(s, 3H, COꢀCH3)], 2.50 (s, 3H, CH3), 7.06 (d, 1H, H2,
3
4J=1.7 Hz), 7.36 (t, 1H, H7, J=7.6 Hz), 7.52 (d, 1H,
H4, 4J=1.3 Hz), 7.72 (d, 1H, H6, 3J=7.0 Hz), 7.95 (d,
3
1H, H8, J=8.3 Hz); 13C NMR (l) 14.9 CH3, 20.8
1
(CO); H NMR (l) 2.25 (s, 3H, CH3), 7.15–7.75 (m,
[2CH3 (Ac)], 109.4 C4, 112.0 C1a, 113.1 C2, 121.2 C8a,
123.3 C7, 124.0 C8, 126.8 C5, 136.0 C6, 150.3 C1, 153.1
C3, 154.8 C5a, 156.8 C4a, 168.2 and 168.6 [2CꢁO (Ac)],
174.3 CꢁO (xanthone). Anal. C18H14O6 (C, H).
15: m.p. 205 °C (40% yield); IR (cm−1) w 1780 (CO
ester), 1660 (CO ketone); 1H NMR (l) 2.48 (s, 3H,
CH3), 2.54 and 2.58 [2(s, 3H, COꢀCH3)], 7.29 (t, 1H,
H7, 3J=7.6 Hz), 7.58 (d, 1H, H6, 3J=7.2 Hz), 8.06 (d,
1H, H8, 3J=7.5 Hz); 13C NMR (l) 15.3 CH3, 20.1 and
20.7 [2CH3 (Ac)], 114.3 C1a, 116.1 C4, 119.0 C2, 121.5
C8a, 124.1 C8, 124.6 C7, 127.5 C5, 136.3 C6, 145.6 C3,
148.9 C1, 151.3 C4a, 153.4 C5a, 166.1 and 168.0 [2CꢁO
(Ac)], 174.4 CꢁO (xanthone). Anal. C18H12Cl2O6 (C, H,
Cl).
3H, H6+H7+H8), 13.30 (m, 2H, OH). Anal.
C14H8Cl2O4 (C, H, Cl).
6.1.3. 1,3-Diacetoxy-5-methylxanthen-9-ones (9, 15)
A stirred suspension of the dihydroxylated xanthone
8, or 14 (57.8 mmol) in acetic anhydride (130 mL) and
pyridine (10 mL) was warmed under reflux for 3 h,
6.1.4. 1,3-Diacetoxy-5-bromomethylxanthen-9-ones (10,
16)
A stirred mixture of the diacetate 9 or 15 (17 mmol),
N-bromosuccinimide (17 mmol) and dibenzoyl pero-
xide (0.42 g, 1.7 mmol) in carbon tetrachloride (110
mL) was heated under reflux for 3–5 h under light
irradiation (2×60 W). The reaction mixture was
cooled to 0 °C, stirred for 2 h and filtered. The resulting
precipitate was washed successively with water (3×15
mL), acetone (2×15 mL) and then with diethyl ether
to give a yellow solid which was recrystallized from
2-butanone.
10: m.p. 198 °C (50% yield); IR (cm−1) w 1780 (CO
1
ester), 1660 (CO ketone); H NMR (l) 2.35 and 2.40
[2(s, 3H, COꢀCH3)], 5.01 (s, 2H, CH2Br), 7.11 (d, 1H,
4
3
H2, J=2.3 Hz), 7.49 (t, 1H, H7, J=7.6 Hz), 7.59 (d,
4
3
1H, H4, J=2.0 Hz), 8.01 (d, 1H, H6, J=7.3 Hz),
8.10 (d, 1H, H8, 3J=8.0 Hz); 13C NMR (l) 20.8 [2CH3
(Ac)], 27.0 CH2Br, 109.4 C4, 112.1 C1a, 113.5 C2,
121.6 C8a, 126.4 C7, 126.7 C8, 127.0 C5, 136.4 C6,
150.4 C1, 152.5 C3, 155.0 C5a, 156.5 C4a, 168.2 and
168.6 [2CꢁO (Ac)], 173.7 CꢁO (xanthone). Anal.
C18H13BrO6 (C, H).
16: m.p. 184 °C (65% yield); IR (cm−1) w 1770 (CO
ester), 1660 (CO ketone); H NMR (l) 2.49 and 2.54
[2(s, 3H, COꢀCH3)], 4.82 (s, 2H, CH2Br), 7.49 (t, 1H,
Fig. 6. Inhibitory effects of compounds 13g, 19g on the growth of C.
albicans (a) and C. krusei (b) (inhibition zones, in mm; values
reported are an average of three independent experiments).
1

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S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
3
3
4
H7, J=7.7 Hz), 7.81 (dd, 1H, H6, J=7.4 Hz, J=
of 1-propanol was stirred at r.t. for 15 min, and then
acetic acid (about 0.5 mL) was added dropwise. The
suspension was stirred for additional 15 min at r.t. and
then heated under reflux for 2 h. The mixture was
cooled to r.t. and filtered to give the desired hydrazone
12 or 18.
3
4
1.6 Hz), 8.20 (dd, 1H, H8, J=8.0 Hz, J=1.6 Hz);
13C NMR (l) 20.1 and 20.6 [2CH3 (Ac)], 25.2 CH2Br,
114.4 C1a, 116.3 C4, 119.6 C2, 122.0 C8a, 124.9 C8,
127.3 C7, 127.3 C5, 136.2 C6, 145.7 C3, 149.2 C1, 151.1
C4a, 152.6 C5a, 166.0 and 167.8 [2CꢁO (Ac)], 173.7
CꢁO (xanthone). Anal. C18H11BrCl2O6 (C, H, Cl).
6.1.6.2. Method B. To a suspension of carboxaldehyde
11 or 17 (2 mmol) and arylhydrazine (2.2 mmol) in
ethanol (40 mL), acetic acid (1 mL) was slowly added.
The mixture was then refluxed for 30 min, cooled to r.t.
and the resulting precipitate was collected by filtration
and purified by crystallization.
6.1.5. General procedure for the preparation of
6,8-diacetoxy-9-oxo-9H-xanthene-4-carboxaldehyde 11
and 6,8-diacetoxy-5,7-dichloro-9-oxo-9H-xanthene-
4-carboxaldehyde 17
To a solution of bis-tetrabutylammonium dichromate
(10 mmol) obtained as previously described [34] in
chloroform (100 mL), 5 mmol of bromomethyl deriva-
tive 10 or 16 was added. The reaction mixture was
heated under reflux for 5 h. After cooling to r.t., the
resulting inorganic precipitate was removed by tritura-
tion with 20 g of silica gel (40–63 mm), filtration, and
washing twice with 50 mL of ethyl acetate. The com-
bined organic layers were concentrated under reduced
pressure to afford a greenish brown-coloured oil. The
product was dissolved in dichloromethane (5 mL) and
further purified on silica gel column (63–200 mm) elu-
ting with dichloromethane–ethyl acetate (9:1) to give
the expected carboxaldehyde. Analytically pure sample
was obtained by crystallization from ethanol.
6.1.6.3. Method C. A stirred mixture of carboxaldehyde
11 or 17 (1 mmol) and a slight excess of the appropriate
arylhydrazine (1.2 mmol) in ethanol (15 mL) was
heated to reflux and monitored by TLC. After 15–30
min, the reaction was judged complete and on cooling,
the mixture was filtered. The amorphous solid obtained
was crystallized from a suitable solvent.
6.1.6.4. Method D. For some compounds, the product
appeared sensitive to heat; in these cases, the reaction
was accomplished by stirring the starting materials in
ethanol at r.t. for 24 h, using the same proportions as in
method C.
11: yellowish white crystals m.p. 172 °C (29% yield);
IR (cm−1) w 1770 (CO ester), 1690 (CO aldehyde), 1660
(CO ketone); 1H NMR (l) 2.36 and 2.40 [2(s, 3H,
Recrystallization solvents and physical data of com-
pounds 12a–j and 18a–j are given in Table 1. Their
spectroscopic data are summarized as follows.
12a: see Section 3. Anal. C24H18N2O6 (C, H, N).
12b: IR (cm−1) w 3300 (NH), 1760 (CO ester), 1650
4
COꢀCH3)], 7.13 (d, 1H, H2, J=2.0 Hz), 7.60 (t, 1H,
H7, 3J=7.6 Hz), 7.61 (d, 1H, H4, 4J=2.4 Hz), 8.25 (d,
3
3
1H, H6, J=7.6 Hz), 8.39 (d, 1H, H8, J=8.0 Hz),
10.67 (s, 1H, CHO); 13C NMR (l) 21.7 and 21.8 [2CH3
(Ac)], 110.6 C5, 113.3 C8a, 114.8 C7, 123.1 C1a, 125.4
C2, 125.4 C4, 133.0 C1, 135.2 C3, 151.3 C8, 156.1 C6,
156.4 C4a, 157.5 C5a, 169.1 and 169.6 [2CꢁO (Ac)],
174.4 CꢁO (xanthone), 188.8 CHO. Anal. C18H12O7 (C,
H).
1
(CO ketone), 1620 (CꢁN), 1520 l (NH); H NMR (l)
2.36 and 2.40 [2(s, 3H, COꢀCH3)], 6.84 (t, 1H, H4%,
3J=7.3 Hz), 7.08 (s, 1H, H7), 7.28 (t, 1H, H5%, 3J=7.4
3
Hz), 7.36 (d, 1H, H6%, J=7.8 Hz), 7.44 (s, 1H, H5),
3
3
7.48 (t, 1H, H2, J=7.5 Hz), 7.64 (d, 1H, H3%, J=8.2
3
17: m.p. 215 °C (26% yield); IR (cm−1) w 1780 (CO
ester), 1700 (CO aldehyde), 1660 (CO ketone); 1H
NMR (l) 2.49 and 2.54 [2(s, 3H, COꢀCH3)], 7.68 (t,
Hz), 8.05 (d, 1H, H1, J=7.4 Hz), 8.37 (d, 1H, H3,
3J=7.4 Hz), 8.90 (s, 1H, H10), 10.24 (s, 1H, NH).
Anal. C24H17ClN2O6 (C, H, N).
3
3
1H, H7, J=7.7 Hz), 8.32 (dd, 1H, H6, J=7.3 Hz,
12c: IR (cm−1) w 3300 (NH), 1770, 1740 (CO ester),
3
4
1
4J=1.7 Hz), 8.43 (dd, 1H, H8, J=7.9 Hz, J=1.9
Hz), 10.69 (s, 1H, CHO); 13C NMR (l) 20.8 and 21.3
[2CH3 (Ac)], 115.3 C8a, 116.5 C5, 119.5 C7, 122.7 C1a,
125.7 C4, 126.2 C2, 133.0 C1, 135.6 C3, 149.4 C8, 145.9
C6, 151.7 C5a, 156.0 C4a, 167.5 and 168.5 [2CꢁO (Ac)],
173.8 CꢁO (xanthone), 187.9 CHO. Anal. C18H10Cl2O7
(C, H, Cl).
1650 (CO ketone), 1620 (CꢁN), 1530 l (NH); H NMR
(l) 2.35 and 2.39 [2(s, 3H, COꢀCH3)], 6.81 (d, 1H, H4%,
3J=7.7 Hz), 7.04 (d, 1H, H6%, 3J=8.0 Hz), 7.08 (s, 1H,
3
H7), 7.19 (s, 1H, H2%), 7.25 (t, 1H, H5%, J=8.0 Hz),
7.44 (s, 1H, H5), 7.49 (t, 1H, H2, J=7.7 Hz), 8.04 (d,
3
3
3
1H, H1, J=7.9 Hz), 8.36 (d, 1H, H3, J=7.5 Hz),
8.50 (s, 1H, H10), 11.04 (s, 1H, NH); 13C NMR (l)
125.2 C1, 124.5 C2, 130.3 C3, 124.5 C4, 151.7 C4a,
156.6 C4b, 108.9 C5, 154.8 C6, 113.2 C7, 150.5 C8,
112.1 C8a, 173.9 C9, 121.8 C9a, 168.1 and 168.6 [2CꢁO
(Ac)], 20.7 and 20.8 [2CH3 (Ac)], 130.5 C10, 146.3 C1%,
111.5 C2%, 133.8 C3%, 118.7 C4%, 130.6 C5%, 110.9 C6%.
Anal. C24H17ClN2O6 (C, H, N).
6.1.6. General procedure for the preparation of
hydrazones (12, 18)
6.1.6.1. Method A. A suspension of 11 or 17 (1 mmol)
and the appropriate arylhydrazine (1.2 mmol) in 15 mL

S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
247
3J=8.5 Hz), 7.12 (s, 1H, H7), 7.42 (d, 1H, H3%,
12d: IR (cm−1) w 3300 (NH), 1770, 1740 (CO ester),
1650 (CO ketone), 1620 (CꢁN), 1560, 1530 l (NH); H
NMR (l) 2.37 and 2.41 [2(s, 3H, COꢀCH3)], 7.11 (d,
3
3J=8.5 Hz), 7.47 (s, 1H, H5), 7.54 (t, 1H, H2, J=7.7
1
3
Hz), 7.64 (s, 1H, H6%), 8.12 (d, 1H, H1, J=7.9 Hz),
3
4
3
8.45 (d, 1H, H3, J=7.6 Hz), 8.99 (s, 1H, H10), 10.49
1H, H7, J=2.2 Hz), 7.16 (d, 2H, H2%+H6%, J=8.8
3
(s, 1H, NH). Anal. C24H16Cl2N2O6 (C, H, N).
Hz), 7.30 (d, 2H, H3%+H5%, J=8.8 Hz), 7.47 (d, 1H,
12j: IR (cm−1) w 3300 (NH), 1770, 1740 (CO ester),
4
3
H5, J=2.2 Hz), 7.50 (t, 1H, H2, J=7.8 Hz), 8.06 (d,
1
3
3
1660 (CO ketone), 1620 (CꢁN), 1560, 1530 l (NH); H
1H, H1, J=6.5 Hz), 8.38 (d, 1H, H3, J=6.5 Hz),
8.48 (s, 1H, H10), 10.90 (s, 1H, NH). Anal.
C24H17ClN2O6 (C, H, N).
NMR (l) 2.36 and 2.40 [2(s, 3H, COꢀCH3)], 7.03 (t,
3
4
1H, H3%, J [H–F]=8.4 Hz), 7.09 (d, 1H, H7, J=1.1
3
12e: IR (cm−1) w 3300 (NH), 1770 (CO ester), 1660
(CO ketone), 1620 (CꢁN), 1560, 1520 l (NH); 1H NMR
(l) 2.36 and 2.40 [2(s, 3H, COꢀCH3)], 6.81 (d, 1H, H6%,
3J=5.2 Hz), 7.07 (s, 1H, H7), 7.13 (t, 1H, H4%, 3J=7.3
Hz), 7.24 (t, 1H, H5%, J=10.3 Hz), 7.43 (d, 1H, H5,
4J=1.1 Hz), 7.49 (t, 1H, H2, 3J=7.6 Hz), 7.59 (dt, 1H,
3
4
H6%, J=9.1 Hz, J [H–F]=6.1 Hz), 8.06 (d, 1H, H1,
3J=7.6 Hz), 8.38 (d, 1H, H3, J=7.6 Hz), 8.75 (s, 1H,
3
3
H10), 10.59 (s, 1H, NH). Anal. C24H16F2N2O6 (C, H,
N).
Hz), 7.17 (d, 1H, H3%, J=9.5 Hz), 7.41 (s, 1H, H5),
7.47 (t, 1H, H2, J=7.5 Hz), 7.59 (t, 1H, H5%, J=7.9
3
3
18a: IR (cm−1) w 3300 (NH), 1780 (CO ester), 1650
3
Hz), 8.04 (d, 1H, H1, J=7.7 Hz), 8.36 (d, 1H, H3,
1
3J=7.3 Hz), 8.75 (s, 1H, H10), 10.60 (s, 1H, NH).
Anal. C24H17FN2O6 (C, H, N).
(CO ketone), 1570 l (NH); H NMR (l) 2.49 and 2.50
3
[2(s, 3H, COꢀCH3)], 6.81 (t, 1H, H4%, J=7.2 Hz), 7.16
3
12f: IR (cm−1) w 3300 (NH), 1770, 1740 (CO ester),
(d, 2H, H2%+H6%, J=7.8 Hz), 7.26 (d, 2H, H3%+
1
3
3
1660 (CO ketone), 1620 (CꢁN), 1560, 1540 l (NH); H
H5%, J=7.8 Hz), 7.50 (t, 1 H, H2, J=7.7 Hz), 8.00
3
4
NMR (l) 2.36 and 2.40 [2(s, 3H, COꢀCH3)], 6.58 (t,
(dd, 1H, H1, J=7.8 Hz, J=1.5 Hz), 8.40 (dd, 1H,
3
3
3
4
1H, H5%, J=8.3 Hz), 6.90 (d, 1H, H6%, J=7.8 Hz),
H3, J=7.7 Hz, J=1.4 Hz), 8.48 (s, 1H, H10), 10.87
(s, 1H, NH); 13C NMR (l) 124.5 C1, 125.1 C2, 130.1
C3, 125.4 C4, 151.1 C4a, 150.8 C4b, 115.2 C5, 148.1
C6, 117.9 C7, 145.0 C8, 113.9 C8a, 173.3 C9, 121.4
C9a, 166.5 and 167.5 [2CꢁO (Ac)], 19.8 and 20.3 [2CH3
(Ac)], 127.9 C10, 144.6 C1%, 112.2 C2%, 129.0 C3%, 119.4
C4%, 129.0 C5%, 112.2 C6%. Anal. C24H16Cl2N2O6 (C, H,
Cl, N).
3
6.96 (d, 1H, H2%, J [H–F]=11.3 Hz), 7.10 (d, 1H, H7,
4J=2.2 Hz), 7.27 (dd, 1H, H4%, J=7.4 Hz, J [H–
3
3
3
F]=14.4 Hz), J [H–F]=11.3 Hz), 7.46 (d, 1H, H5,
4J=2.2 Hz), 7.49 (t, 1H, H2, J=7.6 Hz), 8.06 (dd,
3
3
4
1H, H1, J=7.8 Hz, J=1.7 Hz), 8.40 (dd, 1H, H3,
3J=7.4 Hz, J=1.7 Hz), 8.49 (s, 1H, H10), 10.95 (s,
4
1H, NH). Anal. C24H17FN2O6 (C, H, N).
12g: IR (cm−1) w 3300 (NH), 1770, 1740 (CO ester),
18b: IR (cm−1) w 3300 (NH), 1770 (CO ester), 1660
1
1655 (CO ketone), 1620 (CꢁN), 1560, 1540 l (NH); H
(CO ketone), 1560, 1520 l (NH); 1H NMR (l) 2.49 and
3
NMR (l) 2.35 and 2.38 [2(s, 3H, COꢀCH3)], 7.05 (d,
2.53 [2(s, 3H, COꢀCH3)], 6.86 (td, 1H, H4%, J=7.5
4
4
3
1H, H7, J=2.2 Hz), 7.07–7.14 (m, 4H, H2%+H3%+
Hz, J=1.4 Hz), 7.29 (t, 1H, H5%, J=7.6 Hz), 7.37
4
H5%+H6%), 7.41 (d, 1H, H5, J=2.1 Hz), 7.43 (t, 1H,
(dd, 1H, H6%, 3J=8.0 Hz, 4J=1.4 Hz), 7.55 (t, 1H, H2,
3
3
4
3
H2, J=7.8 Hz), 7.99 (dd, 1H, H1, J=7.8 Hz, J=
3J=7.8 Hz), 7.68 (d, 1H, H3%, J=8.2 Hz), 8.08 (dd,
3
4
3
4
1.6 Hz), 8.31 (dd, 1H, H3, J=7.6 Hz, J=1.5 Hz),
8.39 (s, 1H, H10), 10.70 (s, 1H, NH); 13C NMR (l)
124.6 C1, 124.3 C2, 129.7 C3, 124.8 C4, 151.4 C4a,
156.5 C4b, 108.8 C5, 154.8 C6, 113.1 C 7, 150.4 C8,
112.00 C8a, 173.8 C9, 121.7 C9a, 168.1 and 168.6
[2CꢁO (Ac)], 20.7 and 20.9 [2CH3 (Ac)], 128.7 C10,
141.4 C1%, 113.2 C2%, 115.6 C3%, 156.1 C4%, 115.4 C5%,
113.1 C6%. Anal. C24H17FN2O6 (C, H, N).
1H, H1, J=7.8 Hz, J=1.4 Hz), 8.49 (dd, 1H, H3,
3J=7.7 Hz, J=1.4 Hz), 8.89 (s, 1H, H10), 10.58 (s,
4
1H, NH). Anal. C24H15Cl3N2O6 (C, H, Cl, N).
18c: IR (cm−1) w 3300 (NH), 1790, 1750 (CO ester),
1
1660 (CO ketone), 1560, 1520 l (NH); H NMR (l)
2.49 and 2.55 [2(s, 3H, COꢀCH3)], 6.83 (d, 1H, H4%,
3
3J=8. 0 Hz), 7.05 (d, 1H, H6%, J=8.0 Hz), 7.21 (d,
4
3
1H, H2%, J=1.7 Hz), 7.27 (t, 1H, H5%, J=8.0 Hz),
12h: IR (cm−1) w 3300 (NH), 1760 (CO ester), 1650
7.55 (t, 1H, H2, 3J=7.6 Hz), 8.06 (dd, 1H, H1, 3J=7.6
1
4
3
4
(CO ketone), 1620 (CꢁN), 1570 l (NH); H NMR (l)
Hz, J=1.7 Hz), 8.46 (dd, 1H, H3, J=7.6 Hz, J=
1.7 Hz), 8.51 (s, 1H, H10), 11.06 (s, 1H, NH); 13C
NMR (l) 125.2 C1, 126.0 C2, 131.4 C3, 126.0 C4,
152.5 C4a, 158.3 C4b, 119.6 C5, 147.6 C6, 122.6 C7,
147.4 C8, 115.0 C8a, 173.5 C9, 122.7 C9a, 167.4 and
168.6 [2CꢁO (Ac)], 20.8 [2 CH3 (Ac)], 130.3 C10, 146.5
C1%, 112.6 C2%, 135.1 C3%, 119.8 C4%, 131.2 C5%, 111.8
C6%. Anal. C24H15Cl3N2O6 (C, H, Cl, N).
2.36 and 2.40 [2(s, 3H, COꢀCH3)], 7.10 (d, 1H, H7,
3
4
4J=1.6 Hz), 7.34 (dd, 1H, H5%, J=8.9 Hz, J=1.8
4
Hz), 7.46 (d, 1H, H5, J=1.6 Hz), 7.50 (t, 1H, H2,
3J=7.5 Hz), 7.52 (s, 1H, H3%), 7.65 (d, 1H, H6%,
3J=9.1 Hz), 8.09 (d, 1H, H1, 3J=7.1 Hz), 8.40 (d, 1H,
3
H3, J=7.5 Hz), 8.95 (s, 1H, H10), 10.41 (s, 1H, NH).
Anal. C24H16Cl2N2O6 (C, H, N).
12i: IR (cm−1) w 3300 (NH), 1770, 1750 (CO ester),
18d: IR (cm−1) w 3300 (NH), 1790, 1750 (CO ester),
1
1
1650 (CO ketone), 1620 (CꢁN), 1580 l (NH); H NMR
1660 (CO ketone), 1560, 1530 l (NH); H NMR (l)
(l) 2.37 and 2.41 [2(s, 3H, COꢀCH3)], 6.89 (d, 1H, H4%,
2.49 and 2.54 [2(s, 3H, COꢀCH3)], 7.16 (dd, 2H, H2%+

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3
3
4
2.48 and 2.55 [2(s, 3H, COꢀCH3)], 7.03 (t, 1H, H3%, J
H6%, J=9.1 Hz, J=2.2 Hz), 7.29 (dd, 2H, H3%+
3
3
4
[H–F]=8.8 Hz), 7.25 (d, 1H, H5%, J=10.2 Hz), 7.54
(t, 1H, H2, J=7.4 Hz), 7.61 (dt, 1H, H6%, J=8.8
Hz, J [H–F]=6.4 Hz), 8.07 (d, 1H, H1, J=7.4 Hz),
8.46 (d, 1H, H3, J=8.3 Hz), 8.76 (s, 1H, H10), 10.86
H5%, J=8.7 Hz, J=1.8 Hz), 7.54 (t, 1H, H2, 3J=
3
3
3
4
7.8 Hz), 8.05 (dd, 1H, H1, J=7.8 Hz, J=1.6 Hz),
4
3
3
4
8.43 (dd, 1H, H3, J=7.6 Hz, J=1.8 Hz), 8.49 (s,
1H, H10), 11.01 (s, 1H, NH). Anal. C24H15Cl3N2O6
(C, H, Cl, N).
3
(s, 1H, NH). Anal. C24H14Cl2F2N2O6 (C, H, Cl, N).
18e: IR (cm−1) w 3300 (NH), 1790, 1760 (CO ester),
1
6.1.7. 6,8-Dihydroxy-9-oxo-9H-xanthene-4-
carboxaldehyde arylhydrazones (13, 19)
1660 (CO ketone), 1620 (CꢁN), 1560, 1530 l (NH); H
NMR (l) 2.49 and 2.55 [2(s, 3H, COꢀCH3)], 6.83 (m,
1H, H6%), 7.14 (t, 1H, H4%, 3J=7.8 Hz), 7.18 (ddd,
1H, H3%, 3J [H–F]=12.2 Hz, 3J=8.2 Hz, 4J=1.1
6.1.7.1. Method E. In a typical procedure, to a suspen-
sion of diacetoxyxanthone 12 (0.3 mmol) in 20 mL of
mixture 1-propanol–water (1:1) was added sodium hy-
drogencarbonate (3 mmol), under vigorous stirring.
The reaction mixture was then heated under reflux
until TLC indicated no starting diacetate remained
(1.5–12 h). Evaporation of the solvent gave a residue
which was suspended in water and extracted with ethyl
acetate (3×15 mL). The organic layer was washed
with water, dried on sodium sulphate and evaporated
to afford a gummy residue which was triturated with
hexane or heptane until solid. The product was col-
lected by vacuum filtration, dried and recrystallized.
3
Hz), 7.54 (t, 1H, H2, J=7.6 Hz), 7.62 (td, 1H, H5%,
3J=8.2 Hz, J=1.4 Hz), 8.06 (dd, 1H, H1, J=7.8
4
3
4
3
4
Hz, J=1.6 Hz), 8.47 (dd, 1H, H3, J=7.6 Hz, J=
1.4 Hz), 8.48 (s, 1H, H10), 10.90 (s, 1H, NH). Anal.
C24H15Cl2FN2O6 (C, H, Cl, N).
18f: IR (cm−1) w 3300 (NH), 1780 (CO ester), 1660
1
(CO ketone), 1610 (CꢁN), 1570 l (NH); H NMR (l)
2.49 and 2.55 [2(s, 3H, COꢀCH3)], 6.60 (t, 1H, H5%,
3J=8.3 Hz), 6.91 (d, 1H, H6%, J=8.3 Hz), 6.98 (d,
3
3
3
1H, H2%, J [H–F]=11.5 Hz), 7.27 (dd, 1H, H4%, J
[H–F]=15.1 Hz, J=7.9 Hz), 7.54 (t, 1H, H2, J=
3
3
3
7.7 Hz), 8.06 (d, 1H, H1, J=7.9 Hz), 8.47 (d, 1H,
H3, 3J=7.5 Hz), 8.51 (s, 1H, H10), 11.08 (s, 1H,
NH). Anal. C24H15Cl2FN2O6 (C, H, Cl, N).
6.1.7.2. Method F. A suspension of the appropriate
diacetate 12 (0.5 mmol) in ethanol (5 mL) was treated
with 10% aqueous sodium hydroxide solution (5 mL)
and the reaction mixture was warmed at 55 °C for 30
min, under vigorous stirring. After cooling and neu-
tralization with 1 N hydrochloric acid, the solid pre-
cipitate was collected by filtration, washed with water
and dried to afford the expected diphenol, which was
recrystallized from an appropriate solvent. Recrystal-
lization solvents and physical data of compounds 13–
19 are given in Table 2 while their spectroscopic data
are summarized as follows.
18g: IR (cm−1) w 3300 (NH), 1790, 1750 (CO ester),
1
1660 (CO ketone), 1560, 1530 l (NH); H NMR (l)
2.47 and 2.50 [2(s, 3H, COꢀCH3)], 7.07–7.12 (m, 4H,
H2%+H3%+H5%+H6%), 7.47 (t, 1H, H2, J=7.6 Hz),
3
3
3
7.98 (d, 1H, H1, J=7.5 Hz), 8.35 (d, 1H, H3, J=
7.3 Hz), 8.38 (s, 1H, H10), 10.83 (s, 1H, NH); 13C
NMR (l) 125.0 C1, 124.5 C2, 130.0 C3, 125.3 C4,
155.2 C4a, 157.1 C4b, 115.1 C5, 151.0 C6, 117.9 C7,
150.7 C8, 113.8 C8a, 173.2 C9, 121.3 C9a, 166.4 and
167.5 [2CꢁO (Ac)], 19.8 and 20.3 [2CH3 (Ac)], 127.8
C10, 141.3 C1%, 113.2 C2%, 115.6 C3%, 146.5 C4%, 115.4
C5%, 113.2 C6%. Anal. C24H15Cl2FN2O6 (C, H, Cl, N).
18h: IR (cm−1) w 3300 (NH), 1780 (CO ester), 1660
(CO ketone), 1560, 1520 l (NH); H NMR (l) 2.51
and 2.56 [2(s, 3H, COꢀCH3)], 7.36 (m, 1H, H5%), 7.53
(s, 1H, H3%), 7.57 (t, 1H, H2, J=6.0 Hz), 7.69 (d,
1H, H6%, J=6.5 Hz), 8.12 (d, 1H, H1, J=5.5 Hz),
8.51 (d, 1H, H3, J=5.5 Hz), 8.93 (s, 1H, H10), 10.72
(s, 1H, NH). Anal. C24H14Cl4N2O6 (C, H, Cl, N).
18i: IR (cm−1) w 3300 (NH), 1770 (CO ester), 1660
(CO ketone), 1570 l (NH); 1H NMR (l) 2.50 [2(s,
3H, COꢀCH3)], 6.89 (dd, 1H, H4%, J=8.4 Hz, J=
2.4 Hz), 7.40 (d, 1H, H3%, J=8.4 Hz), 7.58 (t, 1H,
H2, J=7.7 Hz), 7.64 (d, 1H, H6%, J=2.5 Hz), 8.11
(dd, 1H, H1, J=7.7 Hz, J=1.4 Hz), 8.52 (dd, 1H,
H3, J=7.4 Hz, J=1.4 Hz), 8.94 (s, 1H, H10), 10.75
(s, 1H, NH). Anal. C24H14Cl4N2O6 (C, H, Cl, N).
18j: IR (cm−1) w 3300 (NH), 1790, 1760 (CO ester),
13a: IR (cm−1) w 3200 (OH), 3300 (NH), 1650
(CO), 1620 (CꢁN), 1580, 1560 l (NH); H NMR (l)
6.21 (d, 1H, H7, J=1.9 Hz), 6.36 (d, 1H, H5, J=
1
4
4
1
3
1.9 Hz), 6.79 (t, 1H, H4%, J=7.2 Hz), 7.13 (d, 2H,
3
3
H2%+H6%, J=7.9 Hz), 7.24 (t, 2H, H3%+H5%, J=
3
7.7 Hz), 7.43 (t, 1H, H2, 3J=7.7 Hz), 7.99 (d, 1H,
3
3
3
3
H1, J=7.7 Hz), 8.30 (d, 1H, H3, J=7.6 Hz), 8.38
(s, 1H, H10), 10.73 (s, 1H, OH-6), 11.13 (br, 1H,
NH), 12.77 (s, 1H, OH-8); 13C NMR (l) 123.9 C1,
124.0 C2, 129.8 C3, 124.7 C4, 151.9 C4a, 156.9 C4b,
93.9 C5, 165.9 C6, 98.2 C7, 162.8 C8, 102.0 C8a,
179.5 C9, 120.2 C9a, 128.7 C10, 144.8 C1%, 112.2 C2%,
129.0 C3%, 119.2 C4%, 129.0 C5%, 112.2 C6%. Anal.
C20H14N2O4 (C, H, N).
3
3
4
3
3
4
3
4
13b: IR (cm−1) w 3200 (OH), 3300 (NH), 1650
(CO), 1560 l (NH); H NMR (l) 5.80 (s, 1H, H7),
6.02 (s, 1H, H5), 6.82 (t, 1H, H4%, J=7.4 Hz), 7.28
(t, 1H, H5%, J=7.4 Hz), 7.35 (d, 1H, H6%, J=8.1
3
4
1
3
3
3
1
3
1660 (CO ketone), 1570, 1530 l (NH); H NMR (l)
Hz), 7.38 (t, 1H, H2, J=8.1 Hz), 7.64 (d, 1H, H3%,

S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
249
3J=8.1 Hz), 7.99 (d, 1H, H1, 3J=7.6 Hz), 8.26 (d, 1H,
H3, J=7.6 Hz), 8.87 (s, 1H, H10), 10.31 (br s, 2H,
166.0 C6, 98.3 C7, 162.8 C8, 101.9 C8a, 179.5 C9, 120.2
C9a, 128.8 C10, 141.4 C1%, 113.2 C2%, 115.7 C3%, 156.1
C4%, 115.5 C5%, 113.1 C6%. Anal. C20H13FN2O4 (C, H,
N).
3
NH and OH-6), 12.89 (s, 1H, OH-8). Anal.
C20H13ClN2O4 (C, H, N).
13h: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
13c: IR (cm−1) w 3400 (OH), 3300 (NꢀH), 1650
1
1
1570 l (N–H); H NMR (l) 5.83 (s, 1H, H7), 6.04 (s,
(CO), 1560, 1520 l (NH); H NMR (l) 6.08 (d, 1H,
3
4
4
1H, H5), 7.33 (d, 1H, H5%, J=5.4 Hz), 7.39 (d, 1H,
H7, J=1.9 Hz), 6.27 (d, 1H, H5, J=1.8 Hz), 6.79
3
3
4
H6%, J=5.4 Hz), 7.48 (s, 1H, H3%), 7.63 (t, 1H, H2,
(dt, 1H, H4%, J=7.8 Hz, J=1.2 Hz), 7.01 (dd, 1H,
3J=6.5 Hz), 8.01 (d, 1H, H1, 3J=6.0 Hz), 8.27 (d, 1H,
H6%, 3J=8.2 Hz, 4J=1.2 Hz), 7.16 (t, 1H, H2%, 4J=2.0
3
3
H3, J=6.0 Hz), 8.88 (s, 1H, H10), 10.43 (br s, 2H,
Hz), 7.24 (t, 1H, H5%, J=8.0 Hz), 7.43 (t, 1H, H2,
3J=7.7 Hz), 8.03 (dd, 1H, H1, J=7.8 Hz, J=1.6
3
4
NH and OH-6), 12.86 (s, 1H, OH-8). Anal.
C20H12Cl2N2O4 (C, H, N).
3
4
Hz), 8.31 (dd, 1H, H3, J=7.6 Hz, J=1.5 Hz), 8.44
(s, 1H, H10), 10.91 (br s, 2H, NH and OH-6), 12.80 (s,
1H, OH-8); 13C NMR (l) 124.4 C1, 123.6 C2, 129.6
C3, 124.0 C4, 152.0 C4a, 157.1 C4b, 94.6 C5, 170.0 C6,
99.2 C7, 162.7 C8, 100.6 C8a, 178.2 C9, 120.4 C9a,
130.3 C10, 146.3 C1%, 111.3 C2%, 133.8 C3%, 118.5
C4%,130.5 C5%, 110.8 C6%. Anal. C20H13ClN2O4 (C, H,
N).
13i: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
1
1570 l (NH); H NMR (l) 5.53 (s, 1H, H7), 5.75 (s,
3
1H, H5), 6.84 (d, 1H, H4%, J=8.9 Hz), 7.34 (t, 1H,
H2, 3J=7.6 Hz), 7.37 (d, 1H, H3%, 3J=7.6 Hz), 7.58 (s,
3
1H, H6%), 7.95 (d, 1H, H1, J=6.4 Hz), 8.22 (d, 1H,
3
H3, J=7.6 Hz), 8.89 (s, 1H, H10), 10.46 (br s, 2H,
NH and OH-6), 12.92 (s, 1H, OH-8). Anal.
C20H12Cl2N2O4 (C, H, N).
13d: IR (cm−1) w 3200 (OH), 3300 (NH), 1650 (CO),
1560, 1520 l (NH); H NMR (l) 6.22 (s, 1H, H7), 6.38
13j: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
1
3
1
(s, 1H, H5), 7.13 (d, 2H, H2%+H6%, J=8.0 Hz), 7.28
1620 (CꢁN), 1570, 1530 l (NH); H NMR (l) 5.99 (s,
3
3
3
(d, 2H, H3%+H5%, J=7.5 Hz), 7.45 (t, 1H, H2, J=
1H, H7), 6.16 (s, 1H, H5), 7.02 (t, 1H, H3%, J=8.1
3
3
4
7.8 Hz), 8.03 (d, 1H, H1, J=8.0 Hz), 8.32 (d, 1H, H3,
Hz), 7.22 (td, 1H, H5%, J=9.1 Hz, J=2.5 Hz), 7.42
3
3
3J=7.5 Hz), 8.40 (s, 1H, H10), 10.86 (s, 1H, OH-6),
11.18 (br, 1H, NH), 12.77 (s, 1H, OH-8). Anal.
C20H13ClN2O4 (C, H, N).
(t, 1H, H2, J=7.6 Hz), 7.57 (dt, 1H, H6%, J=9.1 Hz,
4J [H–F]=6.4 Hz), 8.02 (d, 1H, H1, J=7.6 Hz), 8.29
3
3
(d, 1H, H3, J=7.6 Hz), 8.70 (s, 1H, H10), 10.58 (s,
13e: IR (cm−1) w 3500 (OH), 3300 (NꢀH), 1650
1H, OH-6), 10.34 (br, 1H, NH), 12.83 (s, 1H, OH-8).
Anal. C20H12F2N2O4 (C, H, N).
1
(CO), 1620 (CꢁN), 1570, 1530 l (NH); H NMR (l)
6.23 (d, 1H, H7, J=1.6 Hz), 6.39 (d, 1H, H5, J=1.6
19a: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
4
4
3
3
1
Hz), 6.82 (dd, 1H, H6%, J=12.0 Hz, J [H–F]=6.5
1620 (CꢁN), 1570 l (NH); H NMR (l) 6.78 (t, 1H,
3
3
3
Hz), 7.14 (t, 1H, H4%, J=7.6 Hz), 7.18 (dd, 1H, H3%,
H4%, J=6.3 Hz), 7.14 (d, 2H, H2%+H6%, J=7.9 Hz),
3
3J=7.6 Hz, 3J [H–F]=11.4 Hz), 7.49 (t, 1H, H2,
7.24 (t, 2H, H3%+H5%, J=7.1 Hz), 7.37 (t, 1H, H2,
3J=7.9 Hz), 7.60 (t, 1H, H5%, J=8.2 Hz), 8.07 (dd,
3J=7.1 Hz), 7.92 (d, 1H, H1, 3J=7.9 Hz), 8.24 (d, 1H,
H3, 3J=6.3 Hz), 8.45 (s, 1H, H10), 10.66 (s, 1H,
OH-6), 10.79 (s, 1H, NH), 13.81 (s, 1H, OH-8). Anal.
C20H12Cl2N2O4 (C, H, N).
3
3
4
1H, H1, J=7.6 Hz, J=1.6 Hz), 8.37 (dd, 1H, H3,
3J=7.9 Hz, J=1.4 Hz), 8.75 (s, 1H, H10), 10.65 (s,
4
1H, OH-6), 11.25 (br, 1H, NH), 12.77 (s, 1H, OH-8).
Anal. C20H13FN2O4 (C, H, N).
19b: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
1
13f: IR (cm−1) w 3200 (OH), 3300 (NH), 1650 (CꢁO),
1570 l (NH); H NMR (l) 6.84 (s, 1H, H4%), 7.28 (s,
1
1560 l (NH); H NMR (l) 6.25 (s, 1H, H7), 6.41 (s,
1H, H5%), 7.36 (s, 1H, H6%), 7.38 (s, 1H, H2), 7.66 (d,
3
3
1H, H5), 6.59 (t, 1H, H5%, J=8.5 Hz), 6.90 (d, 1H,
1H, H3%, J=6.6 Hz), 7.98 (s, 1H, H1), 8.28 (s, 1H,
3
3
H6%, J=8.3 Hz), 6.91 (d, 1H, H2%, J [H–F]=11.1
H3), 8.83 (s, 1H, H10), 10.50 (br s, 2H, NH and
OH-6), 13.83 (s, 1H, OH-8). Anal. C20H11Cl3N2O4 (C,
H, N).
3
3
Hz), 7.27 (dd, 1H, H4%, J=7.9 Hz, J [H–F]=15.0
3
Hz), 7.50 (t, 1H, H2, J=7.6 Hz), 8.08 (d, 1H, H1,
3J=7.8 Hz), 8.39 (d, 1H, H3, J=7.6 Hz), 8.47 (s, 1H,
19c: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
3
1
H10), 10.96 (s, 1H, OH-6), 11.22 (br, 1H, NH), 12.80
(s, 1H, OH-8). Anal. C20H13FN2O4 (C, H, N).
13g: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
1560 l (NH); H NMR (l) 6.81 (s, 1H, H4%), 7.05 (s,
1H, H6%), 7.19 (s, 1H, H2%), 7.25 (s, 1H, H5%), 7.44 (s,
1H, H2), 7.99 (s, 1H, H1), 8.32 (s, 1H, H3), 8.47 (s,
1H, H10), 10.99 (br s, 1H, NH and OH-6), 13.64 (s,
1H, OH-8). Anal. C20H11Cl3N2O4 (C, H, N).
1
1580, 1560 l (N–H); H NMR (l) 6.23 (s, 1H, H7),
6.39 (d, 1H, H5), 7.09–7.11 (m, 4H, H2%+H3%+
H5%+H6%), 7.45 (t, 1H, H2, J=7.5 Hz), 8.02 (d, 1H,
19d: IR (cm−1) w 3500 and 3400 (OH), 3300 (NH),
3
3
3
1
H1, J=7.3 Hz), 8.32 (d, 1H, H3, J=6.5 Hz), 8.39 (s,
1H, H10), 10.75 (s, 1H, OH-6), 10.33 (br, 1H, NH),
12.78 (s, 1H, OH-8); 13C NMR (l) 124.0 C1, 124.1 C2,
129.9 C3, 124.7 C4, 151.9 C4a, 157.0 C4b, 93.9 C5,
1650 (CO), 1560 l (NH); H NMR (l) 7.15 (d, 2H,
3
3
H2%+H6%, J=8.8 Hz), 7.27 (d, 2H, H3%+H5%, J=
3
8.3 Hz), 7.37 (t, 1H, H2, J=7.6 Hz), 7.94 (d, 1H, H1,
3J=6.9 Hz), 8.24 (d, 1H, H3, J=6.9 Hz), 8.46 (s, 1H,
3

250
S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
phloroglucinol and 4-methylsalicylic acid. Subsequent
condensation with a suitable substituted hydrazine
(phenylhydrazine, 3-chlorophenylhydrazine or 4-
fluorophenylhydrazine) afforded the hydrazones 20,
which by hydrolysis gave the free hydroxylated deriva-
tives 21. Physical data of these compounds are listed
in Table 3. Their main spectral characteristics are
given as follows.
H10), 10.90 (br s, 2H, NH and OH-6), 13.79 (s, 1H,
OH-8). Anal. C20H11Cl3N2O4 (C, H, N).
19f: IR (cm−1) w 3400 (OH), 3300 (NH), 1640 (CO),
1
3
1560 l (NH); H NMR (l) 6.56 (t, 1H, H5%, J=8.3
3
Hz), 6.91 (d, 1H, H6%, J=8.3 Hz), 6.95 (d, 1H, H2%,
3J [H–F]=11.6 Hz), 7.25 (dd, 1H, H4%, J [H–F]=
3
3
3
14.8 Hz, J=7.9 Hz), 7.36 (t, 1H, H2, J=7.6 Hz),
3
3
7.95 (d, 1H, H1, J=7.4 Hz), 8.27 (d, 1H, H3, J=
7.9 Hz), 8.48 (s, 1H, H10), 10.97 (br s, 2H, NH and
OH-6), 13.79 (s, 1H, OH-8). Anal. C20H11Cl2FN2O4
(C, H, N).
20a: IR (cm−1) w 3300 (NH), 1760 and 1740 (CO
ester), 1640 (CO ketone), 1620 (CꢁN), 1560, 1540 l
1
(NH); H NMR (l) 2.34 and 2.39 [2(s, 3H, COꢀCH3)],
3
4
19g: IR (cm−1) w 3450 (OH), 3300 (NH), 1650 (CO
6.83 (t, 1H, H4%, J=7.2 Hz), 7.03 (d, 1H, H7, J=
3
1
2.2 Hz), 7.16 (d, 2H, H2%+H6%, J=7.7 Hz), 7.26 (t,
2H, H3%+H5%, J=7.8 Hz), 7.41 (d, 1H, H5, J=2.1
Hz), 7.72 (s, 1H, H4), 7.76 (dd, 1H, H2, J=8.4 Hz,
ketone), 1560, 1530 l (NH); H NMR (l) 7.07–7.14
3
4
(m, 4H, H2%+H3%+H5%+H6%), 7.37 (t, 1H, H2,
3
3
3J=7.4 Hz), 7.93 (d, 1H, H1, J=7.5 Hz), 8.24 (d,
4J=1.0 Hz), 7.94 (s, 1H, H10), 8.07 (d, 1H, H1,
3J=8.3 Hz), 10.77 (s, 1H, NH); 13C NMR (l) 126.1
C1, 121.3 C2, 143.0 C3, 113.6 C4, 155.2 C4a, 157.0
C4b, 109.0 C5, 154.7 C6, 113.2 C7, 150.3 C8, 112.4
C8a, 173.4 C9, 120.1 C9a, 168.1 and 168.7 [2CꢁO
(Ac)], 20.8 [2CH3 (Ac)], 133.7 C10, 144.4 C1%, 112.5
C2%, 129.1 C3%, 119.7 C4%, 129.1 C5%, 112.6 C6%. Anal.
C24H18N2O6 (C, H, N).
3
1H, H3, J=7.4 Hz), 8.44 (s, 1H, H10), 10.80 (br s,
2H, NH and OH-6), 13.80 (s, 1H, OH-8); 13C NMR
(l) 123.7 C1, 123.4 C2, 128.0 C3, 124.3 C4, 150.7
C4a, 151.0 C4b, 95.8 C5, 156.1 C6, 105.4 C7, 167.9
C8, 100.5 C8a, 174.5 C9, 120.4 C9a, 129.0 C10, 141.7
C1%, 113.2 C2%, 115.6 C3%, 156.2 C4%, 115.5 C5%, 113.2
C6%. Anal. C20H11Cl2FN2O4 (C, H, N).
19h: IR (cm−1) w 3400 (OH), 1650 (CO), 1560 l
20c: IR (cm−1) w 3300 (NH), 1760 (CO ester), 1650
(CO ketone), 1620 w(CꢁN), 1570, 1525 l (NH); 1H
NMR (l) 2.32 and 2.37 [2(s, 3H, COꢀCH3)], 6.80 (d,
1
3
(NH); H NMR (l) 7.33 (dd, 1H, H5%, J=8.7 Hz,
4J=2.1 Hz), 7.39 (t, 1H, H2, 3J=7.7 Hz), 7.48 (d,
1H, H3%, J=2.3 Hz), 7.65 (d, 1H, H6%, J=8.9 Hz),
4
3
3
4
1H, H4%, J=7.7 Hz), 7.00 (d, 1H, H7, J=1.2 Hz),
3
3
7.99 (d, 1H, H1, J=7.5 Hz), 8.28 (d, 1H, H3, J=
7.5 Hz), 8.86 (s, 1H, H10), 10.63 (br s, 2H, NH and
OH-6), 13.82 (s, 1H, OH-8). Anal. C20H10Cl4N2O4 (C,
H, N).
3
7.06 (d, 1H, H6%, J=8.0 Hz), 7.19 (s, 1H, H2%), 7.23
(t, 1H, H5%, 3J=8.0 Hz), 7.37 (d, 1H, H5, 4J=1.2
3
Hz), 7.67 (s, 1H, H4), 7.72 (d, 1H, H2, J=8.3 Hz),
7.97 (s, 1H, H10), 8.02 (d, 1H, H1, J=8.3 Hz), 11.25
3
19i: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
(s, 1H, NH); 13C NMR (l) 126.0 C1, 121.4 C2, 142.5
C3, 113.9 C4, 155.1 C4a, 157.0 C4b, 108.9 C5, 154.6
C6, 113.0 C7, 150.3 C8, 112.3 C8a, 173.4 C9, 120.3
C9a, 168.0 and 168.6 [2CꢁO (Ac)], 20.7 [2CH3 (Ac)],
135.2 C10, 146.0 C1%, 111.7 C2%, 133.7 C3%,, 118.9 C4%,
130.5 C5%, 111.1 C6%. Anal. C24H17ClN2O6 (C, H, N).
20g: IR (cm−1) w 3300 (NH), 1760 (CO ester), 1650
1
3
1560 l (NH); H NMR (l) 6.87 (d, 1H, H4%, J=8.3
3
Hz), 7.40 (t, 1H, H2, J=9.2 Hz), 7.42 (d, 1H, H3%,
3J=8.3 Hz), 7.61 (d, 1H, H6%, J=2.8 Hz), 8.00 (d,
4
3
3
1H, H1, J=8.3 Hz), 8.31 (d, 1H, H3, J=7.4 Hz),
8.89 (s, 1H, H10), 10.69 (br s, 2H, NH and OH-6),
13.81 (s, 1H, OH-8). Anal. C20H10Cl4N2O4 (C, H, N).
19j: IR (cm−1) w 3600 and 3450 (OH), 3300 (NH),
1
(CO ketone), 1620 (CꢁN), 1540 l (NH); H NMR (l)
1
1650 (CO), 1570, 1540 l (NH); H NMR (l) 7.01 (t,
2.32 and 2.38 [2(s, 3H, COꢀCH3)], 7.01 (d, 1H, H7,
3
3
4J=2.2 Hz), 7.07–7.14 (m, 4H, H2%+H3%+H5%+
1H, H3%, J [H–F]=8.3 Hz), 7.22 (td, 1H, H5%, J=
8.8 Hz, 4J=2.8 Hz), 7.37 (t, 1H, H2, 3J=7.9 Hz),
7.58 (dt, 1H, H6%, 3J=9.2 Hz, 4J [H–F]=5.5 Hz),
7.95 (d, 1H, H1, J=7.4 Hz), 8.26 (d, 1H, H3, J=
8.3 Hz), 8.71 (s, 1H, H10), 10.77 (br s, 2H, NH and
OH-6), 13.80 (s, 1H, OH-8). Anal. C20H10Cl2F2N2O4
(C, H, N).
4
H6%), 7.36 (d, 1H, H5, J=2.2 Hz), 7.65 (d, 1H, H4,
3
4
4J=1.2 Hz), 7.71 (dd, 1H, H2, J=8.4 Hz, J=1.3
3
3
3
Hz), 7.87 (s, 1H, H10), 8.02 (d, 1H, H1, J=8.3 Hz),
10.77 (s, 1H, NH); 13C NMR (l) 126.0 C1, 121.3 C2,
142.9 C3, 113.5 C4, 155.1 C4a, 157.0 C4b, 108.9 C5,
154.6 C6, 113.0 C7, 150.3 C8, 112.3 C8a, 173.3 C9,
120.0 C9a, 168.0 and 168.6 [2CꢁO (Ac)], 20.7 (2CH3
Ac), 133.7 C10, 141.0 C1%, 113.5 (C2%+C6%), 115.6
C3%, 156.4 C4%, 115.4 C5%. Anal. C24H17FN2O6 (C, H,
N).
6.1.8. 6,8-Diacetoxy-9-oxo-9H-xanthene-3-car-
boxaldehyde arylhydrazones 20 and 6,8-dihydroxy-9-
oxo-9H-xanthene-3-carboxaldehyde arylhydrazones 21
The synthesis of these compounds was carried out
starting from the corresponding 9-oxo-9H-xanthene-3-
carboxaldehyde (0.4 g, 1.2 mmol), obtained by a reac-
tion sequence similar to that shown in Fig. 3, using
21a: IR (cm−1) w 3300 (NH), 1650 (CO), 1560 l
(NH); 1H NMR (l) 6.19 (s, 1H, H7), 6.38 (s, 1H,
H5), 6.83 (t, 1H, H4%, 3J=6.9 Hz), 7.16 (d, 2H,
3
3
H2%+H6%, J=7.5 Hz), 7.26 (t, 2H, H3%+H5%, J=

S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
251
7.5 Hz), 7.68 (s, 1H, H4), 7.73 (d, 1H, H2, 3J=8.0 Hz),
7.93 (s, 1H, H10), 8.07 (d, 1H, H1, J=8.2 Hz), 10.76
C3%, 118.9 C4%, 128.9 C5%, 112.0 C6%. Anal. C24H18N2O6
(C, H, N).
3
22c: IR (cm−1) w 3300 (NH), 1770 (CO ester), 1650
(s, 1H, OH-6), 10.94 (br, 1H, NH), 12.87 (s, 1H,
OH-8); 13C NMR (l) 125.4 C1, 121.0 C2, 143.0 C3,
113.4 C4, 155.8 C4a, 157.3 C4b, 94.0 C5, 165.6 C6, 98.0
C7, 162.8 C8, 102.2 C8a, 179.1 C9, 118.5 C9a, 133.8
C10, 144.4 C1%, 112.5 (C2%+C6%), 129.1 (C3%+C5%),
119.7 C4%. Anal. C20H14N2O4 (C, H, N).
1
(CO ketone), 1620 (CꢁN), 1540 l (NH); H NMR (l)
2.33 and 2.40 [2(s, 3H, COꢀCH3)], 6.77 (d, 1H, H4%,
3J=5.7 Hz), 6.99 (d, 1H, H6%, 3J=6.3 Hz), 7.06 (s, 1H,
3
H7), 7.12 (s, 1H, H2%), 7.22 (t, 1H, H5%, J=7.9 Hz),
3
7.43 (s, 1H, H5), 7.61 (d, 1H, H4, J=6.9 Hz), 7.97 (s,
21c: IR (cm−1) w 3400 (OH), 3200 (NH), 1650 (CO),
1H, H10), 8.20 (m, 2H, H3+H1), 10.68 (s, 1H, NH);
13C NMR (l) 122.9 C1, 132.1 C2, 131.9 C3, 118.2 C4,
154.4 C4a, 156.8 C4b, 109.0 C5, 154.7 C6, 113.2 C7,
150.3 C8, 112.1 C8a, 173.7 C9, 121.4 C9a, 168.0 and
168.5 [2CꢁO (Ac)], 20.7 [2CH3 (Ac)], 136.1 C10, 146.4
C1%, 111.3 C2%, 133.7 C3%, 118.3 C4%, 130.5 C5%, 110.7
C6%. Anal. C24H17ClN2O6 (C, H, N).
1
1620 w(CꢁN), 1560, 1540 l (NH); H NMR (l) 6.20 (s,
3
1H, H7), 6.39 (d, 1H, H5), 6.87 (d, 1H, H4%, J=7.7
3
Hz), 7.08 (d, 1H, H6%, J=7.8 Hz), 7.21 (s, 1H, H2%),
3
7.28 (t, 1H, H5%, J=8.0 Hz), 7.79 (s, 1H, H4), 7.81 (d,
3
1H, H2, J=8.6 Hz), 7.99 (s, 1H, H10), 8.12 (d, 1H,
3
H1, J=8.2 Hz), 11.12 (br, 1H, NH), 10.99 (s, 1H,
22g: IR (cm−1) w 3300 (NH), 1760 (CO ester), 1660
OH-6), 12.90 (s, 1H, OH-8); 13C NMR (l) 126.2 C1,
121.9 C2, 143.4 C3, 114.8 C4, 156.8 C4a, 158.7 C4b,
95.3 C5, 164.3 C6, 99.5 C7, 162.7 C8, 102.6 C8a, 179.7
C9, 120.3 C9a, 136.7 C10, 147.3 C1%, 112.0 C2%, 135.1
C3%, 120.0 C4%, 131.4 C5%, 112.8 C6%. Anal.
C20H13ClN2O4 (C, H, N).
1
(CO ketone), 1630 (CꢁN), 1540 l (NH); H NMR (l)
2.33 and 2.39 [2(s, 3H, COꢀCH3)], 7.06 (d, 1H, H7,
4J=2.1 Hz), 7.08–7.12 (m, 4H, H2%+H3%+H5%+
4
H6%), 7.44 (d, 1H, H5, J=2.2 Hz), 7.61 (d, 1H, H4,
3J=8.7 Hz), 8.00 (s, 1H, H10), 8.16 (dd, 1H, H3,
3J=8.7 Hz, 4J=2.2 Hz), 8.19 (d, 1H, H1, 4J=2.1 Hz),
10.73 (s, 1H, NH); 13C NMR (l) 122.2 C1, 132.6 C2,
131.8 C3, 118.2 C4, 154.2 C4a, 156.8 C4b, 109.0 C5,
154.7 C6, 113.2 C7, 150.3 C8, 112.1 C8a, 173.9 C9,
121.4 C9a, 168.0 and 168.5 [2CꢁO (Ac)], 20.7 [2CH3
(Ac)], 134.5 C10, 141.7 C1%, 113.0 C2%, 115.4 C3%, 155.0
C4%, 115.2 C5%, 113.0 C6%. Anal. C24H17FN2O6 (C, H,
N).
21g: IR (cm−1) w 3300 (NH), 1650 (CO), 1620
1
(CꢁN), 1570, 1520 l (NH); H NMR (l) 6.19 (d, 1H,
4
4
H7, J=1.8 Hz), 6.38 (d, 1H, H5, J=1.8 Hz), 7.09–
7.13 (m, 4H, H2%+H3%+H5%+H6%), 7.69 (s, 1H, H4),
3
7.73 (d, 1H, H2, J=8.5 Hz), 7.91 (s, 1H, H10), 8.06
(d, 1H, H1, J=8.3 Hz), 10.81 (s, 1H, OH-6), 11.04
3
(br, 1H, NH), 12.88 (s, 1H, OH-8); 13C NMR (l) 125.3
C1, 121.0 C2, 143.0 C3, 113.5 C4, 155.7 C4a, 157.3
C4b, 93.9 C5, 165.6 C6, 98.0 C7, 162.7 C8, 102.2 C8a,
179.1 C9, 118.5 C9a, 133.8 C10, 141.1 C1%, 113.5 C2%,
115.6 C3%, 152.1 C4%, 115.5 C5%,113.5 C6%. Anal.
C20H13FN2O4 (C, H, N).
23a: IR (cm−1) w 3500 (OH), 3300 (NH), 1650 (CO),
1
1620 (CꢁN), 1560 l (NH); H NMR (l) 6.22 (s, 1H,
H7), 6.40 (s, 1H, H5), 6.77 (s, 1H, H4%), 7.10 (d, 2H,
3
3
H2%+H6%, J=6.6 Hz), 7.23 (d, 2H, H3%+H5%, J=
3
6.2 Hz), 7.58 (d, 1H, H4, J=7.9 Hz), 7.98 (s, 1H,
H10), 8.17 (d, 1H, H3, J=8.3 Hz), 8.22 (s, 1H, H1),
3
6.1.9. 6,8-Diacetoxy-9-oxo-9H-xanthene-2-car-
boxaldehyde arylhydrazones 22 and 6,8-dihydroxy-9-
oxo-9H-xanthene-2-carboxaldehyde arylhydrazones 23
According to the same protocol above described
compounds 22 and 23 carrying the hydrazone chain at
position 2 on the xanthone nucleus were prepared from
phloroglucinol and 5-methylsalicylic acid as starting
material (Table 4).
10.46 (br s, 2H, NH and OH-6), 12.81 (s, 1H, OH-8);
13C NMR (l) 121.6 C1, 132.2 C2, 131.8 C3, 118.1 C4,
154.8 C4a, 157.2 C4b, 94.0 C5, 165.9 C6, 98.1 C7, 162.7
C8, 102.1 C8a, 179.4 C9, 119.9 C9a, 134.5 C10, 145.0
C1%, 112.0 (C2%+C6%), 128.9 (C3%+C5%), 118.85 C4%.
Anal. C20H14N2O4 (C, H, N).
23c: IR (cm−1) w 3400 (OH), 3300 (NH), 1650 (CO),
22a: IR (cm−1) w 3300 (NH), 1780, 1740 (CO ester),
1660 w(CO ketone), 1620 (CꢁN), 1520 l (NH); 1H
NMR (l) 2.33 and 2.40 [2(s, 3H, COꢀCH3)], 6.77 (t,
1620 (CꢁN); H NMR (l) 6.15 (d, 1H, H7, J=1.9
1
4
4
Hz), 6.33 (d, 1H, H5, J=2.0 Hz), 6.80 (m, 1H, H4%),
7.02 (dd, 1H, H6%, J=8.1 Hz, J=1.2 Hz), 7.14 (t,
1H, H2%, J=2.15 Hz), 7.25 (t, 1H, H5%, J=8.0 Hz),
7.61 (d, 1H, H4, J=8.7 Hz), 8.03 (s, 1H, H10), 8.22
3
4
3
4
3
1H, H4%, J=6.8 Hz), 7.06 (s, 1H, H7), 7.10 (d, 2H,
3
3
3
H2%+H6%, J=7.7 Hz), 7.26 (t, 2H, H3%+H5%, J=
7.3 Hz), 7.43 (s, 1H, H5), 7.60 (d, 1H, H4, 3J=8.5 Hz),
7.95 (s, 1H, H10), 8.17 (d, 1H, H3, J=8.7 Hz), 8.20
(dd, 1H, H3, 3J=8.8 Hz, 4J=2.1 Hz), 8.26 (d, 1H, H1,
4J=2.1 Hz), 10.67 (br s, 1H, NH and OH-6), 12.83 (s,
1H, OH-8); 13C NMR (l) 123.2 C1, 135.0 C2, 132.4
C3, 118.9 C4, 156.3 C4a, 158.6 C4b, 95.4 C5, 162.7 C6,
99.7 C7, 161.7 C8, 102.6 C8a, 179.5 C9, 121.2 C9a,
137.4 C10, 147.8 C1%, 112.3 C2%, 132.8 C3%, 119.2 C4%,
131.3 C5%, 111.6 C6%. Anal. C20H13ClN2O4 (C, H, N).
3
(s, 1H, H1), 10.47 (s, 1H, NH); 13C NMR (l) 122.3 C1,
132.6 C2, 131.8 C3, 118.3 C4, 154.2 C4a, 156.8 C4b,
109.1 C5, 154.8 C6, 113.2 C7, 150.4 C8, 112.2 C8a,
173.8 C9, 121.4 C9a, 168.0 and 168.6 [2CꢁO (Ac)], 20.7
[2CH3 (Ac)]; 134.5 C10, 145.0 C1%, 112.0 C2%, 128.9

252
S. Moreau et al. / European Journal of Medicinal Chemistry 37 (2002) 237–253
23g: IR (cm−1) w 3400 (OH), 3300 (NH), 1660 (CO);
Acknowledgements
1H NMR (l) 6.23 (s, 1H, H7), 6.41 (s, 1H, H5),
7.09–7.11 (m, 4H, H2%+H3%+H5%+H6%), 7.62 (d,
The authors wish to thank F. Duboudin for her help
in the interpretation of mass spectra, and A. Lagarde`re
for her able technical assistance. The secretarial help of
A. Carre`re is also gratefully acknowledged.
3
1H, H4, J=8.6 Hz), 8.00 (s, 1H, H10), 8.20 (d, 1H,
H3, 3J=8.5 Hz), 8.26 (s, 1H, H1), 10.48 (s, 1H, OH-6),
11.17 (s, 1H, NH), 12.84 (s, 1H, OH-8); 13C NMR (l)
122.7 C1, 133.3 C2, 132.4 C3, 118.8 C4, 156.3 C4a,
158.5 C4b, 95.2 C5, 164.2 C6, 99.4 C7, 162.6 C8, 102.7
C8a, 180.2 C9, 121.1 C9a, 135.8 C10, 143.0 C1%, 113.9
(C2%+C6%), 116.2 (C3%+C5%), 157.1 C4%. Anal.
C20H13FN2O4 (C, H, N).
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