Antifungal and antibacterial activity of the newly synthesized 2-xanthone derivatives

Article abstract of DOI:10.1002/ardp.200800089

A series of 2-substituted xanthone derivatives 8 - 20 containing selected allyl, cinnamyl, morpho-line, and imidazole moieties were synthesized and tested for their antifungal and antibacterial in-vitro properties. Of the newly synthesized derivatives, te

Full text of DOI:10.1002/ardp.200800089

Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
H. Marona et al.
9
Full Paper
Antifungal and Antibacterial Activity of the Newly Synthesized
2-Xanthone Derivatives
Henryk Marona1, Natalia Szkaradek1,3, Elzbieta Karczewska2, Danuta Trojanowska2, Alicja Budak2,
Piotr Bober2, Waldemar Przepiꢀrka2, Marek Cegla3, and Edward Szneler4
1 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University
Medical College, Cracow, Poland
2 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Jagiellonian University Medical College,
Cracow, Poland
3 Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Cracow,
Poland
4 Faculty of Chemistry, Jagiellonian University, Cracow, Poland
A series of 2-substituted xanthone derivatives 8–20 containing selected allyl, cinnamyl, morpho-
line, and imidazole moieties were synthesized and tested for their antifungal and antibacterial
in-vitro properties. Of the newly synthesized derivatives, ten revealed antifungal activity espe-
cially against Trichophyton mentagrophytes (the biggest inhibition zones ranged 35 mm for 11 and
13). 2-(3-(Allylamino)propoxy)-9H-xanthen-9-one hydrochloride 9 inhibited growth of all of the
examined fungal species. Significant efficacy against evaluated yeasts and dermatophytes was
also observed for 6-chloro-2-methyl-9H-xanthen-9-one derivatives 11–13 containing encyclic
amine moieties. Additionally, compounds 9, 11, and 12 hindered development of bacteria spe-
cies but in a lesser degree. They were efficacious against Staphylococcus aureus, Escherichia coli,
and Enterococcus faecalis.
Keywords: Antibacterial / Antifungal / Synthesis / Xanthone /
Received: May 8, 2008; accepted: October 7, 2008
DOI 10.1002/ardp.200800089
Nowadays, both naturally occurring and synthetic xan-
thone derivatives are widely used in the therapy of many
diseases. Depending on the kind and place of substitu-
tion in one of the xanthone rings e. g., antitumor [3, 4],
anti-inflammatory [5], antithrombotic [6], anticonvulsant
[7, 8], neuropharmacological [9, 10], modulatory activity
of protein kinase C [11], antihypertensive [12, 13], anti-
malarial [14], antimycobacterial [15, 16], antibacterial
[17], and antifungal [18, 19] effects were described.
Searching for structures with potential biological
activity, we have directed our attention to the xanthone
derivatives, which show antifungal and antibacterial
properties. The emergence of multidrug-resistant bacte-
ria such as methicillin-resistant Staphylococcus aureus
have made treatment of infectious diseases difficult and
have, over the last decades, become a serious medical
problem. As pathogenic bacteria continuously evolve
mechanisms of resistance to currently used antibiotics,
the discovery of novel and potent antibacterial drugs is
Introduction
Biological properties of the xanthone structure had been
investigated since 1967, when I. Cox discovered the anti-
allergic activity of the chromone moiety – bearing the
structural element of xanthone [1]. This structural simi-
larity gave rise to the search for xanthone derivatives
with potential biological activities. Nevertheless,
although advantages of naturally occurring xanthone
derivatives were known for hundreds of years, those bio-
logical benefits were not connected with the xanthone
structure. The plants richest in xanthone derivatives are
belonging to the Guttiferae family, expecially Garcinia
mangostana called “Queen of fruits” [2].
Correspondence: Henryk Marona, Department of Technology and Bio-
technology of Drugs, Faculty of Pharmacy, Jagiellonian University Medi-
cal College, Cracow, 9 Medyczna Str., 30-688 Cracow, Poland.
E-mail: hen.mar@interia.pl
Fax: + 48 12 657-0488
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

10
H. Marona et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
Table 1. In-vitro growth-inhibitory effectsa) of the 2-xanthone derivatives against chosen strains of yeasts, moulds, and dermato-
phytes.
Compound
C. alb.
C. glabr.
C. krus.
C. lus.
C. neof.
A. fum.
T. ment.
8
9
10
11
12
13
14
–
++
–
+++
++
+++
–
–
++
–
++++
+++
+++
–
–
++
–
++
+++
+++
–
–
++
+
+++
+++
+++
–
–
+
–
++
++
++
–
–
++
–
–
–
–
++++
+++
++++
++++
++++
–
–
–
15
16
–
–
+
–
+
–
++
–
–
–
–
–
++++
++
17
18
19
20
–
–
–
–
+
–
–
–
–
–
–
–
+
–
+
–
–
–
–
–
–
–
–
–
++++
+++
++++
–
Terbinafine
–
j
j
j
j
++
++++
a)
Size of growth inhibition zones: 6–7 mm (–), 8–10 mm (+), 11–14 mm (++), 15–19 mm (+++), 20 mm or more (++++) [19]; evalua-
tion was not done (j).
the best way to overcome bacterial resistance and
develop effective therapies [20]. Many studies on antibac-
terial activity of medicinal plants have been made. They
established that almost all species from Guttiferae family
possess antibacterial properties, even against multidrug-
resistant bacteria. Yasunaka et al. [21] ascertained that
this antibacterial activity is connected with the presence
of xanthone derivatives especially 1,3,5,6-tetrahydroxy-2-
(3,3-dimethylallyl)-9H-xanthen-9-one. It is also well
known that compounds with a quinolone moiety demon-
strate antibacterial properties [22]. Thus, in the past
some xanthone analogues of fluoroquinolone had been
synthesized: 1-piperidinyl-2-fluoro-9H-xanthen-9-one, 1-
piperazinyl-2-fluoro-9H-xanthen-9-one which were active
against Staphylococcus aureus (MIC = 50 lg/mL) and 2-flu-
oro-3-piperazinyl-9H-xanthen-9-one which revealed effi-
cacy against Staphylococcus aureus, Escherichia coli, and
Enterococcus faecalis (MIC = 50 lg/mL) [23].
Although there are many commercially available anti-
fungal agents, searching for new antimicrobial struc-
tures also remains a major issue. The outbreak of fungal
infections is partially linked to immuno system failure
caused by ageing, diseases (e. g. AIDS, cancer) [24], immu-
nosuppressive drugs administered in chemotherapy [25],
or the transplantation process [26]. Research activities
have been undertaken both in the group of naturally
occurring [27, 28] and synthetic [18, 19] xanthone deriv-
atives. They stated that some of them reveal significant
antifungal properties, e. g. 1,3,5,6-tetrahydroxy-2-(3,3-
dimethylallyl)-9H-xanthen-9-one mentioned below (MIC
a 10 lg/mL against Candida glabrata) [27].
Herein, we reported the results of a study aimed at
evaluating the potential antifungal and antibacterial
Scheme 1. Synthesis of the compounds 8–20.
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Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
Xanthone Derivatives: Antifungal, Antibacterial Activity
11
Table 2. Size of growth inhibition zones (in mm) for the compounds with antifungal activity used in various concentration (0.25%,
0.5%, 1%).
Compound
Conc.
C. alb.
C. glabr.
C. krus.
C. lus.
C. neof.
A. fum.
T. ment.
9
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
–
–
12
–
–
–
–
–
15
–
–
13
–
–
15
–
–
–
–
–
–
–
–
14
–
–
–
–
–
21
–
–
18
–
–
18
–
–
9
–
–
–
–
–
–
12
–
–
–
–
–
14
–
–
18
–
–
16
–
–
9
–
–
–
–
–
–
14
–
–
8
–
–
19
–
–
17
–
–
18
–
–
11
–
–
–
–
8
9
10
–
–
–
9
9
13
8
9
12
8
9
12
–
–
–
–
–
–
–
–
13
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
15
18
26
–
10
11
12
13
15
16
17
18
19
–
18
11
18
35
13
17
28
11
18
35
23
24
24
–
10
12
9
14
20
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
8
–
–
–
–
–
9
0.25
0.5
1.0
0.25
0.5
1.0
8
16
16
17
25
–
–
activity of 2-xanthone derivatives. Some of them contain zones was 35 mm for both structures (see Table 2). This
structural moieties of the well known antimycotic agents value is smaller than values obtained for commercially
(allyl, cinnamyl, morpholine, imidazole).
available drugs with allyl and / or methylamine moieties
(e. g. terbinafine revealed growth inhibition zone rang-
ing 85 mm in the concentration 8 lg/mL) but bigger than
values obtained for triazoles (e. g. fluconazole revealed
growth inhibition zone ranging 13 mm in the concentra-
tion 32 lg/mL) [29]. Yeasts strains were inhibited by three
to six of the evaluated compounds. Growth of C. albicans
was inhibited by compounds 9, 11, 12, 13 and the biggest
zone of inhibition sized 15 mm. C. lusitaniae species was
sensitive to 9, 10, 11, 12, 17, 13, 15, 19 and the most effec-
tive was 11 (size of growth inhibition zone ranged
19 mm). Growth of C. glabrata was hindered by 9, 12, 11,
13, 15, 17 and size of inhibition zones ranged from 8 mm
for 17 to 21 mm for 11 (see Fig. 1). Inhibitory activity for
C. krusei revealed: 9, 11, 12, 13, 15 and the most active was
12 (growth inhibition zone sized 18 mm). According to
literature data [19], C. krusei growth inhibition zone for
econazole sized 23 mm at the dose of 50 lg per disc. C.
neoformans was sensitive to 9, 11, 12, 13 and the biggest
zone of growth inhibition (13 mm) was observed for 11.
Results
Antifungal activity
The in-vitro antifungal activity of the synthesized com-
pounds against representative strains of yeasts: Candida
albicans ATCC 90028 (C. albicans), Candida glabrata 715/06
(C. glarbata), Candida krusei 617/06 (C. krusei), Candida lusi-
taniae 654/06 (C. lusitaniae), Cryptococcus neoformans 709/
01 (C. neoormansf.), molds: Aspergillus fumigatus 867/06 (A.
fumigatus), and dermatophytes: Trichophyton mentagro-
phytes ATCC 18748 (T. mentagrophytes) was evaluated
according to an agar disc diffusion method.
From the results reported in Table 1, it appears that
among the tested compounds, ten revealed growth inhib-
itory effect and all of them inhibited growth of T. menta-
grophytes. The most active for that kind of dermatophytes
were compounds 11 and 13. Size of growth inhibition
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H. Marona et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
Table 3. In-vitro growth-inhibitory effectsa) of the 2-xanthone derivatives against chosen strains of bacteria.
Compound
S. aureus
E. faecalis
E. coli
K. pneumoniae
P. aeruginosa
8
-
-
-
-
-
9
++
+
+
+
-
10
+
+
-
-
-
11
++
+
+++
+
-
12
++
++
++
-
-
13
+
+
-
-
-
14
-
-
-
-
-
15
++
-
-
-
-
16
-
-
-
-
-
17
+
+
+
-
-
18
+
-
-
-
-
19
-
-
-
-
-
20
-
-
-
-
-
Gentamycine
++++
+++
++++
++
++++
a)
Size of growth inhibition zones: 6-7 mm (–), 8–10 mm (+), 11–14 mm (++), 15–19 mm (+++), 20 mm or more (++++) [19].
Figure 2. Comparison of C. neoformans growth-inhibition zones
for compound 9 used in various concentrations.
Figure 1. Comparison of C. glabrata growth-inhibition zones for
compounds 11 and 13.
Antibacterial activity
The in-vitro antibacterial activity of the synthesized com-
A. fumigatus was sensitive only to the compound number
9.
pounds against representative strains of bacteria: Staphy-
lococcus aureus ATCC – 25923 (S. aureus), Escherichia coli
ATCC – 25922 (E. coli), Pseudomonas aeruginosa ATCC –
27853 (P. aeruginosa), Enterococcus faecalis ATCC – 29212
(E. faecalis), Klebsiella pneumoniae ATCC -700603 (K. pneu-
moniae) was evaluated according to an agar disc diffusion
method.
Data showed above indicate that only compound 9 was
active against all of the tested microorganisms, especially
against T .mentagrophytes (size of growth inhibition zone
Ø = 26 mm). Compounds 11, 12, and 13 inhibited growth
of the examined yeasts and dermatophytes.
Additionally, size of inhibition zones for the com-
pounds used in the various concentrations (1%, 0.5%,
0.25%) was compared. Data are shown in Table 2. Results
indicate that all of the examined compounds used in a
minor concentrations inhibited growth of T. mentagro-
phytes but consequently in a lesser degree. Moreover,
compounds 9, 11, 12, 13 used in minor concentrations
were active against C. neoformans (see Fig. 2).
From the results reported in Table 3 it appears that
among the tested compounds, eight revealed a growth
inhibitory effect, but weaker than gentamycine, which
revealed zones of growth inhibition sized 20 mm or
more for all of the examined bacterial strains. All of
them inhibited growth of S. aureus and the biggest zone
of growth inhibition sized 14 mm for compound 11. On
the contrary P. aeruginosa was resistant to all of the exam-
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Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
Xanthone Derivatives: Antifungal, Antibacterial Activity
13
Table 4. Size of inhibition zones (in mm)for the compounds with antibacterial activity used in various concentration (0.25%, 0.5%,
1%).
Compound
Conc.
S. aureus
E. faecalis
E. coli
K. pneumoniae
P. aeruginosa
9
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
0.25
0.5
1.0
–
–
9
10
–
–
9
–
9
10
–
9
11
–
–
8
–
–
–
–
–
8
–
–
–
–
9
–
–
–
–
8
–
–
–
–
–
8
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
10
12
–
–
9
10
11
12
13
15
17
18
–
–
–
11
14
–
11
13
–
9
10
8
10
11
–
–
8
12
16
–
10
12
–
–
–
–
–
–
–
–
9
–
–
–
–
–
8
–
ined derivatives. Escherichia coli species was sensitive to 9, that among the tested compounds only 9 proved its
11, 12, 17, the most effective was 11 (size of growth inhib- growth inhibitory effect against all of the examined
ition zone ranged 16 mm). Compounds active against E. strains. It was most potent for T. mentagrophytes. Com-
coli were active also against E. faecalis. Additionally, pound 9 possessed the allylamine group – a well known
growth of E. faecalis was inhibited by 10 and 13. The most moiety of the commercially available drugs terbinafine
active was 12 (zone of growth inhibition sized 11 mm). and naftifine. Surprisingly, the structural analogue of 9,
Development of K. pneumoniae was hindered only by 9 compound 8, revealed no efficacy against the evaluated
and 11, size of inhibition zones reached 8 mm for both of microorganisms. We can state that the length of the
them.
linker joining xanthone and allylamine moieties deter-
These data showed that none of the evaluated com- mined antifungal properties. Likewise, another hydroxyl
pounds was active against all of the tested microorgan- analogue of 9, compound 10, exhibited low activity,
isms. Compounds 9 and 11 inhibited growth of four of whereas there are some publications [27] describing that
them.
polyhydroxyxanthone derivatives possess antimicrobial
Compounds used in the minor concentrations (0.5%, effects. It suggested that only hydroxyl groups in the xan-
0.25%) revealed lesser activity than compounds used in thone rings increase antifungal activity. Hydroxyl groups
concentration 1%. Only compound 15 was effective when in the side chains seem not to affect the activity.
used in the 0.25% concentration.
Compounds 10–12 inhibited growth of the examined
yeasts and dermatophytes, especially C. glabrata and T.
mentagrophytes. Surprisingly, we had obtained 11 as the
intermediate product for the synthesis of xanthone ana-
logue naftifine, meanwhile 11 itself revealed significant
Discussion
In previous studies, it was demonstrated that the xan- efficacy. This fact prompted us to synthesize its ethyl ana-
thone derivatives possess microbiological activities [17– logue 12, which also showed antifungal properties. Simi-
19, 27, 28]. These facts and our experience in searching lar data obtained for 10–12 confirmed that the type of
for new compounds prompted us to synthesize a novel chain linking xanthone and amine moieties affects the
series of 2-xanthone derivatives with potential antifungal activity more than the type of the used amine. The same
and/or antibacterial properties. Antifungal study showed relationship could be observed for 14, possessing a car-
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14
H. Marona et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
Table 5. Chemical structures of the tested compounds.
was true for almost all of the tested compounds). Com-
pound 20, similarly to another amide structure 14 was
absolutely inactive against the evaluated strains. These
data were in accordance with former publications [19]
describing that monohalogenated xanthone structures
were more effective than unhalogenated ones.
Compound
R1
R2
The obtained compounds were also investigated
against representative strains of bacteria, however, their
antibacterial activity was weaker than the antifungal. All
of them were ineffective against Pseudomonas aeruginosa.
Still, the most potent was 11, obtained as intermediate
product, which was surprisingly efficacious also against
fungus strains. It should be interesting to modify this
structure in our further investigations.
8
9
N HCl
N HCl
10
11
12
13
We also observed that type and length of the side chain
affects antibacterial activity, likewise antimicrobial activ-
ity. The allylamine moiety was not the factor determin-
ing the antibacterial properties. This was clear, taking
into account the fact that allylamine is a moiety charac-
teristic for antifungal drugs.
When comparing data obtained for 11 and 17 or for 12
and 18, we can state that the monohalogenated xanthone
structure was more effective than the unhalogenated
one (similarly as for antifungal properties).
14
15
Herein, and as mentioned in the literature [23], we also
noticed that diazole rings, such as imidazole revealed
inhibition of bacteria growth.
16
N HCl
Results obtained during our investigation caused us to
carry out additional tests using multidrug-resistant
strains isolated from the nosocomial infections; these
studies are in progress.
17
18
N HCl
N HCl
Financial support of this research was provided by the Polish
State Committee for Scientific Research – Project No. BBNK/
ZDS/000712.
19
20
The authors have declared no conflict of interest.
bonyl group instead of the methylen group in 13; it was
absolutely inactive in these tests.
Experimental
On the other hand, the activity of 15 and 16 was lower
than that of other compounds with a methylen chain. It
seemed to be related to the cyclic instead of linear struc-
ture of the used amine (imidazole, morpholine). Addi-
tionally, morpholinic and azolic antifungal drugs act at
different stages of the ergosterole synthesis than allyla-
minic does, which also could affected their weaker effi-
cacy.
Chemistry
Melting points (m.p.) are uncorrected and were determined
using a Bꢀchi SMP-20 apparatus (Bꢀchi Labortechnik, Flawil,
Switzerland). The infrared spectra were recorded on potassium
bromide pellets using a Jasco FT / IR 410 spectrometer (Jasco Inc.,
Easton, MD, USA). The 1H-NMR spectra were obtained in CDCl3 or
DMSO-d6 with a Varian Mercury-VX 300 NMR spectrometer (Var-
ian Inc., Palo Alto, CA, USA) or a Bruker AMX spectrometer
(Bruker, Karlsruhe, Germany) with 500.13 MHz with TMS or
DMSO as an internal standard respectively.13C-NMR spectra were
In the 6-methoxyxanthone derivatives series (17–20),
antifungal activity was low or absent (with the exception
of activity against Trichophyton mentagrophytes, which
recorded on
a Bruker AMX spectrometer (Bruker) with
500.13 MHz and 125.17 MH, respectively, with TMS in CDCl3 or
DMSO in DMSO-d6 as an internal standard. Results are presented
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Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
Xanthone Derivatives: Antifungal, Antibacterial Activity
15
in the following format; chemical shift d in ppm, multiplicity, J
values in Hertz (Hz), number of protons, proton's position. Multi-
plicities are shown as the abbreviations: s (singlet), brs (broad
singlet), bb (broad bond), d (doublet), dd (doublet of doublets), td
(triplet of doublets), t (triplet), dt (doublet of triplets), m (multip-
let). Elemental analyses were performed on a Elementar Vario EL
III (Elementar Analysensysteme, Hanau, Germany). The purity of
obtained compounds was confirmed by the thin-layer chroma-
tography (TLC), carried out on precoated plates (silica gel 60 F-
254; Merck, Darmstadt, Germany) using the solvents indicated
below. Spots were visualized with UV light. Reagents: 3-chloro-1-
propanol, phosphorus tribromide, allylamine, methylamine,
ethylamine, imidazole, 2,6-dimethylmorpholine, cinnamylbro-
mide, trans-cinnamoyl chloride were supplied by Lancaster Syn-
thesis (Frankfurt am Main, Germany). Solvents were commer-
cially available materials of reagent grade.
General procedure for the preparation of substances
8–20
Compounds 8–18 were obtained by amination of compounds 1,
3–7 with appropriate amines in n-propanol (for 9) or toluene in
a presence of K2CO3, according to the earlier published proce-
dures [31]. Synthesis of 19 and 20 was two steps procedure: ami-
nation with methylamine and reaction of the resulted 6-
methoxy-2-((methylamino)metyl)-9H-xanthen-9-one with cinna-
mylbromide or trans-cinnamoyl chloride in toluene in a pres-
ence of K2CO3. If necessary, resulted bases were converted into
hydrochloride salts in propanol / acetone (4 : 1) with an excess of
ethanol saturated with HCl. The crude products were recrystal-
lized from acetone / ethanol (1 : 3).
2-(2-(Allylamino)ethoxy)-9H-xanthen-9-one 8
Compound 8 was obtained as white solid (yield: 65%); m.p.: 117–
1198C; IR (KBr) m [cm– 1]: 3303, 1616, 1466, 1319, 1209, 912, 757;
1H-NMR (CDCl3, 300 MHz) d [ppm]: 3.06 (t, J = 5.1 Hz, 2H, -CH2-CH2-
NH-), 3.34–3.37 (m, 2H, -NH-CH2-CH=CH2), 4.20 (t, J = 5.1 Hz, 2H,
Ar-O-CH2-), 5.12–5.27 (m, 2H, -CH=CH2), 5.86–5.99 (m, 1H, -
CH=CH2), 7.26–8.36 (m, 7H, Ar-H); Rf = 0.90 (methanol / ethyl ace-
tate (1 : 1)). Anal. calcd. for C18H17NO3: C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.59; H, 5.83; N, 4.62.
General procedure for the preparation of the starting
materials 1–7
Preparation of the 2-(2-bromoethoxy)-9H-xanthen-9-one 1 was
described previously [30]. The analogous method was used for
the formation of 2-(3-bromopropoxy)-9H-xanthen-9-one 3 which
was prepared in the two-steps reaction from 2-hydroxy-9H-
xanthen-9-one using 3-chloro-1-propanol and phosphorus tribro-
mide. The crude products were recrystallized from n-hexane /
toluene (1 : 4).
2-(3-(Allylamino)propoxy)-9H-xanthen-9-one
hydrochloride 9
Compound 9 was obtained as white solid (yield: 70%); m.p.: 194-
1968C; IR (KBr) m [cm– 1]: 3414, 2948, 2434, 1651, 1494, 1218,
1143, 994, 753. Base of compound 9: 1H-NMR (CDCl3, 300 MHz) d
[ppm]: 1.94–2.05 (m, 2H, -CH2-CH2-CH2-), 2.84 (t, J = 7.0 Hz, 2H, -
CH2-CH2-CH2-NH-), 3.28 (dd, J = 1.5 Hz, J = 6.0 Hz, 2H, -NH-CH2-
CH=CH2), 4.16 (t, J = 7.0 Hz, 2H, Ar-O-CH2-), 5.08–5.23 (m, 2H, -
CH=CH2), 5.86-5.99 (m, 1H, -CH=CH2), 7.19-8.36 (m, 7H, Ar-H); Rf =
2-(3-Hydroxypropoxy)-9H-xanthen-9-one 2
Compound 2 was obtained as white solid (yield: 60%); m.p.: 142-
1448C; IR (KBr) m [cm– 1]: 3487, 2948, 1617, 1494, 1271, 1250,
1232, 1150; 1H-NMR (CDCl3, 300 MHz) d [ppm]: 2.07–2.15 (m, 2H,
-CH2-CH2-CH2-), 3.88–3.93 (m, 2H, -CH2-OH), 4.25 (t, J = 6.2 Hz, 2H,
Ar-O-CH2-), 7.27-8.36 (m, 7H, Ar-H); RF = 0.88 (methanol / ethyl ace-
tate (1 : 1)). Anal. calcd. for C16H14O4: C, 71.10; H, 5.22. Found: C,
71.31; H, 5.54.
0.21 (methanol
/ ethyl acetate (1 : 1)). Anal. calcd. for
C19H20NO3Cl: C, 65.99; H, 5.83; N, 4.05. Found: C, 66.20; H, 6.19;
N, 3.98.
2-(3-Bromopropoxy)-9H-xanthen-9-one 3
Compound 3 was obtained as white solid (yield: 50%); m.p.: 146–
1478C; IR (KBr) m [cm– 1]: 1647, 1618, 1465, 1316, 1263, 1227,
1145, 756; 1H-NMR (CDCl3, 300 MHz) d [ppm]: 2.33–2.42 (m, 2H, -
CH2-CH2-CH2-), 3.63 (t, J = 6.4 Hz, 2H, -CH2-Br), 4.23 (t, J = 6.4 Hz,
2H, Ar-O-CH2-), 7.31–8.37 (m, 7H, Ar-H); RF = 0.90 (methanol /
ethyl acetate (1 : 1)). Anal. calcd. for C16H13O3Br: C, 57.68; H, 3.93.
Found: C, 57.72; H, 4.04.
2-(3-(Allylamino)-2-hydroxypropoxy)-9H-xanthen-9-one
hydrochloride 10
Compound 10 was obtained as white solid (yield: 60%); m.p.:
206–2078C; IR (KBr) m [cm– 1]: 3384, 2932, 2788, 1619, 1467,
1215, 1037, 764. Base of compound 10: 1H-NMR (CDCl3, 300 MHz)
d [ppm]: 2.79–2.93 (m, 2H, -CH(OH)-CH2-NH-), 3.26–3.38 (m, 2H, -
NH-CH2-CH=CH2), 4.05–4.17 (m, 3H, Ar-O-CH2-CH(OH)-CH2-),
5.11–5.25 (m, 2H, -CH=CH2), 5.85–5.99 (m, 1H, -CH=CH2), 7.35–
8.36 (m, 7H, Ar-H); Rf = 0.28 (methanol / ethyl acetate (1 : 1)).
Anal. calcd. for C19H20NO4Cl: C, 63.07; H, 5.57; N, 3.87. Found: C,
63.06; H, 5.72; N, 3.75.
2-((Oxiran-2-yl)methoxy)-9H-xanthen-9-one 4
2-((Oxiran-2-yl)methoxy)-9H-xanthen-9-one (4) was obtained from
2-hydroxy-9H-xanthen-9-one as described in [7]. The crude prod-
ucts were recrystallized from ethanol.
6-Chloro-2-((methylamino)methyl)-9H-xanthen-9-one 11
Compound 11 was obtained as white solid (yield: 63%); m.p.:
113–1148C; IR (KBr) m [cm– 1]: 3319, 3063, 2786, 1654, 1444,
1293, 923, 778; 1H-NMR (DMSO-d6, 500.13 MHz) d [ppm]: 2.60 (brs,
1H, -NH-), 3.24 (ddd, J = 1.5 Hz, J = 1.7 Hz, J = 5.7 Hz, 2H, -NH-CH2-),
4.03 (s, 2H, Ar-CH2-), 5.08 (ddd, J = 1.5 Hz, J = 3.6 Hz, J = 10.2 Hz,
1H, =CHH), 5.21 (ddd, J = 1.7, J = 3.6 Hz, J = 17.3 Hz, 1H, =CHH),
5.92 (ddt, J = 5.7 Hz, J = 10.2 Hz, J = 17.3 Hz, 1H, -CH=), 7.46 (dd, J =
7.4 Hz, J = 8.0 Hz, 1H, H-2), 7.52 (dd, J = 2.0 Hz, J = 8.6 Hz, 1H, H-7),
7.89 (dd, J = 0.4 Hz, J = 2.0 Hz, 1H, H-5), 7.91 (dd, J = 1.8 Hz, J =
7.4 Hz, 1H, H-3), 8.07 (dd, J = 1.8 Hz, J = 8.0 Hz, 1H, H-1), 8.17 (dd, J
6-Chloro-2-(bromomethyl)-9H-xanthen-9-one and 2-
(bromomethyl)-6-methoxy-9H-xanthen-9-one 5, 7
Synthesis and properties of the 6-chloro-2-(bromomethyl)-9H-
xanthen-9-one (5) and 2-(bromomethyl)-6-methoxy-9H-xanthen-9-
one (7) were previously reported in [31].
6-Chloro-9-oxo-9H-xanthene-2-carbonyl chloride 6
Preparation and properties of the 6-chloro-9-oxo-9H-xanthene-2-
carbonyl chloride (6) were described elsewere [32].
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16
H. Marona et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
= 0.4 Hz, J = 8.5 Hz, 1H, H-8); 13C-NMR (DMSO-d6, 500.13 MHz) d
[ppm]: 35.40 (-CH3), 53.99 (-CH2-), 117.85 (C-4), 117.98 (C-4), 119.96
(C-8a), 120.61 (C-8b), 124.42 (C-1), 124.72 (C-7), 127.80 (C-8),
135.60 (C-3), 137.53 (C-2), 139.57 (C-6), 154.37 (C-4a), 155.81 (C-
4b), 175.29 (C=O); Rf = 0.12 (methanol / ethyl acetate (1 : 1)). Anal.
calcd. for C15H12NO2Cl: C, 65.82; H, 4.42; N, 5.12. Found: C, 65.70;
H, 4.58; N, 5.15.
(C-7), 127.80 (C-8), 128.83 (C-5'), 134.51 (C-2), 134.93 (C-3), 137.38
(C-2'), 139.75 (C-6), 154.91 (C-4a), 155.79 (C-4ba), 175.12 (C=O); Rf =
0.59 (methanol
/ ethyl acetate (1 : 1)). Anal. calcd. for
C17H11N2O2Cl: C, 65.71; H, 3.56; N, 9.01. Found: C, 65.61; H, 3.71;
N, 8.93.
6-Chloro-2-((2,6-dimethylmorpholino)methyl)-9H-
xanthen-9-one hydrochloride 16
6-Chloro-2-((ethylamino)methyl)-9H-xanthen-9-one 12
Compound 12 was obtained as white solid (yield: 60%); m.p.:
103–1058C; IR (KBr) m [cm– 1]: 3466, 2943, 2794, 1665, 1449,
Compound 16 was obtained as white solid (yield: 60%); m.p.:
260–2628C; IR (KBr) m [cm– 1]: 3431, 2977, 2428, 1658, 1446,
1
1206, 1132, 781; H-NMR (CDCl3, 300 MHz) d [ppm]: 1.10 (d, J =
1
1207, 926, 781; H-NMR (CDCl3, 300 MHz) d [ppm]: 1.15 (t, J =
6.3 Hz, 6H, (CH3)2), 2.62–3.28 (m, 4H, (CH2)2 morphol.), 3.83-4.15
(m, 2H, (CH)2), 4.48 (brs, 2H, Ar-CH2-NH-), 7.56 (dd, J = 1.9 Hz, J =
8.5 Hz, 1H, H-7), 7.76 (d, J = 8.5 Hz, 1H, H-4), 7.90 (d, J = 1.9 Hz, 1H,
H-5), 8.17 (brs, 1H, H-3), 8.21 (d, J = 8.5 Hz, 1H, H-8), 8.40 (brs, 1H,
H-1), 10.96, 11.42 (brs, 1H, -NH+-);13C-NMR (DMSO-d6, 500.13 MHz)
d [ppm]: 18.19 (-CH3), 54.81 (-CH2-morph.), 58.38 (-CH2-), 68.57 (-
CH-), 118.14 (C-5), 118.83 (C-4), 120.03 (C-8a), 121.09 (C-8b), 125.24
(C-7), 127.89 (C-8), 129.55 (C-2), 129.70 (C-1), 138.44 (C-3), 140.07
(C-6), 155.84 (C-4b), 156.97 (C-4a), 175.16 (C=O); Rf = 0.88 (metha-
nol / ethyl acetate (1 : 1)). Anal. calcd. for C20H21NO3Cl2: C, 60.92;
H, 5.37; N, 3.55. Found: C, 60.70; H, 5.63; N, 3.51.
7.2 Hz, 3H, -CH2-CH3), 2.75 (q, J = 7.2 Hz, 2H, -CH2-CH3), 3.91 (s, 2H,
Ar-CH2-NH-), 7.26–8.29 (m, 6H, Ar-H); Rf = 0.15 (methanol / ethyl
acetate (1 : 1)). Hydrochloride of compound 12: Anal. calcd. for
C16H15NO2Cl: C, 59.27; H, 4.66; N, 4.32. Found: C, 58.92; H, 4.84;
N, 4.27.
2-((Allylamino)methyl)- 6-chloro-9H-xanthen-9-one 13
Compound 13 was obtained as white solid (yield: 65%); m.p.: 84–
858C; IR (KBr) m [cm– 1]: 3295, 3009, 1653, 1446, 1304, 1233, 1076,
777; 1H-NMR (DMSO-d6, 500.13 MHz) d [ppm]: 3.14–3.20 (m, 2H, -
CH2-NH-), 3.28 (brs, 1H, -NH-), 3.89 (s, 2H, Ar-CH2-NH-), 5.03–5.25
(m, 2H, =CH2), 5.81–5.96 (m, 1H, =CH-), 7.50 (dd, J = 1.8 Hz, J =
8.6 Hz, 1H, H-7), 7.58 (d, J = 8.7 Hz, 1H, H-4), 7.80 (d, J = 1.8 Hz, 1H,
H-5), 7.83 (dd, J = 2.3 Hz, J = 8.7 Hz, 1H, H-3), 8.10 (d, J = 2.3 Hz, 1H,
H-1), 8.16 (d, J = 8.6 Hz, 1H, H-8); Rf = 0.56 (methanol / ethyl ace-
tate (1 : 1)). Anal. calcd. for C17H14NO2: C, 68.11; H, 4.71; N, 4.67.
Found: C, 68.27; H, 5.03; N, 4.56.
6-Methoxy-2-((methylamino)methyl)-9H-xanthen-9-one
17
Compound 17 was obtained as white solid (yield: 72%); m.p.
109–1118C; IR (KBr) m [cm– 1]: 3304, 2787, 1616, 1441, 1275,
1096, 778; H-NMR (CDCl3, 300 MHz) d [ppm]: 2.28 (s, 3H, CH3-
1
NH), 3.32 (brs, 1H, -NH-), 3.76 (s, 2H, Ar-CH2-NH-), 3.94 (s, 1H, -
OCH3), 7.05 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H, H-7), 7.15 (d, J = 2.4 Hz,
1H, H-5), 7.57 (d, J = 8.6 Hz, 1H, H-4), 7.79 (dd, J = 2.3 Hz, J = 8.6 Hz,
1H, H-3), 8.10 (d, J = 2.3 Hz, 1H, H-1), 8.11 (d, J = 8.8 Hz, 1H, H-8);
13C-NMR (DMSO-d6, 500.13 MHz) d [ppm]: 35.51 (-NH-CH3), 54.19
(Ar-CH2-NH-), 56.14 (Ar-O-CH3), 100.55 (C-5), 113.58 (C-7), 114.95
(C-8a), 117.63 (C-4), 120.77 (C-8b), 124.47 (C-1), 127.58 (C-8),
134.91 (C-3), 137.13 (C-2), 154.53 (C-4a), 157.56 (C-4b), 164.89 (C-
6), 175.00 (C=O); Rf = 0.09 (methanol / ethyl acetate (1 : 1)). Anal.
calcd. for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.48; H,
5.80; N, 5.03.
N-Allyl-6-chloro-9-oxo-9H-xanthen-2-carboxamide 14
Compound 14 was obtained as white solid (yield: 55%); m.p.: 198-
2008C; IR (KBr) m [cm– 1]: 3352, 3085, 2916, 2604, 1670, 1542,
1
1441, 1290, 1073, 925, 764; H-NMR (DMSO-d6, 500.13 MHz) d
[ppm]: 3.91–3.99 (m, 2H, -CH2-NH-), 5.06–5.28 (m, 2H, =CH2),
5.85–6.01 (m, 1H, =CH-), 7.53 (dd, J = 1.9 Hz, J = 8.6 Hz, 1H, H-7),
7.71 (dd, J = 0.5 Hz, J = 8.8 Hz, 1H, H-4), 7.84 (d, J = 1.9 Hz, 1H, H-5),
8.18 (d, J = 8.6 Hz, 1H, H-8), 8.33 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H, H-3),
8.71 (dd, J = 0.5 Hz, J = 2.4 Hz, 1H, H-1), 9.00 (t, J = 5.5 Hz, 1H, -NH-
); 13C-NMR (DMSO-d6, 500.13 MHz) d [ppm]: 41.64 (-HN-CH2-),
115.25 (=CH2), 118.08 (C-5), 118.34 (C-4), 119.95 (C-8a), 120.58 (C-
8b), 125.14 (C-7), 125.26 (C-1), 127.82 (C-8), 130.41 (C-2), 134.28 (C-
3), 135.18 (=CH-), 139.92 (C-6), 155.71 (C-4b), 156.93 (C-4a), 164.33
(-HN-C=O), 175.13 (C=O); Rf = 0.74 (toluene / acethone (5 : 3)). Anal.
calcd. for C17H12NO3Cl: C, 65.08; H, 3.86; N, 4.46. Found: C, 65.28;
H, 4.16; N, 4.54.
2-((Ethylamino)methyl)-6-methoxy-9H-xanthen-9-one
hydrochloride 18
Compound 18 was obtained as white solid (yield: 55%); m.p.:
284–2868C; IR (KBr) m [cm– 1]: 3418, 2938, 2790, 1659, 1452,
1287, 1163, 774. Base of compound 18: 1H-NMR (CDCl3, 300 MHz)
d [ppm]: 1.12 (t, J = 7.2 Hz, 3H, -CH2-CH3), 2.97 (brs, 2H, -CH2-CH3),
3.92 (s, 3H, -OCH3), 4.26 (brs, 2H, Ar-CH2-NH-), 7.01-8.35 (m, 6H, Ar-
H); Rf = 0.14 (methanol / ethyl acetate (1 : 1)). Anal. calcd. for
C17H18NO3Cl: C, 63.85; H, 5.67; N, 4.38. Found: C, 63.73; H, 5.78;
N, 4.14.
2-((1H-Imidazol-1-yl)methyl)-6-chloro-9H-xanthen-9-one
15
Compound 15 was obtained as white solid (yield: 50%); m.p.:
176–1788C. Hydrochloride of compound 15: IR (KBr) m [cm– 1]:
3430, 2947, 2374, 1655, 1444, 1257, 1101, 776; H-NMR (DMSO-
1
(E)-2-((Cinnamyl(methyl)amino)methyl)-6-methoxy-9H-
xanthen-9-one hydrochloride 19
d6, 500.13 MHz) d [ppm]: 5.37 (s, 2H, Ar-CH2-NH-), 6.93 (dd, J =
1.2 Hz, J = 1.2 Hz, 1H, H-5'), 7.24 (dd, J = 1.2 Hz, J = 1.2 Hz, 1H, H-
4'), 7.52 (dd, J = 1.9 Hz, J = 8.6 Hz, 1H, H-7), 7.66 (d, J = 8.6 Hz, 1H,
H-4), 7.78 (dd, J = 2.3 Hz, J = 8.60 Hz, 1H, H-3), 7.82 (dd, J = 1.2 Hz, J
= 1.2 Hz, 1H, H-29), 7.84 (d, J = 1.9 Hz, 1H, H-5), 8.07 (dd, J = 0.5 Hz,
J = 2.3 Hz, 1H, H-1), 8.17 (d, J = 8.60 Hz, 1H, H-8); 13C-NMR (DMSO-
d6, 500.13 MHz) d [ppm]: 48.45 (Ar-CH2-N), 118.02 (C-5), 118.68 (C-
4), 119.44 (C-49), 119.92 (C-8a), 120.93 (C-8b), 124.57 (C-1), 124.91
Compound 19 was obtained as white solid (yield: 60%); m.p.:
231–2338C; IR (KBr) m [cm– 1] 3418, 2938, 2790, 1659, 1452, 1287,
1163, 774. Base of compound 19: 1H-NMR (CDCl3, 300 MHz) d
[ppm]: 2.25 (s, 3H, -N-CH3) 3.22 (dd, J = 1.0 Hz, J = 6.7 Hz, 2H, -N-
CH2-CH=), 3.65 (s, 2H, Ar-CH2-N-), 3.93 (s, 3H, -OCH3), 6.27–6.36
(m, 1H, -CH=CH-Ar), 6.55 (d, J = 15.9 Hz, 1H, -CH=CH-Ar), 6.87–
8.27 (m, 11H, Ar-H); Rf = 0.83 (methanol / ethyl acetate (1 : 1)).
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Arch. Pharm. Chem. Life Sci. 2009, 342, 9–18
Xanthone Derivatives: Antifungal, Antibacterial Activity
17
Anal. calcd. for C25H24NO3Cl: C, 71.17; H, 5.73; N, 3.32. Found: C,
70.82; H, 5.95; N, 3.35.
sterile cotton swab over the entire surfaces of Mueller-Hinton
agar (bioMerieux). The inoculated agar was allowed to dry for 15
to 30 min. Test discs impregnated with the 10 lL of the samples
solution were applied to the inoculated agar. The plates were
inoculated for 24 h in ambient air at 378C. After incubation,
each plate was examined and measured the diameters of com-
plete inhibition zones of bacterial growth, including the diame-
ter of the disc. Additionally, to compare antibacterial potency of
the tested compounds to that of antibacterial drugs and to con-
firm the efficacy of the chosen method, we used gentamycine as
reference.
N-((6-Methoxy-9-oxo-9H-xanthen-2-yl)methyl)-N-
methylcinnamamide 20
Compound 20 was obtained as white solid (yield: 70%); m.p.:
149–1518C; IR (KBr) m [cm– 1] 3415, 2927, 1651, 1450, 1260, 1105,
766;1H-NMR (CDCl3, 300 MHz) d [ppm]: 3.13 (brs, 3H, -N-CH3), 3.94
(s, 3H, -OCH3), 4.81 (s, 2H, Ar-CH2-N-), 6.89–8.27 (m, 13H, Ar-H,
CH=CH); Rf = 0.88 (methanol / ethyl acetate (1 : 1)). Anal. calcd. for
C25H21NO4: C, 75.17; H, 5.30; N, 3.51. Found: C, 74.47; H, 5.33; N,
3.49.
Microbiology
Microorganisms
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